ICARE Newsletter Summer 2020

Guideline-Concordant Care Among Women with Inherited Cancer Gene Mutations

Testing for inherited cancer among breast cancer patients has tremendous potential to guide appropriate care following testing. Yet, a number of efforts suggest that women are not consistently receiving care according to current national guidelines based on their genetic test result. In fact, results from studies suggest many women for whom risk-reducing mastectomy would not be recommended based solely on their genetic test result, may be receiving this procedure. Specifically, high rates of bilateral mastectomy have been reported among those with a BRCA1/2 variant of uncertain significance [1] as well as those with non-BRCA1/2 moderate penetrance genes [2,3], suggesting potential overtreatment. Additionally, a recently published cancer registry-based study suggested that those with a BRCA1/2 mutation may be more likely to receive bilateral mastectomy for a unilateral tumor, less likely to receive post-lumpectomy radiotherapy, and more likely to receive chemotherapy for early-stage, ER/PR-positive disease [2]. Similarly, we have previously reported on risk-reducing oophorectomies conducted among BRCA1/2 carriers, which showed lower rates among Black women compared to non-Hispanic Whites [4]. More recently, our study based directly on ICARE participants, as well as another registry study, suggested there may be potential overtreatment with oophorectomy among women with non-BRCA1/2 inherited breast cancer genes in which oophorectomy is not generally recommended for risk reduction based on current ovarian cancer risk estimates [3,5]. These findings highlight the importance of promoting guideline-adherent care and avoiding overtreatment.6

[1] Kurian, et al. J Clin Oncol. 2017 Apr. PMID: 28402748; [2] Kurian, et al. JAMA Oncol. 2020 Feb. PMID: 32027353; [3] Cragun, et al. Breast Cancer Res Treat. 2020 Jul. PMID: 32445176; [4] Cragun, et al. Cancer. 2017 Jul. PMID: 28182268; [5] Domchek, et al. J Clin Oncol. 2020 May. Available at: https://tinyurl.com/domchek2020; [6] MyGeneCounsel. 2019 Oct. Available at: https://tinyurl.com/MyGeneCounselWhitePaper

ICARE Social Media Post July 2020

Breast Cancer Risks May be Higher in Women with Two CHEK2 Mutations Versus One CHEK2 Mutation

A study comparing women with two CHEK2 mutations to one CHEK2 mutation showed that those with two mutations were:

-more likely to get breast cancer (80.6% versus 41.2%)

-more likely to be diagnosed at or below age 50 (61.3% versus 23.9%)

-more likely to have a second breast cancer diagnosis (22.6% versus 8.1%)

These findings suggest that women with two CHEK2 mutations have higher risks of cancer, which may occur at an earlier age, and may be taken into consideration when managing these women.

Check out the original article at: https://www.ncbi.nlm.nih.gov/pubmed/31993860.

ICARE Social Media Post July 2020

BRCA1/2 and Other Gene Carriers with Breast Cancer Don’t Always Receive Recommended Treatment

BRCA1/2 and other gene mutation carriers with early stage breast cancer are not always receiving cancer treatment as recommended by national guidelines.

Even though more and more people have been tested for hereditary cancer over the years, using this information accurately to guide treatment has not been as successful.

These findings highlight the need for using this information better to help guide appropriate breast cancer treatment, including radiation treatment and chemotherapy.

Check out the full article at https://jamanetwork.com/journals/jamaoncology/fullarticle/2760433.

ICARE Social Media Post June 2020

Community Spotlight: Christy Mattey

In every ICARE Newsletter we feature an ICARE participant as a community spotlight. Our latest community spotlight in our Winter 2017 ICARE Newsletter is Christy Mattey, who was found to have a CHEK2 mutation after a breast cancer diagnosis.

Check out her story at: https://inheritedcancer.net/community-spotlight/

ICARE Social Media Post May 2020

Platinum Based Chemotherapy for Metastatic Pancreatic Cancer

A recent study found that patients with metastatic pancreatic cancer who had mutations in the DNA repair genes (either inherited or just in the tumor) had better clinical outcomes after platinum-based chemotherapy compared to patients without these mutations.

Check out the link to full article: https://clincancerres.aacrjournals.org/content/early/2020/05/20/1078-0432.CCR-20-0418

ICARE Social Media Post May 2020

Cancer Risk Management Among Female BRCA1/2, PALB2, CHEK2, and ATM Carriers in ICARE

A new article was recently published based on data from BRCA1/2, PALB2, CHEK2, and ATM carriers in ICARE. Findings suggest potential overtreatment through risk-reducing surgery among women with pathogenic/likely pathogenic variants in breast cancer genes. This highlights the importance of promoting guideline-adherent, risk-appropriate care.

Check out the full article at https://rdcu.be/b4mbg

ICARE Social Media Post March 2020

Study Based on ICARE Participants with ATM and CHEK2 Mutations

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. A recently published study based on ICARE participants with ATM and CHEK2 mutations suggested that most female family members of ATM and CHEK2 mutation carriers do not qualify for breast MRI screening based on family cancer history alone.

Specifically, results 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.

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.

For help sharing your positive genetic test results with your family members, visit: geneshare.net

Check out the full article at https://www.ncbi.nlm.nih.gov/pubmed/31967672

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 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 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

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 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

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

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 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

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

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 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.