BRCA1/2‐negative hereditary triple‐negative breast cancers exhibit BRCAness. Issue 7 (24th January 2017)

• Record Type: Journal Article
• Authors: Domagala, Pawel; Hybiak, Jolanta; Cybulski, Cezary; Lubinski, Jan
• Is Part Of: International journal of cancer. Volume 140:Issue 7(2017:Apr. 01)
• Page Start: 1545
• Page End: 1550
• Publication Date: 2017-01-24
• Subjects: breast cancer -- triple‐negative -- BRCAness -- BRCA1/2 -- PARP inhibitors; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.30570
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : BRCA1/2 ‐associated breast cancers are sensitive to poly(ADPribose) polymerase (PARP) inhibitors and platinum compounds mainly due to their deficiency in DNA repair via homologous recombination (HR). However, approximately only 15% of triple‐negative breast cancers (TNBCs) are BRCA1/2 ‐associated. TNBCs that exhibit BRCAness (a phenotype reflecting impaired HR in BRCA1/2 ‐negative tumors) are also regarded sensitive to PARP inhibitors and platinum compounds. Thus, we hypothesized that hereditary BRCA1/2 ‐negative TNBCs may exhibit BRCAness. To find a subset of hereditary BRCA1/2 ‐negative TNBCs among 360 TNBCs, we first identified a group of 41 hereditary TNBCs by analyzing the family histories of the patients. Next, we tested this group for the presence of germline BRCA1/2 mutations, and finally, we compared the expression levels of 120 genes involved in HR and five other major mechanisms of DNA damage repair between BRCA1/2 ‐associated and BRCA1/2 ‐negative subgroups of hereditary TNBCs using real‐time PCR arrays. Approximately 73% of the hereditary TNBCs were BRCA1/2 ‐associated and 27% were BRCA1/2 ‐negative. The expression levels of the analyzed genes showed no significant differences between these two subgroups indicating the BRCAness of the BRCA1/2 ‐negative hereditary TNBCs and thereby distinguishing a novel subset of TNBCs as a potential target for PARP inhibitors or platinum‐based therapy. The results show the significance of family history in selecting patients with TNBC for therapies directed at incompetent DNA repair ( e.g ., PARP inhibitors and/or platinum‐based therapies) and indicate that a relatively simple strategy for broadening the target group for these modes of treatment is to identify patients with hereditary TNBCs. Abstract : What's new? Triple‐negative breast cancers (TNBCs) that are positive for BRCA1/2 mutations display impairments in DNA repair via homologous recombination (HR), rendering the tumors sensitive to poly(ADPribose) polymerase (PARP) inhibitors and DNA cross‐linking drugs. Only a minority of TNBC patients, however, carry germline BRCA1/2 aberrations. In the present study, 27% of hereditary TNBCs examined were found to be BRCA1/2 ‐negative, yet showed no significant differences in the expression of HR‐related genes or other DNA damage repair genes when compared with BRCA1/2 ‐associated tumors. The BRCAness phenomenon distinguishes a subset of BRCA1/2 ‐negative hereditary TNBCs, which may be susceptible to PARP inhibitors and platinum‐based therapies.