The Prognostic Value of BRCA1 mRNA Expression Levels Following Neoadjuvant Chemotherapy in Breast Cancer

Abstract

BackgroundA fraction of sporadic breast cancers has low BRCA1 expression. BRCA1 mutation carriers are more likely to achieve a pathological complete response with DNA-damage-based chemotherapy compared to non-mutation carriers. Furthermore, sporadic ovarian cancer patients with low levels of BRCA1 mRNA have longer survival following platinum-based chemotherapy than patients with high levels of BRCA1 mRNA.Methodology/Principal FindingsTumor biopsies were obtained from 86 breast cancer patients who were candidates for neoadjuvant chemotherapy, treated with four cycles of neoadjuvant fluorouracil, epirubicin and cyclophosphamide. Estrogen receptor (ER), progesterone receptor (PR), HER2, cytokeratin 5/6 and vimentin were examined by tissue microarray. HER2 were also assessed by chromogenic in situ hybridization, and BRCA1 mRNA was analyzed in a subset of 41 patients for whom sufficient tumor tissue was available by real-time quantitative PCR. Median time to progression was 42 months and overall survival was 55 months. In the multivariate analysis for time to progression and overall survival for 41 patients in whom BRCA1 could be assessed, low levels of BRCA1 mRNA, positive PR and negative lymph node involvement predicted a significantly lower risk of relapse, low levels of BRCA1 mRNA and positive PR were the only variables associated with significantly longer survival.Conclusions/SignificanceWe provide evidence for a major role for BRCA1 mRNA expression as a marker of time to progression and overall survival in sporadic breast cancers treated with anthracycline-based chemotherapy. These findings can be useful for customizing chemotherapy.

Pretreatment EGFR T790M Mutation and BRCA1 mRNA Expression in Erlotinib-Treated Advanced Non–Small-Cell Lung Cancer Patients with EGFR Mutations

“…(19) Moreover, decreased BRCA1 resulted in increased sensitivity to the DNA crosslinking agents mitomycin C and cisplatin but not to the antimicrotubule paclitaxel. (20) Experimental (21,22) and clinical (22,23) studies, including our own experience, (23)(24)(25) have also indicated a differential effect of BRCA1 expression on chemotherapy. In a phase II study of customized chemotherapy based on BRCA1 mRNA levels, the expression of the receptor-associated protein 80 (RAP80), a ubiquitin-binding protein that interacts with BRCA1, strongly modulated the effect of BRCA1, (26) confirming preclinical evidence (27) that RAP80 is essential for the BRCA1 repair function in an H2AX-dependent manner (Fig.…”

“…In an ancillary analysis, we examined the protein expression of 2 additional genes. Based on our previous experience, (24)(25)(26) in addition to analyzing gene expression as a continuous variable, expression levels were divided into terciles to explore the risk trend of the gene variable and to easily identify groups of gene expression with different risk. Progression-free survival was calculated from the initiation of erlotinib therapy until either tumor progression or death.…”

Genomic instability in breast and ovarian cancers: translation into clinical predictive biomarkers

“…The ultimate goal of treatment remains long-term survival as this is the most objective read-out Although pCR after neoadjuvant therapy has been related to long-term survival, the survival of partial responders cannot be predicted RCT randomized controlled trial, pCR pathological complete remission, RFS recurrence-free survival, DFS disease-free survival, PFS progression-free survival, OS overall-survival (i.e., high levels better clinical response [154] and low levels prolonged survival [155]). However, both studies used different read-outs (clinical response vs. survival), used an arbitrary cut-off for low versus high expression [154], and consisted of small subgroups (highest n = 17).…”

Gene Expression Signature–Based Prognostic Risk Score in Patients with Primary Central Nervous System Lymphoma

“…In addition, a role of BRCA1 in the cellular response to chemotherapy has been discussed (31,32). The expression levels of BRCA1 mRNA or protein predicted survival after chemotherapy for patients with sporadic ovarian (33), breast (34,35), prostate (36), and non-small cell lung cancer (37)(38)(39)(40). Low levels of BRCA1 expression resulted in increased sensitivity to platinum therapy and decreased sensitivity to taxane therapy (33,35,(37)(38)(39)(40).…”