ICARE Newsletter Summer 2020

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

Updates to National Comprehensive Cancer Network (NCCN) Genetic/Familial High-Risk Assessment: Colorectal Guidelines (Version 1.2020, posted July 21, 2020)

For individuals with Lynch Syndrome:

  • Cancer risks were updated based on information from recent studies:
    • Main updates included cancer risks in PMS2 (endometrial, ovarian, and prostate cancer), MSH2 and EPCAM (prostate and brain cancer), and MSH6 (prostate cancer)
  • Cancer risk management was updated to include:
    • Recommendations that differ across the various Lynch Syndrome genes, based on their level and type of cancer risk
    • Specific dosing of aspirin use for MLH1, MSH2, EPCAM, and MSH6 (i.e.,600 mg/daily)
    • Age of colonoscopy for MSH6 and PMS2 was changed to start a bit later, at age 30

For individuals with Familial Adenomatous Polyposis (FAP):

  • Thyroid cancer screening through ultrasound was spaced out to every 2-5 years (from every year)

NCCN bulletin available at:

Updated NCCN guidelines are available free-of-charge at:

ICARE Social Media Post July 2020

Updates to 2020 NCCN Genetic/Familial Colorectal Guidelines

The National Comprehensive Cancer Network (NCCN) released new guidelines for 2020 on July 21, 2020. The big changes included refining some of the risks for genes involved in Lynch Syndrome, and providing specific guidance about cancer screening that may slightly differ by gene.

You can check out the full guidelines by creating a FREE account at: https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf

ICARE Social Media Post March 2020

MSH2: Cancer Risks and Risk Management

Gene: MSH2

Cancer Risks and Management (per NCCN version 3.2019):


Endometrial cancer risk: Elevated at 21%-57% – Consider risk-reducing hysterectomy.

Ovarian cancer risk: Elevated at 10%-38% – Recommend risk-reducing bilateral salpingo-oophorectomy (removal of ovaries and fallopian tubes).

Men and Women:

Colorectal cancer risk: Elevated at 43%-52% – Recommend colonoscopy every 1-2 years starting at age 20-25.

Gastric cancer risk: Elevated at 0.2%-16% – Consider upper endoscopy every 3-5 years beginning at age 40 for select MSH2 carriers (see NCCN for details).

Pancreatic cancer risk: Not well established – Consider MRI/MRCP or endoscopic ultrasound for MSH2 carriers with a family history of pancreatic cancer in first-degree relative.

Urothelial cancer risk: Elevated at 2%-18% – Consider urinalysis annually starting at age 30-35 for MSH2 carriers with a family history of urothelial cancer.


Prostate cancer risk: Elevated at 30%-32% – Manage same as general population.

Inheritance: Autosomal dominant, thus parents, full siblings, and children have a 50% risk for the gene mutation. If both parents have an MSH2 mutation, the child is at risk for autosomal recessive ’Constitutional mismatch repair deficiency’ (CMMRD) syndrome with earlier and higher cancer risks.

Family Testing: At-risk family members should consider genetic counseling and genetic testing. For adult-onset conditions, recommend waiting to perform genetic testing on minors are at least 18 years old.

Reproductive Considerations: Option for preimplantation genetic diagnosis (PGD) may be available to ensure future generations do not inherit the known gene mutation. PGD is a procedure available for certain gene mutations to screen the embryo prior to achievement of pregnancy.

Check out the full management guidelines by creating a FREE account at https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf and https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf

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

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

PMS2 and MSH6 Colorectal Cancer Risks

Individuals with Lynch syndrome have an increased risk of colorectal cancer (CRC) and other cancers. The level of CRC risk is different based on which gene they have a mutation in. Of note, MLH1 and MSH2 carriers have the highest risk of colorectal cancer, generally in the range of 43%-52% by age 70.

A recent study showed that the CRC risk to age 70 in PMS2 carriers was 9.9% for men, and 5.9% for women; and in MSH6 carriers was 10% in men, and 11.7% in women.

These findings are similar to studies that were previously reported and may help to guide cancer risk management tailored to specific Lynch syndrome genes.

Check out the article at https://www.ncbi.nlm.nih.gov/pubmed/31204389

ICARE Social Media Post February 2020

Lynch Syndrome Cancer Risks Across Genes

A worldwide study suggests that risks for cancers for the various Lynch syndrome genes have some differences. The risk of colorectal cancer for those with a mutation in the MLH1, MSH2 and MSH6 genes is higher than what is seen for carriers of a PMS2 mutation.

Additionally, men with MSH2 gene mutations have a higher risk of prostate cancer (~30%), with men over 50 years of age having an even higher risk.

Lastly, people with mutations in MLH1 or MSH2 have a higher risk of cancers of the colorectum, urinary tract, and small bowel, compared to carriers of mutations in other Lynch syndrome genes, with highest risks for urinary tract and small bowel cancer in those over age 50.

Check out the full article at: https://www.ncbi.nlm.nih.gov/pubmed/31337882

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/pdf/genetics_bop.pdf

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 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 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 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

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

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 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

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 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

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 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

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 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 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 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 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.