Testing Beyond BRCA a Growing Approach in Ovarian Cancer Families

Gina Columbus @ginacolumbusonc
Published Online: Thursday, Sep 21, 2017

Ophira M. Ginsburg, MD
Ophira Ginsburg, MD
While there has been several years of research on BRCA mutations in the scope of breast and ovarian cancers, researchers do not have nearly enough data on other mutations patients with ovarian cancer harbor—much less an idea of how to target them with novel therapies.

However, there is hope for such research to emerge. Ophira Ginsburg, MD, director of the High Risk/Cancer Genetics Program at NYU Langone's Perlmutter Cancer Center, spoke on the importance of genetic testing for BRCA and these other genetic mutations in ovarian cancer during the 2017 OncLive® State of the Science SummitTM on Treatment Options in Ovarian Cancer.

“When they are offered genetic counseling for family history of ovarian cancer, whether they’re affected or unaffected, [individuals] will be told not only about BRCA 1/2 and Lynch syndrome, but also that they may indeed qualify for testing of additional genes,” said Ginsburg. “There can be as many as 11-, 16-, 24-, 34-, and even 80-gene panels.” In an interview during the meeting, Ginsburg discussed hereditary ovarian cancer, the occasional reluctance in testing, multigene panels, and the understanding of variants of uncertain significance.

OncLive: What did you focus on in your lecture on genetic testing?

Ginsburg: The talk I gave was about hereditary ovarian cancer and a focus on what are called multigene panels. As we have moved beyond just BRCA or BRCA 1/2, we know that there are many genes involved in hereditary ovarian cancer. I started by showing a family tree that is a classic one for BRCA, and highlighted the importance of offering testing to all women with epithelial ovarian, fallopian tube, or primary peritoneal cancer because a good proportion of those—10 to 15% and, in some populations, 20% if you’re looking at serous papillary ovarian cancer—can have a BRCA 1/2 mutation regardless of the age of the patient and of the family history.

Now, in cases of ovarian cancer families with breast or other cancers, or on their own, that test negative for BRCA 1/2, we are increasingly able to offer what are called multigene panels that include the Lynch syndrome genes. There are a number of genes associated with what used to be called hereditary nonpolyposis colon cancer that [can be found in] other gynecologic malignancies, as well as ovarian cancer. Uterine cancer is extremely important to know about. Families sometimes are referred to us with colon cancer and if a Lynch syndrome gene is found, women really should be counseled for predictive testing and the options for risk reduction should include a discussion about hysterectomy as well as bilateral salpingo-oophorectomy. 

There are other genes now that are also included in the NCCN guidelines that we follow in genetic clinics. The counselors are well versed in keeping up to date with these guidelines for hereditary cancer management, which we take on and discuss with the family. But, in terms of genetic testing, this is important for insurance coverage, as well. Insurers increasingly are asking us to demonstrate that the family meets criteria based on NCCN guidelines for testing of genes, including the multigene panels.

We have the panels, but are we ready? That is a rhetorical question. I know the panels are here; all of us who work in cancer genetics recognize that patients are increasingly asking for these, and the genetic counselors are trained to discuss these more complicated situations. People are increasingly being offered testing for these multigene panels, and 1 of the problems is, in the case of the larger panels, we don’t necessarily know what all the genes do. This is an emerging area; we don’t have the long history that we’ve had with BRCA 1/2.

There are no large prospective cohort studies of 10 or 20 years’ duration to tell us that if you have a mutation in BRIP1, RAD51C, or RAD51D, which are considered moderate ovarian cancer susceptibility genes, then the risk is exactly “X”%. We know for sure that a risk reducing salpingo-oophorectomy will lower the mortality—not to zero of course, but considerably. When you look up hereditary breast and ovarian cancer on any of the major websites or you ask a specialist in the area, we will inform you and your patient that there is some information we don’t have yet. However, our best estimate today is that those moderate risk genes (including BRIP1, RAD51C and RAD51D) confer approximately a 5% to 7% lifetime risk of epithelial ovarian cancer.  

Is that enough to warrant a discussion regarding risk reducing salpingo-oophorectomy? Absolutely. The age at which some of these patients are developing ovarian cancer in the studies for BRIP1, RAD51C, and RAD51D seems to be quite a bit later than what we see in BRCA1/2.

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