ICARE Newsletter Winter 2020

Community Spotlight

I was diagnosed with breast cancer in December 2018 and was found to be PALB2+. The PALB2 gene had not been tested for when my older sister was diagnosed with breast cancer and had genetic testing done four years earlier. This was new! My cancer was very similar to my sister’s, but being PALB2+ changed my treatment plan and informed me of my possible higher cancer risks for recurrence and other cancers. Like my sister, I had one small tumor in one breast. I could have just had a lumpectomy with radiation and chemo (depending on ONCA result) followed by oral medication, and then just live with a risk of recurrence. The treatment option was a skin saving, nipple sparing bilateral mastectomy with FLAP reconstruction followed by 5-10 years of oral medication. This would have reduced my risk of recurrence to below 10%.  It was a no brainer for me — I chose the latter. After my breast surgery, I was then told PALB2 was linked to ovarian cancer, so I started seeing a high-risk gynecologist. After months of discussions with my gynecologist and oncologist, I decided to have an oophorectomy. This was prompted by my PALB2 risk and my adverse reaction to Tamoxifen. The only way to get off the Tamoxifen was to put me into menopause by removing my ovaries, which at the same time, would lower my ovarian cancer risks. Again, this was a no brainer. It’s two years after my diagnosis, and I’m in a really good place. My cancer is nearly behind me, as I don’t think about it on a daily basis. I’m feeling great and look even better 😉 My energy levels are back to normal, I’m playing competitive tennis, and I’m spending time with my family traveling and enjoying life. We look to the future with positivity. We know there is a chance that I have passed the mutation onto my three kids but we feel empowered by the knowledge of knowing about it, and we will test them for it when they get older. My family is empowered too. We recently found out that my mother is PALB2+. Great news, she’s 75 years old and has never had breast cancer! So PALB2 doesn’t necessarily mean a cancer sentence! I have personally known many family and friends diagnosed with breast cancer; my best friend being one who was diagnosed 8 years ago with stage 4, triple positive, metastatic inflammatory breast cancer. She has had radiation, chemo, had her spine rebuilt, and been on numerous clinical trials. She is here today, and her tumor has shrunk by 67%. What I learned from her: “Always have a note taker with you at EVERY appointment because there is always too much info to absorb. Don’t ever give up and never let it define you. Fight your battle your way. And when you need it, ask for help.”

– ICARE Participant, Jennifer Clarke from New Orleans, LA

ICARE Newsletter Winter 2020

Treatment Advances Among Those with Inherited Prostate Cancer Predisposition

A recent study reported a high complete response rate among men with a BRCA1/2 mutation with metastatic, castration-resistant prostate cancer who were treated with niraparib (a PARP inhibitor) of 63% compared to 17% in the non-BRCA1/2 group.1 Based on this data, the Federal Drug Administration (FDA) granted breakthrough therapy designation to niraparib on October 3, 2019 to expand the treatment options for men with BRCA1/2 positive, metastatic, castration-resistant prostate cancer.2

1Smith, et al. Presented at 2019 ESMO Congress. 2019 Sept-Oct. Barcelona, Spain. Abstract LBA50. 2Augenstein S. FDA Grants Breakthrough Therapy Designation to Niraparib for mCRPC. 2019 Oct. Available at: https://tinyurl.com/BRCAassociatedprostatecancer.

Social media post: https://tinyurl.com/ICARE20191220

ICARE Newsletter Winter 2020

New Study Based on ICARE Participants with ATM & CHEK2 Mutations

We are excited to tell you about our recently published results based solely on data from ICARE participants with ATM and CHEK2 mutations. Our findings suggest most female family members of ATM and CHEK2 mutation carriers do not qualify for breast MRI screening based on family cancer history alone. This emphasizes the need to share positive ATM and CHEK2 test results with family members so they can consider undergoing genetic testing themselves, which could impact their eligibility for breast MRI screening. Specifically, women with ATM and CHEK2 mutations have a lifetime breast cancer risk greater than 20%, which is the threshold at which screening through a breast MRI is recommended.  Results of our study showed:

  • Among 56 ATM carriers in ICARE, less than 25% of their close female relatives had a lifetime breast cancer risk >20% based on family cancer history alone.
  • Among 69 CHEK2 carriers in ICARE, less than 15% of their female relatives had a lifetime breast cancer risk >20% based on family history alone.

Consequently, testing in these female family members would identify those who were positive for the same ATM or CHEK2 mutation and therefore have a >20% risk for breast cancer, making them eligible for breast MRI screening.

1Weidner, et al. Cancer. 2020 Jan. PMID: 31967672.

 To help share test results with family members, check out our FREE online resource at: www.GeneSHARE.net

ICARE Newsletter Winter 2020

Treatment Advances Among Those with Inherited Pancreatic Cancer Predisposition

Results from a recent study showed olaparib (a PARP inhibitor) nearly doubled the progression-free survival in BRCA1/2 carriers with metastatic pancreatic cancer.1 Based on this data, the FDA approved the use of olaparib as a first-line maintenance treatment in BRCA1/2 carriers with metastatic, platinum-sensitive pancreatic cancer. This represents another treatment advance in pancreatic cancer and highlights the importance of genetic testing for all patients with pancreatic cancer.

Another recent study among pancreatic cancer patients with a BRCA1/2 or PALB2 mutation showed that response rates after first line treatment with cisplatin/gemcitabine alone was 65.2%, and with addition of veliparib (a PARP inhibitor), it was 74.1%.2 The study evaluated each arm separately and did not compare them. Survival at 2 years and 3 years was also encouraging at 31% and 18%, respectively. These data highlight the importance of conducting testing for inherited cancer among all patients with pancreatic cancer, as this information may guide treatment among those identified to have inherited cancer gene mutations such as BRCA1/2 or PALB2.

1Golan, et al. N Engl J Med. 2019 Jul. PMID: 31157963; 2Helwick, C. The ASCO Post. 2020 Jan. Available at: https://www.ascopost.com/  

Social media post: https://tinyurl.com/ICARE202013  

ICARE Newsletter Winter 2020

PALB2 Mutations & Cancer Risk

A newly published study of 524 families with pathogenic PALB2 mutations from around the world, including almost 50 ICARE participants, represents the largest, most comprehensive effort to evaluate cancer risks.1 Results showed increased risks for female breast cancer (53%), ovarian cancer (5%), pancreatic cancer (2-3%), and male breast cancer (1%). Findings did not suggest higher risks for prostate cancer or colorectal cancer.  Additionally, the risks of breast cancer were highest for younger women and declined with age. Results from this study confirm PALB2 to be an important breast cancer gene, with risks overlapping with BRCA1/2, and highlight the importance of breast cancer risk management among individuals with PALB2 mutations.

1Yang, et al. J Clin Oncol. 2019 Dec. DOI: 10.1200/JCO.19.01907.

Social media post: https://tinyurl.com/ICARE20191216

Video of Dr. Marc Tischkowitz (Senior Author):

ICARE Newsletter Winter 2020

Updates to National Comprehensive Cancer Network (NCCN) Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic

There were significant updates and restructuring of the guidelines, with some highlights included below:

  • Substantial reorganization of the guidelines as follows:
    • Now organized by organ site, rather than primarily by certain high penetrance genes
    • Focused efforts to simplify genetic testing criteria
    • Only one flow diagram included, to outline the ‘genetic testing process’
  • Following scenarios now outlined:
    • Situations in which genetic testing may have low yield
    • Situations where referral to a genetics expert is recommended
  • PALB2: Recognized as a high penetrance gene, for which discussion of risk-reducing mastectomy is appropriate
  • BRCA1/2: Prostate cancer screening to be initiated at age 40
  • Pancreatic screening guidance included:
    • STK11 starting at age 30-35
    • CDKN2A starting at age 40
    • BRCA1/2, ATM, MLH1, MSH2, MSH6, EPCAM, PALB2, or TP53: Only if there is a close family member with pancreatic cancer

For the complete updated versions of the NCCN guidelines, please visit NCCN.org

Follow this link to view our social media post: https://tinyurl.com/ICARE2019124

Full press release available at: https://www.nccn.org/about/news/newsinfo.aspx?NewsID=1790

ICARE Newsletter Winter 2020

Updated Pancreatic Cancer Screening Guidelines through CAPS Consortium

The International Cancer of the Pancreas Screening (CAPS) Consortium recently published updated recommendations about pancreatic cancer screening through MRI/magnetic retrograde cholangiopancreatography (MRCP) and/or an endoscopic ultrasound (EUS).1 Specifically, these guidelines now recommend that individuals with a CDKN2A or STK11 mutation begin screening at age 40. Screening for individuals with a BRCA1/2, ATM, PALB2, MLH1, or MSH2 mutation is only recommended if they have at least one first-degree relative with pancreatic cancer, beginning at age 45-50 or 10 years younger than the youngest relative diagnosed with pancreatic cancer. These guidelines were developed through expert consensus based on existing research; however, there remains a need for more information to understand the benefits and risks of pancreatic cancer screening. Both patients and their treating providers should be aware that these guidelines have some differences from the recently published NCCN genetic/familial breast, ovarian, and pancreatic guidelines, as outlined in the table below.2

Age to Begin Pancreatic Cancer Screening per NCCN & CAPS
Gene NCCN (V.1.2020) CAPS (2019)
STK11 Begin at 30-35 Begin at 40
CDKN2A Begin at 40 Begin at 40
BRCA1/2, PALB2, ATM, MLH1, MSH2, MSH6 Begin at 50 Begin at 45-50
EPCAM, TP53 Begin at 50 Not included

1Goggins, et al. Gut. 2020 Jan. PMID: 31672839; 2NCCN Practice Guidelines. V.1.2020. 2019 Dec. Available at: NCCN.org

Social media post: https://tinyurl.com/ICARE202026  

ICARE Newsletter Winter 2020

Ask the Expert

Through each newsletter, we give our participants an opportunity to have their questions answered by experts. If you have a question you would like addressed, please email the study team at ICARE@InheritedCancer.net for consideration in future newsletters. The following question was addressed by Ben Ho Park, MD, PhD, who is the Donna S. Hall Chair in Breast Cancer, Co-Leader of the Breast Cancer Research Program, Associate Director for Translational Research, and Director of Precision Oncology at Vanderbilt-Ingram Cancer Center. Dr. Park is also a Professor of Medicine and Associate Director for Basic and Translational Research in the Department of Medicine’s Division of Hematology and Oncology.  

Q. How is DNA testing done on someone’s tumor different from testing done on someone’s normal DNA from their blood or saliva sample?

A. When we extract DNA from a biopsy or surgical sample of a tumor, usually it is a mixture of both normal cells and tumor cells. This is because normal cells such as blood vessels and blood cells are found within the tumor itself. However, all tumors arise because of changes in our normal DNA. Sometimes we have inherited DNA changes like BRCA1/2, but all tumors, including BRCA1/2-associated tumors, will have additional DNA changes that are present only in the tumor cells. Usually it takes 3 to 8 DNA changes to make a normal cell cancerous. Therefore, when we analyze these changes using a biopsy or surgical sample, we cannot tell whether the changes are in the tumor cells only, or present in both tumor and normal cells, since it is a mixture of these cells. DNA that has changes in normal cells, like BRCA1/2 mutations, are called “germline”. These are DNA changes that a person was born with and present in almost every cell of their body. These DNA changes can be passed to their children.

The reason it is important to test tumor DNA is because it can help guide treatment based on mutations that are found in the tumor cells. However, we can now identify whether a DNA change is in the germline vs. the tumor only by also testing normal DNA separately, usually through a blood or saliva sample and comparing germline vs. tumor DNA changes. Testing someone’s normal DNA can now help guide treatment since we have newer therapies against germline DNA changes. It can also tell us about future cancer risks and how to best manage those risks, as well as tell us about potential cancer risks for someone’s blood relatives. It is also important to remember that when testing is done on tumor and/or germline DNA, it may also uncover potential germline mutations found in the normal cells that are unexpected and not related to someone’s cancer. However, this information is still potentially important to help guide future cancer risks and management and to inform potential inherited cancer risks for family members.

ICARE Newsletter Winter 2020

Lynch Syndrome Cancer Risks Across Genes

A worldwide study reporting on cancer risks among individuals with mutations in Lynch syndrome genes showed that there are substantial differences in cancer risks across the various genes.1 Specifically, the risk for colorectal cancer in those with  MLH1, MSH2, and MSH6 mutations was substantially higher than what was seen for those with PMS2 mutations. Additionally, the risk for prostate cancer among men with an MSH2 mutation was elevated at ~30% lifetime risk, with higher risks among men over 50 years of age. Additionally, the risks of cancers of the urinary tract and small bowel were higher among those with MLH1 or MSH2 mutations. MLH1 or MSH2 carriers over the age of 50 had the highest risks for urinary tract and small bowel cancers. Another study focused on PMS2 and MSH6 carriers found that overall risks for colorectal cancer to age 70 was 8.7% and 11.8%, respectively.2 For PMS2, colorectal cancer risk for men was 9.9%, whereas for women it was lower at 5.9%. For MSH6, risks were similar between men and women at 10% and 11.7%, respectively. It remains important to refine cancer risks across the various Lynch syndrome genes as this information is needed to develop gene-specific cancer risk management guidelines.

1Dominguez-Valentin, et al. Genet Med. 2020 Jan. PMID: 31337882; 2Suerink et al. Genet Med. 2019 Dec. PMID: 31204389

Social media post: https://tinyurl.com/ICARE202027

ICARE Social Media Post February 2020

Differences in Pancreatic Cancer Screening Recommendations from the National Comprehensive Cancer Network (NCCN) and the International Cancer of the Pancreas Screening (CAPS) Consortium

The National Comprehensive Cancer Network (NCCN) and the International Cancer of the Pancreas Screening (CAPS) Consortium recently updated pancreatic cancer screening recommendations. However, there are some differences between these recommendations. Specifically, screening with annual MRI/magnetic retrograde cholangiopancreatography (MRCP) and/or endoscopic ultrasound (EUS) is recommended as follows for NCCN versus CAPS:

STK11 regardless of family history:

  • NCCN: Consider screening beginning at age 30-35
  • CAPS: Consider screening beginning at age 40

CDKN2A regardless of family history:

  • NCCN: Consider screening beginning at age 40
  • CAPS: Consider screening beginning at age 40

BRCA1/2, PALB2, ATM, MLH1, MSH2 & MSH6 and at least one affected relative with pancreatic cancer:

  • NCCN: If first- or second-degree relative affected, consider screening beginning at age 50
  • CAPS: If first-degree relative affected, consider screening beginning at age 45-50


  • NCCN: If first- or second-degree relative affected, consider screening beginning at age 50
  • CAPS: Not included in screening recommendations

Check out NCCN guidelines by creating a FREE account at https://www.nccn.org/professionals/physician_gls/default.aspx#detection

Check out the full CAPS article at https://www.ncbi.nlm.nih.gov/pubmed/31672839

ICARE Social Media Post February 2020

Updated Pancreatic Cancer Screening Guidelines through the International Cancer of the Pancreas Screening (CAPS) Consortium

The International Cancer of the Pancreas Screening (CAPS) Consortium recently published updated pancreatic cancer screening recommendations. The recommendations include:

  • Screening with MRI/magnetic retrograde cholangiopancreaography (MRCP) and/or endoscopic ultrasound (EUS)

The screening was recommended for the following individuals:

  • CDKN2A and STK11 mutation carriers starting at age 40
  • BRCA1/2, ATM, PALB2, MLH1, and MSH2 mutation carriers (if they have at least one first-degree relative with pancreatic cancer) starting at age 45-50 or 10 years younger than the youngest affected relative

Check out the full article at https://www.ncbi.nlm.nih.gov/pubmed/31672839


These guidelines differ from current NCCN Pancreatic Cancer Screening Guidelines as follows:


  • CAPS: Consider screening beginning at age 40
  • NCCN: Consider screening beginning at age 30-35


  • CAPS: Not included
  • NCCN: Consider screening beginning at age 50


  • Screening recommendations remain the same as CAPS

Check out NCCN guidelines by creating a FREE account at https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf.

ICARE Social Media Post January 2020

Advances in Treatment for Lynch Syndrome-Related Endometrial Cancer

A recent phase II study showed increased response to an immunotherapy drug (avelumab), in women with endometrial cancer with mismatch repair deficiency.

Among women with Lynch Syndrome, the risk for endometrial cancer (which often has mismatch repair deficiency) is raised. This new study shows promising treatment options for women with endometrial cancer and Lynch syndrome with recurrent or persistent endometrial cancer.

Check out the full article at the Journal of Clinical Oncology: https://lnkd.in/embydpk

ICARE Social Media Post January 2020

New Gene: DUOX2

DUOX2 represents a newly identified gene that might predispose patients to thyroid cancer (specifically, ‘non-medullary’ thyroid cancer). The specific gene change (or ‘mutation’) that leads to thyroid cancer predisposition is known as Y1203H

Additional studies are needed to confirm this association. Check it out at ASCO Post: https://tinyurl.com/sw3ew63 𝐨𝐫 you can access the article at https://cancerres.aacrjournals.org/content/early/2019/09/07/0008-5472.CAN-19-0721⁣

ICARE Social Media Post January 2020

New Gene: RABL3

About 10% of pancreatic cancers are thought to be the result of an inherited mutation. All of the genes that predispose patients to pancreatic cancers have not yet been discovered.

Recently, a new gene known as RABL3 was linked to pancreatic cancer. This gene may increase the risk of hereditary pancreatic cancer. Additional studies are needed to confirm this association.

Check it out at: https://www.ncbi.nlm.nih.gov/pubmed/31406347/

ICARE Social Media Post January 2020

Ovarian Cancer Screening in BRCA1 Carriers

A new study of Polish BRCA1 carriers showed that screening through transvaginal ultrasound was not effective or  reliable in detecting ovarian cancer early. Consequently, preventive oophorectomy remains the only proven method to lower ovarian cancer risks and increase survival.

Check out the article at: https://www.ncbi.nlm.nih.gov/pubmed/31500890.

Check out the NCCN ovarian cancer screening recommendations for BRCA1 and other gene mutation carriers: https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf

ICARE Social Media Post January 2020

Racial Disparities in Genetic Testing for Women with Ovarian Cancer

Women of non-European ancestry diagnosed with ovarian cancer have lower rates of referral for genetic testing despite current national guidelines stating ALL women with ovarian cancer and/or a close-blood relative with ovarian cancer should be offered genetic counseling and testing.

One study reported that only 1/3 of Black, Latina, and Asian women were referred for genetic counseling following an ovarian cancer diagnosis, compared to two-third of White women. This study highlights the need to develop strategies such that genetic testing is used across all populations, including racial/ethnic minorities.

Check out the article at: https://www.sciencedirect.com/science/article/pii/S0090825817314555.

ICARE Social Media Post January 2020

Polygenic Risk Scores

A Polygenic Risk Score (PRS) is calculated using genetic differences throughout someone’s DNA, in combination with clinical and family history of cancer. This unique type of score may be utilized to calculate the lifetime risk of breast cancer.

Important facts about PRS’s:

  • Different from BRCA1/2 testing, which look for changes in these specific genes
  • Should NOT be used to diagnose a hereditary cancer predisposition.
  • Should only be used in Caucasian/White women because they have not yet been studied for use in other populations.

For more information go to: https://www.ncbi.nlm.nih.gov/pubmed/30554720

ICARE Social Media Post January 2020

Women with BRCA1/2: Risk-reducing Mastectomy versus Screening

In a study of 5000 healthy female BRCA1/2 carriers (without a breast cancer diagnosis):

  • BRCA1 carriers: after an average of over 10 years follow-up, survival was higher in those who had bilateral mastectomy (99.7%) compared to those who had breast screening through mammograms and breast MRIs (93%).
  • BRCA2 carriers: no significant differences were seen between those who had bilateral mastectomy versus screening.

Although the results of this study provide additional information that may be useful to BRCA carriers, it remains important to remember that cancer risk management decisions are a personal decision. It is important to be aware of the information available to make an informed decision, with guidance from your healthcare provider.

Check out the article at: https://www.ncbi.nlm.nih.gov/pubmed/31302855

ICARE Social Media Post January 2020

Celebrating 10 Years of ICARE


Happy New Year! 2020 represents a decade for ICARE

We are celebrating 10 years of research, education, and engagement, through which we have enrolled nearly 3500 participants, including over 2000 gene mutation carriers, disseminated 15 newsletters, led and collaborated on multiple research projects, and impacted individuals affected by inherited cancer predisposition all over the world.

Let’s take a quick look at what’s happened in the last decade:

2010ICARE was launched.

2012 – First commercially available gene panel test for inherited cancer became available, and ICARE reached 1000 study participants! Cost of testing just for BRCA1 and BRCA2 was over $4000.

2013 –The Supreme Court invalidated the BRCA patent which allowed expanded use of multi-gene panel testing as the BRCA genes could then be added to the panel tests.

2015 – FDA approved the use of PARP inhibitors for BRCA carriers with ovarian cancer which improved treatment options.

2016ICARE reached 1000 BRCA carriers and 2000 study participants!

2017 – The FDA approved immunotherapy treatment for mismatch repair-deficient cancers, which was an important advance for individuals with Lynch syndrome.

2019ICARE reached 3000 study participants!

2020 – Ongoing discovery of new cancer genes and improved technology continues to drive cost of genetic tests down to as low as $250 and lower!

Thank you for your continued support in helping us fulfill our mission to end the cycle of inherited cancer through research, education, and engagement!

ICARE Social Media Post January 2020

Advances in Treatment for Pancreatic Cancer in BRCA Carriers

The FDA approved the use of olaparib, a PARP inhibitor, as first-line maintenance treatment in BRCA1/2 carriers with metastatic, platinum-sensitive, pancreatic cancer.

Platinum-sensitive cancer is a cancer that responds to treatment with drugs that contain the metal platinum, such as carboplatin or cisplatin. Olaparib showed to nearly double the progression-free survival in BRCA1/2 carriers with metastatic pancreatic cancer.

The recent FDA approval to use olaparib as first-line maintenance treatment for BRCA carriers with metastatic pancreatic cancer represents another strategy to improve treatment of pancreatic cancer. It also demonstrates the importance of genetic testing for ALL patients with pancreatic cancer (because it will tell us who has a BRCA mutation, which may then make them eligible for PARP inhibitor treatment).

Check out the articles at: https://www.ncbi.nlm.nih.gov/pubmed/?term=Maintenance+Olaparib+for+Germline+BRCA-Mutated+Metastatic+Pancreatic+Cancer



ICARE Social Media Post December 2019

Evaluation of PARP Inhibitors in BRCA-Associated Prostate Cancer

The FDA granted breakthrough therapy designation to niraparib (a PARP inhibitor) for the treatment of men with BRCA1/2 positive, metastatic castration-resistant, and heavily pre-treated prostate cancer.

Results from a recent study show a 63% complete response rate in men with BRCA1/2 positive, metastatic castration-resistant prostate cancer treated with niraparib compared to 17% in the non- BRCA group.

Previously, niraparib was approved for ovarian cancer. This treatment can help address lack of treatment options for men with BRCA1/2 positive, metastatic castration-resistant prostate cancer.

Check out the articles at https://www.cancernetwork.com/fda/fda-grants-breakthrough-therapy-designation-niraparib-mcrpc and https://www.healio.com/hematology-oncology/prostate-cancer/news/online/%7B22878907-82bd-408e-b99f-b51c50d8c467%7D/fda-grants-breakthrough-therapy-designation-to-zejula-for-prostate-cancer-subtype.

ICARE Social Media Post December 2019

PALB2 Mutations and Cancer Risk

A new published study of 524 families with PALB2 mutations, including our very own ICARE participants, from around the world showed increased risks of female breast, ovarian, pancreatic, and male breast cancer.

The level of risk for female breast cancer is enough to recommend cancer risk management. Cancer risk management includes screening or risk-reducing surgery. For the other cancer risks, especially in the absence of family history of these cancers, no changes in cancer risks management is advised.

Check it out at https://ascopubs.org/doi/10.1200/JCO.19.01907, and https://www.nccn.org/about/news/newsinfo.aspx?NewsID=1790.

ICARE Social Media Post December 2019

American College of Medical Genetics and Genomics: Points-to-Consider Document: “Is there Evidence to Support BRCA1/2 and Other Inherited Breast Cancer Genetic Testing for all Breast Cancer Patients?”











The American College of Medical Genetics and Genomics (ACMG) put forth a Points-to-Consider document: “Is there Evidence to Support BRCA1/2 and Other Inherited Breast Cancer Genetic Testing for all Breast Cancer Patients?” The document discusses:

1) Current data to support testing in breast cancer patients
2) Factors that should guide testing such as age, tumor characteristics, and family history

Currently there is insufficient evidence to recommend testing in all women with breast cancer. However, as more information becomes available, testing criteria may change. Professional organizations need to work together to harmonize and implement evidence-based recommendations.

Check It out at: https://www.nature.com/articles/s41436-019-0712-x

ICARE Social Media Post December 2019

Patient Reported Outcomes In A Study of PARP Inhibitors in BRCA Carriers with Metastatic Breast Cancer

Did you know? PROs are impacting treatment advances in metastatic breast cancer. Olaparib increased progression-free survival among BRCA carriers with metastatic HER2- breast cancer. Thanks to patient reported outcomes, a new study now suggests it also improved patients’ quality of life!

Check it out the new article published in October 2019 directly at https://www.ncbi.nlm.nih.gov/pubmed/31446213!

ICARE Social Media Post December 2019

Updates to National Comprehensive Cancer Network (NCCN) Genetic/Familial Breast, Ovarian, and Pancreatic Guidelines (V1.2020)

We are excited to share the latest version of the NCCN Genetic/Familial Breast, Ovarian and Pancreatic Guidelines (V1.2020), which were just updated. Some of the changes made include:

  • PALB2 was added as a high penetrance gene (similar to BRCA1, BRCA2, CDH1, PTEN and TP53)
  • It is appropriate to consider risk reducing mastectomy for cancer risk management (as well as high risk screening through mammograms and MRIs).
  • The age at which screening for prostate cancer among men with a BRCA2 mutation was lowered from 45 to 40.
  • Pancreatic cancer screening:
    • Individuals with STK11 (which leads to Peutz-Jeghers Syndrome) or CDKN2A mutations has been added
    • ONLY a consideration in patients with a mutation in BRCA1/2, ATM, MLH1, MSH2, EPCAM, PALB2, and TP53 IF there is a close family member (first or second degree relative on the same side of the family) with pancreatic cancer
  • The guidelines also outline situations in which there is a very low chance of finding a mutation (i.e., pathogenic/likely pathogenic variant).

To see the full version of the guidelines, go to nccn.org, where they will ask you to create a username and password (which anyone can do), after which you will be able to view whichever guidelines you want. Check it out at https://www.nccn.org/about/news/newsinfo.aspx?NewsID=1790!

ICARE Social Media Post December 2019

Explaining Patient Reported Outcomes

The National Quality Forum defines patient reported outcomes (PROs) as “any report of the status of a patient’s health condition that comes directly from the patient.” PROs have the potential to increase overall outcomes and care process and enhance patient and family centered care.

ICARE Social Media Post November 2019

Educational Resources: The Family Link Between Breast and Ovarian Cancer in Black Women

The differences seen in access to healthcare across different racial groups are known as health disparities. To address the gap in awareness, we have pursued efforts to raise awareness about inherited breast cancer among African Americans.

We are excited to introduce you to another invaluable resource, the Breast Cancer Genetics Research and Education for African American Women (BGREAT) initiative. We developed a brochure that exclusively increases awareness of the breast and ovarian cancer risk in African Americans. It was 𝘳𝘦𝘲𝘶𝘦𝘴𝘵𝘦𝘥 and 𝘵𝘦𝘴𝘵𝘦𝘥 by the community and we have disseminated >25,000 copies across the United States!

Feel free to share this incredible resource with anyone who may be interested! Check it out at https://inheritedcancer.net/wp-content/uploads/BGREAT-HBOC-Brochure.pdf.

ICARE Social Media Post November 2019

High Frequency of BRCA in Unselected Women with Metastatic Breast Cancer

Did you know? National practice guidelines currently recommend ALL women with metastatic (HER2-) breast cancer to get genetic testing for inherited cancer (including BRCA1/2 testing), because it can guide eligibility for treatment with PARP inhibitors.

A new study led by our colleague at the Vanderbilt-Ingram Cancer Center, Dr. Ben Park, suggests that more women with metastatic breast cancer have BRCA1/2 mutations than previously thought. In fact, of the 100 women with metastatic breast cancer tested through this study, 6% had BRCA1/2 mutations!

Findings from this study highlight the importance of genetic testing for ALL women with metastatic breast cancer to help guide their treatment, AND further guide risk management for themselves and their at-risk family members.

Check out the study at the following link: https://www.ncbi.nlm.nih.gov/pubmed/31465090

ICARE Social Media Post October 2019

Lifestyle Factors Associated with Familial and Inherited Breast Cancer Risks

Body mass index (BMI) is an indicator of fat content in the body. A lower body mass index may reduce breast cancer risk in women, including those with a family history of breast cancer. However, a new study reported that higher BMI also increases breast cancer risk in the general population and those with a family history of breast cancer after menopause.

Maintaining a healthy weight throughout adulthood is important in ALL women, including those with a family history of breast cancer. These findings were recently published in Breast Cancer Research (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215632/)

2) A new study suggests that regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) might also lower breast cancer risk in women in BRCA1/2 carriers AND those with family history of breast cancer.

These findings were recently published in Breast Cancer Research (https://breast-cancer-research.biomedcentral.com/track/pdf/10.1186/s13058-019-1135-y)

ICARE Social Media Post October 2019

Physical Activity Associated with Familial and Inherited Breast Cancer Risks

BRCA1/2 carriers may benefit from physical activity to reduce breast cancer risks, just like women in the general population! We know that women in the general population benefit from physical activity to reduce their breast cancer risk, but a recent study showed that this benefit also extends to those with a BRCA1/2 mutation and those with a family history of breast cancer.

This study showed that breast cancer risk could be lowered by 20% for those with the highest physical activity levels. This risk reduction was equally seen among women in the general population, those with familial risk (family history of breast cancer), and those with a BRCA1/2 mutation.

Physical activity does not have to be painful and boring, there are many fun ways you can stay active such as walking in your favorite park, attending your favorite yoga class, chasing after your grandchildren, and walking a race for a good cause with your friends and family!

These findings were recently published in Cancer Research (https://www.ncbi.nlm.nih.gov/pubmed/31578201)

ICARE Social Media Post October 2019

BRCA Testing In Black Women

Did you know? Although BRCA testing has been around for over TWO decades, not all populations have benefitted equally from testing. In fact, our previous research has shown that black patients are less aware of BUT interested in genetic testing…when they know about it.

In addition, healthcare providers are less likely to identify and suggest BRCA testing among young black women with breast cancer compared to white women. What’s concerning is that black women are more likely to get breast cancer early and/or triple-negative disease, which are both hallmarks for inherited disease.

Check it out at https://bgreatinitiative.inheritedcancer.net/newsletters/

ICARE Social Media Post October 2019

Inherited Breast Cancer Among Latina Women

Latina women are at risk for inherited breast cancer:

Breast cancer mortality rates are higher among Latina women compared to non-Hispanic White women. Latina women also have a higher prevalence of triple-negative breast cancer when compared to with non-Hispanic White women.

Latina women are diagnosed with breast cancer at earlier ages, 56 years versus 63 years for non-Hispanic White women. They are also more likely to develop triple-negative breast cancer.

According to the NCCN guidelines, genetic testing for inherited breast cancer should be offered to:

1) ALL Latina women diagnosed with breast cancer at 45 or younger and/or

2) Latina women with a diagnosis of triple-negative breast cancer at £ 60 years.

Additional information can be found at Cancer Epidemiology, Biomarkers & Prevention at https://cebp.aacrjournals.org/content/early/2019/10/02/1055-9965.EPI-19-0035.full-text.pdf!

ICARE Social Media Post October 2019

Advances in Treatment for Advanced Breast Cancer in BRCA Carriers

Monotherapy with PARP inhibitors is FDA-approved for patients with metastatic breast cancer with BRCA mutations. BUT, does adding additional drugs (called ‘combination therapy’) help?

In BRCA carriers with metastatic breast cancer, the combination of veliparib AND chemotherapy with platinum-based agents (carboplatin) and taxanes (paclitaxel) led to a longer duration of progression free survival (disease that did not progress), compared to those treated with ONLY chemotherapy. The duration of progression free survival was DOUBLE with veliparib/chemotherapy 3 years after treatment.

Additional information can be found at ESMO 2019’s BROCADE 3 abstract.

ICARE Social Media Post October 2019

Advances in Early Stage Breast Cancer Treatment for BRCA Carriers

New benefits from a PARP inhibitor, talazoparib, among BRCA carriers with early stage breast cancer. The current FDA approvals for the use of PARP inhibitors is limited to women with metastatic (stage IV) breast cancer. These drugs are being tested in early stage breast cancer to shrink down the tumor (called neoadjuvant treatment) before surgery to remove it.

Specifically, 6 months of neoadjuvant talazoparib monotherapy (treatment with only talazoparib) resulted in significantly improved rates of complete response in patients with operable (stage I-III) breast cancer.

Look for other treatment advances in BRCA carriers in our newsletter at https://inheritedcancer.net/newsletters/.

ICARE Social Media Post October 2019

Male Breast Cancer Risk

Did you know? Beyonce’s father, Matthew Knowles, was diagnosed with breast cancer. He states, “we used to think this was only an issue for women, but this is male or female.” According to CBS news, “he is hoping that sharing his story as man with breast cancer will shine a light on the risk men can face.”

Surprisingly, less than 20% of women diagnosed with breast cancer who are at high risk for a BRCA mutation are tested. Even lower rates of genetic testing are seen among African Americans, who are less aware of their risk for a BRCA mutation.

Let’s talk facts. All men with breast cancer should be offered BRCA testing. 6-8% of men with breast cancer will have a BRCA2 mutation. Matthew’s children have a 50/50 chance of inheriting this BRCA2 mutation. Women with the mutation, have a 60-70% risk to develop breast cancer. The BRCA2 gene raises the chance for ovarian cancer in women, aggressive prostate cancer in men and pancreatic cancer in both sexes. See our previous post about new targeted treatment options for cancer patients with a BRCA2 mutation.

Genetic testing for inherited cancer genes (such as BRCA1/2) can be done through a simple blood or saliva sample. Detecting a mutation allows people to be proactive about their health by finding cancer early or preventing it all together.  Check out resources to ‘end the cycle of inherited cancer through research, education, and engagement’ at http://inheritedcancer.net/

ICARE Social Media Post September 2019

Family Sharing Resources: GeneSHARE

With the tremendous advances in gene-based care among those with inherited cancer risk, we are trying to develop tools and strategies to make it easier for more people to benefit from genetic education and testing. We are proud to introduce you to GeneSHARE, a free online toolkit for YOU, to help share positive test results with your family members. We are particularly excited to share the personalized letter generator to share your genetic test results with family members. Check it out at https://inheritedcancer.net/family_sharing_letter.

ICARE Newsletter Summer 2019

Ask the Expert

The following question was addressed by Gillian Hooker, PhD, ScM, LCGC, who is the president-elect for the National Society of Genetic Counselors, Adjunct Associate Professor in the Division of Genetic Medicine at the Vanderbilt University Medical Center, and the Vice President of Clinical Development for Concert Genetics in Nashville, TN.

Q. Why was the BRCA1/2 mutation detected through genetic testing ordered by my healthcare provider but not found on my 23andMe® genetic test?

A. This is not unexpected. There are thousands of different mutations in the BRCA1 and BRCA2 (BRCA1/2) genes found among families with inherited cancers. When testing is ordered by a healthcare provider, the vast majority of mutations in these genes can be detected if they are there.  However, BRCA1/2 at-home genetic testing done by 23andMe® looks for only 3 specific mutations in the BRCA1/2 genes found mostly in people of Ashkenazi Jewish descent. This testing does not look for the thousands of other mutations that have been found in the BRCA1/2  In fact, a study published last year looked at 49 different patients who learned from at-home testing that they had mutations.1 When these samples were tested again after a healthcare provider ordered the test, 40% of the mutations were not found (i.e., they were ‘false positives’).  Other “mutations” were present, but turned out to be benign, non-harmful genetic changes after further inspection. These findings highlight the shortcomings of at home genetic testing, and the potential for miscommunication, misinformation, and distress as eloquently articulated in a recent article by Dorothy Pomerantz.2 We recommend reaching out to your doctor or a genetic counselor if you have questions about these tests.

1Tandy-Connors, et al. Genet Med. 2018 Dec. PMID: 29565420.
2Pomerantz D. “23andMe had devastating news about my health. I wish a person had delivered it.” Stat News, available at: https://www.statnews.com/2019/08/08/23andme-genetic-test-revealed-high-cancer-risk/

ICARE Newsletter Summer 2019

Ovarian Cancer Treatment Advances for BRCA1/2 Carriers

A recently reported study of women with ovarian cancer and homologous recombination deficiency (HRD) who received a PARP inhibitor (niraparib) as fourth line or later treatment showed potential clinical benefit. Specifically, median overall survival after treatment was 19 months in the HRD-positive group (including those with BRCA1/2 mutations) compared to 15.5 months in the HRD-negative group. In fact, the subgroup with BRCA1/2 mutations had a median overall survival of 26 months. These results suggest possible expansion for use of this class of drugs beyond those with BRCA1/2 mutations to a broader patient population with HRD-positive ovarian cancer.

Moore, et al. Lancet Oncol. 2019 May. PMID 30948273.

ICARE Newsletter Summer 2019

Updates to National Comprehensive Cancer Network (NCCN) Genetic/Familial High-Risk Assessment: Colorectal Guidelines

(Version 1.2019, posted July 3, 2019)

For Individuals with Lynch Syndrome:

  • The cancer risk table was updated:
    • Addition of new cancer risks by specific genes: breast and bladder cancers
    • Updates of cancer risks by specific genes: ovarian, prostate, gastric, pancreatic, urothelial, small bowel, and brain/CNS cancers
    • Removal of reference to sebaceous neoplasms
  • Recommendations for cancer risk management were updated for colon, gastric, small bowel, urothelial, and prostate cancers:
    • For MSH6 carriers: consideration of colonoscopy at age 30 y or 10 y younger than age of any relative with colorectal cancer
    • Initiation of gastric and small bowel cancer surveillance was updated to 40 y
    • Surveillance for urothelial cancer may be considered in individuals with a family history of urothelial cancer or MSH2 mutations (especially males)

For Individuals with Attenuated Familial Adenomatous Polyposis (AFAP) and MUTYH-Associated Polyposis:

  • Colonoscopy frequency was increased to every 1-2 y

For the complete updated versions of the NCCN Guidelines, please visit NCCN.org

ICARE Newsletter Summer 2019

New Information About Cancer Risks for Inherited Cancer Genes: BRCA1/2

Looking at pregnancy history and breast cancer risk, a recent study of almost 8,000 women with BRCA1/2 mutations evaluated breast cancer risks related to pregnancy.1 Findings suggested the overall number of pregnancies was not associated with breast cancer risk in BRCA1 carriers; however, BRCA1 carriers with one pregnancy were at higher risk for breast cancer when compared to those with no pregnancies or more than one pregnancy. In contrast, among BRCA2 carriers, more pregnancies were associated with a lower breast cancer risk. Additionally, longer duration of breastfeeding in BRCA1 carriers lowered breast cancer risks. Looking at risks of contralateral breast cancer after removal of the ovaries, in a study of over 2,000 women with a BRCA1 or BRCA2 mutation and almost 10 years of follow-up, results suggested that removal of the ovaries did not reduce the chance of developing a second new breast cancer.2 This finding did not change with type of BRCA1/2 mutation or age at diagnosis of the first breast cancer. Overall, these findings suggest that removing the ovaries in BRCA1/2 carriers with breast cancer may not reduce their risk for developing another breast cancer. Looking at Non-Hodgkin lymphoma risks, in a study of pediatric cancer survivors, results suggested that children and adolescents with a BRCA2 mutation may have a higher risk for non-Hodgkin lymphoma, with a significant association (Odds Ratio of 5; 95% Confidence Interval: 2.1-10.2).3 These findings contribute to refining cancer risks among those with BRCA1/2 mutations and require confirmation through other studies.

 1Terry, et al. JNCI Cancer Spectr. 2018 Dec. PMID: 30873510.
2Kotsopoulos, et al. Breast Cancer Res Treat. 2019 Jun. PMID: 30756284.
3Wang, et al. JAMA Oncol. 2019 Jul. PMID: 31343663.

ICARE Newsletter Summer 2019

Community Spotlight

Life was great at 45. I had nothing more than a few headaches and was a tad overweight. After a friend was diagnosed with breast cancer, I realized I had not had a mammogram in a couple of years, so I scheduled an appointment. One mass was found, but it was benign and nothing to worry about. The mass continued to grow, and again, a biopsy confirmed it was benign. The mass was removed, and I went on with my life. A few months later, I returned for a follow-up appointment. It felt like a blow to my chest as the doctor confirmed I had a rare malignant phyllodes tumor in one breast. Because of the rarity of this type of cancer, I was offered genetic testing. A few months later, I was diagnosed with Li-Fraumeni syndrome (due to a TP53 mutation), a rare condition that greatly increases the risk for many types of cancers.

I have three children ages 11, 22, and 27. My 11-year-old was diagnosed with autism at age 3, which has prepared me to advocate like no other. Although there is so much more to my story, when faced with challenges, I prefer to come through and share the answers I have collected throughout my journey. I’m just starting, but here are a few tips I have used to cope:

  1. Brainstorm your thoughts in a journal. I have learned there are so many things I can’t control, but so many more that I can.
  2. Get your life in order and encourage your family and friends to do the same. With or without Li-Fraumeni syndrome, we are all guaranteed a death which can happen at any moment. As crazy as it sounds, while journaling, I realized that death was not my real fear. My real fear was leaving my son, and what his life would look like if I was not here to take care of him. Insurance policies, wills, trusts, and written expectations for my son are no longer something just on a to-do list.
  3. Get organized. I’m still figuring this out, but the appointments and test results can take over your life quite literally. Getting a calendar and establishing systems that work for you is a must.
  4. Research solutions and take an active role in your care. Ask questions no matter how silly they may seem. Always ask, “Is that the best we can do, and what are my other options?”
  5. Take your time when making decisions. Never allow anyone to pressure you into making a decision. Sometimes you have to take a step back and seek wise counsel.
  6. Create a “worry” section in your journal. As things pop up in my mind, I write them in the “worry” section of my journal and tell those thoughts that we can talk about them later during my worry time. “Worry time” is time I set aside to worry so that my day is not consumed with worry, which helps me stay focused on positive things. Typically, by the time “worry time” comes around, I have either found a solution, or I’m over it!
  7. This probably should have been number 1 on the list but seek therapy. A few weeks in I realized the thoughts about “what if” were consuming me. Depression is real. Get a good therapist. It may take several sessions with several therapists but talking it out can be a game changer.

Hope this helps because I’m out of space. Sending great vibes and love your way!

―ICARE participant, Angela Watson, from Memphis, Tennessee

ICARE Newsletter Summer 2019

Pancreatic Cancer Treatment Advances for BRCA1/2 Carriers

Results from a clinical trial of individuals with a BRCA1/2 mutation and pancreatic cancer showed that patients who received a PARP inhibitor (olaparib) for maintenance treatment had almost half the risk of their disease progressing when compared to receiving a placebo.1 In fact, after 2 years, 22.1% of patients who received olaparib had no disease progression compared to 9.6% of those receiving a placebo.1 In October 2018, Lynparza (olaparib) received orphan drug designation for pancreatic cancer through the U.S. Food and Drug Administration. Another study of a PARP inhibitor called rucaparib, presented at the 2019 AACR meeting, showed that BRCA1/2 or PALB2 carriers with advanced, platinum-sensitive, pancreatic cancer seemed to benefit from this maintenance treatment.2 In fact, of the 19 patients assessed so far, one had a complete response and six had a partial response to the treatment.2 These results remain preliminary and require more proof that they are true, but represent another possible treatment advance for those with pancreatic cancer and BRCA1/2 or PALB2 mutations. These results also highlight the importance for both germline (inherited) and tumor (somatic) testing among patients with pancreatic cancer.

1Golan, et al. N Engl J Med. 2019 July. PMID 31157963.
2Reiss Binder, et al. Abstract CT234. AACR Annual Meeting, presented 2019 April.

ICARE Newsletter Summer 2019

New Information About Cancer Risks for Inherited Cancer Genes: CHEK2

In a study of inherited mutations in the CHEK2 gene, findings suggest there were two specific mutations that could predispose men to testicular germ cell tumors (TGCT). Specifically, 205 men with these tumors were tested for 48 DNA repair genes, and findings were then tested in other patient populations. These findings suggest that CHEK2 mutations might predispose to TGCT, and also identify new avenues to explore treatments.

AlDubayan, et al. JAMA Oncol. 2019 Apr. PMID: 30676620.

ICARE Newsletter Summer 2019

New Information About Cancer Risks for Inherited Cancer Genes: DICER1

In a study of over 100 individuals with a DICER1 mutation, findings suggest that 5.3% of individuals had developed cancer by age 10, and 19.3% by age 50. After age 10, cancer risks for women were higher compared to men. Specific cancers for which risks were high included gynecologic and thyroid cancers. These findings are important to characterize cancers and natural history of the condition among those with DICER1 mutations, which is tremendously important for genetic counseling, risk counseling, and follow-up care.

Stewart, et al. J Clin Oncol. 2019 March. PMID: 30715996.

ICARE Newsletter Summer 2019

Expansion of Criteria for BRCA1/2 Testing through the USPSTF

The U.S. Preventive Services Task Force (USPSTF) came out with new genetic testing guidelines for the BRCA1/2 genes, which has garnered substantial media attention. This task force consists of a team of primary care and preventive medicine healthcare experts to lower the chance of a conflict of interest  (which is also the reason that subspecialty providers who practice in the area of clinical cancer genetics were excluded from this group, but who may be consulted to provide input).  For the current guideline, essentially a three-step process was included: 1) a brief risk assessment for BRCA1/2 risk by primary care providers with a validated tool; 2) referral to genetic counseling if positive; and 3) BRCA1/2 testing if indicated.

A substantial update to the guideline is that it now covers more women at-risk for a BRCA1/2 mutation.  Specifically, guidelines now include women with a history of breast, ovarian, fallopian tube, and peritoneal cancer who are disease-free, as well as those with ancestry prone to BRCA1/2 mutations, such as Ashkenazi Jewish women.  Some of the items that were not addressed include: 1) other cancers associated with the BRCA1/2 genes, including male breast cancer, prostate cancer, or pancreatic cancer; 2) other inherited breast or ovarian cancer genes (this is especially relevant as  most providers are not just testing for the BRCA1/2 genes, but other genes as well through multi-gene panel tests); 3) existing disparities in testing across racial/ethnic groups, and how these new guidelines may affect existing disparities; and 4) lack of accounting for some of the subtle nuances of treating those with a BRCA1 or BRCA2 mutation by outlining the differences in type of breast cancer that each primarily predisposes someone to (i.e., triple negative breast cancer) and providing evidence to support hormone receptor blockers for prevention.












US Preventive Services Task Force, Owens et al. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2019 Aug. PMID: 31429903. Available at: https://jamanetwork.com/journals/jama/fullarticle/2748515

ICARE Newsletter Summer 2019

Prostate Cancer Treatment Advances for BRCA1/2 Carriers

There is now information to suggest that identifying inherited mutations in DNA repair genes, such as BRCA1/2 and other genes, in men with metastatic prostate cancer may open doors for other treatment options. Results of a phase 2 clinical trial among men with metastatic and heavily pre-treated prostate cancer were presented at the American Society of Clinical Oncology 2019 meeting.1 Mateo and colleagues found that treatment with a PARP inhibitor (olaparib) was promising among those with BRCA1/2 mutations (24 of 30 patients) and PALB2 mutations (4 of 7 patients), while patients with other inherited genes also showed some response.1 Another recent study suggested that men with metastatic prostate cancer and a BRCA2 mutation who received androgen blockers for their initial treatment had better outcomes compared with those who received taxanes.2 This suggests that BRCA2 status may guide initial treatments among metastatic prostate cancer patients.2

 1Mateo, et al. J Clin Oncol. 2019 May. DOI: 10.1200/JCO.2019.37.15_suppl.5005.
 2Castro, et al. J Clin Oncol. 2019 Feb. PMID 30625039.

ICARE Newsletter Summer 2019

Expanding Our Thinking About Cancer Risks in TP53 Mutations and Li-Fraumeni Syndrome

Since expanded genetic testing has become available through multigene panel tests, studies have suggested that many people identified to have TP53 mutations do not have a typical personal or family history, which is usually seen with Li-Fraumeni syndrome (LFS). A recent study looking at over 300 individuals with TP53 mutations (identified through multi-gene panel testing) suggested that the level of cancer risks was dependent on the type of mutations within the TP53 gene. Specifically, those with a loss-of-function mutation (i.e., causing the protein produced from the TP53 gene to lose its function) tended to have stronger, more classic family histories suggestive of LFS, compared to those with other types of mutations (i.e., dominant-negative missense, other missense, splice site, or in-frame deletion). Although these findings require confirmation through other studies, this type of information may eventually become very helpful for genetic counseling by refining cancer risks and guiding follow-up care among individuals with TP53 mutations.

Rana, et al. Genet Med. 2019 May. PMID: 31105275.

ICARE Newsletter Summer 2019

New Information About Cancer Risks for Inherited Cancer Genes: HAUS6, KANLS1, PCR1

Through a study of over 13,000 patients with serous ovarian cancers and almost 41,000 controls, 34 genes that raise the risk for ovarian cancer were identified. Additional laboratory studies were conducted to further characterize some of these genes, suggesting that three of these new genes may be essential (HAUS6, KANLS1, and PRC1). This study has expanded the list of genes that raise the risk for ovarian cancer, and this information may eventually be used to identify those at highest risk for the disease.

Gusev, et al. Nat Genet 2019 May. PMID: 31043753

ICARE Newsletter Winter 2019

Other Advances in Cancer Treatment Among Cancer Patients with Inherited Disease: Familial Adenomatous Polyposis (FAP)

A new drug (sorafenib) showed promising results among patients with desmoid tumors, which are a type of tumor for which patients with Familial Adenomatous Polyposis (FAP) due to APC gene mutations are at risk. These tumors frequently grow and encompass internal organs and can be hard to remove surgically. The newly published research showed that treatment with sorafenib doubled the rate of progression-free survival at 2 years among patients with advanced or refractory desmoid tumors. The drug also reduced the risk of death by 87% compared to the placebo, with no major safety concerns. These advances serve to highlight some of the recent breakthroughs in the treatment of tumors among those with inherited cancer predisposition.

Gounder MM, et al. N Engl J Med. 2018 Dec 20. doi: 10.1056/NEJMoa1805052.

ICARE Newsletter Winter 2019

Advances in Biomarkers to Detect Pancreatic Cancer Early

Early detection of pancreatic cancer is tremendously important, given that most patients who develop the disease are diagnosed at a later stage of the disease when it is usually incurable. Although screening through imaging studies has been proposed (i.e., magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic ultrasound),1 data to support this type of screening as an evidence-based recommendation continues to be collected. Consequently, there has been longstanding interest in developing blood tests for early detection of pancreatic cancer. One such effort is represented in a recent study in which a metabolite panel in combination with CA19-9, TIMP1, and LRG1 were shown to be of potential use in the early detection of pancreatic cancer compared to a protein panel alone.2 These types of efforts are hoped to culminate in the development of a blood test that is reliable in detecting pancreatic cancer early, at a stage when it may be curable.

1Canto MI, et al. Gut. 2012 Nov. PMID: 23135763.
2Fahrmann JF, et al. J Natl Cancer Inst. 2018 Aug 18. PMID: 30137376.

ICARE Newsletter Winter 2019

Community Spotlight

When I was 50 years old I was in pretty good physical shape and I thought I was finally getting six pack abs. I was wrong – those abs were a large football sized tumor, along with a variety of smaller tumors. I was diagnosed with Stage 4 ovarian cancer. I had a hysterectomy and fibroid removal when I was 40 years old, but we left the ovaries because of my age – if only I knew then what I know now.  

My mom died of adenocarcinoma (lung cancer common in non-smokers) at 62 years old. My middle sister had Acute Lymphoblastic Leukemia in her 20’s (twice)! My dad (a few years after donating bone marrow to my sister – he is a hero) was diagnosed with Post-Polio Syndrome and Multiple Sclerosis – and that is just my immediate family’s medical history! Based on this and my personal history, genetic testing was a no brainer for me. It turns out I carry the BRIP1 gene. My youngest sister decided to have a hysterectomy with her ovaries removed at age 47 after learning about my genetic test results – if she had to do it over again, she may have had genetic testing of her own and regular screenings instead (because menopause is not fun). I am grateful to be able to share this information, especially if it can help protect future generations. It took very little effort to get genetic testing and if I can help a family member (or anyone for that matter) by sharing my genetic makeup, it is the least I can do to contribute to the prevention and early detection of cancer. To me, genetic testing is a way for me to help someone else. If there is a possibility of treating, preventing, orcuring cancer, I am all IN – take all the blood, genes, and body parts you want!  

I am not sure how or why, but I am one of the lucky few. I know a lot of women are in a constant battle trying to get where I am – 4 years with no evidence of disease (NED). I will do anything I can to help, and I am grateful to the scientists and doctors working so hard to find a cure or better ways to detect cancer early.  

―ICARE Participant, Kelly Frank, from Montana

ICARE Newsletter Winter 2019

Other Advances in Cancer Treatment Among Cancer Patients with Inherited Disease: Lynch Syndrome

Pertaining to metastatic prostate cancer, recently published data reported 8.1% of men with advanced prostate cancer had evidence of mismatch repair (MMR) mutations in their tumors. These types of mutations are frequently seen in tumors among Lynch syndrome patients. In addition, men with this type of tumor had much poorer survival. Tumors with MMR defects are thought to generate more antigens and be more responsive to a new class of drugs called immunotherapy. The researchers are now planning to conduct a new clinical trial to test the effectiveness of immunotherapy (through checkpoint inhibitors) in this group of patients with particularly aggressive prostate cancer. These advances serve to highlight some of the recent breakthroughs in the treatment of tumors among those with inherited cancer predisposition.

Nava Rodrigues D, et al. J Clin Invest. 2019 Oct 1. PMID: 30179225.

ICARE Newsletter Winter 2019

New Genes: GALNT12

A gene called GALNT12 may be yet another inherited colorectal cancer gene,1 as originally suggested by prior studies.2 The current study screened almost 500 colorectal cancer patients and identified 8 rare variants that may be disease causing. The frequency of variants among colorectal cancer patients was much higher than that observed among population-matched healthy controls, providing additional evidence to suggest this gene predisposes to inherited colorectal cancer. There remains a need to collect more data to confirm these findings.

1Evans DR, et al. Hum Mutat. 2018 Aug. PMID: 29749045.
2Clarke E, et al. Hum Mutat. 2012 Jul. PMID: 22461326.

ICARE Newsletter Winter 2019

Other Advances in Cancer Treatment Among Cancer Patients with Inherited Disease: von Hippel-Lindau (VHL) Disease

Additional exciting advances include the results of a new drug (pazopanib) to treat an inherited cancer condition called von Hippel-Lindau Disease (VHL), in which patients are predisposed to kidney cancers, pancreatic tumors, and hemangioblastomas (i.e., tumors involving the blood vessels). Study results showed that among 31 patients with VHL, overall response rate with the drug was 42%, with responses of 52% for renal cell carcinomas, 53% for pancreatic lesions, and 4% for CNS hemangioblastomas. Results are encouraging, and this may be a treatment option for individuals with VHL and growing or unresectable lesions, although safety and activity for these indications warrants further study. These advances serve to highlight some of the recent breakthroughs in the treatment of tumors among those with inherited cancer predisposition.

Jonasch E, et al. Lancet Oncol. 2018 Sept 17. doi 10.1016/S1470-2045(18)30487-X.

ICARE Newsletter Winter 2019

Basal Cell Cancers May Be a Risk Factor to Predict Inherited Cancer Predisposition

An interesting area of progress to identify individuals with inherited risks included a study of over 13,000 individuals with six or more basal cell cancers (BCC) evaluated through a claims database. Results indicated ~20% of these individuals had a germline mutation in a DNA repair gene, including BRCA1/2, PALB2, and the Lynch syndrome genes, among others. Furthermore, these individuals had over a 3-fold risk of other malignancies. These findings suggest that frequent BCC may represent a marker to identify potential inherited cancer risk.

Cho HG, et al. JCI Insight. 2018 Aug 9. PMID: 30089731.

ICARE Newsletter Winter 2019

New Research and Approvals of PARP Inhibitor Drugs to Treat Prostate Cancer in BRCA Carriers

Treatment among patients with metastatic castration-resistant prostate cancer: A PARP inhibitor (rucaparib) was granted a breakthrough therapy designation in October 2018 for monotherapy (i.e., sole treatment) among men with metastatic castration-resistant prostate cancer (with a BRCA1/2 mutation) who have received at least one prior androgen receptor-directed treatment and taxane-based chemotherapy. This designation was granted based on results of the phase II TRITON2 study, some results of which have been presented at national meeting, but not yet published.

ICARE Newsletter Winter 2019

Ask the Expert

The following question was addressed by Georgia Wiesner, MD, MS, a nationally renowned clinical cancer geneticist, who is an Ingram Professor of Cancer Research, Professor of Medicine in the Division of Genetic Medicine, and the Director of the Clinical and Translational Hereditary Cancer Program for the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

Q. What are the reproductive options for people with a BRCA mutation who do not want to pass their mutation on to their future children?

A. It is important to realize that pregnancy can be achieved without worry about passing on a gene mutation to future

generations. There are several options for couples, including adoption, gamete (egg or sperm) donation, and preimplantation genetic diagnosis (PGD) with in vitro fertilization (IVF). PGD begins with the normal process of IVF including egg retrieval and fertilization of the egg in a laboratory. When the fertilized egg (or “embryo”) reaches the 8-cell stage, one cell is removed to test it for the familial mutation. Then, embryos without the mutation can be selectively implanted using standard IVF procedures. However, the process of PGD with IVF requires confirmation prior to any procedure so that the lab can unambiguously detect the familial mutation. It can also be costly and may not be covered by insurance and involves invasive procedures. Therefore, couples considering PGD should be counseled by an experienced provider prior to any attempts to achieve a pregnancy. This process may also be relevant to individuals with other inherited gene mutations.

ICARE Newsletter Winter 2019

New Research and Approvals of PARP Inhibitor Drugs to Treat Breast Cancer in BRCA Carriers

Treatment among patients with advanced or metastatic breast cancer: A PARP inhibitor (talazoparib) was approved by the FDA on October 16, 2018 for BRCA carriers with HER2-negative locally advanced or metastatic breast cancer, based on results of the EMBRACA trial outlined in the last ICARE newsletter.

Litton JK, et al. N Engl J Med. 2018 Aug 23. PMID: 30110579.

ICARE Newsletter Winter 2019

Expansion of Lynch Syndrome Tumor Spectrum Which May Have Treatment Implications

Although the Lynch syndrome tumor spectrum is thought to be limited to cancers of the colorectum, endometrium, ovaries, stomach, and a few other cancer types, a recent article suggested there might be a broader tumor spectrum than previously considered. Furthermore, colorectal and endometrial cancers which develop among Lynch syndrome patients frequently are determined on tumor testing to have high microsatellite instability (MSI-H) or mismatch repair deficiency (MMR-D). The recently published study tested tumors in over 15,000 cancer patients with over 50 cancer types and found that among patients identified to have Lynch syndrome (based on germline DNA testing), 50% had tumors at sites other than the colorectum or endometrium, including urothelial, prostate, pancreas, adrenocortical, small bowel, sarcoma, mesothelioma, melanoma, gastric, and germ cell tumors. The investigators concluded that MSI-H/MMR-D predicts the presence of Lynch syndrome across a much broader tumor spectrum than currently appreciated and suggested that any patient with this tumor characteristic should receive a germline genetic assessment for Lynch syndrome regardless of cancer type or family history. This is particularly important given that Lynch syndrome tumors often respond to a new class of drugs (immunotherapy); thus, this information may help to guide cancer treatments.

Latham A, et al. J Clin Oncol. 2018 Oct 30. PMID: 30376427.

ICARE Newsletter Winter 2019

Refining Treatment for Aggressive Prostate Cancer in Men with BRCA2

A recent study reported that a large proportion of men with aggressive prostate cancer have inherited cancer gene mutations. Specifically, among 400 patients with castration-resistant prostate cancer, 16.2% had a germline mutation in a DNA damage repair gene, including 3% with a BRCA2 mutation. Among BRCA2 carriers, survival was 17.4 months, which was much lower than the 33.2 months observed among non-carriers. Furthermore, the subset of BRCA2 carriers who received first-line treatment with abiraterone or enzalutamide had better outcomes than those who received taxanes. Consequently, these findings suggest that determination of BRCA2 status may help to guide initial treatment of metastatic prostate cancer among BRCA2 carriers, although additional studies are needed to confirm these results.

Castro E, et al. J Clin Oncol. 2019 Jan 9. PMID: 30625039.

ICARE Newsletter Winter 2019

New Research and Approvals of PARP Inhibitor Drugs to Treat Ovarian Cancer in BRCA Carriers

First line maintenance treatment among patients newly diagnosed with advanced ovarian cancer: The results of a trial using a PARP inhibitor (olaparib) as maintenance treatment among ovarian cancer patients with advanced disease, a BRCA mutation, and complete or partial response to platinum-based chemotherapy showed that survival at 3 years was 60% among those who got the drug versus 27% among those who did not. Investigators concluded that among those with successful first-line chemotherapy, “The use of maintenance therapy with olaparib provided a substantial benefit among women with newly diagnosed advanced ovarian cancer and a BRCA mutation, with a 70% lower risk of disease progression or death with olaparib than with placebo.” Soon after publication of these results, on December 19, 2018, the FDA approved olaparib for maintenance treatment of BRCA-mutation advanced ovarian cancer.

Moore K, et al. N Engl J Med. 2018 Dec 27. PMID: 30345884.

ICARE Newsletter Winter 2019

High Proportion of Inherited Genes Detected Among Patients with Advanced Renal Cancer

In a study of advanced renal cell cancer patients, inherited cancer gene mutations were identified in 16%, of which 5.5% had mutations in genes related to renal cell cancer. Among the subgroup with non-clear cell renal cancer, about a fifth had an inherited cancer gene mutation, half of which had a gene mutation that could guide treatment. These findings suggest that more advanced renal cell cancers may arise in individuals with inherited cancer predisposition and are important to identify given their potential importance to guide treatment, inform future cancer risks, and provide patients with the potential to share test results with their family members.

Carlo MI, et al. JAMA Oncol. 2018 Sept 1. PMID: 29978187.

ICARE Newsletter Winter 2019

Testing Interpretation and Variant Reclassification

Results of germline genetic testing generally yield three types of test results: Deleterious (positive), Negative (no mutation detected), and Variant of Uncertain Significance (VUS). As more genes are tested, the chance for a positive result goes up, as does the chance of receiving a VUS result.1 VUS results tell us that it remains uncertain whether the test result is positive or negative. A recently published study demonstrated that most VUS results are downgraded to negative over time.2 Specifically, of more than 25,000 VUS results reported through a single testing laboratory, about a quarter were reclassified over time, of which over 90% were downgraded to negative (benign or likely benign). Information from this study is important when counseling patients with VUS results, informing them that most VUS results that are reclassified are downgraded, and explaining that VUS results are generally not used to direct medical care. On the topic of interpretation of genetic test results, another paper reported on a novel method to better classify BRCA1 mutations as positive or negative, through tracking how cells with specific BRCA1 changes, growing in lab dishes, respond.3 These types of efforts are important to better classify gene changes identified through genetic testing, and hopefully will serve to reduce the number of VUS results received by patients in the future. Finally, as knowledge expands, it becomes more important to make interpretation of genetic test information widely available for it to be maximally used to improve patient care. To that effect, a recent report outlined a global resource that includes data on more than 20,000 unique BRCA1 and BRCA2 variants, called the “BRCA Exchange”.4 Over 6,100 variants in this database have been classified by an expert panel, and approximately 3,700 are established to be positive (i.e., they raise the risk for cancer). This dataset was set up to pull in information from existing clinical databases, including the Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database, as well as other databases and data worldwide. It has a single-point-of-access website (https://brcaexchange.org/) and serves to demonstrate that this type of widespread data sharing across multiple entities is possible for other inherited cancer genes and genes associated with other diseases.

1Kurian AW, et al. JAMA. 2018 Aug 1. PMID: 29801090.
2Mersch J, et al. JAMA. 2018 Sept 25. PMID: 30264118.
3Findlay GM, et al. Nature. 2018 Oct. PMID: 30209399.
4Cline MS, et al. PLoS Genet. 2018 Dec 26. PMID: 30586411.

ICARE Newsletter Winter 2019

New Online Risk Calculator to More Accurately Predict Breast Cancer Risk

Prediction of breast cancer risk is important to identify those at highest and lowest risks, to help guide screening. A previously developed risk algorithm called Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) was recently extended to include truncating mutations in the BRCA genes, PALB2, CHEK2, and ATM. This online risk calculator could help healthcare providers more accurately predict breast cancer risks in patients. To access the risk calculator, please visit: https://ccge.medschl.cam.ac.uk/boadicea/.

Lee A, et al. Genet Med. 2019 Jan 15. PMID: 30643217.

ICARE Newsletter Summer 2018

The Role of Inherited Genes Increasingly Recognized in Pancreatic Cancer

A number of recent studies have suggested that a substantial number of individuals with pancreatic cancer have a mutation in an inherited cancer gene.  In a study of over 300 patients with pancreatic cancer (and with one or two family members with pancreatic cancer), 12% were found to have a mutation in 1 of 11 genes, most commonly BRCA2 and ATM.1 In a subsequently published study of 274 patients with pancreatic cancer (unselected for family history), almost 9% had a mutation in an inherited cancer gene.2 Through another large study of over 3000 pancreatic cancer patients, mutations in 6 genes associated with pancreatic cancer were found in 5.5% of these patients (including 7.9% and 5.2% of patients with and without a family history of pancreatic cancer).3 Most recently, ~10% of almost 300 unselected pancreatic cancer patients were found to have a mutation in an inherited cancer gene, most of which were genes known to be associated with pancreatic cancer.4 Many of these individuals did not meet current clinical criteria to warrant testing. Taken together, these findings highlight the importance of broadly considering testing for inherited cancer genes among individuals with pancreatic cancer, which is particularly important given the advances in targeted therapeutics.

1Chaffee KG, et al. Genet Med. 2018 Jan. PMID:  28726808.
2Young EL, et al. BMC Cancer. 2018 Jun 27. PMID: 29945567.
3Hu C, et al. JAMA. 2018 Jun 19. PMID:29922827.
4Brand R, et al, Cancer.2018 Aug 1. PMID: 30067863.

ICARE Newsletter Summer 2018

Community Spotlight

I was aware from a very young age that breast cancer was part of our family. I knew that my great-grandmother (whom I never met) had breast cancer and my grandmother was diagnosed in her 50’s. While I didn’t grow up being afraid of the disease, I was far more aware of it than were any of my friends. My mom was diagnosed with a uterine sarcoma in her mid-40’s and breast cancer at age 48, and again at age 54. She underwent a few grueling surgeries, but was spared chemotherapy and radiation. She also had her ovaries removed prophylactically, years before it was considered a “viable” option. My grandmother died in her 70’s from complications of ovarian cancer, and my mom lived until she was 81 when she succumbed to Alzheimer’s disease.

When I learned about genetic testing for the BRCA genes in spring of 2000, my mother and I had testing through Vanderbilt’s genetic counseling program and learned we were both BRCA2 positive; my two sisters tested negative. After much research—I met with numerous oncologists, surgeons, and plastic surgeons, and learned everything I could about possible insurance ramifications to any decisions I might make—I decided to have a complete hysterectomy and a prophylactic bilateral mastectomy with reconstruction.

During this time, I turned to FORCE (Facing Our Risk of Cancer Empowered) for much of my research and critical emotional support. My family was extremely supportive; my husband was “all in” despite having no prior experience with cancer. I felt lucky to have three healthy children (ages 3, 6, and 9 at the time) and was ready to undergo these surgeries to lower my cancer risks. The surgeries didn’t scare me because I had watched my mother successfully undergo tough surgeries. Primarily, I was afraid of the unknown.

It’s been 17 years since then, and I have no regrets. I’m eternally grateful for the research dedicated to hereditary cancers, the familial support I received, and the peace of mind my surgeries brought. I participate in ICARE and other related activities in hopes that continued research will positively impact all of us with hereditary cancers, and especially my three children who are now young adults. From my mom, I gleaned two thoughts I hope I’ve passed on to my children: live every day to the fullest; and knowledge is power. Because of my mother’s legacy and willingness to tackle this very tough issue, my kids are armed with information they can use as they grapple with difficult decisions in the years ahead.

  ―ICARE Participant, Patricia Blumenthal

ICARE Newsletter Summer 2018

Updates to NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian Guidelines

(Version 1.2019, posted July 11, 2018)

  • Regardless of family history, some individuals with a hereditary breast- and ovarian-related cancer may benefit from genetic testing to determine eligibility for targeted treatment
  • The multi-gene testing section table was updated with:
    • A potential association of ATM with ovarian cancer risk
    • Potential increased risk of BARD1 with breast cancer
    • Risk of breast cancer in BRIP1 was changed from no increased risk to unknown/insufficient evidence

For the complete updated versions of the NCCN Guidelines, please visit NCCN.org

ICARE Newsletter Summer 2018

Prevention of Colorectal Cancer Among Individuals with Familial Adenomatous Polyposis (FAP)

Through a randomized trial, patients with FAP were treated with sulindac and erlotinib versus placebo for 6 months. Results of the study showed that those treated with sulindac and erlotinib had 70% fewer polyps than those in the placebo group. The lower number of polyps was seen in both those with an intact colorectum and those who had had their colon removed and only had a rectal pouch or rectum. However, there was a high rate of side effects, most commonly skin and oral mucosal findings, which may limit the use of these medications at the doses used in the current study. Additional research is needed to follow patients for a longer time period to determine the effect of these medications on patient outcomes.

Samadder NJ, et al. JAMA Oncol. 2018 May 1. PMID: 29423501.

ICARE Newsletter Summer 2018

NTHL1: A New Gene for Inherited Colorectal Cancers

In a study of 51 individuals with multiple colon polyps drawn from 48 families, genetic testing through whole-exome sequencing identified 7 individuals (from 3 unrelated families) to have a mutation in both copies of their NTHL1 gene, and pedigree structure was consistent with autosomal recessive inheritance.1 All these individuals had colorectal cancer and a large number of adenomas (ranging from 8-50), and none of the 8 cancers or adenomas tested showed microsatellite instability. There were also individuals who developed endometrial and duodenal cancer. A subsequent study of over 2400 families confirmed the association between this gene and colorectal cancer risk.2

1Weren RD, et al. Nat Genet. 2015 Jun. PMID: 25938944.
2Broderick P, et al. Gastroenterology. 2017 Jan. PMID: 27713038.

ICARE Newsletter Summer 2018

Updates to NCCN Genetic/Familial High-Risk Assessment: Colorectal Guidelines

For Individuals with Lynch Syndrome:

  • Surveillance for gastric and small bowel cancer now indicates there is no clear data to support this, but surveillance can be performed every 3-5 years starting at age 40
  • Lack of evidence to make a recommendation for pancreatic or prostate cancer screening, beyond those already recommended through other NCCN Guideline panels
  • Increased breast cancer risk was acknowledged, however there is not enough evidence to support increased screening above what is recommended for the general population

In the multi-gene testing section:

  • New genes added for colorectal cancer risk included NTHL1 and MSH3 (‘biallelic’ mutations)
  • Indicated lack of data to determine screening recommendations among those with single (heterozygous) mutation in MUTYH and a second degree relative with colorectal cancer

For the complete updated versions of the NCCN Guidelines, please visit NCCN.org

ICARE Newsletter Summer 2018

Another PARP-Inhibitor Trial Among BRCA Carriers with Advanced Breast Cancer

In a Phase 3 clinical trial among BRCA carriers with advanced breast cancer, an oral PARP Inhibitor (talazoparib) was compared to standard chemotherapy.  Among those who received the PARP inhibitor, risk of disease progression or death was 46% lower, and the response rate was double. Furthermore, the side effect profile, quality-of-life measures, and breast cancer symptoms were more favorable in the PARP inhibitor group. These findings indicate that talazoparib among this group of patients results in longer progression-free survival than standard chemotherapy, with better patient-reported outcomes.

Litton JK, et al.. N Engl J Med. 2018 Aug 15. PMID: 30110579.

ICARE Newsletter Summer 2018

Inherited Leukemias: The Importance of TP53/Li-Fraumeni Syndrome and Other Genes

It has long been established that the risk for developing leukemia in childhood is high among individuals with Li-Fraumeni Syndrome; however, better understanding the characteristics of leukemia among these individuals is important to guide treatment approaches. In a study of children with Acute Lymphocytic Leukemia (ALL), those with a germline TP53 mutation (compared to those without a mutation) were older (median age of 15.5 years, compared to 7.3 years), were at a much higher risk of second cancers (25.1% versus 0.7%), and were more likely to have hypodiploid ALL (65.4% versus 1.2%), with poorer outcomes.1 This information may be important to guide treatment among these individuals, including type and timing of treatment.

In addition to Li-Fraumeni Syndrome, there are several other conditions that are associated with inherited susceptibility to leukemia among individuals of all ages, including those associated with bone marrow failure syndromes, those in which myelodysplastic syndrome is seen before the onset of leukemia, and those with primarily a leukemia risk.2 Patients with inherited hematologic malignancy syndromes may present without classic clinical signs of a particular familial syndrome or even a family history.3 As more patients with inherited forms are diagnosed, there remains a need for developing evidence-based recommendations because current recommendations are primarily based on expert consensus.4

1Qian M, et al. J Clin Oncol. 2018 Feb 20. PMID: 29300620.
2McReynolds LJ, et al. Hematology Am Soc Hematol Educ Program. 2017 Dec 8. PMID:29222262.
3Furutani et al. J Clin Oncol. 2017 Mar 20. PMID: 28297620.
4Godley LA, et al. Blood. 2017 Jul 27. PMID: 28600339.

ICARE Newsletter Summer 2018

Differences in Breast Cancer Risks Among Women with Lynch Syndrome

Breast cancer risks were recently reported among a sample of 423 women with mutations in one of the Lynch syndrome genes (MLH1, MSH2, MSH6, or PMS2).1 Results indicated that breast cancer risks were substantially higher among those with MSH6 and PMS2 mutations, compared to MLH1 and MSH2 mutations. In fact, breast cancer risk to age 60 was 37.7% for PMS2, 31.1% for MSH6, 16.1% for MSH2, and 15.5% for MHL1. These findings are consistent with another recent study of 528 patients with Lynch syndrome gene mutation (including MLH1, MSH2, MSH6, PMS2, and EPCAM) in which PMS2 and MSH6 mutations were much more frequent among those with only breast cancer, whereas MLH1 and MSH2 mutations were much more frequent among those with only colorectal cancer.2 These studies highlight how the risk profile among patients with Lynch syndrome is continuing to evolve as more individuals are tested through multi-gene panel testing, with particular focus on the complexities of the PMS2 mutation carrier phenotype.3

1Roberts ME, et al. Genet Med. 2018 Jan 18. PMID: 29345684.
2Espenschied CR, et al. J Clin Oncol. 2017 Aug 1. PMID: 28514183.
3Blount J, et al. Clin Genet. 2018 Jul. PMID: 29286535.

ICARE Newsletter Summer 2018

New Data to Suggest Additional Genes Associated with Breast and Ovarian Cancer

A recent study reported on cancer risks among over 10,000 cancer patients across the United States who had genetic testing. Findings suggest breast cancer risks were associated with ATM, CHEK2, and PALB2, as expected; but an association was also found with MSH6 (in line with other recently published data, as outlined in another article in this newsletter). Regarding ovarian cancer risks, associations were found with MSH6 and RAD51C, as previously reported; however, risks were also reported with TP53 and ATM. These data provide new insight on both previously confirmed well-established breast and ovarian cancer genes, while implicating additional genes not currently established to be associated with these cancers.

Lu H, et al. JAMA Oncol. 2018 Aug 16. PMID: 30128536.

ICARE Newsletter Summer 2018

Refining Cancer Risks Among Individuals with Lynch Syndrome

Over the past year, multiple studies have refined risks and types of cancer among individuals with Lynch syndrome. Through a Scandinavian study, risks for 13 types of cancer (with colorectal cancers being excluded), were reported to be elevated with differences related to gender, age, and the gene in which mutation was present. Incidence rates of cancer peaked by age as follows: between age 30-49, ovarian cancer; between age 50-69, endometrial, breast, renal cell and brain cancers; after age 70, urothelial, small bowel, stomach, pancreatic cancer and skin tumors. This is yet another study that may eventually be used to individualize cancer risk management among patients.

Therkildsen C, et al. Br J Cancer. 2017 Nov 21. PMID: 29065108.

ICARE Newsletter Summer 2018

Ask the Expert

The following question was addressed by Ronald D. Alvarez, MD, MBA who is Professor, Chairman, and Clinical Service Chief of the Department of Obstetrics and Gynecology at Vanderbilt University Medical Center in Nashville, Tennessee. Dr. Alvarez has been the recipient of several National Cancer Institute (NCI) and other industry funded grants in support of his research in gene therapeutics for ovarian cancer. He has served on the editorial board of Gynecologic Oncology and currently serves as Director of the Gynecologic Oncology Division for the American Board of Obstetrics and Gynecology.

Q. After an ovarian cancer diagnosis, should women with a BRCA mutation consider a risk-reducing mastectomy?

A. Among women with ovarian cancer who are found to have a BRCA1 or BRCA2 mutation, there is a lack of clear guidance as to when and in whom to consider risk-reducing mastectomy. In a study based on BRCA carriers (which included ICARE participants), 4% of these women developed breast cancer ten years following the ovarian cancer diagnosis. However, benefits of mastectomy (as well as breast MRI for early breast cancer detection) were primarily seen among women who had survived 10 years following their ovarian cancer diagnosis (without any disease recurrence) or had early stage (stage I or II) ovarian cancer. Consequently, risk-reducing mastectomy or breast MRI may be considered among BRCA carriers with ovarian cancer without a personal history of breast cancer and no evidence for recurrence for 10 years, as well as among those with early stage disease.

McGee J, et al. Gynecol Oncol. 2017 May. PMID: 28314588.

ICARE Newsletter Winter 2018

Community Spotlight

A cancer diagnosis is a life-changing event for every patient and their extended family. However, how we respond to this diagnosis are as individual as our very existence as evidenced by our looks and personalities. Following my diagnosis of stage 4 prostate cancer in 2014 at age 54 which had spread to my bones, I was initially crushed, especially when I found out that I was in the very small percentage for whom there really was no cure. I then did what I always do, just like I did when my son with Down’s syndrome was born – I tried to gather all the knowledge to make the best decisions to move forward. As with my son, who is now a 22 year old with a loving personality and working, my goal is to pursue the best outcome possible.

With a background of many immediate and extended family members with cancer, the decision to do genetic testing was easy, through which I found out that I was positive for the BRCA2 genetic mutation, which was not very surprising. Since all four of my children are now young adults between 21-33 years old, we had a great discussion about future testing and what this means. To my knowledge, none of them have completed testing yet, but they have all been like their old man…happy to have the knowledge to help them make good decisions on their own future preventive care. I am also personally glad they are armed with good information.

As for my own future, so far I am exceeding expectations. The first treatment was expected to last 18-24 months, but mine lasted 40 months! Now moving into what is called “advanced prostate cancer” I continue to be happy that my quality of life is still good. I also continue to rest in my faith and trust God for whatever future that remains.

  ―Ben Williams, Colonel, US Army, Retired

ICARE Newsletter Winter 2018

Advances in the Understanding of Inherited Prostate Cancer

Findings through a recent study reported that inherited cancer gene mutations were present in 8.2% of those with advanced or metastatic prostate cancer, which provides additional support to include this group of men in broader testing, particularly as targeted treatments based on inherited gene mutations becomes increasingly available.1 Another recent study suggested that those with a stronger family history of prostate cancer were more likely to present with more advanced prostate cancer, suggesting that familial or hereditary prostate cancer may be associated with a more aggressive disease.2 In view of these and other recent advances in the understanding about inherited prostate cancers, a group of experts convened to develop a consensus statement to guide the identification, management, and testing of men at risk for inherited prostate cancer.3 Overall, there was broad agreement for discussion of prostate cancer screening among BRCA2 carriers. Furthermore, there was moderate consensus that BRCA2 should be factored into management decisions from an early stage in the patient’s treatment, with stronger consensus that this is very important to consider among those with advanced or metastatic disease. Genetic testing for all men with metastatic castration-resistant prostate cancer regardless of family history was also considered to be important to inform prognosis and targeted therapy, particularly for the BRCA1 and BRCA2 genes, and possibly for the ATM gene.

1Thalgott et al. World J Urol. 2017 Nov 21. PMID:29164326.
2Giri et al. JCO Precision Oncology 2017 May 4;1, 1-17.
3Giri et al. J Clin Oncol. 2017 Dec 13. PMID:29236593.

ICARE Newsletter Winter 2018

The Role of “Non-Truncating” Mutations in RAD51D on Ovarian Cancer Risk

As testing has broadened to include newer inherited cancer genes, studies have suggested that mutations which shorten the protein (“truncating mutations”) in the RAD51D gene are associated with ovarian cancer.  However, a recent study examined ovarian cancer risks for a “non-truncating” change (a single base pair within the gene is changed which is called a missense mutation) in the RAD51D gene. The study was focused on a French-Canadian population in which a specific missense change (c.620C>T) is particularly common.  Findings showed that this change substantially raised the risk for high-grade serous ovarian cancer, which was seen in 3.8% of ovarian cancer patients and 0.2% of controls.  Furthermore, laboratory studies showed that this gene change may confer sensitivity to PARP inhibitors.  This is the first study to confirm a missense mutation in RAD51D and suggests that PARP-inhibitor therapies may be of use among this group of ovarian cancer patients.

Rivera et al. Cancer Res. 2017 Aug 15;77(16):4517-4529. PMID: 28646019.

ICARE Newsletter Winter 2018

Updates to NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian Guidelines

(Version 1.2018, posted Oct. 3, 2017)

  • Metastatic prostate cancer was added as an indication for evaluation and testing for the BRCA1 and BRCA2 genes
  • Among BRCA1, BRCA2, TP53 and PTEN carriers, women between ages 25-29 may consider having an annual mammogram with consideration of tomosynthesis if a breast MRI is not available.
  • Among female BRCA2 carriers, language regarding age of risk-reducing salpingo-oophorectomy (surgical removal of one or both ovaries and fallopian tubes) was updated to indicate that it may be delayed to age 40-45
  • The table for other inherited breast and ovarian cancer genes was updated per the recent advances.

For the complete updated versions of the NCCN Guidelines, please visit NCCN.org

ICARE Newsletter Winter 2018

Getting Closer to Detecting Cancers Early Through a Blood Test?

A recent study reported on a single blood test, named “CancerSEEK”, which can screen for 8 common types of cancer (ovarian, liver, stomach, pancreas, esophagus, colorectal, lung, and breast) and may help to identify the location at which the cancer started. This test evaluated the blood from over 1000 patients with Stage 1 to 3 cancers that were non-metastatic. The test’s ability to detect these cancers was 70% on average, ranging from as high as 98% for ovarian cancer to as low as 33% for breast cancer. This test measures circulating tumor DNA and 8 proteins, and the data is analyzed using machine-based learning. The researchers are conducting additional testing, and the hope is this test will be successful in screening for cancer when in its earliest stage and more treatable.1

Cohen et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018 Jan 18. [Epub ahead of print] PMID: 29348365

ICARE Newsletter Winter 2018

Advances in New Treatments for Individuals with Lynch Syndrome

A recently published phase II clinical trial investigated the use of a new class of drugs (called PD-1 Inhibitors) in DNA mismatch repair-deficient/ microsatellite instability-high colorectal tumors (which are features seen in the majority of colorectal tumors from individuals with Lynch Syndrome) among patients with metastatic disease.1 Investigators found patients who received two PD-1 Inhibitors (compared to just one PD-1 inhibitor, which had already shown to be of benefit2) had better response rates which lasted longer while maintaining the safety of the drug. Overall, 50% of these patients did not have progression of their colorectal cancer after 2 years. This treatment strategy represents a promising new option. Additional studies are already underway to evaluate this drug combination as a first line of treatment.

1Overman et al. J Clin Oncol. 2018 Jan 20:JCO2017769901. PMID:29355075.
2Overman et al. Lancet Oncol. 2017 Sep;18(9):1182-1191. PMID:28734759.

ICARE Newsletter Winter 2018

Refining Risks and Outcomes of Breast Cancer in BRCA Carriers

In an effort to further study breast cancer risks among BRCA carriers, a recently published study compared breast cancer risks among those with and without a close family member (first-degree relative) with breast cancer.1 Findings showed that risk for breast cancer by age 80 was 60.8% in BRCA1 carriers and 63.1% among BRCA2 carriers, with similar risk levels among those with and without breast cancer in a close relative. These findings suggest that breast cancer risks remain high among BRCA carriers, regardless of whether a woman has a close relative with breast cancer, thus cancer risk management should be the same for these women.

In considering outcomes of breast cancer, prior studies have not yet provided evidence to draw a definitive conclusion about whether BRCA carrier patients with breast cancer do better, worse, or no different, compared to patients with ‘sporadic’ (or non-hereditary) breast cancer. A new study was recently published to answer this question.2 In this study, breast cancer patients diagnosed at or below age 40 (within 12 months of their diagnosis) were followed over time to compare the outcome between those with and without a BRCA mutation. Findings from this study showed that BRCA carriers had similar overall survival to non-carriers. Furthermore, the study showed that those with a BRCA mutation and triple-negative breast cancer may have a better outcome (as defined by survival) in the first few years after diagnosis.

1Metcalfe et al. Clin Genet. 2017 Dec 5. PMID:29206279.
2Copson et al. Lancet Oncol. 2018 Jan 11. PMID 29337092.

ICARE Newsletter Winter 2018

FDA Approval of PARP Inhibitor (Lynparza) for Treatment of Advanced Breast Cancer

On January 12, 2018, the FDA approved the first PARP Inhibitor (Lynparza) for treatment in patients with advanced breast cancer due to inherited BRCA mutations.1 This drug is already approved for certain BRCA carriers for advanced ovarian cancer. PARP inhibitors were originally developed to target the specific pathway through which cancer develops among those with a BRCA mutation. This latest approval demonstrates that developing drugs to target the underlying genetic cause of cancer can be used across cancer types. The approval of this drug was based on a recently published trial which showed that the drug delayed disease progression, which may help preserve quality of life by delaying the use of chemotherapy.2 It remains to be determined whether further improvements in treatment with this drug can be achieved through using it in combination with other drugs.

2Robson et al. N Engl J Med. 2017 Aug 10;377(6):523-533. PMID: 28578601.

ICARE Newsletter Winter 2018

Ask the Expert

The following question was addressed by Dr. Ingrid Meszoely is a breast surgeon and Clinical Director of the Vanderbilt Breast Center at One Hundred Oaks. She leads a high-risk clinic, through which she and her team of nurse practitioners manage patients with inherited breast cancer predisposition. Her research interests include both clinical and translational breast cancer-related research.

Q. Is it reasonable to consider hormonal replacement therapy (HRT) in BRCA carriers without breast cancer, after a prophylactic oophorectomy (surgical removal of one or both ovaries)?

A. There have been prior concerns that HRT may raise the risk of breast cancer among BRCA carriers, yet data from multiple studies which have evaluated this question have been reassuring. Specifically, three studies (observational and retrospective studies) have been completed in BRCA mutation carriers without a history of breast cancer, in which HRT did not raise the subsequent risk of breast cancer, nor did it appear to reduce the protective effect of oophorectomy on breast cancer risk.1,2,3 While it would be ideal to confirm these findings through a randomized control trial, data are currently reassuring that HRT is an option that may be considered among BRCA carriers, particularly those with severe menopausal symptoms or other issues that compromise their quality of life. In fact, a recent study on a group of 178 premenopausal women at high risk for ovarian cancer reported that about one third (n=57) opted for risk-reducing salpingo-oophorectomy (RRSO; removal of both ovaries and fallopian tubes).4 Of those with RRSO, 27 used HRT after surgery and 30 did not. HRT users had less menopausal side effects (i.e., endocrine symptoms, sexual symptoms) compared to those with did not use HRT, suggesting the potential benefits of this treatment in the first year following RRSO.

1Eisen, A. et al. J Natl Cancer Inst. 2008 Oct 1;100(19), 1361-7. PMID:18812548.
2Rebbeck, T.R., et al. J Clin Oncol. 2005 Nov 1;23(31), 7804-10. PMID:16219936.
3Kotsopoulos et al. Breast Cancer Res Treat. 2016 Jan;155(2):365-73. PMID:26780555.
4Vermeulen et al. Eur J Cancer. 2017 Oct;84:159-167. PMID: 28818705.

ICARE Newsletter Winter 2018

Study Suggests Inherited Cancer Genes Are Important in Pancreatic Cancer

In a recent study which included over 800 patients with pancreatic ductal cancer, inherited cancer gene mutations were found in a much higher proportion than expected. Almost 5% of these patients had mutations identified in inherited cancer genes, the majority of which were in genes thought to be associated with pancreatic cancer (including BRCA2, ATM, BRCA1, PALB2, MLH1, CDKN2A, and TP53).  Those that had mutations identified tended to be younger on average, however most did not have a family history of cancer that would suggest the presence of inherited mutations. These findings demonstrate that a meaningful number of patients with inherited risk for pancreatic cancer will be missed if relying on only family history. With the development of drugs to target cancers which develop among those with inherited disease, this study shows that relying too heavily on family history may lead to missing patients who would otherwise be eligible for these targeted treatments.

Shindo et al. J Clin Oncol. 2017 Oct 20;35(30):3382-3390. PMID: 28767289.

ICARE Newsletter Winter 2018

Advances in Cancer Screening Among Li-Fraumeni Syndrome Patients

Several research groups from around the world that have conducted cancer screening among patients with Li-Fraumeni syndrome and a germline TP53 mutation have recently reported on their observations. Specifically, the National Cancer Institute group demonstrated that screening inclusive of rapid total body MRI detected cancers at an early stage,1 similar to findings published through other recent smaller studies.2,3 Collectively, these findings demonstrated the extensive screening advised for many Li-Fraumeni patients is feasible; however, some of this screening may lead to false positives (i.e., a positive finding on a cancer screening test that ends up not being cancer) as well as cancer overdiagnosis.Through a recent effort to look at whole body MRI in Li-Fraumeni syndrome patients across several previously published studies, data suggested that this screening test may be clinically useful and an important part of cancer risk management. Additionally, we recently published an article focused on ICARE participants with a germline TP53 mutation, who were identified based on a multi-gene panel test.6 We found that many of these individuals did not have a family history that would identify them as having Li-Fraumeni syndrome, which suggests that cancer risk in some of these ‘non-characteristic’ families may not be as high as those with a classic family history of Li-Fraumeni syndrome. This brings up the question about what screening is most appropriate for them. Overall, these articles all highlight the need to generate more evidence to refine screening practices among individuals with Li-Fraumeni Syndrome.

1Mai et al. JAMA Oncol. 2017 Dec 1;3(12):1640-1645. PMID:28772286.
2Ballinger et al. JAMA Oncol. 2017 Dec 1;3(12):1735-1736. PMID:28772290.
3Ruijs et al. JAMA Oncol. 2017 Dec 1;3(12):1733-1734. PMID:28772294.
4Asdahl PH, Ojha RP, Hasle H. JAMA Oncol. 2017 Dec 1;3(12):1645-1646. PMID:28772307.
5Ballinger et al. JAMA Oncol. 2017 Dec 1;3(12):1634-1639.PMID:28772291.
6Pal et al. South Med J. 2017 Oct;110(10):643-648. PMID:28973705.

ICARE Newsletter Summer 2017

Ask the Expert

The following question was addressed by Dr. Steven Narod who is a Tier I Canada Research Chair in Breast Cancer and a senior scientist at the Women’s College Research Institute in Toronto, Canada. Dr. Narod is a world-leader in the field of breast and ovarian cancer genetics.

Q. In women with a BRCA mutation and ovarian cancer, who might benefit the most from MRI screening or mastectomy?

A. Although risk-reducing mastectomy (RRM) and MRI screening are routinely offered to unaffected BRCA carriers, there are limited studies to guide whether those with a history of ovarian cancer would also benefit from RRM or MRI screening. We recently studied this question among 509 BRCA carriers with ovarian cancer through our registry database.1 We found that twenty (3.9%) patients developed breast cancer within the 10 years following their ovarian cancer diagnosis. Through simulation results, we were able to show limited benefit from MRI screening or RRM among most patients. However, our data suggests that women who had already survived 10 years or more following ovarian cancer or those with early stage ovarian cancer (stage I or II) could benefit from MRI or RRM. Based on these findings, we suggest that BRCA carriers with an ovarian cancer diagnosis and no prior history of breast cancer may benefit from MRI or RRM when they are 10 years out from their ovarian cancer diagnosis without a recurrence, or if they were diagnosed with early stage ovarian cancer.

ICARE Newsletter Summer 2017

Emerging FDA Approvals of Immunotherapy Among Patients With Metastatic MSI-H Cancers

Over the last few years, immunotherapy has emerged as an exciting new class of drugs. As early as 2015, immunotherapy through PD-1 Inhibitors among patients with MSI-H colorectal cancers was shown to be of potential benefit.1 As many individuals with Lynch Syndrome have cancers that are MSI-H and mismatch repair deficient, this class of drugs was thought to represent a class of ‘targeted treatments’ for individuals with this syndrome.

More recently, the FDA granted accelerated approval for the use of a PD-1 Inhibitor (nivolumab) for the treatment of patients with MSI-H or mismatch repair deficient metastatic colorectal cancer that has progressed after standard treatment through fluoropyrimidine, oxaliplatin, and irinotecan.2 The approval was based on results of the Phase II CheckMate-142 trial, where almost a third of patients who received nivolumab experienced some benefit from it.3 These exciting advances illustrate the expanded treatment options that are being evaluated and approved for those with inherited forms of cancer.

1Le et al. N Engl J Med. 2015 Jun 25;372(26): 2509-20. PMID:26028255.
3Overman et al. Lancet Oncol. 2017 Jun 19. [Epub ahead of print] PMID: 28734759.

ICARE Newsletter Summer 2017

Breast and Ovarian Cancer Risks Among BRCA Carriers Followed Over Time

Findings from an international study of over 6000 women with a BRCA1 mutation and almost 4000 women with a BRCA2 mutation followed for an average of 5 years were recently published.1 Results showed the risk of breast cancer by age 80 was ~70% for both BRCA1 and BRCA2 carriers. Rates of breast cancer increased until age 30-40 in BRCA1 carriers and 40-50 in BRCA2 carriers, after which they remained constant over time to age 80. Risk of ovarian cancer by age 80 was 44% among BRCA1 carriers and 17% among BRCA2 carriers. Among women with a prior breast cancer diagnosis, the risk of developing another new breast cancer in the other breast (called “contralateral breast cancer”) after 20 years was 40% for BRCA1 carriers and 26% for BRCA2 carriers. Overall, the risk of breast cancer was higher in individuals who had more relatives with breast cancer. Consistent with findings published by Rebbeck et al. in 2015 in JAMA, there were certain locations of the gene mutation that presented a higher risk for breast cancer2 – specifically, risks of breast cancer were higher for: 1) BRCA1 if the mutation was outside the region between c.2282-c.4071 and 2) BRCA2 if the mutation was outside the region between c.2831-c.6401. Ultimately, findings from the current study provide information to better predict cancer risks based on family history and mutation location, which may contribute to developing and improving personalized cancer risk management for women with mutations in these genes.

1Kuchenbaecker et al.  JAMA. 2017 Jun 20;317(23):2402-2416. PMID: 28632866.
2Rebbeck et al.  JAMA 2015 Apr 7;313(13):1347-61. PMID: 25849179.

ICARE Newsletter Summer 2017

Community Spotlight

After a long rainy summer filled with doctor visits, I was finally diagnosed with triple-negative inflammatory breast cancer (TN IBC) at the age of 49. I completed treatment in June 2008 and was grateful to have a new phase to my vocabulary – NED, ‘no evidence of disease’. Since there was no cancer history in my family tree, genetic testing was not offered to me. Fast forward to 2013, with a stronger knowledge base of BRCA gene testing, my medical team suggested I be tested and I agreed. My test results revealed that I carried a BRCA1 mutation, which meant that my children could have the gene as well. I strongly feel that any tool that can be of help to my family to be educated is important, as well as helping medical advancement. This testing could let my children and grandchildren know if they are at risk for breast and ovarian cancers. My three daughters subsequently had testing and my oldest daughter, Natalie, was also found to have this mutation. As Natalie has so eloquently stated after finding out, “I’m glad I’m armed with this knowledge so I can make informed decisions.” [https://www.theibcnetwork.org/moms-daughters/].

After my diagnosis of IBC, I was shocked at how little information was available regarding this type of breast cancer, and even more shocked at the lack of research and education considering it was first written about in the 1800’s. I formed the IBC Network Foundation, to encourage education and fund research for this orphaned form of breast cancer. I am pleased that we have managed to put almost 1 million dollars to research in five years. Our impact is now global, as we also have a sister charity in the UK funding research.

Vanderbilt is a leading cancer center, but I became familiar with some interest in TN IBC over a chance meeting with some researchers at a conference. I was pleased to see their passion and therefore saw the need for funding. Our foundation has committed to funding TN research at Vanderbilt.

Upon learning about the Inherited Cancer Registry (ICARE) based at Vanderbilt, I was excited to join to contribute to the research mission, as well as being given the opportunity to receive regular research and clinical updates. As much as it might seem frightening to some to join a registry like this, I am grateful for the opportunity to help pay it forward by supporting inherited cancer studies in the hopes we can all live well and have long healthy lives. 

Terry Arnold, ICARE Participant

ICARE Newsletter Summer 2017

New Results of a PARP Inhibitor Study Among BRCA Carriers with Metastatic Breast Cancer

Over the last decade, a new class of drugs called “PARP Inhibitors” has been evaluated as a form of targeted treatment among BRCA carriers. Results were recently reported from a Phase 3 clinical trial among BRCA carriers with HER2-negative metastatic breast cancer who received two or less prior chemotherapy regimens for their metastatic disease. Study participants received either the PARP inhibitor (olaparib) or standard treatment, and the primary outcome measured was progression-free survival (i.e. the length of time during and after the treatment where the cancer does not get worse). Of the 302 women who participated in this study, progression-free survival was ~3 months longer among those who received olaparib compared to standard treatment. Side effects from treatment and treatment discontinuation were also lower in the olaparib group.  Furthermore, progression of disease or death was 42% lower among those given olaparib. Although no PARP inhibitor is yet FDA-approved for breast cancer, these results demonstrate the type of evidence needed to move a drug from the clinical trials setting to an FDA-approved treatment and highlight the expansion of personalized treatments among BRCA carriers.

Robson et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017 Jun 4. PMID: 28578601.

ICARE Newsletter Summer 2017

What Are the Benefits of Adding a Mammogram to MRI for Breast Cancer Screening Among Women with BRCA Mutations?

Recently, researchers evaluated the benefit of adding a mammogram to MRI for breast cancer screening among ~2000 women with a BRCA1 or BRCA2 mutation. Results indicated that the addition of mammography to MRI did not substantially raise the chance of detecting breast cancer in the overall group. However, one-third of breast cancer cases diagnosed among women age 40 and below with a BRCA2 mutation were detected by mammograms alone. Consequently, this study suggests a limited benefit from mammography over and above MRI among BRCA1 carriers, but a potential benefit among BRCA2 carriers, particularly those at or below age 40. This type of information may eventually help tailor screening approaches among BRCA carriers.

Phi et al. Br J Cancer. 2016 Mar 15;114(6):631-7. PMID: 26908327.

ICARE Newsletter Summer 2017

What Are New and Subsequent Cancer Risks Among Patients with Li-Fraumeni Syndrome?

Although individuals with Li-Fraumeni Syndrome (LFS), due to mutations in the TP53 gene, have a very high lifetime risk of cancer, risks of initial and subsequent cancers are not well defined. Through a group of patients with the classic form of LFS, researchers at the National Cancer Institute estimated their cancer risks. They evaluated a total of 286 individuals with TP53 mutations from 107 families, and found of women 50% had developed cancer by age 31 and of men 50% had developed cancer by age 46. This suggests that on average women with LFS tend to develop cancer earlier than their male counterparts. For women, cancer risk was the contributing highest after age 20, mainly due to high risks of breast cancer. This differed in men, where the risk was highest in childhood and later adulthood. Among both sexes, almost 100% of individuals had developed cancer by age 70. Cancer risks outlined by type of cancer developed by age 70 among women and men with LFS are shown in the table below.

Cancer Type

Cancer Risks by Age 70



Breast cancer



Soft tissue sarcoma



Brain cancer






Of individuals who developed cancer, about half went on to develop at least one more cancer after an average timeframe of 10 years.  Furthermore, having been diagnosed with one cancer did not lower their risk of developing a subsequent cancer.  The new information from this study helps to refine cancer risk estimates among those with LFS, which is needed to guide their cancer risk management strategies.

Mai et al. Cancer. 2016 Dec 1;122(23):3673-3681. PMID: 27496084.

ICARE Newsletter Summer 2017

Breast and Ovarian Cancer Associations for Genes Tested Through Multi-Gene Panels

As testing for multiple genes at the same time (“multi-gene panel testing”) has become increasingly available with tremendous advances in genetic testing technology, it has become critical to evaluate and refine cancer associations and levels of risk for many of these genes now tested. Through a commercial laboratory database of almost 100,000 results of multi-gene panel testing, associations between mutations in specific genes with breast and ovarian cancers were evaluated. Findings indicated that 8 genes were associated with breast cancer and 11 genes were associated with ovarian cancer. Most had previously been confirmed in association with breast cancer, including ATM, BRCA1, BRCA2, CHEK2, PALB2, PTEN, and TP53. An additional newer gene, BARD1, was also found to be associated with breast cancer in this dataset, but remains a gene for which data continues to emerge to help determine whether a true association with breast cancer exists.  Similarly, for ovarian cancer, most genes identified to have an association were consistent with data from prior studies, including BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, STK11, RAD51C, and RAD51D. Additional genes that were shown to have an association with ovarian cancer in this dataset included ATM and NBN, however additional research is needed to determine if an association with ovarian cancer truly exists. Ultimately, there remains a great need to continue to evaluate cancer risks for inherited genes for which we have limited information about level of risk and types of associated cancer.

Kurian et al. JCO Precision Oncology. 2017 :1, 1-12

ICARE Newsletter Winter 2017

Community Spotlight

On my 43rd birthday I was diagnosed with an advanced stage breast cancer. Although my BRCA1 and BRCA2 results were surprisingly negative, I was certain there must be a genetic component to my breast cancer since I was diagnosed at a fairly young age. I remained in contact with my geneticist, Dr. Georgia Wiesner, and in 2016 she suggested I have more genetic testing for inherited breast cancer through a multi-gene test, which wasn’t available in 2011 when I was initially diagnosed. As a result of my additional testing performed through Dr. Wiesner, I found out I was positive for the CHEK2 mutation which not only explains my personal history of breast cancer but affords me the knowledge of additional screenings I may choose to have in the future. There was not a lot of information on the CHEK2 mutation and I found myself very fortunate to find a closed support group on social media for women and men that have also tested positive for a CHEK2 mutation (Facebook CHEK2 Mutation Support Group). I subsequently brought a family member to Moffitt for testing, at which time I came to know about and enroll in the Inherited Cancer Registry (ICARE) and am passionately dedicated to helping find answers with regards to how our genes may play a significant role in our cancer diagnosis and potentially our clinical outcome.                                              

If you are interested in joining this CHEK2 support group on Facebook, simply search for “CHEK2 Mutation Support Group” and request to join. As this is a private group, moderators will screen individuals who request to be added to the group.

ICARE Newsletter Winter 2017

Newly Approved PARP-Inhibitor (Rucaparib) to Treat BRCA Carriers with Ovarian Cancer

The FDA just approved another PARP inhibitor, rucaparib, for BRCA carriers with ovarian cancer who have already been treated with two or more chemotherapies. Among those with BRCA-mutant ovarian cancers, 54% had a partial or complete response to the drug with a median duration response of 9.2 months. The agency also approved a companion diagnostic test through Foundation Medicine, FoundationFocusTM which may be used in tandem. FoundationFocus CDxBRCA is a tissue-based test that detects tumor BRCA1 and BRCA2 mutations (germline and/or somatic) in ovarian cancer.

What remains interesting is that despite the availability of the companion diagnostic test, FoundationFocus, this test may not be required to determine eligibility for the drug – in fact, those determined to have a germline mutation in BRCA1/2 through any commercial laboratory may be eligible to receive this drug.

ICARE Newsletter Winter 2017

Characterizing Breast Cancers That Develop Among Women with a CHEK2 Mutation

With increasing use of multi-gene panel tests, one of the genes in which mutations are frequently detected among breast cancer patients and others is the CHEK2 gene. This gene has been shown to have a 2-3 fold excess risk for breast cancer. There are many CHEK2 mutations that have been identified that generally fall into two broad categories: those that prematurely shorten the protein that is made from the gene (called “truncating” mutations) and those that change a single base pair within the gene that impairs it from working normally (called “missense” mutations). Most completed studies have focused on a specific “truncating” mutation called “1100delC”, as it is a relatively common change particularly among European populations.

A few studies have tried to assess if breast cancers associated with CHEK2 mutations may have specific characteristics, although results have not been consistent. For example, a study from 2014 which included 3 CHEK2 truncating mutations (including the 1100delC mutation) found no differences in survival between those with and without mutations,2 while an earlier study from 2012 suggested that these CHEK2-associated breast cancers might have a poorer prognosis.1 More recently, a study focused on a CHEK2 missense mutation (p.1157T) suggested this change was not associated with poorer prognosis. Overall, there is currently insufficient evidence to conclude an association between a CHEK2 mutation and poorer breast cancer prognosis; however, additional studies are warranted to better understand this relationship.

1Weischer M, et al. J Clin Oncol. 2012 Dec 10. PMID: 23109706.
2Huzarski T, et al. Breast Cancer Res Treat. 2014 Apr. PMID: 24557336.
3Muranen TA, et al. Breast Cancer Res. 2016 Oct 3. PMID: 27716369.

ICARE Newsletter Winter 2017

New Study Suggesting BRCA1/2 and ATM Are Associated with Aggressive Prostate Cancer

Among 799 patients with prostate cancer, the rate of BRCA1/2 mutations was much higher among those who passed away of prostate cancer (6.07%) compared to those with low risk disease (1.44%).1 Among the group that died of prostate cancer, those with BRCA1/2 or ATM mutations passed away at an earlier age and had a shorter survival time compared to date of diagnosis. These findings suggest that prostate cancer patients with inherited mutations in BRCA1/2 and ATM have a poorer prognosis, with a higher risk of dying at an earlier age. These results are consistent with results of prior efforts, and highlight the importance of genetic testing among these patients to inform decisions regarding prostate cancer screening and treatment.

1Na R, et al. Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death. Eur Urol. 2016 Dec 9. [Epub ahead of print]; PMID: 27989354.

ICARE Newsletter Winter 2017

NCCN Guidelines Version 1.2017: Genetic/Familial High-Risk Assessment: Breast and Ovarian

Additional guidance pertaining to cancer risk management was provided in the most recent version of the NCCN Guidelines for inherited breast and ovarian cancer. These guidelines now include an expanded table outlining cancer risks and management for each gene, taking into account the age at initiation of each risk management modality as well as footnotes to highlight some of the nuances concerning particular mutations in specific genes. For example, among ATM and CHEK2 carriers, recommended age at initiation of high-risk breast screening with breast MRI is 40 years. Furthermore, the higher breast cancer risks associated with the ATM 7271T>G missense mutation is included as a footnote, as is the fact that the data on increased breast cancer risks associated with NBN is almost solely derived from the 657del5 truncating mutation. The full guidelines may be accessed through the NCCN website (www.nccn.org).

ICARE Newsletter Winter 2017

A Newly Identified Inherited Colon Cancer Gene: FAN1

There continues to be rapid advances in identifying new genes involved in inherited cancer risk.  An example of yet another recently identified gene is FAN1, in which a nonsense variant (i.e. the premature change or loss of a protein) was identified following exome sequencing in 3 individuals from a family who met clinical criteria for Lynch syndrome yet did not have any mutations identified in Lynch genes and had mismatch-proficient tumors. The FAN1 gene is involved in the Fanconi anemia DNA repair pathway, but is not known to be a gene involved in Fanconi anemia (a condition which can cause bone marrow failure). Study investigators subsequently tested an additional 176 families with family histories of colorectal cancer and identified FAN1 mutations in ~3%, of which all met clinical criteria for Lynch syndrome and also had mismatch proficient tumors.  These findings suggest that mutations in the FAN1 gene may lead to inherited susceptibility to colorectal cancer.  Additional studies are needed to determine the proportion of inherited colorectal cancer that may be due to mutations in this gene, as well as the level of risk incurred by mutations in this gene.

Seguí N,et al. Germline Mutations in FAN1 Cause Hereditary Colorectal Cancer by Impairing DNA Repair. Gastroenterology. 2015 Jun 4. PMID: 26052075.

ICARE Newsletter Winter 2017

Ask the Expert

The following question was addressed by Dr. Steven Narod who is a Tier I Canada Research Chair in Breast Cancer and a senior scientist at the Women’s College Research Institute in Toronto, Canada. Dr. Narod is a world-leader in the field of breast and ovarian cancer genetics.

Q. Does salpingo-oophorectomy reduce the risk of breast cancer in those with BRCA mutations

A. Among women in the general population, risk-reducing salpingo-oophorectomy (RRSO) (i.e. removal of the ovaries and fallopian tubes) is recommended to reduce the risk of ovarian and fallopian tube cancer. The removal of the ovaries may reduce the risk of breast cancer as well. In the general population removal of the ovaries before menopause cuts the risk of breast cancer by 30% or more. Similarly, early studies in BRCAcarriers in the United States (US) suggested that removal of the ovaries also cuts their breast cancer risk by half or more, especially when done at an early age. However, a recent Dutch study did not observe a reduced risk of breast cancer after RRSO in BRCA1 carriers.1 The authors of this Dutch study suggest that previous findings may have been due to the design of the studies and how the data was analyzed and casts doubt on the earlier studies. The original US-based study teams subsequently re-analyzed their data but still concluded that RRSO reduced breast cancer risk among BRCA1 and BRCA2 carriers.2

Subsequently, our group led an international study with data from many centers (including ICARE participants) and included almost 4000 BRCA carriers. These women were followed for up to ten years for new cases of breast cancer. The study showed that RRSO reduced the risk of breast cancer risk in BRCA2 carriers, but did not reduce breast cancer risk among BRCA1 carriers.3

Taken together, data suggest there is a benefit of RRSO to lower breast cancer risk among BRCA2 carriers, but not BRCA1 carriers. However, given the strong protective effect of oophorectomy on ovarian cancer risk and on all-cause mortality we recommend an oophorectomy for BRCA1 carriers at age 35 and for BRCA2 carriers at age 40.4

1Heemskerk-Gerritsen BA, et al. J Natl Cancer Inst. 2015 Mar 18. PMID: 25788320.
2Chai X, et al. J Natl Cancer Inst. 2015 Aug 11. PMID: 26264690.
3Kotsopoulos J, et al. J Natl Cancer Inst. 2016 Sep 6. PMID: 27601060.
4Finch AP, et al. J Clin Oncol. 2014 May 20.PMID: 24567435 

ICARE Newsletter Winter 2017

The Potential Promise of Immunotherapy Targeted to Those with Bi-Allelic Mutations in Lynch Syndrome Genes

People with Lynch Syndrome have a non-working Lynch gene (“mutation”), while the other copy of that gene is normal (recognizing that all of these genes come in pairs, with one member of the pair coming from each parent). Over the last few years, there has been an increased realization that some individuals have a mutation in both copies of their Lynch gene, which leads to a condition called Constitutional Mismatch Repair Deficiency (CMMRD). Those affected with CMMRD often develop cancer in childhood, with the most frequent types of cancer being brain tumors, gastrointestinal (colon or small bowel) cancers, and leukemias.1 Screening guidelines for children with CMMRD, developed through consortium-based efforts, include upper and lower GI scopes and brain imaging in childhood, followed by additional screening in adulthood.2 These efforts form the basis of collecting data to someday develop evidence-based screening guidelines.

Recently, a study of tumors from children with CMMRD showed some unique findings. Specifically, these tumors accumulate mutations at a very high rate (~600 mutations/cell cycle) but do not exceed ~20,000 mutations in <6 months.3 This finding suggests a new mechanism of cancer progression. The exciting component of this is now that the high mutation load and threshold effect are known, this information can be used to target more effective treatments for these cancers. To this end, high mutation load (which also leads to high neoantigen loads) may respond to immune checkpoint inhibition, which is a new class of immunotherapy drugs. In fact, a recent study demonstrated that neoantigen loads of individuals with CMMRD was substantially higher than those without the condition.4 Furthermore, based on this preclinical data, study investigators treated two siblings with CMMRD with recurrent glioblastoma multiforme (a rare and aggressive form of brain cancer) with an immune checkpoint inhibitor (PD-1 inhibitor) called nivolumab, which led to a clinically significant response and substantial shrinkage of the tumor on MRI scans. These findings suggest that cancers with exceptionally high mutation loads may more likely respond to immunotherapy because there is a higher chance they have specific neoantigens which activate T cells. Taken together, it is possible that all CMMRD-related cancers may benefit from this type of treatment approach. To investigate this further, a group of international researchers has developed a pilot study of nivolumab in pediatric patients with hypermutated cancers (clinicaltrials.gov identifier NCT02992964) and anticipates beginning enrolling patients in early 2017.

1Bakry D, et al. Eur J Cancer. 2014 Mar. PMID: 24440087.
2Durno CA, et al. Eur J Cancer. 2015 May. PMID: 25883011.
3Shlien A, et al. Nat Genet. 2015 Mar. PMID:25642631.
4Bouffet E, et al. J Clin Oncol. 2016 Jul 1. PMID: 27001570.

ICARE Newsletter Winter 2017

How Does Having a Mother with Breast Cancer and a BRCA Mutation Affect Adolescent Girls?

A recent study compared psychosocial adjustment and risk perception among 11 to 19 year old daughters of women with breast cancer, comparing those with a BRCA mutation versus those without.1 The overall findings from the study were reassuring, suggesting that adolescent girls from BRCA-positive families had higher self-esteem and similar psychosocial adjustment compared to their peers without a family history of breast cancer. On the other hand, not surprisingly, girls from BRCA-positive families experienced more distress related to breast cancer and being susceptible to the disease compared to girls without a family history of breast cancer. Overall, study findings suggest there remains a need to better understand how being from a BRCA-positive family may impact adolescent girls, in order to develop strategies which address any psychosocial concerns that may be demonstrated.

1Bradbury AR, et ak. Psychosocial Adjustment and Perceived Risk Among Adolescent Girls From Families With BRCA1/2 or Breast Cancer History. J Clin Oncol. 2016 Oct 1;34(28):3409-16. PubMed PMID: 27551110.

ICARE Newsletter Summer 2016

Cancer Chemoprevention in Individuals with Familial Adenomatous Polyposis (FAP)

Prior research has demonstrated that NSAIDs significantly reduce colonic and rectal polyp burden among individuals with FAP although their impact on outcomes remains to be determined.1,2 Recent data extended these results to the small intestine through completion of a randomized clinical trial among patients with FAP which demonstrated that use of sulindac and erlotinib compared with placebo led to lower duodenal (part of the small intestine) polyp burden at six months.3 However, grade 1 or 2 adverse events (i.e., side effects) were more common in the group that received the drug (the majority of which included an acne-like rash) which may limit use of these medications at the doses given in this study. Given results of this preliminary study, it is important to evaluate these drugs in a larger population of patients with FAP with a longer follow-up period to determine if these observations lead to improved clinical outcomes among these individuals.

1Giardiello FM, et al. N Engl J Med. 1993;328(18):1313-1316.PMID: 8385741.
2Giardiello FM, et al. N Engl J Med. 2002;346 (14):1054-1059.PMID:11932472.
3Samadder NJ, et al. JAMA. 2016 Mar 22-29;315(12):1266-75.PMID: 27002448.

ICARE Newsletter Summer 2016

Practice Guideline Updates for NCCN Genetic/Familial High-Risk Assessment

The National Comprehensive Cancer Network (NCCN) is a network of oncology healthcare providers who work together to develop best practice guidelines for the delivery of cancer care. Given the increasing use of testing for mutations in several inherited cancer genes at one time (called “multi-gene panel testing”), the Breast/Ovarian and Colorectal Panels sought to provide medical management guidance when using this testing approach. To access current NCCN guidelines, visit: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

Breast and Ovarian (v2.2016)

Cancer risk management recommendations for some of the newer inherited breast and ovarian cancer genes were recently added. Based on emerging data, risk-reducing salpingo-oophorectomy became a consideration for women with mutations in BRIP1, RAD51C and RAD51D. Also, risk-reducing mastectomy became a consideration for women with a PALB2 mutation.

ICARE Newsletter Summer 2016

What Are the Endometrial Cancer Risks Among BRCA Carriers?

Although BRCA mutations confer increased risk for ovarian, fallopian tube, and primary peritoneal cancer, there have been limited and conflicting risks reported for endometrial cancer. Consequently, current practice guidelines only recommend the removal of the fallopian tubes and ovaries as a risk-reducing option for BRCA carriers.1 Specifically, through a prospective study of 4500 women with a BRCA mutation, there were 17 women identified with endometrial cancers (13 in BRCA1 and 4 in BRCA2) with an average follow-up time of 5.7 years.2 This suggested an overall endometrial cancer risk of 2-fold; although risks were higher (~4-fold) in those who received tamoxifen. The incidence of endometrial cancer was 2% at 10-years among those treated with tamoxifen. A subsequent study by the same group suggested the increased endometrial cancer risks among those with a history of tamoxifen use was associated with progesterone-only hormone replacement therapy, which warrants further study.3 These findings suggest that tamoxifen contributed substantially to the endometrial cancers seen among BRCA1 mutation carriers, although the actual risk is still fairly small. Consequently, in those considering tamoxifen, it may be important to discuss hysterectomy at the time of risk-reducing salpingo-oophorectomy (RRSO).

More recently, a prospective study of almost 1,100 BRCA carriers who had previously undergone removal of their tubes and ovaries, demonstrated an increased risk in BRCA1 carriers for a type of endometrial cancer called serous/serous-like. In this study, 8 women with endometrial cancer (of which 5 were serous/serous-like) were identified over an average follow-up time of 5.1 years.4 This suggested an overall elevation in endometrial cancer risk of almost 2-fold. The association of serous/serous-like endometrial cancer is particularly relevant as it only accounts for approximately 10% of endometrial cancer cases in the general population and is typically associated with aggressive disease and poor prognosis. As eloquently reviewed in the Leath et al editorial for this article,5 the risk of serous endometrial cancer among BRCA1 carriers may warrant a discussion of the potential risks and benefits of hysterectomy at the time of RRSO as well as a discussion about the limitations of our current knowledge in order for patients to make an individualized decision. In fact, a recent report of cancer risks among relatives of over 1000 BRCA mutation carriers detected no increased risk of endometrial cancer,6 highlighting the limited (if any) elevation of endometrial cancer risk. Taken together, these findings emphasize the need for further studies to refine risks and determine the need for hysterectomy both at time of RRSO as well as the role (if any) of risk-reducing hysterectomy among those who have already had an RRSO (as the risk of a second surgery may be greater than the risk of endometrial cancer).

1National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Genetic Familial High-Risk Assessment: Breast and Ovarian. Version 1.2016. Retrieved from: www.nccn.org.
2Segev Y, et al. Gynecol Oncol. 2013 Jul;130(1):127-31. PMID: 23562522.
3Segev Y, et al. Fam Cancer. 2015 Sep;14(3):383-91. PMID: 25838159.
4Shu CA, et al. JAMA Oncol. 2016 Jun 30. PMID: 27367496.
5Leath CA, et al. JAMA Oncol. 2016 Jun 30. PMID: 27367041.
6Streff H, et al. Oncologist. 2016 Jul;21(7):869-74. PMID: 27306910.

ICARE Newsletter Summer 2016

CHEK2 *1100delC Mutation Carriers: Breast Cancer Risk by Age and Tumor Type and Other Associated Cancer Risks

The CHEK2 *1100delC mutation is the most common “truncating” mutation (causing a shortened protein) in the CHEK2 gene among Europeans, with lifetime breast cancer risk in the range of 20-30% among female carriers. Results of data pooled from over 30 studies which included 40,000 breast cancer cases and 40,000 controls, showed that estrogen receptor (ER) positive breast cancer was significantly (i.e., 2.5-fold) more common for  CHEK2 *1100delC carriers compared to non-carriers.1 Furthermore, breast cancer risk decreased with advancing age. CHEK2 mutation status and other familial risk factors may now be taken into account through a publicly available risk model, called BOADICEA, to provide women with a more precise estimate of their lifetime breast cancer risk.2 Another recent Dutch study3 reported that risks of developing cancers other than breast cancer among CHEK2 *1100delC mutation carriers was 15% to 82% higher than non-carriers; however, the exact risks by cancer type could not be calculated. Although these results are based on the *1100delC mutation, it is possible that this information may be applied to those with other truncating mutations in the CHEK2 gene. This type of data is crucial to help refine the level of cancer risk and the types of associated cancers among those with mutations in moderate risk genes as well as newer genes to best guide cancer risk management strategies.

1Schmidt, MK, et al. J Clin Oncol. 2016 Aug 10;34(23):2750-60. PMID: 27269948.
2Lee, A et al. Genet Med. 2016  Apr 14 . PMID: 27464310. 3Näslund-Koch, C., et al. J Clin Oncol. 2016 Apr 10;34(11):1208-16. PMID: 26884562.

ICARE Newsletter Summer 2016

Practice Guideline Updates for NCCN Genetic/Familial High-Risk Assessment

The National Comprehensive Cancer Network (NCCN) is a network of oncology healthcare providers who work together to develop best practice guidelines for the delivery of cancer care. Given the increasing use of testing for mutations in several inherited cancer genes at one time (called “multi-gene panel testing”), the Breast/Ovarian and Colorectal Panels sought to provide medical management guidance when using this testing approach. To access current NCCN guidelines, visit: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

Colorectal (v1.2016)

The current version was significantly changed to include risk level and recommended management for several newer genes associated with colorectal cancer risk as outlined below:

  • High-Risk Colorectal Cancer Genes (GREM1, POLD1, POLE): Begin colonoscopy between age 25-30 and repeat every 2-3 years if normal. If polyps are found, repeat colonoscopy every 1-2 years. Surgical consideration if polyp number becomes unmanageable.
  • Low/Moderate-Risk Colorectal Cancer Genes (APC (I1307K variant), BLM (single carrier), CHEK2, GALNT12, MUTYH (single carrier)): For carriers without a personal history of colon cancer who have a first-degree relative (parent, sibling, child) with colorectal cancer: colonoscopy every 5 years beginning at age 40 or 10 years prior to the earliest diagnosis of colon cancer in the first-degree relative. For patients without a personal history of colon cancer who do not have a first-degree relative with colorectal cancer: colonoscopy every 5 years beginning at age 40.
  • Lynch Syndrome (LS) (MLH1, MSH2, MSH6, PMS2, EPCAM): Begin colorectal screening at the same age and interval regardless of which of the five LS genes has a mutation. This is an important update for individuals with LS to share with at-risk family members as this may help to inform the age at which relatives may consider predictive testing for a known familial mutation. The updated NCCN colorectal cancer screening guidelines for LS are as follows:

LS Genes

Colorectal Cancer Risk
by Age 70

Updated Colorectal Cancer Screening

  • MLH1/MSH2: 52-82% 
  • MSH6: 10-22%
  • PMS2: 15-20%
  • Begin colonoscopy at 20-25 years old or 2-5 years prior to the earliest colon cancer in the family if diagnosed < age 25
  • Repeat every 1-2 years

ICARE Newsletter Summer 2016

Risk of Second Cancers Among Those with PTEN Mutations

A recently published study to evaluate the risk of second cancers among PTEN mutation carriers showed that women with breast cancer had a 10-year second breast cancer cumulative risk of almost 30%. Overall, the risk of second primary cancers was almost 8-fold that of the general population, primarily due to the higher risks of cancer of the breast (almost 9-fold), thyroid (almost 6-fold), and uterus (14-fold). These findings reiterate the importance of cancer risk management options among PTEN mutation carriers in order to detect cancers early or prevent them altogether.

Ngeow J, et al. J Clin Oncol. 2014 Jun 10;32(17):1818-24. PMID: 24778394.

ICARE Newsletter Summer 2016

Ask the Expert

The following question was addressed by Dr. Christine Laronga at the Moffitt Cancer Center:

Q. How should bone health be monitored in women with a BRCA mutation after removal of the ovaries (i.e., risk-reducing salpingo-oophorectomy (RRSO))?

A. Women with a BRCA mutation have a substantially high risk to develop ovarian cancer in their lifetime, yet there is currently no reliable screening method to detect ovarian cancer before it spreads beyond the ovaries.  Consequently, RRSO among BRCA carriers is generally recommended around age 35-40, recognizing that childbearing plans are a consideration when deciding on age at which to have this surgery. However, this surgery also leads to early menopause which affects bone health. A recent study looked at women with a BRCA mutation who had undergone RRSO and showed that only 44% of these women had gotten at least one DXA scan (which is a radiological test that measures bone density). Of these women, 32% had normal results, 55.6% had osteopenia (reduced bone density), and 12.1% had osteoporosis. Additionally, 4% of women had a fracture (not related to trauma) after surgery. Low bone density was not related to age, breast cancer history, prior chemotherapy, or hormone receptor blocker treatment, suggesting that this was mainly due to removal of the ovaries. These findings suggest that RRSO in BRCA carriers is a strong risk factor for bone loss – as a result, it may be prudent to offer these women screening for bone health following RRSO to allow for timely intervention. Furthermore, although there is a lack of data regarding the best interval for bone density screening among carriers following RRSO, obtaining a baseline DXA and then screening every two years is reasonable to consider in these women.

Garcia C, et al. Gynecol Oncol. 2015 Sep;138(3):723-6. PMID: 26086567.

ICARE Newsletter Summer 2016

Surveillance Among Individuals with Li-Fraumeni Syndrome (LFS): An 11 Year Follow-Up Study

Results from the original screening protocol for LFS1 were recently updated following collection of 11 years of follow-up data.2 Through this study, 89 patients with LFS were given the option of a clinical surveillance protocol consisting of a physical examination as well as frequent biochemical and imaging studies. Forty asymptomatic tumors were detected in 32% of the TP53 mutation carriers who chose clinical surveillance. Overall survival was much higher in the surveillance group (almost 90%) compared to the non-surveillance group (~60%). These data imply benefits from ongoing comprehensive cancer surveillance with early detection of tumors with suggestions that overall survival may be improved. 

1Villani et al. Lancet Oncol. 2011 June. PMID: 21601526.
2Villani et al. Lancet Oncol. 2016 Aug 5. PMID: 27501770.

ICARE Newsletter Summer 2016

Inherited Cancer Genes and Metastatic Prostate Cancer

Several prior studies have suggested that men with a BRCA mutation (primarily BRCA2) tend to develop an aggressive form of prostate cancer that is more likely to metastasize. These findings were recently extended through a new study published in the New England Journal of Medicine.1 In this study, almost 700 men with metastatic prostate cancer, unselected for strong family history or young age, were tested for mutations in 20 inherited cancer risk genes involved in repairing DNA damage.  Germline (inherited) mutations were identified in 82 men (11.8%), of which the most frequently mutated gene was BRCA2 (5.3%). Mutation frequency among those with metastatic prostate cancer was substantially higher than those with localized disease where only 4.6% were identified to have a mutation (p<0.001). Notably, unpublished findings presented during the 2016 American Urological Association Meeting suggested that among men with prostate cancer, BRCA mutations were significantly more common among African Americans (7.2%) compared to Caucasians (2.1%), with borderline significant results (p=0.052) of a shorter time to metastasis among African Americans. 2 Taken together, the much higher than expected frequency of inherited mutations identified among men with metastatic prostate cancer regardless of age or family history (even more so among those who are African American) in conjunction with potential relevance to targeted treatments suggest that it may be appropriate to offer genetic testing for inherited cancer genes involved in DNA repair to all men with metastatic prostate cancer.

1Pritchard CC, et al. N Engl J Med. 2016 Jul 6. PMID: 27433846.
2Petrovics G., et al.  Higher Frequency of Germline BRCA1 and BRCA2 Mutations in African American Prostate Cancer.  Presented at the 2016 American Urological Association as Abstract #MP39-18.

ICARE Newsletter Summer 2016

Community Spotlight

When I was diagnosed with cancer the first time at age 38, my sister (a breast cancer survivor since the age of 29) was positive we had a BRCA gene mutation. However, after we both had genetic testing done in 2006 the results showed we didn’t. Doctors said they were surprised we did not have a mutation in one of the BRCA genes, but believed we probably had another gene mutation that was not yet identified. In 2011, we were asked to participate in a genetic study called Whole Genome Analysis of High Risk Cancer Families through the Genetics Program at the University of North Carolina at Chapel Hill. We both had our DNA sequenced and were found to have a mutation in the PALB2 gene. The genetic study asked if other family members would be willing to be tested and out of the 19 members tested, 18 were positive for PALB2. Since my second battle with breast cancer this past year, I am more committed to help in whatever way I can help find a cure and find answers as to how our genes play a crucial role with cancer. 

Cynthia Cardenas Schweitzer, ICARE participant

ICARE Newsletter Summer 2016

An Approach to Making Risk Management Recommendations for Newer Inherited Cancer Genes

A recent article sought to develop an approach to cancer risk management among individuals with mutations in newer inherited cancer genes, many of which result in a moderate (rather than ‘high’) cancer risk. Overall, the investigators suggest a framework that takes the age-specific, lifetime, and absolute cancer risks into account for inherited cancer genes where there is a proven association with cancer predisposition based on published data.  They then suggest that cancer risk management should be initiated in women with pathogenic mutations in these inherited genes at the age when their 5-year cancer risk would approach that at which screening would routinely be initiated in women in the general population (which in the U.S. is approximately 1% for breast cancer). Given the lack of data on many of these newer genes to inform best surveillance strategies, investigators offer management suggestions with the hope of providing assistance to clinicians in managing patients as more definitive data emerges. The need to collect data among those with mutations in these newer genes (such as ATM, CHEK2, NBN, PALB2, BRIP1, RAD51C, and RAD51D) highlights the importance of participating in research registry efforts such as ICARE.

Tung N, et al. Nat Rev Clin Oncol. 2016 Jun 14. PMID: 27296296.

ICARE Newsletter Winter 2016

Improving Our Understanding of Cancer Risks Among Individuals with Li-Fraumeni Syndrome

A recent study from France included over 400 patients with Li-Fraumeni Syndrome (all of whom had an inherited TP53 gene mutation). Cancer types among children and adults differed, with the main cancer types among children being osteosarcomas, adrenocortical carcinomas, central nervous system (CNS) tumors and soft tissue sarcomas; whereas among adults, the main cancer types were breast cancer and soft tissue sarcomas. 

The study also evaluated whether the type of mutation was associated with a specific presentation of cancer.  What they found was that average age at which cancer presented was substantially lower among those who had a ‘dominant negative’ missense mutation (21.3 years) compared to those with all types of loss-of-function mutations (28.5 years) or genomic rearrangements (35.8 years).  With the exception of children with adrenocortical carcinoma, most affected children had dominant-negative missense mutations.

Among women ages 30 or younger with breast cancer, TP53 mutations were detected in 6%.  Breast cancer pathology reports were evaluated in a group of TP53 carriers, and showed that 55% were HER2 receptor positive and 37% were triple positive (i.e., ER, PR and HER2 receptor positive).  Among women with breast cancer and a TP53 mutation, the development of contralateral breast cancer (cancer in the opposite breast) was very high at 31% compared to an estimated 10% contralateral breast cancer risk among women in the general population.

There was a high rate (43%) of multiple primary cancers among TP53 mutation carriers, the majority of which were cancers that developed following an initial cancer diagnosis.  Treatment records were available on a subset of patients who received radiation treatment for their first tumor which showed that 30% developed secondary tumors in the radiation field, within 2-26 years (mean, 10.7 years) following their initial cancer treatment.

With the increasing use of multi-gene tests, mutations in TP53 are unexpectedly being identified in individuals without a family history characteristic of Li-Fraumeni Syndrome.2

Consequently, clinicians and researchers are pursuing efforts to better understand the expanding cancer risks and how cancer presents among some of these individuals who are unexpectedly found to have a TP53 mutation, which is needed to further tailor their medical care.

1Bougeard G et al. J Clin Oncol. 2015 Jul 20;33(21):2345-52. PMID: 26014290
2Kamihara J,et al. Hum Mutat. 2014 Jun;35(6):654-62. PMID: 24706533

ICARE Newsletter Winter 2016

How Much Does Age at First Breast Cancer Affect the Risk of Contralateral Breast Cancer Risk in BRCA Carriers?

A recently published study of Dutch patients (including 200 BRCA1 carriers, 71 BRCA2 carriers, and 6023 non-carriers) showed that the contralateral breast cancer (breast cancer in the opposite breast) risks at 10 years was 21.1% for BRCA1, 10.8% for BRCA2, and 5.1% for non-carriers. Among BRCA mutation carriers, it was important to take age at diagnosis of the first breast cancer into account to refine the 10-year risk of a second breast cancer diagnosis as follows: for those diagnosed at age 40 or younger, risks were 25.5% for BRCA1 and 17.2% for BRCA2; for those diagnosed between 41-49 years, risks were 15.6% for BRCA1 and 7.2% for BRCA2.  These findings show that it is important to provide age-specific risk estimates to BRCA mutation carriers as part of the counseling process in order for patients to make informed decisions about their cancer risk management.

 van den Broek AJ, et al. J Clin Oncol. 2015 Dec 23.PMID: 26700119.

ICARE Newsletter Winter 2016

Ask the Expert

The following question was addressed by Dr. Christine Laronga at the Moffitt Cancer Center:

Q. As a BRCA carrier, is it reasonable for me to consider nipple-sparing mastectomy (compared to total mastectomy) to reduce my future risks of breast cancer?

A. One  strategy to manage the high (60-70%) lifetime breast cancer risk among women with a BRCA mutation is risk-reducing bilateral total mastectomy (not subcutaneous mastectomy where a rim of breast tissue is intentionally left on the underside of the breast skin to afford a more natural feel to the reconstructed breast). This procedure reduces the risk of developing breast cancer by 90% or more.  In the past, the entire breast with the overlying nipple and areolar disk was removed when performing this surgery, but more recently there has been an increase interest in preserving the nipple (“nipple-sparing” mastectomy). For many women, the nipple is what defines the breast as a breast.  Prior studies have shown that some patients have psychosocial benefit when the nipple-areolar complex is spared, and for some, the inability to preserve the nipple may be a barrier to even consider mastectomy.

A recent study measured the amount of breast tissue that remains when the nipple is spared with a standard retroareolar margin of 5 mm, and found that this only encompasses 1.3% less of the total at-risk breast tissue among women with BRCA mutations.1 Additionally, two recent studies showed that among BRCA carriers with nipple-sparing mastectomy, fewer than 2% developed subsequent cancers and none were in the nipple-areolar complex.2,3  Furthermore, there was a low rate of complications and no evidence that safety in the cancer setting was compromised.  Although there remains a need for studies with a longer follow-up time, currently available information suggests that it is reasonable for women with a BRCA mutation to consider nipple-sparing mastectomy for both breast cancer risk-reduction and treatment.

From a surgical standpoint, there are different ways of reducing the amount of remaining breast tissue when performing this surgery.  When choosing this surgery, it is important to go to a surgeon who is experienced in this procedure in order to maximize risk reduction and minimize complication rates. 

1Baltzer HL et al. Ann Surg Oncol. 2014 May;21(5):1583-8. PMID: 24526546
2Yao K et al. Ann Surg Oncol. 2015 Feb;22(2):370-6. PMID: 25023546
3Manning AT et al. Br J Surg. 2015 Oct;102(11):1354-9. PMID: 26313374

ICARE Newsletter Winter 2016

Community Spotlight

I was first diagnosed with breast cancer when I was 56 years old.  Because of my strong family history of breast cancer, I was referred for genetic counseling and had BRCA testing at that time. Recently, I was diagnosed with breast cancer again. When I went to see my surgeon, she advised me to have more genetic testing for inherited breast cancer through multi-gene tests, which were not yet available when I first had my testing. Through this testing, I was found to have a PALB2 gene mutation, which explains my personal and family history of breast cancer. I recently enrolled in the Inherited Cancer Registry, as I am interested in participating in research in any way that I can to learn more about inherited cancers in people with a PALB2 mutation.

Mari-Lynn Slayton, ICARE participant

ICARE Newsletter Winter 2016

Potential Use of PARP-Inhibitors Among Men with Prostate Cancer Who Carry a Mutation in BRCA or Other DNA-Repair Gene

A recent study published in the New England Journal of Medicine suggests that PARP-Inhibitors may be of potential use in men who are no longer responding to standard treatments and carry either somatic (i.e., tumor) and/or germline (inherited) mutations in DNA-repair genes (i.e., BRCA1/2, ATM, Fanconi Anemia genes and CHEK2).1 Of 49 men with prostate cancer evaluated through the study, 16 (33%) had somatic mutations in DNA-repair genes.  Of these 16 patients, 14 (88%) responded to the PARP-inhibitor drug (Olaparib), including all 7 patients with BRCA2 mutations (3 with germline mutations and the other 4 with somatic mutations only) and 4 of the 5 ATM mutation carriers. These findings further demonstrate the potential importance of PARP-inhibitors among men with DNA-repair gene mutations in their prostate cancers; however, further studies are needed before these drugs can be considered for routine clinical use.

1Mateo J, et al. NEJM. 2015 Oct 29;373(18):1697-708. PMID: 26510020.

ICARE Newsletter Winter 2016

The Importance of Sharing Genetic Test Results with Family Members

Once an individual has had genetic testing for inherited cancer predisposition this information could help their close family members.  For example, when a BRCA mutation or a mutation in another inherited cancer gene is found, it is important for close family members (with or without a diagnosis of cancer) to know so they too can be proactive with cancer risk management and prevention options if they are identified to also have the familial mutation.  It is usually up to the first individual in the family identified with a mutation to share their positive genetic test result with their relatives.  Unfortunately, prior US-based studies suggest low rates of testing among at-risk family members1 the reasons for which are unclear, although higher rates of testing among family members were reported in a study conducted in Spain.2

It is also important for individuals who are the first person in their family to have genetic testing for inherited cancer and receive a negative result to share their results with family members. This may help to prevent unnecessary testing in the family and/or clarify the meaning of their negative result.

Tools exist to help facilitate sharing of positive test results among family members. These tools include creating a ‘family sharing letter’ to briefly describe the mutation that was found, what it means, and where relatives can access more information. 

1Barsevick AM et al. J Fam Psychol. 2008 Apr;22(2):303-12. PMID: 18410217.
2Sanz J et al. Fam Cancer. 2010 Sep;9(3):297-304. PMID: 20091130.

ICARE Newsletter Winter 2016

What Is the Risk for Ovarian Cancer Among Women with Mutations in Newer Ovarian Cancer Genes?

The most common form of inherited ovarian cancer is due to mutations in the BRCA1 and BRCA2 genes, which are present in 10-15% of women with ovarian cancer and lead to an ovarian cancer risk of up to 44% and 27%, respectively.  Another set of genes known to raise ovarian cancer risks are the mismatch repair genes (i.e., MLH1, MSH2, MSH6, PMS2, EPCAM) which lead to Lynch Syndrome.  Mutations in these genes result in a lifetime risk of ovarian cancer in the range of 10-12%. 

Technological advances that make it possible to test for multiple inherited cancer genes at the same time have led to the suggestion that 20-25% of women with ovarian cancer may have an inherited mutation in a cancer predisposing gene.1  There have been several inherited cancer genes identified among women with ovarian cancer (e.g., RAD51C, RAD51D, BRIP1), however it has only recently become possible to gather enough information to tell us how high the lifetime ovarian cancer risk may be for women with mutations in some of these genes.

It is important to figure out the level of ovarian cancer risk to determine whether removal of the ovaries for risk reduction is appropriate. Generally, a lifetime risk in the range of ~10% is reasonable to consider risk-reducing salpingo-oophorectomy (i.e., removal of the ovaries and fallopian tubes). The lifetime risk for developing ovarian cancer among women in the general population is between 1-2%.

Recently published data has provided some clarification of risks for mutations in the ovarian cancer genes outlined in the table, where an association with ovarian cancer has been suspected:

Gene Risk Estimated Lifetime Risk by age 80
RAD51C 5-6 fold2,3,4 to 16 fold5 ~9%3
RAD51D 6-12 fold4,5,6,7 10%7
BRIP1 3-9 fold6,8,9 5.8%8
PALB2 Current data fails to clearly support a high risk for ovarian cancer6,8,10,11

This new information will help individuals with mutations in these genes and their providers determine an individualized cancer risk management plan.

1Walsh T et al. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. PMID: 22006311
2Pelttari LM et al. Hum Mol Genet. 2011 Aug 15;20(16):3278-88. PMID: 21616938
3Loveday C. Nat Genet. 2012 Apr 26; 44(5):475-6 PMID: 22538716
4Song H et al. J Clin Oncol. 2015 Sep 10;33(26):2901-7. Epub 2015 Aug 10. PMID: 26261251
5Pelttari LM et al. J Med Genet. 2012 Jul;49(7):429-32. PMID: 22652533
6Norquist BM et al. JAMA Oncol. 2015 Dec 30:1-9. PMID: 26720728
7Loveday C. Nat Genet. 2011 Aug 7;43(9):879-82. PMID: 21822267
8Ramus SJ et al. J Natl Cancer Inst. 2015 Aug 27;107(11). PMID: 26315354
9Rafnar T et al. Nat Genet. 2011 Oct 2;43(11):1104-7. PMID: 21964575
10Kanchi KL et al. Nat Commun. 2014;5:3156. PMID: 24448499
11Antoniou AC et al. N Engl J Med. 2014 Aug 7;371(6):497-506. PMID: 25099575.

ICARE Newsletter Winter 2016

More Information About the Inherited Component of Pancreatic Cancer

Although pancreatic cancer is one of the cancer types seen among individuals with mutations in inherited cancer genes (including BRCA2 and BRCA1), the proportion of individuals with pancreatic cancer who have an inherited cause has remained uncertain.  To further clarify the role of BRCA1 and BRCA2 (BRCA), over 300 patients with pancreatic cancer were tested for BRCA mutations.1  BRCA mutations were identified in 4.6% of patients, of which almost 80% were in BRCA2 (with the remainder in BRCA1).  Many of the patients identified with BRCA mutations did not have a strong family history of breast and/or ovarian cancer.  Furthermore, individuals of Ashkenazi Jewish ancestry were more likely to have a BRCA mutation compared to all others.

More recently, another study tested 96 patients with pancreatic cancer for 22 inherited cancer genes, of which 14 mutations were identified in 13 patients (13.5%).2 Nine individuals (9.4%) were identified with mutations in established inherited pancreatic cancer genes of varying risks (i.e., BRCA1, BRCA2, PALB2, MSH6, and ATM). These findings suggest that inherited genes may be a contributing factor in a substantial proportion of individuals with pancreatic cancer.  However, more studies are needed to refine the level of pancreatic cancer risk in order to determine who to target for high-risk screening (recognizing that evidence-based screening strategies for the early detection of pancreatic cancer do not currently exist and remain an active area of research).  Finally, identification of inherited pancreatic cancer predisposition may contribute to targeted treatment approaches. 

1Holter S et al. JCO. 2015 May 4. PMID: 25940717.
2Hu C,et al. CEBP. 2015 Oct 19. PMID: 26483394.

ICARE Newsletter Summer 2015

The Rapid Pace of Discovering More Inherited Cancer Genes Continues

Over the last few months, a number of additional genes associated with inherited cancer predisposition have been identified. A few of these genes include: 1) the RECQL gene which appears to be another rare gene involved in inherited breast cancer1; 2) the SMAD9 gene associated with hamartomatous polyposis and ganglioneuromas of the intestinal tract2; 3) the FOCAD gene associated with polyposis and the development of colorectal cancer3; and 4) the Inositol Polyphosphate Multikinase (IPMK) gene involved in the development of intestinal carcinoids.4 These newly discovered genes require further study before they can be added to clinical tests widely offered to patients. 

Recently discovered genes that have started to be offered through clinical testing laboratories include those associated with colorectal cancers (GREM1, POLD1, and POLE), rhabdoid tumors (SMARCA4), and uveal and skin melanomas, as well as other cancers (BAP1).

These genes by no means represent a comprehensive list of new inherited cancer genes; rather they serve to highlight the rapid pace at which new cancer genes continue to be identified. We anticipate that next-generation sequencing technologies and new gene discoveries will continue to result in making new testing options more rapidly available. Consequently, it is important for individuals with personal and/or family histories suggestive of inherited cancer, where an underlying genetic reason has not yet been identified, to periodically check in with their healthcare providers to see if additional genetic testing may be available and/or warranted.

1.Cybulski C et al. Germline RECQL mutations are associated with breast cancer susceptibility. Nat Genet. 2015 Jun;47(6):643-6. PMID: 25915596.2.Ngeow J et al. Exome Sequencing Reveals Germline SMAD9 Mutation that Reduces PTEN Expression and is Associated with Hamartomatous Polyposis and Gastrointestinal Ganglioneuromas. Gastroenterology. 2015 Jun 26. PMID: 26122142.3.Weren RD et al. Germline deletions in the tumour suppressor gene FOCAD are associated with polyposis and colorectal cancer development. J Pathol. 2015 Jun;236(2):155-164. PMID: 25712196.4.Sei Y et al. A Hereditary Form of Small Intestinal Carcinoid Associated With a Germline Mutation in Inositol Polyphosphate Multikinase. Gastroenterology. 2015 Jul;149(1):67-78. PMID: 25865046.

ICARE Newsletter Summer 2015

Location and Type of BRCA1/2 Mutation May Impact Breast and Ovarian Cancer Risks

A study of almost 20,000 BRCA1 carriers and 12,000 BRCA2 carriers demonstrated differences in breast and ovarian cancer risks depending on the location and type of mutation. Although all regions are associated with increased risk for breast and ovarian cancers among BRCA1/2 carriers, there were specific regions that were associated with even higher cancer risks. Specifically, within BRCA1, there were three breast cancer cluster regions located at: 1) c.179-c.505; 2) c.4328-c.4945; and 3) c.5261-c.5563. There was also an ovarian cancer cluster region from c.1380-c.4062.  In BRCA2, there were multiple breast cancer cluster regions spanning c.1-c.596, c.772-c.1806 and c.7394-c.8904.  There were also ovarian cancer cluster regions located at: 1) c.3249-c.5681, adjacent to c.5946delT (i.e., 6174delT) and 2) c6645-c.7471. Furthermore, nonsense mutations (point mutations resulting in a shorter and unfinished protein product) were associated with earlier age of breast cancer diagnosis and differential breast or ovarian cancer risks for both BRCA1 and BRCA2. Overall, this worldwide effort represents the largest study to date to evaluate breast and ovarian cancer risks by location and type of BRCA1/2 mutation. Although results suggest variations in risk, these data require validation prior to BRCA1/2 carriers using the information for cancer prevention decision-making.

Rebbeck TR et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA. 2015 Apr 7;313(13):1347-61. PMID: 25849179.

ICARE Newsletter Summer 2015

Advances in Preventive and Treatment Approaches for Individuals with Lynch Syndrome

A study of over 1800 individuals with a mutation in one of the Lynch Syndrome genes was recently completed to assess whether aspirin and ibuprofen use may reduce colon cancer risk. Results showed that in those who took aspirin or ibuprofen for between 1 month and 4.9 years, the colon cancer risks were lower than those with less than one month of use.  This study provides additional evidence that both aspirin and ibuprofen may be an effective strategy to help reduce colorectal cancer risk among those with Lynch syndrome, where individuals currently rely solely on frequent colonoscopies for risk reduction. We encourage patients to speak with their healthcare provider about this study to determine if the addition of these medications would be right for them.

Pertaining to treatment of colorectal cancers, a new class of drugs that target the immune system (called PD-1 Inhibitors) has been shown to have potential efficacy in colorectal cancers with the MSI-H phenotype.  Given that most colorectal cancers in individuals with Lynch syndrome are MSI-H, this drug could potentially represent a targeted treatment for these individuals.  However, prior to becoming standard treatment in the clinical setting, clinical trials are needed.  These are currently being conducted to evaluate PD-1 inhibitors in individuals with MSI-H colorectal cancers. As clinical trials continue, we will monitor this exciting advancement for individuals with Lynch Syndrome.

 Ait Ouakrim D et al. Aspirin, Ibuprofen, and the Risk of Colorectal Cancer in Lynch Syndrome. J Natl Cancer Inst. 2015 Jun 24;107(9). PMID: 26109217

ICARE Newsletter Summer 2015

Breast Cancer Risks and Outcomes Among Women with a PALB2 Mutation

Through a recent study of over 12,000 Polish women with breast cancer, PALB2 mutations were detected in almost 1%.  In this study, about one third of those with a PALB2 mutation had triple negative (lacking estrogen, progesterone and HER2 receptors) breast cancer and the average age at breast cancer diagnosis was 53.3 years.  Breast tumors of 2 cm or larger had substantially worse outcomes (i.e., 32.4% 10-year survival) compared with tumors smaller than 2 cm (i.e., 82.4% 10-year survival). 

Overall, the study findings confirm a substantially elevated risk of breast cancer (24-40%) among women with a PALB2 mutation up to age 75.  The five-year cumulative incidence of contralateral breast cancer was 10% among those with a PALB2 mutation, compared to 17% among those with a BRCA1 mutation and 3% among those without a mutation in either gene.  Survival at 10 years was also worse in women with a PALB2 mutation at just under 50%, compared to 72.0% among those with a BRCA1 mutation, and 74.7% among those without a mutation in either gene. 

Given a possible association of poorer outcomes among women with breast cancers larger than 2 cm, focused efforts should be made to detect small cancers among women with a PALB2 mutation through various screening procedures. Furthermore, as early data suggests women with PALB2-associated breast cancer may develop more aggressive disease, it is important to study breast cancer characteristics and outcomes in PALB2 carriers through larger studies.

Ultimately, personalized treatments may be important for these women, thus it is vital to collect details about pathological features (receptor status), treatment (including chemotherapy regimen) and follow-up.  Only through these types of research efforts will we be able to learn more about this important gene and figure out how to better care for those with mutations. As outlined on the last page of this newsletter, we are currently recruiting 500 PALB2 mutation carriers to determine breast cancer characteristics and outcomes.

Cybulski C,et al. Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol. 2015 Jun;16(6):638-44. PMID: 25959805.

ICARE Newsletter Summer 2015

2015 NCCN Clinical Practice Guideline Update

Breast and Ovarian Management Based on Genetic Test Resultsa


Recommend Breast MRIc
(>20% lifetime risk of breast cancerd)

Recommend Risk-reducing salpingo-oophorectomy Discuss Option of Risk-reducing mastectomy
Intervention warranted based on gene and/or risk level ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, STK11, TP53 BRCA1, BRCA2, Lynch syndromee BRCA1, BRCA2, CDH1, PTEN, TP53
Insufficient evidence for











Note: To access full guidelines document, refer to www.nccn.org

aOther genes may be included in mutli-gene testing. cSee NCCN Guidelines for Breast Cancer Screening and Diagnosis.  dMay be modified based on family history or specific gene mutation. eSee NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal.

ICARE Newsletter Summer 2015

Ask the Expert

The following question was addressed to Dr. Steven Narod who is a Tier I Canada Research Chair in Breast Cancer and a senior scientist at Women’s College Research Institute in Toronto, Canada. Dr. Narod is a world-leader in the field of breast and ovarian cancer genetics. Over the course of his career, he has profoundly shaped current knowledge about cancer risks, prevention and screening amongst carriers of BRCA1 and BRCA2 mutations.

Q. As a BRCA mutation carrier, will salpingectomy (removal of the fallopian tubes while keeping the ovaries) lower my risk for developing ovarian cancer?

A. As many ovarian cancers originate in the fallopian tubes, bilateral salpingectomy has been proposed as a consideration among BRCA carriers who are not ready to remove their ovaries.1 Specifically, bilateral salpingectomy has been suggested as an interim procedure to reduce ovarian cancer risk after childbearing is complete, followed by later oophorectomy (removal of the ovaries). At this time there is no data to prove that salpingectomy reduces ovarian cancer risk among BRCA carriers and the benefit is based on theory. In contrast, bilateral salpingo-oophorectomy (i.e., removal of the ovaries and the fallopian tubes) has been shown to reduce the risk of ovarian cancer and of all cause of death dramatically.2 Bilateral salpingectomy has gained interest because it preserves ovarian function, which prevents premature menopause and its associated adverse effects experienced by some women but it cannot yet be assumed to be equivalent to oophorectomy.

1. Walker JL et al. Society of Gynecologic Oncology recommendations for the prevention of ovarian cancer. Cancer. 2015 Mar 27. PMID: 25820366.
Finch AP et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol. 2014 May 20;32(15):1547-53. PMID: 24567435.

ICARE Newsletter Winter 2015

Highlights of the 2014 National Comprehensive Cancer Network (NCCN) Update

Genetic/Familial High-Risk Assessment: Breast and Ovarian Guidelines

  • For breast cancer screening in BRCA carriers, yearly MRI is recommended starting at age 25; mammograms may be considered in instances where MRI is unavailable or individualized based on earliest age of onset in the family. From age 30-75, annual mammogram and breast MRI is recommended.  Above age 75, management should be considered on an individual basis.
  • In male BRCA carriers, prostate cancer screening through annual PSA and digital rectal exam starting at age 40 was recommended in BRCA2 carriers and a consideration in BRCA1
  • Modifications to TP53 testing and management recommendations
  • Refinement of screening recommendations in PTEN mutation carriers
  • Expansion of the multi-gene testing section including considerations when assessing mutations in less characterized genes and general recommendations.

To access the full guidelines document, refer to www.nccn.org

ICARE Newsletter Winter 2015

Highlights of the 2014 National Comprehensive Cancer Network (NCCN) Update

Genetic/Familial High-Risk Assessment: Colorectal Guidelines

  • Recommendation that tumors from newly diagnosed colorectal cancer patients be screened for Lynch syndrome (called “Universal Tumor Screening”).
  • A new algorithm was created for Routine Tumor Testing Criteria for Lynch Syndrome
  • Surveillance/Management recommendations were refined by gene for the various Lynch Syndrome genes.
  • Management recommendations were refined for other inherited colorectal cancers, including Familial Adenomatous Polyposis, Peutz-Jeghers Syndrome, Juvenile Polyposis Syndromes, and Colonic Adenomatous Polyposis of Unknown Etiology.

To access the full guidelines document, refer to www.nccn.org

ICARE Newsletter Winter 2015

PALB2: A Third Important Gene for Inherited Breast Cancer

Following the publication of an important article in the New England Journal of Medicine (NEJM) in August 2014, germline PALB2 gene mutations were confirmed as the third most important gene for inherited breast cancer, following BRCA1 and BRCA2.1 PALB2 stands for “partner and localizer of BRCA2” and is located on chromosome 16. Studies suggest that PALB2 mutations may account for ~2-3% of inherited breast cancer, highlighting its importance as a breast cancer predisposition gene. In those with PALB2 mutations, prior studies suggest: 1) breast cancer risks in women range from two to six-fold; 2) breast cancer risks in men appear to be 8-fold or higher; and 3) risk of pancreatic cancer, although poorly defined, may also be elevated.

While the increased risk of breast cancer in those with a PALB2 mutation has been known for years, genetic testing was not routinely performed because mutations were thought to be rare and cancer risks were unclear. However, declining genetic testing costs due to next-generation sequencing (NGS) technology have revolutionized genetic testing practices through development of multi-gene tests that include BRCA, PALB2, and multiple other genes in one test. As a result, individuals are increasingly being identified with PALB2 mutations. 

The recent NEJM article is the first to broadly address the absolute risk of breast cancer in PALB2 carriers. This international study was based on 154 families with PALB2 mutations, including 311 women and 51 men. In this study, breast cancer risk estimates in those with PALB2 mutations: 1) ranged from 33-58% by age 70 in women depending on family history; and 2) were just over 8-fold in men (although results did not reach statistical significance). Results also suggested that women with a PALB2 mutation were slightly more likely to develop triple negative breast cancer, which is an aggressive type of breast cancer resistant to hormone treatment with a higher chance of recurrence.

“Since the BRCA1 and BRCA2 genes were discovered in the mid-90s, no other genes of similar importance have been found. PALB2 is a potential candidate to be ‘BRCA3’. As mutations in this gene are uncommon, obtaining accurate risk figures is only possible through large international collaborations like this” said lead author of the study, Dr. Marc Tischkowitz from the Department of Medical Genetics at the University of Cambridge, “Now that we have identified this gene, we are in a position to provide genetic counseling and advice. If a woman is found to carry this mutation, we would recommend additional surveillance, such as MRI breast screening.”

Interestingly, PALB2-associated cancers may be sensitive to a new class of drugs known as PARP inhibitors, which are currently under investigation for BRCA-associated cancers. Thus it is possible that these drugs may also work in PALB2-associated cancers.      

There are early suggestions that women with PALB2-associated breast cancer may develop more aggressive disease.2 However, most studies are based on small numbers, thus it remains important to study breast cancer characteristics and outcomes in PALB2 carriers through larger studies. Only through these types of research efforts will we be able to learn more about this important gene and figure out how to better help those with mutations. We are currently recruiting 500 PALB2 mutation carriers to determine breast cancer characteristics and outcomes.

1. Antoniou AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. New England Journal of Medicine. Aug 7 2014; 371(6):497-506. 2. Heikkinen T, Karkkainen H, Aaltonen K, et al. The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype. Clinical Cancer Research. May 1 2009; 15(9):3214-3222.

ICARE Newsletter Winter 2015

The First PARP-Inhibitor to Be Approved for Clinical Use in BRCA Carriers

More frequently, cancer drugs are being developed to treat tumors based on their molecular make-up. PARP inhibitors are the first class of drugs specifically developed to treat BRCA-related tumors through targeting the DNA repair pathway. The PARP Inhibitors target this pathway and cause cancer cells to die while healthy cells are spared.

Although PARP inhibitors were developed almost a decade ago, they were only recently approved for clinical use through the U.S. Food and Drug Administration (FDA) after extensive evaluation through clinical trials. Specifically, the PARP inhibitor called Olaparib (Lynparza) was approved for use in BRCA carriers with advanced ovarian cancer treated with three or more prior lines of chemotherapy. 

The effectiveness of this PARP inhibitor, Olaparib, was examined in a study of 137 women with BRCA mutations and advanced ovarian cancer. Results showed that about a third of patients had partial shrinkage or complete disappearance of their ovarian tumor for an average of 8 months. These findings led the FDA to grant accelerated approval of this drug to treat life-threatening disease (because results of the clinical trial showed likely clinical benefit to patients).

Olaparib constitutes the first of a new class of drugs (i.e., PARP inhibitors) for treating ovarian cancer. This drug serves as an example of how the understanding of the underlying molecular mechanisms by which cancer develops can lead to more personalized and effective treatments.

There are many open clinical trials that continue to evaluate PARP inhibitors to determine: 1) when to start treatment with these agents in ovarian cancer patients; 2) whether they work in other BRCA-associated cancers such as breast cancer, pancreatic cancer and prostate cancer (among others); and 3) whether they may also be of benefit to individuals without germline BRCA mutations. Thus it is important to continue evaluating these drugs through clinical trials to determine how they may be best used to treat and perhaps prevent cancer.

ICARE Newsletter Winter 2015

Discovery of New Colorectal Cancer Genes

New inherited cancer genes continue to be discovered with the exciting advances made possible through next-generation sequencing technologies. Recent studies identified that the POL genes predispose to inherited colorectal cancer.1,2,3 In one study, Niemenen and colleagues studied a four-generation family with Lynch Syndrome with no evidence of mismatch repair deficiency.2 Through various means (including genetic linkage, exome sequencing, tumor studies, and functional investigations), they were able to identify a new gene called RPS20 which may be the underlying factor predisposing this family to colorectal cancer.

In another study, Palles and colleagues studied three large families with a dominant pattern of inherited colorectal cancer and multiple adenomas through whole genome sequencing.3 Through these efforts, they identified germline DNA polymerase gene mutations (i.e., POLE and POLD1) as high penetrance genes predisposing to multiple colorectal adenomas and early onset colorectal cancer. Subsequently, a Dutch study of 1188 patients with familial colorectal cancer and polyposis identified three patients with POLE mutations. These patients developed multiple colorectal adenomas, two of whom showed early onset colorectal cancer. Tumors from all three patients were microsatellite unstable and immunohistochemistry showed deficiency of MSH6/MSH2. These findings suggest evaluation of the POLE gene in microsatellite unstable colorectal cancers, especially when testing for other established Lynch syndrome gene mutations has not detected a mutation.

These advances serve to highlight the rapid pace at which new cancer genes continue to be identified. In addition to these new discoveries, next-generation sequencing technologies are also expected to make new testing options more quickly available. Consequently, it is important for individuals from high-risk families (particularly those with results that are ‘uninformative negative’ – i.e., where testing has not yet identified an inherited gene mutation) to periodically ask their healthcare providers whether additional testing options are available for them.

1. Elsayed FA, et al. European Journal of Human Genetics : EJHG. Nov 5 2014. 2. Nieminen TT, et al. Gastroenterology. Sep 2014;147(3):595-598 e595. 3. Palles C, et al. Nat Genet. Feb 2013;45(2):136-144.

ICARE Newsletter Winter 2015

Ask the Expert

The following question was addressed to Dr. Steven Narod who is a Tier I Canada Research Chair in Breast Cancer and a senior scientist at Women’s College Research Institute in Toronto, Canada. Dr. Narod is a world-leader in the field of breast and ovarian cancer genetics. Over the course of his career, he has profoundly shaped current knowledge about cancer risks, prevention and screening amongst carriers of BRCA1 and BRCA2 mutations.

Q. As a BRCA mutation carrier, how much does Tamoxifen reduce my chance of developing contralateral breast cancer?

A. Following an initial breast cancer diagnosis in BRCA mutation carriers, the annual risk for developing contralateral breast cancer (i.e., breast cancer in the other breast) is 3%.1 We have mainly relied on studies evaluating contralateral breast cancer risk reduction with Tamoxifen. These studies have suggested that in women with breast cancer and a BRCA mutation, Tamoxifen reduces the lifetime risk of contralateral breast cancer by ~50%, particularly among those who still have their ovaries.3, 4, 5 Only one study to date with fewer than 20 carriers evaluated Tamoxifen for primary breast cancer prevention and showed risk reduction in BRCA2; however, risk reduction was not confirmed in BRCA1 (but it is important to note that this was a small sample size because there might not have been enough women to find an effect).2 Consequently, Tamoxifen may be considered in BRCA carriers with at risk breast tissue, especially among those who are premenopausal and have their ovaries.

More recently, we evaluated how the duration of Tamoxifen use affected contralateral breast cancer risk.6 We found that the risk of contralateral breast cancer was reduced by about half in those who used Tamoxifen for a short time (less than one year). These results do not imply any changes to the recommended course of Tamoxifen in the context of a breast cancer diagnosis because the primary goal in this situation would be to reduce risk of recurrence. However these results may be relevant for women without a breast cancer diagnosis who are considering Tamoxifen for primary prevention. In these women, consideration of a short course of Tamoxifen may be preferred over the recommended 5-year course, particularly given that many women are reluctant to take the drug because of the fear of side effects.7

Ultimately, we urge women to have a balanced discussion of the potential benefits and harms of Tamoxifen with their healthcare providers to enable them to make an informed decision about using this medication.

1. Metcalfe K, et al. British Journal of Cancer. Apr 26 2011;104(9):1384-1392. 2. King MC, et al. Jama. Nov 14 2001;286(18):2251-2256. 3. Gronwald J, et al. International Journal of Cancer.May 1 2006;118(9):2281-2284. 4. Narod SA, et al. Lancet. Dec 2 2000;356(9245):1876-1881. 5. Phillips KA, et al. J Clin Oncol. Sep 1 2013;31(25):3091-3099. 6. Gronwald J, et al. Breast Cancer Res Treat. Jul 2014;146(2):421-427. 7. Cuzick J, et al. Lancet. Mar 22 2014;383(9922):1041-1048.

ICARE Newsletter Summer 2014

Is Breast Cancer Risk Affected by Timing of Oral Contraceptives in BRCA1 Carriers?

Although oral contraceptives (OC) reduce the risk of ovarian cancer in BRCA carriers,1 it is possible that they may raise breast cancer risk. Thus it is important to understand whether age at OC use is a factor when determining impact on breast cancer risk. To address this question, a recent study (which included data from ICARE participants) of ~5000 women with BRCA1 mutations suggested that use of OC before age 25 increases the risk of early-onset breast cancer, and that the risk becomes higher when used for longer periods of time. Two groups were compared (one with breast cancer and one without) to determine whether age at which OC was used impacted breast cancer risk.  Among BRCA1 carriers, breast cancer risk was higher in those who started OC use before age 20 (Odds Ratio (OR): 1.45; 95% CI 1.20; p=0.0001), and also possibly higher in those between ages 20-25 (OR 1.19; 95% CI 0.99-1.42; p=0.06).

Higher breast cancer risk was limited to breast cancer diagnosed before the age of 40. Overall, the authors reported that the risk of early-onset breast cancer increased by 11% with each additional year of OC use when it was started before the age of 20. However, in those diagnosed with breast cancer at or after the age of 40, there was no increased risk of breast cancer based on OC use. These findings suggest that OC use for the purpose of preventing ovarian cancer should be avoided prior to the age of 25.

1.Kotsopoulos J, et al. Breast Cancer Res Treat. 2014 Feb;143(3):579-86. PMID: 24458845.

ICARE Newsletter Summer 2014

What Are Factors That Modify Cancer Risk in BRCA Carriers?

Since the discovery of the BRCA genes about two decades ago, a number of studies have reported on factors that may modify cancer risks in those who carry gene mutations. Recently, results of previously published studies were collected through a comprehensive literature review to estimate the overall effects of various risk modifiers in BRCA carriers. Results suggested that giving birth for the first time at an earlier age was likely protective against breast cancer risk. Regarding ovarian cancer, breast feeding and tubal ligation reduced risks in BRCA1 carriers, and use of oral contraceptives reduced risks in both BRCA1 and BRCA2 carriers. Interestingly, smoking raised the risk of breast cancer in only BRCA2 mutation carriers. These findings suggest that sufficient information exists on some risk factors, which may be useful when counseling patients about cancer risks or lifestyle factors to modify risks in BRCA carriers.

Friebel TM, et al. J Natl Cancer Inst. 2014 Jun;106(6). PMID: 24824314.

ICARE Newsletter Summer 2014

Is There a Higher Risk of Prostate Cancer in Individuals with Lynch Syndrome?

Over the last few years, there have been studies to suggest that men with Lynch Syndrome may have a higher risk for developing prostate cancer.1,2,3,4,5 The results of these studies have differed as to whether there is an association with an aggressive form of disease. For example, some studies report the risk of developing prostate cancer as high as 30% by age 70 with detection of aggressive tumors with a Gleason score of 8 or higher.3 In contrast, a more recent study suggested a nearly 5-fold increased risk of developing prostate cancer, but these cancers did not appear to occur at an early age nor were they more likely to be the aggressive subtype.4 Another study found an increased prostate cancer risk, but it was specific to men with MSH2 mutations,5 similar to findings of a 10-fold increased risk of prostate cancer in MSH2 carriers reported in yet another study.1

Further studies to clarify the risks of and outcomes from prostate cancer are needed, as the data on prostate cancer risk in men with Lynch Syndrome remain preliminary. Consequently, the 2014 national practice guidelines available through NCCN do not include prostate in the Lynch Syndrome-associated cancers.6

1. Barrow PJ et al. Fam Cancer. 2013 Mar;12(1):57-63. PMID: 23054215.2. Watson P ,et al. Fam Cancer.2005;4(3):245-8. PMID: 16136385.3. Grindedal EM, et al. Cancer Epidemiol Biomarkers Prev. 2009 Sep;18(9):2460-7. PMID: 19723918.4. Haraldsdottir S, et al. Genet Med. 2014 Jan 16. PMID: 24434690.5. Engel C, et al. J Clin Oncol. 2012 Dec 10;30(35):4409-15. PMID: 23091106.6. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology.  Genetic/Familial High-Risk Assessment: Colorectal Cancer. Version 2.2014

ICARE Newsletter Summer 2014

Early Results to Suggest That PSA Screening May Help to Detect Prostate Cancer Early in Men with BRCA Mutations

Over the last few years, there have been a number of studies to suggest that men with BRCA mutations, particularly BRCA2, have a higher risk of developing aggressive prostate cancer. It remains uncertain whether these men might benefit from screening through the prostate-specific antigen (PSA) test. Within the last few years, PSA screening guidelines in the United States were revised, and no longer recommend screening for all men in the general population.1 However, use of the PSA test in targeted screening for high risk men remains under active study. The initial results from an international study suggested PSA screening may be useful in detecting prostate cancer early among BRCA carriers.2  Specifically, the investigators recruited almost 2500 men, of whom 59 were subsequently diagnosed with prostate cancer (including 18 BRCA1 carriers and 24 BRCA2 carriers). Based on a PSA threshold of 3.0 ng/ml, almost half of BRCA2 carriers who had a biopsy were diagnosed with prostate cancer, which is much higher than the proportions reported when screening the general population for prostate cancer. Most of the men with a BRCA2 mutation who developed prostate cancer had intermediate- or high-risk disease, which is considered to be clinically important and requires treatment. These preliminary results suggest that targeted PSA screening in BRCA carriers may be useful to detect a high proportion of those who develop aggressive prostate cancer.

1.http://www.uspreventiveservicestaskforce.org/prostatecancerscreening/prostatefinalrs.htm2. Bancroft et al.Eur Urol. 2014 Jan 15. pii: S0302-2838(14)00004-9. PMID: 24484606

ICARE Newsletter Summer 2014

Ask the Expert

The following question was addressed by Dr. Steven Narod who is a Tier I Canada Research Chair in Breast Cancer and a senior scientist at Women’s College Research Institute in Toronto, Canada.  Dr. Narod is a world-leader in the field of breast and ovarian cancer genetics. Over the course of his career, he has profoundly shaped current knowledge about cancer risks, prevention and screening amongst carriers of BRCA1 and BRCA2 mutations.

Q. As a BRCA mutation carrier, am I at an increased risk for endometrial cancer? Should I have a hysterectomy?

A. Most published studies in BRCA mutation carriers have reported that there is not a substantially higher risk of endometrial cancer. In fact, a recent report of 4456 BRCA carriers suggested that any increased incidence of uterine cancer among mutation carriers was related to the use of tamoxifen.1Results from this study indicated that even with tamoxifen use, the excess risk of endometrial cancer was small, with a 10-year cumulative risk of 2%. It has been suggested that these risks can be further reduced given the option of raloxifene (which does not raise uterine cancer risk) or aromatase inhibitors (which can be used in postmenopausal women for breast cancer prevention). As a result of our current understanding of this topic, I believe that there is no compelling reason to perform a hysterectomy to reduce the risk of uterine cancer in BRCA mutation carriers during preventive surgery to remove the ovaries and fallopian tubes. Nevertheless, it is important that the healthcare provider discuss the actual risks with the patients prior to surgery so that they can make a properly informed decision.

Segev Y, et al. Gynecol Oncol. 2013 Jul;130(1):127-31. PMID: 23562522.

ICARE Newsletter Summer 2014

New Study to Suggest Benefits of Oophorectomy in BRCA Mutation Carriers

A recent study published in the Journal of Clinical Oncology reported that prophylactic oophorectomy resulted in reducing the risk of ovarian cancer by 80%, and reduced all-cause mortality by 77%.1 The authors reported results on almost 5800 women, of whom 186 developed either ovarian, fallopian tube or peritoneal cancer. Women who had bilateral oophorectomy had a hazard ratio of 0.2 (95% CI: 0.13-0.39; p<0.001), meaning that their risk of developing ovarian cancer was reduced by 80% following the preventive removal of the ovaries. The hazard ratio for all-cause mortality to age 70 was 0.23 (95% CI: 0.13-0.39; p<0.001), which means that the risk of dying from any cause was substantially reduced by having the oophorectomy. The finding on all- cause mortality is striking and has important clinical implications. Specifically, these findings suggest the age distribution of ovarian cancers should not be the sole criterion for determining the best age at which to advise preventive surgery of the ovaries in BRCA mutation carriers. This is because removal of the ovaries may not just prevent ovarian cancer, but there may be additional benefits (particularly the reduction of breast cancer risk). However, there remain important quality of life issues to consider which need to be balanced with the probable gains in life expectancy. It is also important to note that the study did not uniformly collect information on whether the fallopian tubes were removed along with the ovaries. Nevertheless, it is now clearly evident that for the greatest reduction of ovarian cancer risk, removal of the fallopian tubes along with the ovaries is recommended. 

Furthermore, study findings imply that identifying BRCA mutations carriers in countries with limited resources to offer breast MRI screening or bilateral prophylactic mastectomy may still reduce mortality if these patients have access to salpingo-oophorectomy. Ultimately, it remains important to assess the long-term effects of removing the ovaries and fallopian tubes, and continue to work on designing effective treatments and preventive strategies.

1. Finch A et al. J Clin Oncol. 2014 May 20;32(15):1547-53. PMID: 24567435

ICARE Newsletter Winter 2014

Recent Evidence to Suggest That Individuals with Germline Mutations in the PTEN gene (Which Leads to Cowden Syndrome) May Have Higher Renal Cancer Risks

Cowden Syndrome is an inherited condition that leads to higher risks for breast and thyroid cancer, and possibly other cancers.1 There have been a few recent studies that suggest that this condition also puts individuals at a higher risk for kidney cancer. Specifically, Tan et al2 reported a lifetime risk of 30.6% (95% CI: 17.8-49.4) for kidney cancer. More recently, two additional studies also suggested higher risks of kidney cancer,3,4 although not as high as reported in the Tan study. Based on this data, authors of these studies have suggested individuals with Cowden Syndrome might consider yearly renal ultrasounds around the age of 40 (or alternatively, 10 years earlier than the earliest diagnosis in the family).

1. Pilarski R. J Genet Couns. 2009 Feb;18(1):13-27. PMID: 18972196.2. Bubien V et al. J Med Genet. 2013 Apr;50(4):255-63. PMID: 23335809.3. Tan MH et al. Clin Cancer Res. 2012 Jan 15;18(2):400-7. PMID: 2225225 4. Nieuwenhuis MH et al. Fam Cancer.2013 Aug 11. PMID: 23934601.

ICARE Newsletter Winter 2014

Tamoxifen May Reduce Contralateral Breast Cancer Risk in BRCA Carriers

There have been suggestions that Tamoxifen may reduce risks for contralateral breast cancer (i.e., breast cancer in the other breast) in BRCA carriers if taken after the initial breast cancer diagnosis, based mainly on retrospective studies. Only one prospective study has looked at this question, and showed that Tamoxifen may be useful in BRCA2, but did not find an association in BRCA1 (however there were less than 20 BRCA carriers in this study, which is limiting).1 More recently, a study led by Australian researchers investigated almost 2500 women based on combined prospective and retrospective data.2 Although this was a nonrandomized design, the study was able to demonstrate that Tamoxifen use was significantly associated with a reduction in contralateral breast cancer risk in both BRCA1 and BRCA2 mutation carriers. These findings suggest that Tamoxifen may be considered for breast cancer prevention in BRCA carriers with breast tissue, particularly those who are pre-menopausal and have their ovaries. A balanced discussion of the potential benefits and harms of Tamoxifen enables these women to make an informed decision as to whether they may wish to consider this medication.

1. King MC et al. JAMA. 2001 Nov 14;286(18):2251-6. PMID: 11710890.2. Phillips KA et al.  J Clin Oncol. 2013 Sep 1;31(25):3091-9. PMID: 23918944.

ICARE Newsletter Winter 2014

Ask the Expert

The following question was addressed by Dr. Laronga who is a breast surgeon based at the Moffitt Cancer Center:

Q. What are the risks of breast cancer after ovarian cancer in BRCA carriers? What risk management options are recommended?

A. BRCA carriers remain at a higher risk of breast cancer, even after having ovarian cancer; yet there is little information as to how high this risk might be. Recently, a study of women with ovarian cancer and a BRCA mutation who were followed up for an average of almost six years showed that ~10% went on to develop breast cancer.1Thus, most women (i.e., ~90% or higher) did not develop breast cancer, even when looking at 10-year survival rates. The risk of breast cancer in women with ovarian cancer was actually lower than in BRCA carriers without ovarian cancer. Study authors suggest that non-surgical management of breast cancer risk may be appropriate for these women. At Moffitt, ovarian cancer survivors with BRCA mutations are generally offered breast cancer screening recommended by the National Comprehensive Cancer Network (NCCN).2 In addition, these women are offered consultation with a breast surgical oncologist to discuss prophylactic mastectomy after they are cancer-free five years out from their initial ovarian cancer diagnosis.

1. Domchek SM et al. Risk of metachronous breast cancer after BRCA mutation-associated ovarian cancer. Cancer. 2013 Apr 1;119(7):1344-8. PubMed PMID:23165893. 2. NCCN guidelines, 2013 Genetic/Familial High-risk Assessment: Breast and Ovarian. in NCCN Practice Guidelines V.4.2013 edn Vol. 2013 (National Comprehensive Cancer Network, Fort Washington, PA, 2013).

ICARE Newsletter Winter 2014

Contralateral Mastectomy May Improve Survival in BRCA Mutation Carriers

It has been established that women who carry a germline BRCA mutation face breast cancer risks of 60-70% in their lifetime. After an initial breast cancer diagnosis, these women face a high risk for contralateral breast cancer. Some women with BRCA mutations move forward with contralateral mastectomy when they develop their first breast cancer diagnosis (as part of their breast cancer treatment); however it remains unclear whether contralateral mastectomy reduced the breast cancer-related mortality in these women. Recently, Dr. Kelly Metcalfe published a study1 based on 390 women with stage I or II breast cancer and a BRCA mutation followed for up to 20 years from diagnosis.  Of these women, 209 were treated with unilateral mastectomy compared to 181 treated with bilateral mastectomy. Results indicated that women with BRCA-associated breast cancer treated with bilateral mastectomy were 48% less likely to die of breast cancer within 20 years of diagnosis than women treated with unilateral mastectomy (even after controlling for age).  This is among the largest and longest running studies to evaluate long-term survival of BRCA-associated breast cancers, comparing type of surgery at initial diagnosis. Study findings suggest that bilateral mastectomy should be discussed as an option for young women with a BRCA mutation and early stage breast cancer. However, despite the long follow-up and large sample size, further research is needed to confirm these findings given the small numbers of “events” (i.e., second breast cancers) in participants. Ultimately, emerging data on personalized chemotherapeutic and biologic treatments for BRCA-related breast cancers coupled with study findings suggest that women with newly-diagnosed breast cancer might benefit from the knowledge that they carry a BRCA mutation.

Metcalfe et al. 2014 BMJ. 2014 Feb 11;348:g226. PMID: 24519767

ICARE Newsletter Summer 2013

Sharing BRCA Test Results with Adolescent and Young Adult Children—What Does the Latest Research Show?

While there are specific recommendations against BRCA testing for minors,1 guidelines are less clear about whether parents should share their own test results with their children. Because there are no recommended surveillance or risk reduction options prior to age 25 for known BRCA mutation carriers, there has been debate about balancing the benefits of sharing parents’ test results with the possible negative psychosocial outcomes. The largest published study on this topic included 253 parents who had undergone BRCA testing and their reports of sharing test results with children, ranging in age from ages 10 to 25. Of the 505 children, parents shared test results with 66%. For those who shared true negative results, children often expressed relief. However, the authors encourage parents to take this opportunity to discuss the continued benefits of positive health behaviors (e.g., diet, physical activity); despite decreased cancer risk based on BRCA test results. Importantly, parents sharing BRCA positive or variant of uncertain significance results perceived distress more frequently than those sharing negative results.2 Parents considering sharing test results with children may benefit from consultation with a genetic and/or other health care professional with expertise in family communication to help ensure that information is presented in a way that is age-appropriate, helps to reduce distress, and achieves positive psychosocial and behavioral outcomes.

1. Borry P, et al. Clin Genet 70:374-81, 2006. 2. Bradbury AR, et al. Cancer, 2012.

ICARE Newsletter Summer 2013

US Preventive Services Task Force (USPSTF) Guidelines for Inherited Breast and Ovarian Cancer and Implications to the Affordable Care Act (ACA)

Recently, the USPSTF released updated draft guidelines in April 2013 (from those previously published in 2005) for inherited breast and ovarian cancer due to germline BRCA1 and BRCA2 gene mutations.1 USPSTF is comprised of primary care providers who review the available literature and issue guidelines about risk assessment, testing and management based on available evidence. Subsequently, the Department of Health and Human Services, the Department of Labor, and the Department of Treasury issued a clarification addressing coverage for BRCA testing under the Affordable Care Act (ACA). Specifically, they indicated that asymptomatic, high-risk women (as defined per the USPSTF guidelines) with a family history of breast or ovarian cancer will be able to get tested for the breast cancer risk genes BRCA1 and BRCA2 with no co-pay.2 This rule applies to non-grandfathered health insurance plans and will likely broaden access to BRCA testing, as implementation of the ACA moves forward.


ICARE Newsletter Summer 2013

Male BRCA Carriers Have Poorer Outcomes from Prostate Cancer

Over the last few years, a number of studies have suggested that men with germline BRCA mutations (especially BRCA2) have poorer outcomes when they develop prostate cancer. In fact, a recent study of 2019 patients with prostate cancer, including 18 BRCA1 carriers, 61 BRCA2 carriers, and 1940 noncarriers indicated that germline mutations were more frequently associated with: higher Gleason score, later stage (T3/T4), nodal involvement, and metastatic disease present at diagnosis. Thus, these findings suggest that when men with BRCA mutations develop prostate cancer, it is more likely to be an aggressive subtype of the disease which may be related to the poorer outcomes observed. Consequently, study authors suggested that consideration should be given for tailoring clinical management for these patients, especially because most BRCA carriers with prostate cancer are currently treated through following the same protocols used for noncarriers (due to lack of studies focused on evaluating tailored management strategies in this group of men).

Furthermore, although clinical trials in this group are needed, authors suggested the following as a consideration: “radical treatment with either surgery or radiotherapy seems to be preferable to active surveillance for these patients, even for cases classified as low risk.”

Castro et al. J Clin Oncol. 2013 May 10;31(14):1748-57.

ICARE Newsletter Summer 2013

Oophorectomy Following Menopause

Prior studies have indicated that removal of the ovaries and fallopian tubes reduces the ovarian cancer risk by ~80% and breast cancer risk by ~50%, particularly when performed pre-menopausally. However a recent case control study of 2854 pairs of women with a BRCA1 or BRCA2 mutation with or without breast cancer showed that the risk of breast cancer was lowered more in those with surgical menopause (OR, 0.52; 95% CI, 0.40–0.66) compared to those with natural menopause (OR, 0.81; 95% CI, 0.62–1.07). Interestingly, this study also found that there was a significant reduction in breast cancer risk even in women who had their ovaries removed after they went through natural menopause (OR, 0.13; 95% CI, 0.02–0.54; P = 0.006). This is an important finding because women with BRCA mutations who remove their ovaries after menopause typically do so to lower their ovarian cancer risk – however, this study suggests that they also may be reducing their breast cancer risk at the same time. Finding from this study also highlight the importance for better understanding the protective effect of oophorectomy, as this has very important implications for chemoprevention.

Kotsopoulos J, et al. Cancer Epidemiol Biomarkers Prev. 2012 Jul; 21(7):1089-96.

ICARE Newsletter Summer 2013

BRCA Testing: Supreme Court Update

In a landmark decision regarding the patenting of human genes on Thursday June 13, 2013, the Supreme Court of the United States unanimously ruled that human genes may not be patented. The case specifically concerned the BRCA1 and BRCA2 gene patents, held by the Utah-based company, Myriad Genetics. In the ruling, Justice Clarence Thomas wrote for the court: “Myriad did not create anything. To be sure, it found an important and useful gene, but separating that gene from its surrounding genetic material is not an act of invention.” As a result of this ruling, it is widely believed the cost of testing (currently over $4000 for full gene sequencing and large rearrangement testing when performed through Myriad) will decrease, there will be opportunities for second opinions, and innovation pertaining to BRCA testing may be enhanced. Immediately after the decision, several companies (e.g., GeneDx, Pathway Genomics, Quest Diagnostics, Ambry Genetics, DNATraits, and University of Washington) announced plans to launch tests that include the BRCA genes, at a cost as low as $995.

ICARE Newsletter Summer 2013

Ask the Expert

The following question was addressed by Dr. Pal, who is a Clinical Geneticist based at the Moffitt Cancer Center:

Q. Does exposure to radiation increase breast cancer risk in BRCA mutation carriers?

A. A number of studies have been conducted to evaluate whether BRCA mutation carriers may be more prone to radiation-induced breast cancer than women without mutations. Two studies failed to provide convincing evidence about the link between ionizing radiation exposure and breast cancer risk in BRCA mutation carriers.1,2  On the other hand, a large international study including 1601 mutation carriers reported a higher breast cancer risk among women exposed to chest X-rays (hazard ratio (HR): 1.54).  Breast cancer risk was highest among women age ≤ 40 with any x-ray exposure , and women born after 1949 with x-ray exposure before age 20.3  Some of these participants were included in a larger international study of 1993 mutation carriers where age-specific total diagnostic radiation exposure (i.e., chest x-rays, mammography, fluoroscopy, and computed tomography) was estimated from self-reported questionnaire data.4 Results indicated that those exposed before age 30 had an increased risk (HR: 1.90; 95% CI: 1.20-3.00), compared to those never exposed. However, this risk was primarily driven by non-mammographic radiation exposure in women younger than age 20 (HR: 1.62; 95% CI: 1.02-2.58).

Ultimately, it is important to weigh potential risks versus benefits regarding routine use of mammographic screening in conjunction with magnetic resonance imaging (MRI) in BRCA mutation carriers, particularly in women below age 30. As there is no clear evidence to suggest that mammograms significantly increase the breast cancer risk in BRCA mutation carriers at the current time, the main question that remains is whether mammograms are useful prior to age 30. Currently, NCCN guidelines5 recommend annual mammography and MRI screening beginning at age 25 years, although some clinics may hold off on the mammography until age 30 after a balanced discussion of risks versus benefits with patients has occurred.

1. Narod SA, et al. Lancet Oncol 7 (5): 402-6, 2006. 2. Goldfrank D, et al. Cancer Epidemiol Biomarkers Prev 15 (11): 2311-3, 2006. 3. Andrieu N, et al. J Clin Oncol 24 (21): 3361-6, 2006. 4. Pijpe A, et al. BMJ 345: e5660, 2012. 5. NCCN Practice Guidelines 2013; V.2.2013: http://www.nccn.org/professionals/physician_gls/recently_updated.asp.

ICARE Newsletter Winter 2013

Ask the Expert

The following question was addressed by Dr. Lora Thompson, a Clinical Psychologist at the Moffitt Cancer Center:                                                            

Q. How do I talk to family members about my genetic test results?

A. The ability to share risk information with family members is a common reason why many individuals undergo genetic testing. Family members may feel appreciative of the information so they can have the opportunity to learn about their personal risk of cancer and to consider cancer prevention and surveillance strategies. However, when others disagree with your decision to undergo testing, being the “gatekeeper” of genetic information can be a burden. Research on genetic test result disclosure has found that less open communication was associated with higher levels of distress in individuals undergoing genetic testing, even when their results were negative.1


 Below are some tips for communicating results:2,3

  • Before receiving your result, begin thinking about how, when, and with whom you will share the information.
  • Be sure that you have a good understanding of what your result means. This may be especially important if you receive a positive or uninformative result.
  • Ask your genetic counselor to help you prepare a letter or information sheet that you can provide family members.
  • Practice what you plan to say and anticipate what questions you might receive.
  • Have a trusted individual available for support.

Some families may still experience tension during the sharing process even when the tested individual practices good communication skills. In this case, consider seeking additional help from a professional with expertise in working with families, such as a psychologist, social worker, or licensed counselor. Remember that your responsibility after receiving your genetic test result is to pass on information. It is up to each family member to decide how to react emotionally and whether to pursue genetic counseling and testing.

1. van Oostrom, I, et al. Clin Genet 71, 35-42 (2007). 2. DeMarco, TA, et al. Breast Disease 27, 127-136 (2007). 3. Seymour, KC, et al. J Genet Counsel 19(4), 330-342 (2010).

ICARE Newsletter Winter 2013

Points to Consider Regarding Bilateral Salpingectomy as a Risk Reduction Procedure for Ovarian Cancer

Over the last few years, there has been evidence to suggest that a substantial proportion of ovarian cancer may start in the fallopian tubes, although some cancer clearly arises in the ovary.  As a result, removal of both fallopian tubes (called ‘bilateral salpingectomy’) has been suggested as an interim procedure to reduce risk in BRCA mutation carriers.1,2  But it is still very important to remember that there are no data available to tell us how effective this procedure is at reducing the future risk of ovarian cancer.

In essence, bilateral salpingectomy preserves ovarian function, thus it does not put premenopausal patients into premature menopause.   The procedure can be done through a minimally invasive approach, and may allow patients to defer removing their ovaries until they are closer to menopause.  In fact, a small study of 14 young BRCA mutation carriers documented the procedure as feasible.3 However, this study could not assess how effective the procedure was in reducing future ovarian cancer risk, nor was it able to assess whether the procedure had an effect on ovarian function.  Ultimately, until the usefulness of bilateral salpingectomy is more fully assessed, patients need to remember that this procedure does not eliminate their cancer risks as completely as if they had undergone a bilateral salpingo-oophorectomy (i.e. removal of both ovaries as well as the fallopian tubes).  As much as salpingectomy may become an important ovarian cancer risk reduction measure, it is exceedingly important to further study the validity of the procedure as a risk-reducing intervention in the context of research efforts.

1. Greene MH, et al. Am J Obstet Gynecol. 2011 Jan;204(1):19.e1-6. 2. Dietl J, et al. Hum Reprod. 2011 Nov;26(11):2918-24. 3. Leblanc E, et al. Gynecol Oncol. 2011 Jun 1;121(3):472-6.

ICARE Newsletter Winter 2013

The Selection of Chemotherapy in BRCA Patients with Pancreatic Cancer

Some evidence suggests that individuals with BRCA mutations who develop pancreatic cancer may benefit from specific chemotherapy regimens. In a recent review of this topic, Kim et al reported on a study of 5 patients with BRCA mutations (4 BRCA2 and 1 BRCA1) who were treated with a platinum-based chemotherapy regimen.1 Of these patients, 3 had advanced disease and all had some response to platinum; an additional 2 patients had resectable and locally advanced disease, both of whom were downstaged after receiving platinum as part of their treatment and eventually underwent resection of their tumor. Another study was conducted based on 15 BRCA carriers with pancreatic cancer.2 Of these patients, 4 received a PARP inhibitor alone or in combination with chemotherapy, of which 3 demonstrated an initial radiographic response and one patient had stable disease for 6 months. Six patients received platinum-based chemotherapy as first line treatment for metastatic disease, of whom five had a radiographic partial response.

These studies add to the limited literature to suggest that therapeutic agents that target DNA repair (e.g., PARP inhibitors, Platinum-based agents) may offer benefit when treating BRCA-associated pancreatic cancers, even in advanced stages. However, the numbers reported remain very small and it is critical to perform prospective studies in individuals with BRCA-associated pancreatic cancers to truly determine the efficacy of targeted therapies.   

1. Kim R, et al. JOP. 2012 Mar 10;13(2):180-1. 2. Lowery MA, et al. Oncologist. 2011;16(10):1397-402.

ICARE Newsletter Winter 2013

Is Lynch Syndrome Associated with Breast Cancer?

The cancer spectrum typically seen in individuals with Lynch Syndrome includes cancers of the colon, endometrium, ovary, stomach, and other cancers (including cancer of the renal pelvis, ureter, small bowel and pancreas).  The issue of whether breast cancer risk is elevated in those with Lynch syndrome has been controversial, with conflicting results between various studies.  However, the largest prospective study recently reported an almost 4-fold increased risk for breast cancer.1 This same group subsequently looked at the risk for breast cancer in those with a prior diagnosis of colorectal cancer.  Their results showed an almost 2-fold elevated risk.2 However, further studies are needed to determine absolute risks and age distribution before breast surveillance guidelines can be developed for those with Lynch Syndrome.  At this time, it is recommended that women with Lynch Syndrome continue to follow the general population breast cancer screening guidelines.

1. Win AK, et al. J Clin Oncol. 2012 Mar 20;30(9):958-64. 2. Win AK, et al. J Natl Cancer Inst. 2012 Sep 19;104(18):1363-72.

ICARE Newsletter Summer 2012

Ask the Expert: What are the risks of hormone replacement therapy (HRT) on breast cancer risk in women with BRCA mutations?

The following questions were addressed by Drs. Pal and Lancaster at the Moffitt Cancer Center:

Q. What are the risks of hormone replacement therapy (HRT) on breast cancer risk in women with BRCA mutations?

A. Concern about HRT in BRCA carriers is its potential to raise the risk of breast cancer, as seen in the general population.1-3 However, two studies in BRCA mutation carriers reported that HRT did not increase the subsequent risk of breast cancer, nor did it appear to reduce the protective effect of oophorectomy on breast cancer risk.4,5 Recent results from the Women’s Health Initiative in the general population also provide reassurance as to estrogen use for about 5 years in terms of breast cancer risk and mortality.6

1. Chen, C.L., et al. JAMA. 287, 734-41 (2002). 2. Rossouw, J.E., et al. JAMA. 288, 321-33 (2002). 3. Chlebowski, R.T., et al. JAMA 289, 3243-5 (2003). 4. Eisen, A. et al. J Natl Cancer Inst 100, 1361-7 (2008). 5. Rebbeck, T.R., et al. J Clin Oncol 23, 7804-10 (2005). 6. Anderson G.L., et al. Lancet Oncol, 13(5), 476-86 (2012).

ICARE Newsletter Summer 2012

New Study Suggests Breast Cancer Risk for Non-Carriers of Family-Specific BRCA Mutations Is Not Increased

Data from a population-based study was recently reported to estimate breast cancer risk among family members who tested negative for a known BRCA1/2 family mutation (i.e., non-carriers). The study included 3047 women diagnosed with breast cancer. Results from the study indicated there was no increased risk for breast cancer in non-carriers as compared to family members of breast cancer patients who tested negative for a BRCA gene mutation. These results support clinical practice to advise patients who test negative for family-specific BRCA mutations that their breast cancer risks are not elevated. Furthermore, in the absence of other strong risk factors, authors suggest that non-carriers should follow general population guidelines for breast cancer screening.

Kurian AW, et al. J Clin Oncol. 2011 Dec 1;29(34):4505-9.

ICARE Newsletter Summer 2012

Emerging Cancer Panels for Testing Patients for Inherited Cancer Predisposition

Genetic testing for inherited cancer predisposition is typically performed by testing for one condition at a time. However, with the tremendous advances in genetic testing technologies over the last few years, the cost of testing has plummeted. To put this into perspective, the first human genome cost 2-3 billion dollars to sequence and took over 10 years to complete. Based on newer technologies, the current cost  of sequencing a human genome is less than $10,000 and takes 4-6 weeks to complete. As such, it has become realistic to test for multiple inherited cancer conditions at the same time through “cancer panels”. These panels consist of several genes for conditions at a cost that is comparable to genetic testing for one condition. Insurance reimbursement for testing has been encouraging. An example of when to consider this test is for an individual with breast cancer in whom there is a strong family history of cancer, but the BRCA1 and BRCA2 testing (comprehensive BRACAnalysis® and comprehensive rearrangement testing (BART)) did not identify a mutation to be present. For more information about this testing, contact your local genetics professional.

ICARE Newsletter Summer 2012

Ask the Expert: What are the recommendations for screening following prophylactic surgeries?

The following questions were addressed by Drs. Pal and Lancaster at the Moffitt Cancer Center:

Q. What are the recommendations for screening following prophylactic surgeries?

A. In BRCA mutation carriers, bilateral prophylactic mastectomy reduces the risk of breast cancer by over 90%. It essentially lowers the risk of breast cancer to below that of the general population. Similarly, in those with bilateral prophylactic salpingooophorectomy (BPSO), risk of ovarian cancer is reduced by 80% or more. At the Moffitt Cancer Center, BRCA mutation carriers who have undergone a bilateral mastectomy are screened through clinical exams, and no imaging studies are routinely recommended. In those with BPSO, CA-125 levels (measured through a blood test) are ordered yearly, and no transvaginal ultrasounds are routinely recommended. These recommendations are based on clinical judgment of our team, and there is no data at this time to determine the necessity of this (or any) screening regimen in these individuals following prophylactic surgery.

ICARE Newsletter Summer 2012

Prostate Cancer Screening Recommendations for Men with BRCA Mutations

Over the last few years, there have been several studies that suggest that men with BRCA mutations are at a higher risk for developing and dying from aggressive prostate cancer. It is possible that PSA testing may be of benefit in men with BRCA mutations. However, until the utility of PSA is determined in these men, national practice guidelines continue to recommend annual prostate cancer screening (through PSA test and digital rectal exam) starting at age 40 in men with BRCA mutations. Of note, new recommendations were set forth by the U.S. Preventive Services Task Force (USPSTF) which consists of a panel of national experts. Part of their mission is to make recommendations about preventive services, such as the use of PSA screening in men. The task force revised their position on PSA screening and recently recommended against routine prostate screening for everyone. However, in May 2012, they included the following caveat: This recommendation also does not include the use of the PSA test for surveillance after diagnosis or treatment of prostate cancer and does not consider PSA-based testing in men with known BRCA gene mutations who may be at increased risk for prostate cancer.” Thus, they now indicate that those who may be at a higher risk for prostate cancer, such as BRCA mutation carriers, are not part of the recommendations and therefore it is reasonable to continue screening these individuals using the PSA test.

US Preventive Services Task Force, Moyer et al. Screening for Prostate Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2012 May. PMID: 22801674. Available at: https://www.annals.org/aim/fullarticle/doi/10.7326/0003-4819-157-2-201207170-00459

ICARE Newsletter Summer 2011

Ask the Expert

We are fortunate to have Dr.  Alvaro Monteiro, who is a molecular geneticist and expert on the BRCA1 and BRCA2 genes, as a member of our team. For our first ICARE newsletter, Dr. Monteiro teaches us about Variants of Uncertain Significance.

Q. What is a Variant of Uncertain Significance (VUS) test result? How do researchers learn more information about variants?

A. A variant of uncertain significance test result is when a change is found in the tested DNA for which there is no clear answer to determine if the change leads to an increased risk of developing cancer. To determine whether a particular variant is linked to increased cancer risk, researchers use a series of tools that include studying families with the variant (to determine whether the variant tracks with cancer), comparing the gene code in different species (for example dog, mouse, chicken and fish) to determine the importance of this particular area in the gene (important areas of the gene stay the same with different species), computer programs, and functional tests that study how the gene may work (or not work) with the variant.