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Genetic variants in ovarian cancer: Where we are today
Jayanthi Lea, MD, FACOG, FACS, Patricia Duniven Fletcher Distinguished Professorship in Gynecological Oncology, associate professor of gynecologic oncology and program director for gynecologic oncology at UT Southwestern Medical Center, spoke with Healio about genetic variants linked to ovarian cancer, how the identification of these variants changed prevention and treatment strategies, and updated guidance on genetic testing that physicians should be aware of and share with their patients.
What genetic variants have been linked to ovarian cancer? How significant is their impact on disease risk and progression?
About 20% to 25% of women diagnosed with ovarian cancer have a hereditary tendency to develop this disease. The most significant risk factor for ovarian cancer is an inherited genetic mutation in one of two genes: BRCA1 and BRCA2. The mutations in either of these genes are responsible for about 10% to 15% of all ovarian cancers.
Another known genetic link to ovarian cancer is an inherited syndrome called hereditary nonpolyposis colorectal cancer (HNPCC), otherwise known as Lynch syndrome. Although HNPCC poses the greatest risk for colorectal cancer, women with HNPCC have about a 12% lifetime risk of developing ovarian cancer, and about a 40% to 60% chance of developing uterine cancer. These risks are considerably higher than that of women with average risk, which is about 1.4%.
Although it accounts for only a limited number of cases, the genetic contribution to ovarian cancer is a very strong risk factor. So whenever we see these patients, we have to elicit the family history because that will definitely clue us in to who may benefit from genetic consultation and counseling.
Other gene mutations that have been linked to ovarian cancer include the tumor-suppressor gene p53, which has been linked to Li-Fraumeni syndrome, and several other genes that are involved in double-stranded DNA breaks, such as RAD51C and RAD51D. The latter two carry a sixfold increased risk for ovarian cancer.
Recently, studies have shown that genetic variants such as single-nucleotide polymorphisms (SNPs), which are common, account for inherited risk for ovarian cancer. There are about 30 known risk variants. Women carrying the greatest number of SNPs may carry a slightly higher risk of 2.8%, which is barely higher than the average risk. The clinical applicability of this is unclear because risk-reducing surgery is typically offered to women who have a lifetime risk of 10% or more.
In conclusion, the well-known genetic risks are BRCA1 and BRCA2 deleterious mutations, as well as Lynch syndrome. But there are other genes that have been associated with ovarian cancer and much more in the pipeline as we continue our scientific inquiry.
How does the role of these genetic variants vary by patient population and ovarian cancer type?
There are many different types of ovarian cancers. Epithelial ovarian cancers are by far the most common. Then there are stromal cell tumors, germ cell tumors and tumors involving the ovary that are metastatic from a different location.
Epithelial ovarian cancer is a very heterogenous disease with five major histological subtypes: high-grade serous carcinoma, which accounts for approximately 70% of all epithelial cancers; clear-cell carcinoma, which accounts for 10%; endometrioid, which accounts for 10%; mucinous carcinoma, which accounts for about 3%; and low-grade serous carcinoma, which accounts for 4% to 5%. These subtypes differ in terms of histopathology, morphology and genomics. All of these subtypes are considered distinct diseases that really require a careful diagnosis.
Based on molecular profiles, disease development and prognosis, these different histological subtypes can be hierarchically grouped into type 1 cancers and type 2 cancers. Type 1 cancers are generally slow-growing. They encompass low-grade serous, low-grade endometrioid, mucinous and clear cell carcinomas. They are typically characterized by mutations in genes such as KRAS, BRAF, PIK3CA, and by absence, TP53 mutations. When looking at high-grade serous ovarian cancers, p53 mutations are very common. Other mutations often involved in type 1 tumors are PTEN and ARID1A, which is common in clear cell carcinoma.
Type 2 tumors are highly aggressive and encompass high-grade serous tumors, as well as high-grade endometrioid and undifferentiated carcinomas, with disruptions in p53 (that being the most common) as well as BRCA1, BRCA2 and DNA mismatch repair gene mutations.
As far as ethnic variability, women of Eastern European origin and women of Ashkenazi Jewish descent are at a higher risk for carrying BRCA1 and BRCA2 mutations. But we need to remember that all women diagnosed with ovarian cancer have a 30% risk of carrying a gene that may be inherited. Every woman who is diagnosed with ovarian cancer must undergo genetic testing to make sure that she does not carry a gene that can be passed along. There are many benefits to screening. Identifying BRCA1 and BRCA2 mutations can help prevent other diseases, including breast cancer, genitourinary cancer, colorectal cancer and brain cancer.
How has the identification of genetic variants advanced ovarian cancer management and treatment?
The identification of these genetic variants allows patients the opportunity to reduce their risk for ovarian cancer by undergoing a risk-reducing surgery that removes both ovaries and fallopian tubes. National Comprehensive Cancer Network guidelines recommend that patients with BRCA1 genetic mutations have an oophorectomy and salpingectomy between the ages of 35 and 40 years, and that those who carry BRCA2 genetic mutations have a risk-reducing salpingo-oophorectomy performed between the ages of 40 and 45 years. These are very general guidelines by the NCCN. Practice is individualized to a certain extent when we consider a patient’s family history and how tolerant they are to the risk.
The identification of these variants also helps with therapy. We take an individual’s tumor genetics into consideration when we plan treatment. Genetic testing of tumor tissue at several timepoints during treatment may afford unique opportunities for patients to be treated with an FDA-approved targeted therapy.
Several poly(ADP-ribose) polymerase (PARP) inhibitors have been approved by the FDA, specifically for patients with a BRCA mutation or patients who have tumors that test positive for homologous recombination deficiency. PARP inhibitors are very effective in killing tumors that are defective in the BRCA1 or BRCA2 genes through the concept of synthetic lethality. It is suggested that PARP inhibitors can cause an increase in the DNA single-strand breaks, which are then converted during replication to irreparable, toxic double-stranded breaks in women who have BRCA1 or BRCA2 mutations in their tumor cells. The same concept can also be applied to tumors that are deficient in homologous recombination.
PARP inhibitors have shown an improvement in PFS in the maintenance setting for patients with recurrent platinum-sensitive ovarian cancer. Patients with a BRCA mutation or homologous recombination deficiency in their tumor have been shown to gain the most benefit. For example, in one study, BRCA-mutated patients with platinum-sensitive ovarian cancer who responded to a platinum-based therapy had PFS of almost 1.5 years while on a PARP inhibitor for maintenance therapy compared with a similar group of patients who were treated with placebo. Similarly, phase 3 trials have demonstrated that maintenance therapy with a PARP inhibitor in the front-line setting decreased disease progression or death by almost 70%, specifically in patients who have BRCA mutations. So, we made considerable strides by incorporating genetic mutations into our treatment paradigm.
From a genetic standpoint, this is where we are today. We are utilizing information that we get from patients and incorporating that into screening and treatment. We really are trying to inquire about the genetic makeup of a patient’s tumor, not only during primary treatment, but also during recurrences. When I treat my patients, I attempt, if possible, to get biopsies of recurring cancers to identify what mutations might be present or absent. There may be new drugs targeting those mutations that might benefit our patients.
The U.S. Preventive Services Task Force recently released a draft recommendation that urges clinicians to screen certain women for BRCA1 or BRCA2 mutations. These women include those with a family history of certain types of cancer or with an ethnicity or ancestry that is associated with a higher risk for BRCA1 or BRCA2 mutations. What impact will this guidance have on patient care?
The ultimate impact of genetic testing is to identify all individuals who would be at risk for cancer before they are affected and to maximize the opportunity for prevention and early detection. All physicians and other health care providers should be made aware of these recommendations and be empowered to speak to their patients about these guidelines. A study that looked at the national estimates of genetic testing among women with a history of breast or ovarian cancer showed 15% of women with a history of ovarian cancer had a discussion about genetic testing, 13% were advised to undergo genetic testing and only 10% underwent testing. It is a little disappointing when you look at these results. Fewer than 1 in 5 individuals with a history of breast cancer or ovarian cancer who met NCCN criteria underwent genetic testing. It seems to me that most providers are not discussing testing with their patients and that patient uptake is low. I think there are definite barriers from the provider standpoint and the patient standpoint. Yes, we have guidelines. But we also need to identify how these barriers to screening and testing can be overcome. Providers have a big job ahead of them in knowing that these guidelines exist and educating patients, as well as the public. It is a matter of telling every patient who has ovarian cancer that they need to see a geneticist.
Some large trials of new agents have been negative overall but have included small clusters of patients who responded very well. Is it worth revisiting these trials to determine if genetic variants may have determined success in those patients?
Yes. A specific genetic signal that is associated with response to a drug is very important because it will allow us to plan more targeted trials. The most popular ones to date are BRCA-driven trials. The vast majority of trials are essentially targeted drugs given to all-comers and seeing what the response is to all-comers, or a targeted drug in combination with chemotherapy. There are a few trials that actually require you to screen patients’ tumors prior to enrollment. I think those trials are aimed exactly at this concept.
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