Wonderful. Well, hello, everyone. My name is Jillian O'Donnell. I'm a second year fellow in GYN oncology at the University of North Carolina at Chapel Hill. Thank you so much for the opportunity to present to you today and for your interest in my talk entitled BRCA mutations for the gynecologic oncologist. So BRCA1 and BRCA2 are genes that are essential to the homologous recombination pathway for DNA repair. Mutations in these genes substantially increase the risk of developing cancer and are responsible for approximately 15% of all breast and ovarian cancers. Germline BRCA mutations are inherited in autosomal dominant fashion. The risk of inheriting a BRCA mutation is 1 in 400 in the general population. There are several high-risk groups, including Ashkenazi Jewish patients with a risk of 2.5% and Icelandic patients with a risk of 0.6%. This table shows the risk of developing various cancers in patients with BRCA1 or BRCA2 mutations. For patients with a BRCA1 mutation, the risk of developing breast cancer is approximately 72%, peaking between the ages of 30 and 40. These patients also have around a 40% chance of developing ovarian cancer, a 0.6% chance of developing serous endometrial cancer, and a 1% chance of developing pancreatic cancer, and 9% chance of developing prostate cancer in our male patients. For a patient with BRCA2 mutation, the risk of breast cancer approaches 70% with a peak age between 40 and 50. These patients have a 20% chance of developing ovarian cancer, about a 5% risk of pancreatic cancer, and a 33% risk of prostate cancer in our male patients. These mutations also increase the risk for colorectal cancer, melanoma, and gastric and biliary cancers, although the exact percentage risk hasn't definitively been described. So we know that BRCA mutations are prevalent in our patients and that they pose significant cancer risk. Next, we'll talk about which patients need testing for these mutations. The first category of patients we'll discuss are patients with a personal history of cancer. Every patient who has been diagnosed with epithelial ovarian, primary peritoneal, or fallopian tube cancer should be tested for a BRCA mutation. For patients with breast cancer, any diagnosis before the age of 45 to 50 or any Ashkenazi Jewish patient should be tested. Any diagnosis of triple negative breast cancer before the age of 60 should be tested, and patients with two or more primary breast cancers with the first diagnosis before the age of 50 should also be tested. In addition, any male patient with breast cancer should undergo genetic testing. Also, any patient with exocrine pancreatic cancer or metastatic prostate cancer should be tested. All patients with breast cancer who have a relative with breast cancer diagnosis before the age of 50 or any of the aforementioned cancers should be referred for testing. Patients with somatic BRCA mutations identified on tumor sequencing should undergo germline testing as well. We'll talk about the difference between somatic and germline testing in a few minutes. Next, we'll talk about which patients without a personal history of cancer should be tested for BRCA mutations. Any patient with a first or second degree relative who meets any of the criteria from the past two slides should be referred for testing. This includes patients with any biologic relative with a BRCA1 or BRCA2 mutation. Any Ashkenazi Jewish patient or any patient with a greater than 5% risk on risk assessment models should be tested. There are two types of tests that can identify BRCA mutations, and it's important to know the difference between them. The first is testing to identify germline mutations. I think all my slides are…never mind. Okay, so the first is testing to identify germline mutations. This is a blood or saliva test that finds mutations in BRCA1 and BRCA2 that the patient was born with and are present in every cell in the patient's body. Germline mutations can be passed on to patients' offspring. The second type is somatic testing. This is generally conducted with tumor tissue and locates mutations that occur during cancer development and are not present in the patient's healthy cells. These mutations cannot be passed on to a patient's offspring. It's also important to understand which settings require germline testing and which require somatic testing. When testing women without a personal history of cancer, patients should always get germline testing. This helps to define their personal cancer risk and informs decision-making regarding risk reduction strategies. For patients with a personal history of cancer, germline testing should be undertaken first. Sometimes tumor testing is performed for other reasons, but detection of a mutation on somatic testing does not preclude the need for germline testing. In fact, upwards of 5% of germline mutations are missed when performing somatic testing alone. If germline testing is negative in these patients, somatic testing should be performed. This information can be helpful in prognostication and therapeutic decision-making. It's also important to understand the role of genetic counseling. Patients should be referred first to a genetic counselor prior to undergoing any genetic testing. Genetic counselors can perform a thorough medical history and pedigree, employ mathematical risk assessment models, make careful recommendations for genetic testing, and discuss the implications of this testing, including financial and legal considerations with patients. This is an incredibly useful resource that should be utilized for patients when at all possible. Now we'll shift gears and talk about how we as gynecologic oncologists should manage patients that come to us with these mutations. First, we'll talk about patients who have been diagnosed with a BRCA1 or BRCA mutation but have not developed cancer. Patients with a BRCA1 mutation should undergo risk-reducing surgery to include a bilateral salpingo-oophorectomy with or without hysterectomy at age 35 to 40 or at completion of childbearing. Patients with a BRCA2 mutation should undergo bilateral salpingo-oophorectomy but do not need to have the hysterectomy. Although screening for ovarian cancer hasn't been shown to improve outcomes, we offer our patients a pelvic ultrasound with a CA125 every six months starting at age 30 until they have their risk-reducing surgery. Some providers also offer combined hormonal oral contraceptive pills for ovarian cancer risk reduction, but the risk of breast cancer with added hormones should be carefully considered. Although we don't generally manage the breast cancer portion of these patients' care, we'll briefly review for completeness. For breast cancer prevention, these patients can be offered prophylactic bilateral mastectomies. Patients who do not desire surgery can be treated with tamoxifen or aromatase inhibitors for chemo prevention. These patients also undergo intensified screening as outlined in the table. At age 18, patients should start self-breast exams. At 25, patients should undergo a clinical breast exam every six to 12 months, and at age 30, patients should receive alternating every six-month mammograms and breast MRIs for screening purposes. Next, we'll talk about how to manage patients with BRCA mutations who have developed ovarian cancer. An estimated 13 to 15 percent of epithelial ovarian cancers are associated with BRCA mutations. The Cancer Genome Atlas Project found that among 316 patients, 3 percent had somatic mutations, 9 percent have BRCA1 mutations, and 8 percent have BRCA2 mutations. Patients with BRCA-associated ovarian cancer tend to have earlier onset of disease, more platinum-sensitive tumors, longer platinum-free intervals, and improved progression-free survival and overall survival when compared to the non-BRCA-associated population. The management of these cancers with BRCA mutations largely mirrors that of non-BRCA mutant tumors. This includes debulking surgery and platinum-based chemotherapy on either a neoadjuvant or adjuvant basis, depending on the clinical scenario. This paradigm has a few exceptions. For instance, patients with BRCA mutations may benefit more from IP chemotherapy, however, mutation status must be assessed at initial diagnosis for this to be clinically relevant. Patients with BRCA mutations are excellent candidates for a new class of drugs called PARP inhibitors. Poly-ADP-ribose polymerase, or PARP, is a key enzyme in the base excision repair pathway for single-stranded DNA damage. You'll recall that BRCA-mutated tumors are unable to execute homologous recombination, which is a necessary pathway for double-stranded DNA damage, so these cells must resort to single-stranded DNA repair almost exclusively. By blocking this pathway with a drug, we're able to induce synthetic lethality. Cancer cells cannot repair DNA damage unless they die. These agents have been studied and approved for use in a variety of clinical settings, summarized in this table. The use of these agents also requires genetic counseling and testing at diagnosis. So, today we reviewed the importance of identifying patients at risk for BRCA mutations. We also reviewed the necessity for appropriate referrals, genetic counseling, and testing. We now know the preventative and screening and risk-reducing measures that we should recommend, and we're aware of the management differences presented by these patients. A few references, and thank you so much again for the opportunity to speak with you. Please don't hesitate to ask any questions that you might have.

BRCA mutations

GYN oncology

DNA repair

breast cancer

ovarian cancer