Huma Q. Rana, MD
The benefits of genetic testing in gynecologic oncology are 3-fold, as it can inform individual and familial risk of developing a malignancy, alert patients to potential screening and preventative measures, and guide patients to potential targeted therapies, explained Huma Q. Rana, MD.
Over the years, genetic testing has become much more comprehensive in nature, said Rana, clinical director, Cancer Genetics and Prevention, Dana-Farber Cancer Institute, and instructor of medicine, Harvard Medical School.
“Often, genetics was the afterthought,” she said. “Now, we think about this early and upfront.”
In a presentation during the 2018 OncLive®
State of the Science Summit™ on Ovarian Cancer, Rana discussed the evolution of genetic testing in ovarian cancer and the genes that are associated with an increased risk of subsequent cancer development.
In contemporary care, age and family history alone are insufficient in alerting providers to a potential underlying mutation, said Rana. In 2011, a study published in Proceedings of the National Academy of Sciences of the United States of America
revealed a high percentage of identifiable mutations in women with no family history of cancer.1
In the study, 360 women with primary ovarian, peritoneal, or fallopian tube carcinoma, unselected for age and family history underwent genetic testing. Of those women, 24% harbored a mutation in 1 of the following genes: BRCA1/2, MSH6, PALB2, RAD51C, TP53, BARD1, BRIP1, CHEK2, MRE11, NBN, RAD50
. The latter 6, had not previously been associated with hereditary risk, said Rana. Moreover, 30% of women had no family history of cancer, and 37% of women were aged ≥60 years at the time of diagnosis.
“Age at diagnosis and family history are imperfect markers of who has a germline mutation,” said Rana.
Since then, the National Comprehensive Cancer Network, the American Society of Clinical Oncology, and the Society of Gynecologic Oncology have expanded the parameters for testing to include all women with a diagnosis of ovarian, fallopian tube, or peritoneal cancer. Included in this recommendation are first and second-degree relatives, she explained.
Now, the germline mutations that are accounted for on most panels include: BRCA1/2, MLH1, MSH2, MSH6, PMS2, ATM, BARD1, BRIP1, CHEK2, NBN, PALB2, RAD51C, RAD51D, APC, AXIN2, FANCC, MUTYH
, and TP53
Of known tumor suppressor genes, BRCA1/2
is perhaps the most well-known, as it is associated with a heightened risk of developing subsequent breast (40%), contralateral breast (40%-60%), and ovarian cancer (BRCA1
: 40%; BRCA2
: 15%-20%). In addition, patients who have a BRCA2
mutation carry a 3% to 5% increased risk of pancreatic cancer, melanoma, and prostate cancer.3-5
However, interventional strategies are available to these women, explained Rana. After identifying a BRCA
mutation, Rana explained that intensive surveillance is recommended with annual breast magnetic resonance imaging beginning as early as age 25. By age 30, women should be incorporating mammograms into their routine care. For men, prostate-specific antigen testing and digital rectal exams are recommended beginning at age 40.
To further reduce the risk of developing a malignancy, preventative surgery can be offered by way of bilateral mastectomy or removal of the ovaries and fallopian tubes. Further, chemoprevention with tamoxifen, raloxifene, exemestane, or birth control are often tabled as additional options.
Although there are several assays from which to choose, they are almost always going to be pan-cancer panels, explained Rana. These account for known high-risk genes, including BRCA1/2, DICER1
, and those associated with Lynch syndrome (MLH1, MSH2, MSH6
, and PMS2
). Also included on the panel are genes that carry moderate risk, including BRIP1, RAD51C, RAD51D
, and those of unknown risk, which include PALB2, ATM, BARD1, and CHEK2
“In parallel, trials were going on that were changing the nature of this information and its use. We learned that homologous recombination–deficient tumors may be more susceptible to PARP inhibitors...and that led to this incredible paradigm shift to genetic testing that’s more treatment-focused,” said Rana.
Even so, rates of genetic testing remain low. To counteract low compliance rates, Rana recommended including a genetic counselor into a patient’s appointment in clinic. Additionally, video counseling has been put forward as a potential way to improve the rate of testing in newly diagnosed patients.