Abstract
PurposeThis study sought to assess the prevalence of common germline mutations in several genes engaged in the repair of DNA double-strand break by homologous recombination in patients with triple-negative breast cancers and hereditary non-triple-negative breast cancers. Tumors deficient in this type of DNA damage repair are known to be especially sensitive to DNA cross-linking agents (e.g., platinum drugs) and to poly(ADP-ribose) polymerase (PARP) inhibitors.MethodsGenetic testing was performed for 36 common germline mutations in genes engaged in the repair of DNA by homologous recombination, i.e., BRCA1, BRCA2, CHEK2, NBN, ATM, PALB2, BARD1, and RAD51D, in 202 consecutive patients with triple-negative breast cancers and hereditary non-triple-negative breast cancers.ResultsThirty five (22.2%) of 158 patients in the triple-negative group carried mutations in genes involved in DNA repair by homologous recombination, while 10 (22.7%) of the 44 patients in the hereditary non-triple-negative group carried such mutations. Mutations in BRCA1 were most frequent in patients with triple-negative breast cancer (18.4%), and mutations in CHEK2 were most frequent in patients with hereditary non-triple-negative breast cancers (15.9%). In addition, in the triple-negative group, mutations in CHEK2, NBN, and ATM (3.8% combined) were found, while mutations in BRCA1, NBN, and PALB2 (6.8% combined) were identified in the hereditary non-triple-negative group.ConclusionsIdentifying mutations in genes engaged in DNA damage repair by homologous recombination other than BRCA1/2 can substantially increase the proportion of patients with triple-negative breast cancer and hereditary non-triple-negative breast cancer who may be eligible for therapy using PARP inhibitors and platinum drugs.
Highlights
Triple-negative breast cancer (TNBC), i.e., breast cancer characterized by no immunohistochemical expression of the estrogen receptor (ER) or progesterone receptor (PR) and the absence of human epidermal growth factor receptor 2 (HER-2) overexpression, accounts for 15–20% of breast cancer cases [1]
Mutations in BRCA1 were most frequent in patients with triple-negative breast cancer (18.4%), and mutations in CHEK2 were most frequent in patients with hereditary non-triple-negative breast cancers (15.9%)
Identifying mutations in genes engaged in DNA damage repair by homologous recombination other than BRCA1/2 can substantially increase the proportion of patients with triplenegative breast cancer and hereditary non-triple-negative breast cancer who may be eligible for therapy using poly(ADP-ribose) polymerase (PARP) inhibitors and platinum drugs
Summary
Triple-negative breast cancer (TNBC), i.e., breast cancer characterized by no immunohistochemical expression of the estrogen receptor (ER) or progesterone receptor (PR) and the absence of human epidermal growth factor receptor 2 (HER-2) overexpression, accounts for 15–20% of breast cancer cases [1]. Patients with TNBC are characterized by a high risk of relapse, poor prognosis and insensitivity to anti-estrogen and anti-HER2 targeted therapies [2]. This subset of breast cancers is mainly responsible for the difficulties encountered during efforts to improve the survival of patients with breast cancer. TNBCs constitute approximately 80% of BRCA1-associated breast cancers [3]. BRCA1/2 mutations have only been found in a subset of patients with TNBC [4]. 30% of all hereditary breast cancer patients and the majority of breast and ovarian cancer patients harbor germline mutations in the BRCA1/2 genes [5]
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