Abstract
Platinum-based chemotherapy is the standard first-line treatment for non-oncogene- addicted non-small cell lung cancers (NSCLCs) and the analysis of multiple DNA repair genes could improve current models for predicting chemosensitivity. We investigated the potential predictive role of components of the 53BP1 pathway in conjunction with BRCA1. The mRNA expression of BRCA1, MDC1, CASPASE3, UBC13, RNF8, 53BP1, PIAS4, UBC9 and MMSET was analyzed by real-time PCR in 115 advanced NSCLC patients treated with first-line platinum-based chemotherapy. Patients expressing low levels of both BRCA1 and 53BP1 obtained a median progression-free survival of 10.3 months and overall survival of 19.3 months, while among those with low BRCA1 and high 53BP1 progression-free survival was 5.9 months (P less than 0.0001) and overall survival was 8.2 months (P=0.001). The expression of 53BP1 refines BRCA1-based predictive modeling to identify patients most likely to benefit from platinum-based chemotherapy.
Highlights
The standard first-line treatment of advanced nonsmall-cell lung cancer (NSCLC) in patients with wild-type epidermal growth factor receptor (EGFR) is platinumbased chemotherapy
The retrospective analysis of patients enrolled in the trial showed that mRNA expression levels of receptor associated protein 80 (RAP80), which is involved in the recruitment of BRCA1 to DNA damage sites, was able to refine the BRCA1-based predictive model in patients expressing low levels of BRCA1 treated with platinumbased chemotherapy [16]
While preclinical findings and retrospective studies have indicated that BRCA1 is a differential modulator of outcome to taxane- and platinum-based chemotherapy [7, 8, 10, 11, 31], to date no results are available to support the routine clinical use of BRCA1 expression as a predictive marker
Summary
The standard first-line treatment of advanced nonsmall-cell lung cancer (NSCLC) in patients with wild-type epidermal growth factor receptor (EGFR) is platinumbased chemotherapy. BRCA1 is a main component of DNA doublestrand break repair through the error-free mechanism of homologous recombination [4]. The pivotal role of BRCA1 in double-strand break repair may be modulated by interaction with other components of homologous recombination [5]. The results of a prospective phase II trial demonstrated the feasibility of assessing BRCA1 mRNA expression by real-time PCR in the clinical setting, and additional retrospective analyses indicated that other DNA repair components could modulate the BRCA1 predictive model. The retrospective analysis of patients enrolled in the trial showed that mRNA expression levels of receptor associated protein 80 (RAP80), which is involved in the recruitment of BRCA1 to DNA damage sites, was able to refine the BRCA1-based predictive model in patients expressing low levels of BRCA1 treated with platinumbased chemotherapy [16]
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