Q&A: Familial and Genetic Risk in Ovarian Cancer
Malignant ovarian neoplasms are a significant cause of cancer mortality in women.[1] Important risk factors include age, family history of breast or ovarian cancer (OC), personal history of breast cancer, endometriosis, and pelvic inflammatory disease.[2] Maurie Markman, MD, is president of medicine & science at City of Hope, and he talked to Medscape about the clinical implications of familial and genetic risk in OC.
What is the importance of genetics in OC?
We know a lot about OC genetics compared to when I started in this area. This is a fascinating part of medical history from over 50 years ago when nobody talked about OC. Patients would tell you that a family member — their mother, sister, or grandmother — had died of something that involved the stomach area. Historically, however, if you went back, there was no way of knowing if it was OC or gastric cancer because gastric cancer was extremely common. Additionally, there was nothing you could do about genetic risk at the time, nor much appreciation of how substantial this risk really is. The cumulative OC risk to age 80 years for women with BRCA1 is 36%-53% and 11%-25% for BRCA2 carriers.[3]
What do we know about familial and genetic risk in OC?
All patients diagnosed with OC should receive germline genetic testing. This is a decade-old recommendation from the National Comprehensive Cancer Network, American Society of Clinical Oncology,[4] Society of Gynecologic Oncology,[5] and European Society for Medical Oncology[6] and it still isn't done. This recommendation is based not only on the increased risk for OC in patients with genetic mutations, including BRCA1 , BRCA2 , MLH1 , MSH2 , or MSH6 (the Lynch syndrome genes), but also due to its implications to patient management and risk-reduction strategies. There is evidence showing that most eligible patients are not offered genetic testing, and the main factors associated with this noncompliance are older age, ethnicity, and insurance coverage.[7] This is a real problem. All healthcare providers, not just gynecologic oncologists, should be aware of the importance of germline genetic testing.
Can you tell us more about the implications of genetic testing to patient management?
The first implication is to the patient diagnosed with OC. BRCA1 and BRCA2 are tumor-suppressor genes involved in DNA repair, and their loss may cause cancer or change its course. BRCA1/BRCA2 mutation is recognized as a genetic marker for targeted therapy. There is overwhelming evidence that poly(ADP-ribose) polymerase (PARP) inhibitors have incredible impact on overall survival in OC as first-line, second-line, or later maintenance therapy in patients with platinum-sensitive relapsed tumors.[8,9] The impact on survival is enormous. This is not a treatment decision up for debate, and you won't know which patient will benefit from PARP inhibitors unless you carry out genetic testing.
Beyond patient management, what is the impact of germline genetic testing?
Germline testing helps determine a person's genetic predisposition to OC which is different from somatic testing of cancerous cells.[10] The impact extends to the patient's family and their support system. Family members, both male and female, could be at risk for genetic discrimination, including problems with life and health insurance, relationships, and even employment based on cancer risk. Genetic counselors are fundamental to guide patients and healthcare providers to understand the risks associated with pathogenic mutations and to decide on risk-reduction options. Today, genetic testing is strongly recommended because there are risk-reduction strategies that outweigh these negative risks I just mentioned.[4,5,6]
When should genetic testing be offered to family members?
Personal circumstances and preferences, such as family planning and reproductive options, should guide discussions about screening recommendations. Genetic testing is recommended to individuals with significant family history of OC and those from populations with high pathologic variant carrier frequencies, including Ashkenazi Jews, for example.[4,5,6] For asymptomatic women without a known high-risk hereditary cancer syndrome, the US Preventive Services Task Force recommends no screening for OC.
What are the strategies for risk reduction?
The most effective approach to prevent ovarian and fallopian tube cancers is risk-reducing bilateral salpingo-oophorectomy.[11] Typically, it is recommended to patients with pathologic variants in BRCA1/2, BRIP1, RAD51C, RAD51D , or MLH1, MSH2 , and MSH6 . Surgery can reduce the risk for gynecologic tumors by 80%-90% and decrease the all-cause mortality by 77%. The timing of surgery is also influenced by the patient's age, desire for pregnancy, family history, and the consequences of premature menopause.
Can you tell us more about ongoing clinical trials about OC that could change clinical practice?
I can mention two different approaches that could change clinical practice: bilateral salpingectomy for OC prevention and antibody-drug conjugates (ADCs) for the treatment of patients with poor survival prospects. Based on a theory that most OCs originate in the fimbriated end of the fallopian tube and then spread to the ovary, the hypothesis is that surgical resection of the fallopian tubes in women with increased risk may prevent the development of epithelial OC and avoid premature menopause.[12] We still need to know more about surgery eligibility and long-term survival outcomes.
Very interesting. What are ADCs?
ADCs are targeted therapies consisting of monoclonal antibodies capable of delivering cytotoxic drugs, the payload, directly to the tumor site while reducing systemic exposure and toxicity. Ideally, the payload should be released in the intracellular space.[13] Currently, there are many clinical trials trying to identify suitable targets and clinically effective therapies that could increase overall survivor in patients with OC.[14]
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