Customized Treatment in Non-Small-Cell Lung Cancer Based on EGFR Mutations and BRCA1 mRNA Expression

Abstract

BackgroundMedian survival is 10 months and 2-year survival is 20% in metastatic non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. A small fraction of non-squamous cell lung cancers harbor EGFR mutations, with improved outcome to gefitinib and erlotinib. Experimental evidence suggests that BRCA1 overexpression enhances sensitivity to docetaxel and resistance to cisplatin. RAP80 and Abraxas are interacting proteins that form complexes with BRCA1 and could modulate the effect of BRCA1. In order to further examine the effect of EGFR mutations and BRCA1 mRNA levels on outcome in advanced NSCLC, we performed a prospective non-randomized phase II clinical trial, testing the hypothesis that customized therapy would confer improved outcome over non-customized therapy. In an exploratory analysis, we also examined the effect of RAP80 and Abraxas mRNA levels.Methodology/Principal FindingsWe treated 123 metastatic non-squamous cell lung carcinoma patients using a customized approach. RNA and DNA were isolated from microdissected specimens from paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those without EGFR mutations received chemotherapy with or without cisplatin based on their BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus docetaxel; high, docetaxel alone. An exploratory analysis examined RAP80 and Abraxas expression. Median survival exceeded 28 months for 12 patients with EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. Median survival was influenced by RAP80 expression in the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, median survival exceeded 26 months. RAP80 was a significant factor for survival in patients treated according to BRCA1 levels (hazard ratio, 1.3 [95% CI, 1–1.7]; P = 0.05).Conclusions/SignificanceChemotherapy customized according to BRCA1 expression levels is associated with excellent median and 2-year survival for some subsets of NSCLC patients , and RAP80 could play a crucial modulating effect on this model of customized chemotherapy.Trial RegistrationClinicalTrials.gov NCT00883480

Methylation of breast cancer susceptibility gene 1 (BRCA1) predicts recurrence in patients with curatively resected stage I non–small cell lung cancer

“…A growing body of evidence indicates that BRCA1 plays a central role in DNA repair and in cell cycle control. 31,32 A lack of functional BRCA1 leads to increased sensitivity of tumor cells to molecular damage, suggesting that BRCA1 could be used as a predictive molecular marker to identify patients who would benefit from specific anticancer therapies. According to the results of several investigations, BRCA1 confers sensitivity to apoptosis induced by antimicrotubule drugs (eg, paclitaxel and vincristine), but induces resistance to DNA-damaging agents (eg, cisplatin and etoposide) and radiotherapy.…”

Association of EGFR mutations with low BRCA1 gene expression in non-small cell lung cancer

“…EGFR and DNA repair pathways have been linked in preclinical studies, possibly through BRCA1, with implications for platinum-based therapy (22)(23)(24). A multi-center trial has shown that EGFR mutation was highly associated with a low mRNA expression level of ERCC1 in NSCLC (6).…”

How close are we to customizing chemotherapy in early non-small cell lung cancer?

“…In addition to a close correlation with BRCA1, RAP-80 expression was identified as an independent predictor for OS. Although, qualitatively, the two biomarkers share the same predictive value for differential tumor sensitivity to taxane-and platinum-based chemotherapy, it was shown that RAP-80 can modulate the effect of BRCA1 [Rosell et al 2009]. There are no data for this interaction in the early-stage setting.…”