Customized treatment in non-small-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression

Abstract

Background: Median 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 findings: We 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/significance: Chemotherapy 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 registration: (ClinicalTrials.gov) NCT00883480.

Figure 1. Consolidated Standards of Reporting Trials diagram showing flow of patients through study.

Between March 2005 and July 2007, a total of 123 patients from 25 centers were enrolled in the study. Reasons for patient withdrawal: 3 patients had no tumor cells in the biopsy; 5 patients had less than 50 tumor cells in the biopsy, making it impossible to assure correct results; 19 patients were wild-type EGFR but with insufficient tumor sample after EGFR assessment for BRCA1 expression analysis; 2 patients refused to participate; and 6 patients were withdrawn by their physician due to clinical factors unrelated to the study. The two patients in the EGFR group who were not evaluable for response died within a month of entering the study; the 13 patients in the BRCA1 who were not evaluable for response received >3 cycles of treatment.

Figure 2. Median survival according to treatment group.

Median survival was not reached for 12 patients in the EGFR group, 11 months for 38 patients in the low BRCA1 group, 9 months for 40 patients in the intermediate BRCA1 group, and 11 months for 33 patients in the high BRCA1 group (P = 0.01) (see Table 2).

Figure 3. Median survival for patients with low BRCA1 levels, treated with cisplatin plus gemcitabine, according to RAP 80 mRNA expression.

Median survival was not reached for 11 patients with low RAP 80 levels, 8 months for 9 patients with intermediate RAP 80 levels, and 7 months for 5 patients with high RAP 80 levels (P = 0.006).