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Coding Variants in Five Breast Cancer Risk Genes Linked to Contralateral Breast Cancer

NEW YORK – New research suggests germline alterations affecting coding portions of five known breast cancer susceptibility genes can bump up the risk of breast cancer patients developing a subsequent tumor in the opposite breast, known as contralateral breast cancer (CBC).

The results painted a nuanced picture of CBC risk associated with pathogenic, likely pathogenic, or protein-truncating variants across breast cancer risk genes, while highlighting more tenuous ties between those variants and breast cancer survival.

"Our results have the potential to improve [breast cancer] risk counseling, prognostic estimates, and prediction models for [breast cancer] outcome," senior and co-corresponding author Marjanka Schmidt, an epidemiologist and breast cancer researcher at the Netherlands Cancer Institute, and her colleagues wrote in the American Journal of Human Genetics on Thursday, calling the new results "relevant to improve treatment, follow-up, and screening of women diagnosed with [breast cancer]."

For their study, the investigators brought together targeted gene panel sequencing data for 34,401 breast cancer patients of European ancestry enrolled in dozens of prior studies through the Breast Cancer Association Consortium, searching for CBC- and breast cancer survival-related variants in nine known risk genes: BRCA1/2, TP53, CHEK2, PALB2, ATM, BARD1, RAD51C, and RAD51D.

After profiling protein-truncating variants and pathogenic or likely pathogenic missense variants in that set of genes, they expanded their search to similar variants in 25 genes with suspected ties to breast cancer, which unearthed additional associations with several genes that did not reach statistical significance.

Over an average of 10.9 years of follow-up, at least 3,449 of the patients in the study died of the breast cancer, within nearly 6,900 deaths overall, the team explained, while 676 individuals developed CBC.

The team noted that 103 of the 676 CBC cases occurred in individuals known to carry pathogenic, likely pathogenic, or protein-truncating variants in breast cancer susceptibility genes.

Specifically, the risk of a second cancer in the opposite breast was increased in individuals with certain coding variants in the BRCA1, BRCA2, and TP53 genes, ranging from just over a 2.3-fold increase in the BRCA2 variant carriers to more than an eightfold increase in individuals with germline variants in TP53. CBC risk was also at least doubled in patients carrying protein-truncating variants in the CHEK2 or PALB2 genes.

These findings "are consistent with recent studies and support the general hypothesis that mutations that predispose to a first [breast cancer] also predispose to a second [breast cancer]," the authors explained.

In addition, the team found more modest ties between the cancer gene variants and breast cancer-specific survival, specifically for germline variants in TP53 and protein-truncating variants in CHEK2. Variants in BRCA2 appeared to coincide with survival within a subset of patients with estrogen receptor-positive forms of breast cancer.

Because they did not have access to detailed treatment histories for the breast cancer patients involved, though, the researchers noted that risk of a second breast cancer may have been lowered in some patients as a result of their treatment of their earlier breast cancer, including prophylactic contralateral mastectomy surgeries.

"Contralateral mastectomy virtually eliminates the risk of developing CBC, which in turn might affect [breast cancer-specific survival] because CBC occurrence is associated with poorer prognosis," the authors explained.