Expert Highlights Importance of Genetic Testing in Gynecologic Cancers


According to Huma Q. Rana, MD, genetic testing provides valuable benefit in the treatment landscape of gynecologic cancers. It can inform physicians of the individual and familial risk for developing a malignancy, alert patients of potential screening and preventative measures, and guide selection of potential targeted therapies.

Huma Q. Rana, MD

Huma Q. Rana, MD

Huma Q. Rana, MD

According to Huma Q. Rana, MD, genetic testing provides valuable benefit in the treatment landscape of gynecologic cancers. It can inform physicians of the individual and familial risk for developing a malignancy, alert patients of potential screening and preventative measures, and guide selection of potential targeted therapies.

Genetic testing has become much more comprehensive in nature over the years, 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.”

Rana recently 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 inProceedings of the National Academy of Sciences of the United States of Americarevealed 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, andTP53.2

Of known tumor suppressor genes,BRCA1/2is 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 aBRCA2mutation 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 aBRCAmutation, 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, includingBRCA1/2, DICER1, Peutz-Jeghers/STK11, and those associated with Lynch syndrome (MLH1, MSH2, MSH6, andPMS2). Also included on the panel are genes that carry moderate risk, includingBRIP1, RAD51C, RAD51D, and those of unknown risk, which includePALB2, 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.

A retrospective study done by West Cancer Center showed that, as opposed to traditional counseling, video counseling resulted in significantly higher rates of counseling adherence. Of 3 providers in the area, a total of 267 patients had been seen with a traditional consultation. Subsequent follow-up revealed that 29% (77) of patients proceeded with testing. The same design was conducted with 295 patients but with a video consultation. Subsequent follow-up showed that 55% (162) of patients underwent subsequent testing.6

“We know that when we identify a mutation, that can be particularly difficult for patients and their family members. Usually over time, those feelings of distress decrease, but you certainly don’t want to feel that you’ve added to someone’s burden when they’re already dealing with a cancer diagnosis,” concluded Rana. “Trying to do these things in as patient-focused of a manner as possible is quite important.”


  1. Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.Proc Natl Acad Sci U S A. 2011;108(44):18032-18037. doi: 10.1073/pnas.1115052108.
  2. Carter N, Marshall M, Susswein L, et al. Germline pathogenic variants identified in women with ovarian tumors.Gynecol Oncol. 2018;151(3):481-488. doi: 10.1016/j.ygyno.2018.09.030.
  3. Begg CB. On the use of familial aggregation in population-based case probands for calculating penetrance.J Natl Cancer Inst. 2002;94(16):1221-1226. doi: 10.1093/jnci/94.16.1221.
  4. Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers.J Natl Cancer Inst. 1999;91(15):1310-1316.
  5. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium.Am J Hum Genet. 1998;62(3):676-689.
  6. Watson CH, Ulm M, Blackburn P, et al. Video-assisted genetic counseling in patients with ovarian, fallopian and peritoneal carcinoma.Gynecol Oncol. 2016;143(1):109-112. doi: 10.1016/j.ygyno.2016.07.094.
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