Abstract
BackgroundBRCA1 is a main component of homologous recombination and induces resistance to platinum in preclinical models. It has been studied as a potential predictive marker in lung cancer. Several proteins modulate the function of BRCA1. The E3 ubiquitin ligase HERC2 facilitates the assembly of the RNF8-UBC13 complex to recruit BRCA1 to DNA damage sites. The combined analysis of multiple components of the pathway leading to the recruitment of BRCA1 at DNA damage sites has the potentiality to improve the BRCA1 predictive model.MethodsWe retrospectively analyzed 71 paraffin-embedded tumor samples from advanced non-small-cell lung cancer patients treated with first-line platinum based chemotherapy and measured the mRNA expression levels of BRCA1, RNF8, UBC13 and HERC2 using real-time PCR. The mRNA expression was categorized using median value as cut-off point.ResultsThe median progression-free survival of all 71 patients was 7.2 months whereas the median overall survival of the study population was 10.7 months. Among patients with low BRCA1 expression, the median PFS was 7.4 months in the presence of low HERC2 levels and 5.9 months for patients expressing high HERC2 levels (p = 0.01). The median OS was 15.3 months for patients expressing low levels of both genes and 7.4 months for those with low BRCA1 but high HERC2 (p = 0.008). The multivariate analysis showed that among patients with Eastern Cooperative Oncology Group performance status 0–1, the combined low expression of both BRCA1 and HERC2 clearly reduced the risk of progression (p = 0.03) and of death (p = 0.004).ConclusionsThese findings confirm the potentiality of integrated DNA repair components analysis in predicting the sensitivity to platinum in lung cancer. The study indicates a predictive role for HERC2 mRNA expression and paves the way for further refinement of the BRCA1 predictive model.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2339-5) contains supplementary material, which is available to authorized users.
Highlights
Breast cancer susceptibility gene 1 (BRCA1) is a main component of homologous recombination and induces resistance to platinum in preclinical models
Low mRNA expression of BRCA1 was associated with longer survival in non-smallcell lung cancer (NSCLC) patients treated with cisplatin-based neoadjuvant chemotherapy [7], while the clinical feasibility of prospectively assessing BRCA1 mRNA expression was later demonstrated in a prospective phase II trial in advanced NSCLC patients [8]
Despite these encouraging preliminary results, a phase III randomized trial (NCT00617656/ GECP-BREC) comparing non-biomarker-directed therapy with treatment based on the mRNA expression levels of BRCA1 and receptor-associated protein 80 (RAP80) was recently closed prematurely, since the interim analysis showed a detrimental effect in terms of progression free survival (PFS) in patients allocated to the experimental arm [9, 10]
Summary
BRCA1 is a main component of homologous recombination and induces resistance to platinum in preclinical models. Low mRNA expression of BRCA1 was associated with longer survival in NSCLC patients treated with cisplatin-based neoadjuvant chemotherapy [7], while the clinical feasibility of prospectively assessing BRCA1 mRNA expression was later demonstrated in a prospective phase II trial in advanced NSCLC patients [8] Despite these encouraging preliminary results, a phase III randomized trial (NCT00617656/ GECP-BREC) comparing non-biomarker-directed therapy with treatment based on the mRNA expression levels of BRCA1 and receptor-associated protein 80 (RAP80) was recently closed prematurely, since the interim analysis showed a detrimental effect in terms of progression free survival (PFS) in patients allocated to the experimental arm (hazard ratio [HR], 1.35; p = 0.03) [9, 10]. Retrospective analyses had demonstrated that RAP80 mRNA expression could affect the predictive capacity of BRCA1 [8, 12]
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