Shift Toward Comprehensive Marker Evaluation, Universal Screening for Breast Cancer Risk Assessment

Paralleling trends in other clinical areas, breast cancer risk testing is transitioning from single-marker testing to more comprehensive analysis. This broadened focus extends to both wider analysis of BRCA mutations and multigene panels, as well as the potential use of comprehensive sequencing to thoroughly assess a woman’s breast cancer risk. Expansion of the scope of testing comes amid other calls to scale BRCA screening to include all women, regardless of familial cancer history, as part of routine medical care. Previous estimates show that of the 5 percent to 10 percent of hereditary breast cancer cases, only about one-fourth involve single-gene conditions. BRCA1/2 are the most notable of the known genes conferring a higher breast and ovarian cancer risk. But there are other recognized high-risk cancer genes associated with other cancers in addition to breast and ovarian cancer, such as PTEN, p53, CDH1, and STK11. There are also moderate- to low-penetrance breast cancer genes (PALB2, CHEK2, ATM) that are being incorporated into multigene panels. The challenge posed with incorporation of these genes into analysis is a lack of consensus around guidelines for how to provide ongoing management for patients testing positive for these gene mutations. Further fueling debate over the best way to assess breast cancer risk was the call this fall for preemptive, universal BRCA screening by a prominent researcher. While the downside of population-based screening is the concern that screening may increase unnecessary, invasive diagnostics and overtreatment, the hope is that expanded screening may identify women with higher genetic risk not eligible for screening based on family history. Calls for Universal BRCA Screening Mary-Claire King, Ph.D., from the University of Washington, Seattle, who was awarded the 2014 Lasker-Koshland Special Achievement Award in Medical Science in part for her discovery of BRCA1, says that it is time to offer universal BRCA1/2 testing to all women, and that other genes could be phased into the screening process as evidence justifies. “To identify a woman as a [BRCA] carrier only after she develops cancer is a failure of cancer prevention,” write King and colleagues in a Sept. 17 editorial published in the Journal of the American Medical Association. They say that genetic screening of every woman, at roughly age 30 as part of routine medical care, will better identify high-risk women who would benefit from special screening and preventive measures. They say this marked departure from current practice and U.S. Preventive Services Task Force recommendations is necessary in light of new research showing that general screening can identify many carriers not eligible for screening based on family history. This new evidence (of which King was a co-author) was published in the Sept. 30 issue of the Proceedings of the National Academies of Science. The researchers identified 175 male BRCA1/2 mutation carriers and offered genetic testing to all of their female relatives. These men were viewed as a “gateway to families,” since the men were not affected by breast cancer and the subsequently screened women were not identified based on a personal or family cancer history. Since the index men were all healthy, Ashkenazi Jews, screening was limited to the three loss-of-function mutations most common in this population. The researchers found that, as expected, those with BRCA mutations had very high cancer risks. For BRCA1 mutation carriers, the combined risk of developing either breast or ovarian cancer ranged from 60 percent by age 60 to 83 percent by age 80, while for BRCA2 carriers the risk was 33 percent by age 60 and 76 percent by age 80. Importantly, the authors say that 50 percent of families identified carrying BRCA1 or BRCA2 mutations had no history of breast or ovarian cancer that would have triggered genetic screening. Yet female mutation carriers from these low-cancer-incidence families had cancer risks that were similar to female carriers from families with high cancer incidence. The big question is, are these results applicable to more diverse populations, as in the United States? King and colleagues say yes, despite the additional number of cancer-predisposing BRCA1/2 mutations present in the U.S. population. “Testing for BRCA1 and BRCA2 should focus solely on unambiguously loss-of-function mutations with definitive effect on cancer risk,” writes King, acknowledging the challenge posed by other variants of unknown significance (VUS). “A VUS can increase confusion and compromise clinical management; for population-based screening, these variants should not be reported. . . . If any VUS ultimately proves causal for breast or ovarian cancer, it should be integrated into future testing. Meanwhile, waiting for a perfect test denies women excellent resources that are now available.” Will Sequencing-Based Screening Better Identify At-Risk Women? As it is believed that the accuracy of breast cancer risk assessment may be improved with an examination of a larger number of genetic markers, some are wondering whether universal screening via sequencing may become an increasingly cost-effective strategy to identify and then target the women who would benefit from aggressive preventive efforts. A study published online Oct. 23 in Cancer Epidemiology, Biomarkers, & Prevention found that personalized breast cancer preventive strategies based on genome sequencing will bring greater gains in disease prevention than previously projected. “The main takeaway message is we can be more optimistic than previously predicted about the value of genomic sequencing,” Alice Whittemore, Ph.D., from Stanford University, said in a statement. She tells DTET that comprehensive panels are currently being developed and are in the early stages of use by her colleagues in high-risk cancer clinics with the hope that improving risk assessment can lead to personalization of breast cancer prevention strategies. The Stanford researchers developed a computational model to estimate a woman’s lifetime probability of developing breast cancer. This risk score was calculated as the sum of the breast cancer-related genetic variants a woman carries multiplied by the effect of the variants. The group used published data (allele frequencies and effect size) for all 86 breast cancer susceptibility variants known at the time of the study (the number of identified variants has since increased). They estimate that using those 86 variants, the risk score for the population as a whole is 0.35, higher than a previous study’s estimated risk score of 0.07 derived using the seven loci known in 2008. The researchers say that targeting those in the top 25 percent of the risk distribution using sequencing of the currently known genetic alterations would identify approximately half of all future breast cancer cases, compared to estimates of 35 percent of future cases identified based on the 2008 variants. “As we keep identifying additional breast cancer variants that can further explain the difference between my risk versus yours, the variance of the genetic risk score in the population will increase, and the potential utility of genomic sequencing will grow,” said lead author Weiva Sieh, M.D., Ph.D., in a statement. Takeaway: Researchers are evaluating the most cost-effective means to assess women’s breast cancer risk with increasing emphasis on comprehensive mutational analysis and possibly routine, universal screening as part of wellness care.   Side Box: Quest Extends BRCAvantage At the beginning of November, Quest Diagnostics (Madison, N.J.) announced it has extended its BRCAvantage lab-developed test initially launched back in October 2013 for assessing genetic breast cancer risk. The BRCAvantage Plus now screens for mutations (point mutations, deletions, and duplications) in the BRCA1 and BRCA2 genes as well as in five additional genes: TP53, PTEN, CDH1, STK11, and PALB2. Quest says that the test can be ordered as single-gene tests, a comprehensive panel, or with a reflex option, which tests the non-BRCA genes if BRCA1/2 results are negative. The company cited data that the addition of the five non-BRCA genes account for an additional 3 percent to 4.5 percent of inherited breast cancers in addition to the 15 percent to 20 percent of inherited breast cancers accounted for by mutations in the BRCA1/2 genes.