Study Identifies Breast Cancer Risk and Disease-Causing Mutations in Women Over 65

A study presented at the American Society of Human Genetics 2020 Virtual Meeting provided estimates of prevalence and breast cancer risks associated with pathogenic variants (PVs) in known breast cancer predisposition genes for the US population in women over the age of 65.¹

Women with onset of breast cancer over age 65 typically do not qualify for genetic testing, however this study demonstrated that frequency of PVs and risk of breast cancer is not negligible in this patient population.

“The median age of diagnosis for BC is 62 years, yet little is known about the frequency of pathogenic variants (PVs) in BC cancer predisposition genes in women over the age of 65, who represent a large percentage of women with BC, but often do not qualify for genetic testing,” the investigators wrote in an abstract. “The purpose of this study was to investigate the frequency of PVs in predisposition genes and to estimate residual risk of [breast cancer] in women over the age of 65.”

In this study, research sequenced germline DNA from women over the age of 65 from population-based studies in the CARRIERS consortium to identify PVs in cancer predisposition genes using a custom multigene amplicon-based panel. In total, 26,707 women over the age of 65 were included in this study, with 13,762 (51.5%) cases and 12,945 (48.5%) controls. Notably, family history of breast cancer was present for 26% of cases and 18% of controls.

The frequency of PVs in 12 established breast cancer predisposition genes was found to be 3.18% for cases and 1.48% for controls. Genes with the highest frequencies observed included ATM (0.48%), BRCA1 (0.18%), BRCA2 (0.49%), CHEK2 (0.67%), and PALB2 (0.23%).

“This shows that a large number of women in this age category are predisposed to breast and other cancers,” Nicholas Boddicker, PhD, a research associate at the Mayo Clinic, explained in a press release.²

Moreover, genes revealed to be associated with moderate risk of breast cancer included BRCA1 (OR, 3.37; 95% I, 1.68-7.51), BRCA2 (OR, 2.64; 95% CI, 1.78-4.02), PALB2 (OR, 3.09; 95% CI, 1.71-5.98), and CHEK2 (OR, 2.13; 95% CI, 1.53-3.02). However, ATM (OR, 1.38; 95% CI, 0.96-2.00) was not significantly associated with risk of breast cancer (P = .086).

Further, investigators found that the residual risk of breast cancer between the ages of 66 and 85 was 9.8% (95% CI, 6.8%-14.4%) for ATM, 18.3% (95% CI, 9.5%-35.7%) for BRCA1, 18.6% (95% CI, 12.5%-28.0%) for BRCA2, 14.9% (95% CI, 10.8%-20.6%) for CHEK2, and 15.8% (95% CI, 9.0%-28.3%) for PALB2. For the general population, residual risk of breast cancer was 6.8%.

According to Boddicker, the frequency of disease-causing variants and the risks presented in this study can be used to inform cancer screening, risk management, and possibly clinical testing guidelines for women over 65.

“In this study, women over 65 with no prior breast cancer found to have pathogenic variants in one of several genes would have remaining risk of breast cancer nearing 20% and could qualify for MRI surveillance in addition to mammography,” he said. “Without genetic testing, many of these women would not normally be screened this way.”

Moving forward, the investigators indicated there are further areas which need to be explored, including combining other factors and measurements of risk with genetic testing to help better personalize risk estimates for women. In addition, more efforts to characterize these effects in other racial and ethnic groups are also still needed.

References:

1. Boddicker NJ, Hart S, Yadav S, et al. Residual breast cancer risk in genetically predisposed women diagnosed over age 65. Presented at the American Society of Human Genetics 2020 Virtual Meeting. Abstract #: 2412.

2. Breast Cancer Risk and Disease-Causing Mutations in Women Over Age 65 [news release]. Rockville, Maryland. Published October 26, 2020. Accessed November 17, 2020. https://www.ashg.org/publications-news/press-releases/breast-cancer-risk-disease-causing-mutations-women-over-age-65/