Experts Offer Insight on BRCA1/2 Testing and Prophylactic Procedures

Maurie Markman, MD

The increased risk of developing breast and ovarian cancer associated with mutations in the BRCA1/2 genes has generated a host of recommendations on early detection and prophylactic strategies for those deemed at higher risk. Optimal testing strategies, including when to start testing and which prophylactic approach to pursue, have remained a topic of debate.

A controversial paper published by the discoverer of the BRCA gene, Mary-Claire King,PhD, recently suggested that current screening strategies were inadequate (JAMA. 2014;312[11]:1091- 1092). The paper detailed that BRCA mutations are not commonly identified until after a cancer diagnosis, which King labeled as a failure of cancer prevention. To address the problem, King, from the University of Washington, recommended that all women should be tested for BRCA mutations starting at age 30.

A panel of experts discussed these recommendations during an OncLive Peer Exchange® discussion that was moderated by Maurie Markman, MD, from Cancer Treatment Centers of America. The discussion included insights from Michael J. Birrer, MD, PhD, Robert A. Burger, MD, Warner K. Huh, MD, and James Tate Thigpen, MD.

Michael J. Birrer, MD, PhD

During the discussion, panelists agreed upon the importance of genetic screening, but disagreed with some of King’s finer points. Birrer, from the Massachusetts General Hospital, felt strongly that germline testing should be conducted for women diagnosed with ovarian cancer, but that testing for the general population was a different issue.

“[King’s paper is] looking at the general population with a broad screening approach in sequencing both BRCA1 and 2,” Birrer said. “One needs to recognize that ovarian cancer is still a rare tumor. This is going to be extremely costly and I think not particularly cost-effective. I would not support this in the general population at this time.”

Rather than screening the entire population, panelists felt that testing should be limited to those at high-risk of having an alteration. Universal testing could be considered in certain high-risk groups, such as in the Ashkenazi Jewish population, noted Burger, from the University of Pennsylvania.

The primary evidence for the theory of population-based screening came from a study conducted in Israel, according to King. In this study, over 8000 Ashkenazi Jewish men were enrolled and screened for three loss-of-function mutations that cumulatively account for the majority of inherited cancer risk due to BRCA in this population. In total, 175 men were identified as carriers of BRCA mutations, with genetic testing offered to all female relatives.

Robert A. Burger, MD

Women identified in this way, and found to carry a BRCA mutation themselves, had high cancer risks. Among carriers of BRCA1, the risk of developing breast or ovarian cancer was 60% (margin of error 7%) by age 60 years and 83% (margin of error 7%) by age 80 years. Among carriers of BRCA2, risk was 33% (margin of error 9%) by age 60 and 76% (margin of error 13%) by age 80 years.

These risks were higher at every age, among women born more recently versus those born earlier, King wrote. This trend has been observed in other studies and, according to the paper, “likely reflects increasing prevalence of nongenetic risk factors for breast cancer, including earlier age of menarche and later ages of childbearing, factors related to improved nutrition and education for women in modern society.”

In the study, 50% of families found to harbor a BRCA mutation had no history of breast or ovarian cancer to garner clinical attention. Female BRCA carriers from these lower-cancer-risk families had similar risks compared with their counterparts from higher-cancer-risk families. This, King writes, highlights the need for population-based screening.

The Peer Exchange panel did not dismiss the utility of genetic screening, but rather questioned the feasibility to be implemented in the general population.

Huh, from the UAB Comprehensive Cancer Center Birmingham, cited counseling as his main concern. The healthcare system in the United States is not currently in a place to provide genetic counseling for all women who test positive, Huh said.

Despite challenges, the efficacy of prophylactic procedures highlights the need for genetic screening and early detection. A bilateral prophylactic oophorectomy is typically performed to reduce the risk of ovarian cancer, but can also reduce the risk of breast cancer. This procedure can reduce the risk of ovarian cancer by 90% and the risk of breast cancer among women at high risk by 50%, according to the National Cancer Institute.

Warner K. Huh, MD

“When you look at women who happen to be BRCA-positive, there’s no question that a prophylactic oophorectomy is probably the best preventative strategy,” Huh said.

A bilateral prophylactic mastectomy can reduce the risk of breast cancer by at least 95% in women harboring a BRCA mutation. In women with a strong family history of breast cancer, the reduction in risk is up to 90%. Together, oophorectomy and mastectomy can effectively prevent the development of cancer in many women.

“The problem with it is the timing, and obviously you don’t want to do it too early and incur early menopause in women and then the intended consequences of that and hormone replacement,” Huh said.

Counseling women about early menopause and the reduction of their cancer risk can be challenging. Thigpen, from the University of Mississippi School of Medicine, said it is crucial to inform patients that prophylactic procedures do not reduce cancer risk to zero. “How many years before the anticipated diagnosis would confer the highest level of protection?

James Tate Thigpen, MD

I don’t think we know the answer,” Birrer said. “Case control studies have really not demonstrated any mathematical equation that will really help us decide what the time is where protection is afforded based on an early intervention.”

While the benefits of genetic testing and prophy lactic procedures are unquestioned, the controversy over implementing screening to the whole population remains up for debate.