The contribution of hereditary cancer syndromes to many gynecologic malignancies has been increasingly recognized over the past decade. As they often serve as primary care providers, ob/gyns are uniquely positioned to help identify at-risk women before they develop cancer. Identification of these women is important so they may be offered increased screening or risk-reduction measures that have proven benefits for improving survival. The most common syndromes related to breast and gynecologic cancers are highlighted in Table 1.
Though most cancers are sporadic, women with a known deleterious genetic mutation have significantly increased risks of developing a malignancy (Table 2). Of gynecologic cancers, ovarian cancer is most often associated with an inherited susceptibility gene, which can occur in about 20% of cases. The majority of hereditary breast and ovarian cancers are due to BRCA mutations; however, a significant portion are related to several other gene mutations (RAD51C, RAD51D, BRIP1, Lynch genes).1 In contrast, only 4% to 5% of non-hereditary breast cancers are related to BRCA1 and 2, with an even lower percentage due to other genes (PTEN, TP53, PALB-2, CDH, STK-11).2 Similarly, very few endometrial cancers are hereditary with about 3% to 5% associated with Lynch syndrome and some are even more rarely related to Cowden’s syndrome (PTEN), Li-Fraumeni (TP53), or Peutz-Jeghers (STK11).2 All of these cancer syndromes are autosomal-dominant and have implications not only for a patient, but also for her family.2
Identification of high-risk women and genetic testing
There are several features in a woman’s personal or family history that should raise suspicion for potential involvement of an underlying genetic mutation and prompt genetic counseling/testing (Table 3). Most cancer syndromes will affect multiple generations, and diagnoses will occur at an earlier age than in sporadic malignancies. Male and triple-negative breast cancers (negative for estrogen, progesterone receptors and HER2/neu amplification) are also hallmarks of hereditary cancers, as is having a relative affected by 2 primary malignancies.2 In addition, any woman who has a close relative with a known cancer-susceptibility gene mutation should be referred for testing.3
When possible, genetic testing in a family should start with a cancer-affected individual. The affected person is the most likely in the family to carry a mutation and from whom a negative result is most informative—meaning, that if full genetic testing is negative, there is no identifiable mutation as the cause of the cancer and thus no benefit to testing cancer-unaffected individuals within that same familial lineage. But if a deleterious mutation is found in the person with cancer, directed genetic testing can then be initiated in other family members to determine if they carry the gene (true positives who need further tailored screening and risk reduction measures) or they do not (true negatives who can likely go back to population cancer screening). If the cancer-affected relative is not available, the closest relation to the affected family member is the next best option.
In 2014, the Society of Gynecologic Oncology recommended genetic testing for all women with epithelial ovarian cancer.4 As more women are undergoing testing and technology has evolved to make testing cheaper and faster, more and more cancer susceptibility genes are being identified. This has contributed to increasing the utilization of gene panel testing.1 While testing upwards of 20 to 50 genes may increase the likelihood of finding a deleterious mutation, it also leads to discovery of more uncertain results, such as variants of uncertain significance (VUS) or deleterious genes with moderate risk or penetrance, for which there is far less data on which to base management decisions. A VUS is a change in the gene that has not yet been associated with causing a cancer, most often because there is not yet enough information about the specific variant to determine if it is benign versus cancer-causing. Most of these mutations are reclassified as benign when more data become available over time.
Interpreting these test results has important implications. For women with known mutations in well-described cancer genes, evidence-based screening and risk reduction strategies are described below. However, care must be taken not to apply the same guidelines to women found to have a VUS, as that does not imply increased cancer risk; it is simply a variation whose significance remains unclear.5 In addition, women with a VUS or an entirely negative genetic result may remain at significantly increased cancer risk as current testing doesn’t eliminate the possibilities of increased familial cancer risk because causative mutations exist that have yet to be discovered. Management of these potentially high-risk women should be individualized with the aid of a genetic counselor or a provider with experience in hereditary cancer syndromes as they may still benefit from more intensive screening/risk reduction measures even in the face of negative genetic testing results.