Fergus Couch, Ph.D., Chair of the Division of Experimental Pathology and Laboratory Medicine, recently hosted a Twitter Chat with the Breast Cancer Research Foundation (BCRF) on breast cancer genetics. Following the recent publication of a series of papers in Nature and Nature Genetics led by Dr. Couch and his international colleagues, BCRF posted a story describing the studies’ results on the discovery of additional gene variants associated with breast cancer risk. In case you missed the chat, below is a full transcript.
Question: What are CHEK2 gene mutations and their impact on breast cancer risk?
Dr. Fergus Couch: CHEK2 mutations are seen in as many breast cancer patients as BRCA mutations. The risk is a 2.5- to 3-fold increase over the general population. Women with CHEK2 mutations can benefit from MRI screening for breast cancer.
Question: Besides BRCA1 and BRCA2, are there any other genes associated with breast cancer?
FC: There are several other genes. PALB2 is high risk like the BRCA genes; CHEK2, ATM, and RAD51D are moderate risk; and TP53, PTEN, and CDH1 are all high risk but are associated with syndromes with multiple cancers. All of these genes are on gene testing panels. CHEK2 and ATM mutations are as common as BRCA1/2. The others are rare and are seen in 1 in 500 to 1 in 1,000 women with breast cancer.
Question: Is HER2-positive breast cancer hereditary?
FC: About 5% of HER2 positive breast cancers are caused by mutations in predisposition genes. CHEK2, ATM, and BRCA2 are the most common in this type of breast cancer.
Question: Is triple negative breast cancer hereditary?
FC: About 15% of triple negative breast cancer is caused by mutations in predisposition genes. BRCA1 and BRCA2 alone account for about 10%. CHEK2 and ATM do not seem to be involved. Instead BARD1, RAD51D, and PALB2 have become important.
Question: I was diagnosed with stage 3 breast cancer at age 29 and was positive for BRCA2. How worried should I be about my ovarian health and other cancers?
FC: BRCA2 does cause ovarian cancer. However, we generally do not see an earlier age of diagnosis for ovarian cancer with mutations in this gene. The average age is still over 60. Many physicians recommend prophylactic surgery in the 35 to 40 age range to remove the ovaries in order to reduce risk of ovarian and breast cancer.
Question: How will the latest discovery of the new genetic variants impact genetic testing in patients? When can we expect these to appear on new gene panels?
FC: The new common variants will help to personalize risk for each individual by putting women into higher and lower risk categories compared to the whole population. Some testing companies already offer the PRS score along with their gene panels.
Question: What are the biggest challenges in your research area?
FC: Finding enough women from the same family with the same mutation is challenging and limits our ability to track how individual mutations influence cancer risk.
Question: I was diagnosed with breast cancer at age 30. I have a strong family history of breast cancer, but I tested negative for BRCA. What research is being done to find more genetic ties to breast cancer other than BRCA?
FC: We are constantly finding new genetic risk variants. The current research focuses on understanding how much they influence risk and how prevalent they are in the population.
Question: I am 21 years old, and I have a strong family history of breast cancer, but I have not been diagnosed myself. What steps should I take, including genetic testing, to better understand/reduce my breast cancer risk?
FC: I suggest that you make an appointment with a genetic counselor or cancer genetics doctor to discuss your concerns.
Question: I have a strong family history of cancer. My father had prostate cancer, and his two sisters had breast cancer. They had a cousin with prostate cancer and one with testicular cancer. Are these cancers linked?
FC: Prostate and breast cancer can be caused by several breast cancer genes. BRCA2 is most important. I suggest you speak with a clinical genetics physician or counselor to discuss your family history and possible genetic testing.
Question: My grandmother, my mother, and I were all diagnosed with breast cancer in our late 40s. I am BRCA negative, but the doctors have said that there is probably a hereditary link. What’s the best advice you can give my 23-year-old daughter?
FC: We cannot explain at least 50% of families with several breast cancers. Your daughter might benefit from an appointment with a clinical genetics physician or counselor.
Question: Are PARP inhibitors a viable treatment option for those who are BRCA1 and/or CHEK2 positive? If so, why?
FC: PARP inhibitors have been approved for use in metastatic ovarian & breast cancer patients. These drugs are very effective in BRCA1/2 patients, but their utility for patients with mutations in other genes such as CHEK2 is not known. Studies are underway to resolve this.
Question: Would Keytruda (pembrolizumab) be a viable treatment option for women with CHEK2 and/or BRCA1 mutations? I understand there is disagreement over whether breast cancer tumors are immunogenic or not.
FC: This is better answered by an oncologist. From my understanding, there is debate about the utility of this drug for breast cancer and for those with BRCA or CHEK2 mutations. BRCA tumors often have a strong immune cell presence, so there is real interest in understanding if these immune cells can be reactivated to target the tumor cells. Several clinical trials are underway in an effort to answer this question.
Question: How often should we redo our genetic test because of improvement in finding new mutations?
FC: If you previously had a panel test, then there is really no need for another test. When new breast cancer genes are discovered and added to gene panels, it might be useful to consider additional testing, but that is a number of years away. If you only had BRCA1/2 testing, then a full panel test could be of value.
Question: Are certain mutations more likely to be seen in people of certain races or ethnicities?
FC: The frequencies of mutations in panel genes certainly varies by ethnicity, but BRCA1, BRCA2, CHEK2, and ATM still seem to be the most common in all populations. Recent studies suggest that other genes like RAD51D and BARD1 may be important for testing of African Americans because these genes cause triple negative breast cancer, which is very common in that population.