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Evidence-Based Oncology August 2019

The Impact of Germline Testing for Hereditary Cancer Postdiagnosis

Kelly Owens, PhD; Lisa Schlager; and Piri L. Welcsh, PhD
Authors from Facing Our Risk of Cancer Empowered (FORCE), a nonprofit organization focused on hereditary cancer, discuss the importance of genetic testing, guidelines, and coverage considerations.
Germline testing is a key issue for the constituents of Facing Our Risk of Cancer Empowered (FORCE), a nonprofit organization focused on hereditary cancer. Its mission is to improve the lives of the millions of men, women, and families facing increased risk of breast, ovarian, pancreatic, prostate, colorectal, and endometrial cancers. Our community includes people with a BRCA, ATM, PALB2, CHEK2, PTEN, or other inherited gene mutation and those facing Lynch syndrome. We accomplish this mission through education, support, advocacy, and research.

Germline Mutations Can Raise Cancer Risk

Germline mutations are associated with an increased risk of a variety of cancers. The most common mutations are among Lynch syndrome and BRCA1/2 genes, affecting approximately 1 in 279 and 1 in 400 Americans, respectively.1,2 For women with germline mutations in BRCA1 or BRCA2, the risk of breast cancer by age 80 is 72% for BRCA1 carriers and 69% for BRCA2 carriers,3 compared with 13% for the general population.4 Similarly, the risk of ovarian cancer rises from a lifetime risk of 1.3% in the general populationto a risk of 44% for BRCA1 carriers and 17% for BRCA2 carriers.4 For those with mutations in Lynch syndrome genes, lifetime risk of colorectal cancer is up to 68%5 versus 4.2% in the general population.3 Lynch syndrome is also associated with elevated risk of endometrial cancer (up to 60% lifetime risk versus 2.7% in the general population) and ovarian cancer (up to 24% lifetime risk) depending on which Lynch gene is mutated.6 Among those with pancreatic cancer, 5.5% have inherited mutations in a high-risk cancer gene.7 Up to 10% of men with advanced prostate cancer have a pathogenic mutation in a cancer-predisposing gene.8


Evidence-based guidelines and recommendations from a broad range of professional societies support the use of germline genetic testing in certain patients. The National Comprehensive Cancer Network (NCCN) provides guidelines that outline how to best screen for, prevent, and treat cancer, including determining who should be offered genetic testing for hereditary cancer risk and how individuals should be followed after testing. The American Society of Clinical Oncology states that recognition and management of individuals with an inherited susceptibility to cancer are core elements of oncology care.9 The Society of Gynecologic Oncology (SGO) recommends genetic testing for all women who received diagnoses of epithelial ovarian, tubal, and peritoneal cancers, even in the absence of a family history.10

Additionally, SGO guidelines indicate that all women who receive a diagnosis of endometrial cancer should undergo systematic clinical screening for Lynch syndrome and/or molecular screening when resources are available.11 The American Society of Breast Surgeons recommends genetic testing for all patients with a personal history of breast cancer. This group also suggests updated testing for previously tested patients for whom no pathogenic variant was identified.12 The American College of Medical Genetics and National Society of Genetic Counselors offer guidelines on referral and testing for 28 of the most common hereditary cancer susceptibility syndromes.13


For many hereditary cancers, knowledge of a pathogenic mutation prior to the onset of cancer can inform screening, result in earlier detection of cancer at more treatable stages, and allow prevention options such as prophylactic surgery. For those with cancer, germline testing informs choices for care and treatment. Importantly, knowledge of an inherited mutation can alert extended family members to their cancer risk.

Among those with cancer diagnoses, heritable mutations confer significant risk of increased morbidity and additional primary cancers. This information gives physicians more accurate assessments of cancer risk for other organs and allows tailoring of healthcare strategies that may reduce the morbidity and mortality associated with these syndromes. 

The following are a few examples where knowledge of a pathogenic mutation conveys clinically actionable interventions for those who have cancer.


People with inherited mutations may respond differently to certain types of treatment regardless of the cancer site involved.

• In the case of patients with BRCA1 and BRCA2 germline mutations, a class of targeted therapies known as poly (ADP-ribose) polymerase (PARP) inhibitors has shown benefit for treating multiple tumor types. PARP inhibitors are approved for treating breast and ovarian cancer in people with germline BRCA mutations; however, ongoing research suggests that these drugs also may offer benefits for patients with pancreatic and prostate cancers.

    »» People with Lynch syndrome are more likely to have cancers with a genetic feature called microsatellite instability–high (MSI-H). Pembrolizumab is an immunotherapy with FDA approval to treat any MSI-H advanced cancers.14

Breast Cancer

Response to treatment differs significantly based on mutation status. For instance, BRCA1 mutation carriers with hormone-negative breast cancers show less sensitivity to taxane chemotherapy.15 Germline BRCA mutations are positive selection criteria for use of platinum-based regimen and potentially PARP inhibitors.16 An estimated 20% of patient with triple-negative breast cancer (TNBC) are BRCA mutation carriers, and 70% of breast cancers that develop in BRCA1 mutation carriers are triple-negative. A germline BRCA mutation has been used to identify patients with TNBC who will best respond to carboplatin therapy. As such, the BRCA-mutated TNBC subgroup should receive platinum derivatives as part of their neoadjuvant (and/or adjuvant) treatment.

A germline mutation may also affect surgical decision making in breast cancer. Although someone without a germline mutation may opt for lumpectomy and radiation,

a woman with a BRCA or PALB2- mutation, for instance, would be advised to undergo a double mastectomy. Rates of contralateral breast cancer after either breast-conserving therapy or unilateral mastectomy are increased in women with BRCA1/2 mutations compared with patients who have sporadic breast cancer. Similarly, women with breast cancer who test positive for a BRCA mutation are at significantly increased risk of developing ovarian cancer. Knowledge of this risk enables the patient and her healthcare team to be more aware and vigilant regarding additional primary cancers.

Colorectal Cancer

There is considerable stage-independent variability in colorectal cancer outcomes that may reflect variation in microsatellite instability (MSI) status. Many colorectal cancer patients benefit from MSI testing before the cancer is advanced or metastatic.6 Lynch syndrome patients account for 3% of colorectal cancer patients.17 Risk of uterine and ovarian cancer, as well as gastric, urinary tract, and small bowel cancer, rises in Lynch syndrome patients. Knowledge of these risks leads to greater patient and provider awareness, which may result in earlier diagnosis of additional primary cancers. 

Ovarian Cancer

More than 1 in 5 ovarian carcinomas are associated with germline mutations, and approximately 15% are attributable to a BRCA mutation. An additional 5% to 6% are the result of a germline mutation in BRIP1, RAD51D, RAD51C, PALB2, BARD1,TP53, or a Lynch syndrome gene (MLH1, MSH2, MSH6, PMS2).18

    Studies confirm that women with germline BRCA cancers often behave and respond to treatment differently than sporadic cancers.19 Specifically, ovarian cancer patients with with germline BRCA cancers have a better response to platinum therapy compared with patients who do not have BRCA mutations.20 Likewise, BRCA mutation carriers appear to be more sensitive to the benefits of intraperitoneal chemotherapy.21,22

Prostate Cancer

Germline testing may have significant diagnostic and therapeutic utility for patients with prostate cancer, as demonstrated by the identification of pathogenic germline alterations in men with castration-resistant prostate cancer who respond to PARP inhibition as suggested by clinical trials.23 Aggressive therapy in early-stage

BRCA-positive prostate cancers, particularly those with germline BRCA2 mutations, is indicated. This includes a combination of early radical local treatment (eg, radical prostatectomy or radiotherapy) with adjuvant systemic therapy. A 2018 study confirmed that much like BRCA2-related breast and ovarian cancers, men with BRCA2-associated castration-resistant prostate cancers respond better to carboplatin-based chemotherapy than do men with non–BRCA-positive prostate cancers.

       There is growing evidence of the presence of germline mutations in men with prostate cancer and the clinical utility of these findings. A recent study reported in JAMA Oncology by Nicolosi et al found that 17% of men with prostate cancer had germline genetic mutations. BRCA variants accounted for more than 30% of the mutations, and a number of variants with known therapeutic implications (CHEK2, ATM, PALB2, MUTYH, etc.) were identified.23 Testing men with earlier-stage disease who meet family history criteria offers an opportunity to provide the appropriate treatment regimen and inform them about their increased risk of other cancers.

In addition to guiding optimal surgical and therapeutic decisions, germline testing identifies patients for whom there may be contraindications. For instance, patients with Lynch syndrome with stage II MSI-H tumors do not benefit from fluorouracil adjuvant therapy.24 In the case of breast cancer, patients who are not carriers of a BRCA1/2 mutation are suitable for accelerated partial breast irradiation.25


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