Prevalence of Germline Mutations in Genes Engaged in DNA Damage Repair by Homologous Recombination in Patients with Triple-Negative and Hereditary Non-Triple-Negative Breast Cancers

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.

Associations of pathogenic mutations responsible for breast cancer risk with histology and immunohistochemistry in Romanian population

“…Data from the literature argue that CHEK2 mutations are associated with ER-positive types according to a study from 2009 conducted on Polish population [23], which is supported also by a recent article stating that the carriers of CHEK2 mutations associate luminal tumors rather than TNBC [9].…”

“…However, knowing the association of BRCA1 mutations with TNBC can open new opportunities for treatment using the platinum agents or poly ADP ribose polymerase inhibitors (PARP inhibitors) [9].…”

Synthetic Lethality Exploitation by an Anti–Trop-2-SN-38 Antibody–Drug Conjugate, IMMU-132, Plus PARP Inhibitors in BRCA1/2–wild-type Triple-Negative Breast Cancer

“…Many other BRCA1/2--wild-type TNBCs occur as sporadic tumors that share traits with germline BRCA-mutated tumors and are termed to have BRCAness (39,40). For example, analysis of germline mutations in 158 TNBC patients demonstrated that in addition to BRCA1 mutations (17% of patients), mutations of the CHEK2 checkpoint kinase 2 gene, nibrin NBN gene, and ATM genes also were found (3.9%), and are themselves involved in various aspects of the HRR pathway (41)(42)(43). Overall, the evidence suggests that besides BRCA1/2 status, many other genes contribute to the BRCAness of TNBC.…”

The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families?

“…Table 3A and 3B summarizes the primary aim of these studies, the inclusion criteria, the list of genes included in the selected panels and the results of ten published studies that included more than 500 patients who had undergone diagnostic multigene panel testing for HBOC [18-20, 22-23, 25, 27-28, 30-31]. One study was excluded from this review despite the high number of patients, because the authors chose to study only 36 known pathogenic mutations in the selected HBOC genes [14]. The highest number of patients included was 10030, most of whom had HBOC, although one study was limited to unselected TNBC patient [31] and another one to OC [29].…”

“…The majority of these genes are part of the DNA repair/BRCA pathway [13][14][15][16]. NGS has made it possible for clinicians to order a single test that evaluates multiple genes simultaneously in a cost-effective and efficient fashion, thus enabling a more complete genetic evaluation [17].…”