Could Summing Up Breast Cancer Risk Alleles Reduce Unneeded Mammograms?

Common breast cancer risk alleles are correlated with both the incidence of breast cancer and mortality, and using these alleles along with other factors could identify women at very low risk of breast cancer who could potentially avoid mammography, according to a general population study conducted in Denmark.

The risk of breast cancer according to a number of common alleles was defined in a large 2015 study published in the Journal of the National Cancer Institute. However, that study used a polygenic risk score to stratify risk and largely included individuals used to discover the variants before validating them separately. According to Stig E. Bojesen, MD, PhD, of Copenhagen University Hospital in Denmark, and colleagues, several questions remained unanswered: whether a test using those alleles can actually predict breast cancer risk (and specifically cancers with life expectancy impact rather than indolent tumors) in the general population, and whether it is also connected with other cancers.

The new study used the sum of alleles previously reported rather than the “more conventional” polygenic risk score. “Apart from being intuitively understandable as a simple sum, we speculated that the breast cancer allele sum rather than the polygenic risk score would be more sensitive in detecting associations with other endpoints,” the authors wrote. The study was published online ahead of print in Annals of Oncology.

In total, the analysis included 35,441 individuals (19,010 women) from the Copenhagen City Heart Study and the Copenhagen General Population Study, who were followed for up to 21 years. Individuals were genotyped for 72 loci, each with 0-2 alleles. A total of 1,301 women developed breast cancer during the follow-up period, and 4,972 women and men developed other cancers.

The cumulative incidence of breast cancer increased across allele sum quintiles (log-rank trend P = 1 × 10^–12). There was no trend, however, across the alleles as regards to other cancers.

Using the first allele sum quintile as a reference, women in the fifth quintile had a breast cancer risk of 1.82 (95% CI, 1.53–2.18). An adjusted analysis showed an increase in breast cancer risk per allele of 1.04, and an increase in mortality risk of 1.05 per allele.

Women in Denmark are offered screening beginning at age 50. In 50-year-old women included in this study, the average 5-year breast cancer risk was 1.5% overall; those in the first allele sum quintile had a risk of 1.1%, and this rose through the quintiles to 1.4%, 1.6%, 1.7%, and 2.1% for those in the fifth quintile. Among those aged 50 to 54 years, 72% would fall below a 1.5% risk cutoff for mammography; adding allele sum to current risk assessment methods would put 25% of women below the cutoff for screening.

“Taken individually, each breast cancer risk allele association is too weak to be useful in a clinical setting,” the authors wrote. “However, as a sum, in combination with age, familial breast cancer, and nulliparity, they can help to identify women with an absolute risk below the current risk cutoff … and potentially to reduce the number of women who are offered screening mammography by almost one fourth.”