Cancer Prevention Strategies Linked to Mortality Reduction in BRCA Carriers

By Mike Basset

Risk management strategies including bilateral salpingo-oophorectomy (BSO) for ovarian cancer and MRI surveillance for breast cancer were associated with a significant reduction in mortality for women with BRCA1/2 sequence variations, according to results from two cohort studies published in JAMA Oncology.

In the first study, after adjusting for age, BRCA sequence variation, country of residence, and oophorectomy status, the hazard ratio for breast cancer mortality associated with MRI surveillance was 0.23 (95% CI 0.11-0.48, P=0.001), reported Steven A. Narod, MD, of Women’s College Hospital in Toronto, and colleagues in the Hereditary Breast Cancer Clinical Study Group.

However, MRI surveillance was only associated with a significant reduction in breast cancer mortality for women with BRCA1 sequence variations (age-adjusted HR 0.20, 95% CI 0.10-0.43, P<0.001), not women with BRCA2sequence variations (age-adjusted HR 0.87, 95% CI 0.10-17.25, P=0.93).

In the second study, BSO was associated with a significant reduction in all-cause mortality (age-adjusted HR 0.32, 95% CI 0.24-0.42, P<0.001), with age-adjusted HRs of 0.28 (95% CI 0.20-0.38, P<0.001) and 0.43 (95% CI 0.22-0.90, P=0.03) for women with BRCA1 and BRCA2 sequence variations, respectively, noted Narod and team.

These studies show that cancer risk management strategies “can save lives,” wrote Meghna S. Trivedi, MD, and Katrina A. Armstrong, MD, both of the Vagelos College of Physicians and Surgeons at Columbia University in New York City, in an editorial accompanying the two studies. “Demonstration of a mortality benefit from a screening and prevention intervention provides strong evidence in support of their use, aligning with the recommendations of NCCN [National Comprehensive Cancer Network] guidelines.”

They noted that while the studies provide more evidence that BRCA1/2 carriers should be encouraged to pursue risk-reducing BSO and breast MRI surveillance, the challenge will be providing equitable access to and coverage of these strategies.

“Given the strong body of evidence that now exists, insurers should no longer refuse to cover these risk management measures because of insufficient data,” they wrote.

MRI Surveillance

Women with a BRCA1 or BRCA2 sequence variation are recommended to undergo annual screening with MRI from age 25 or 30 to 70 in the U.S. While MRI surveillance has been shown to be effective in downstaging breast cancers, its association with mortality risk has not been well defined, Narod and colleagues noted.

For their study, they included 2,488 women (mean age at study entry 41.2 years) from 59 centers in 11 countries who had a BRCA1 (n=2,004) or BRCA2 (n=484) sequence variation. Of these participants, 70.6% had at least one screening MRI examination.

Patients completed a baseline questionnaire from 1995 to 2015 and a follow-up questionnaire every 2 years to document screening histories, incident cancers, and vital status. Women who had breast cancer, a screening MRI examination, or bilateral mastectomy prior to enrollment were excluded.

Participants were followed from age 30 (or the date of the baseline questionnaire, whichever was later) until age 75, the last follow-up, or death from breast cancer.

After a mean follow-up of 9.2 years, 13.8% of patients developed breast cancer, and 1.4% died of breast cancer.

Women who did not undergo MRI surveillance had a cumulative risk of breast cancer mortality at 20 years from baseline of 14.9% compared with 3.2% among those who underwent MRI surveillance (a mean of 4.7 screening MRIs).

In addition, the cumulative risk of breast cancer mortality from ages 30 to 75 was 20.5% for those who did not undergo MRI surveillance compared with 5.5% among those who did (P<0.001).

While the authors cautioned the study was not designed to compare MRI versus mammography, they noted that 86.7% of women in the no-MRI surveillance group had at least one screening mammogram, with a hazard ratio for breast cancer mortality for MRI-exposed women compared with mammography-exposed women of 0.27 (95% CI 0.12-0.58, P<0.001).

Preventive BSO

Women with a germline pathogenic or likely pathogenic variant in BRCA1 or BRCA2 are advised to undergo BSO before the ages of 40 and 45, respectively, to reduce their risk of developing ovarian and fallopian tube cancer, Narod and colleagues said.

Their international, longitudinal cohort study included 4,332 women (mean age 42.6 years) with BRCA1/2 sequence variations, of whom 67.8% chose to undergo a preventive oophorectomy at a mean age of 45.4.

Women were followed from ages 35 to 75 for incident cancers and deaths.

After a mean follow-up of 9 years, 851 women had developed cancer and 228 had died (57 due to ovarian or fallopian tube cancer, 58 due to breast cancer, 16 due to peritoneal cancer, and 97 due to other causes). Among those who had an oophorectomy, the all-cause mortality rate was 3.8% compared with 8.3% among women who did not have an oophorectomy.

The estimated cumulative all-cause mortality rate to age 75 for women with BRCA1 sequence variations who had an oophorectomy at age 35 was 25%, compared with 62% for women who did not have an oophorectomy. These rates were 14% and 28%, respectively, for women with BRCA2 sequence variations.

“The data on relative cancer rates, the estimated HRs, and the prevalence of occult cancers by age at oophorectomy support the current National Comprehensive Cancer Network guidelines for oophorectomy between ages 35 and 40 years for women with BRCA1 sequence variations and before age 45 years for women with BRCA2 sequence variations,” Narod and colleagues wrote. “We hope that the findings in this study will reassure women with a positive genetic test result who face high risks of breast and ovarian cancer.”