MCPH1 (BRIT1) and outcome to erlotinib in non-small cell lung cancer (NSCLC) patients (p) harboring EGFR mutations.

Abstract

e18131 Background: Progression-free survival (PFS) in EGFR-mutant NSCLC p treated with erlotinib can range from a few months (m) to more than two years, but genetic influences on the duration of response remain unclear. The cytotoxic effect of erlotinib has been related to several proteins that regulate DNA damage response (eg, BRCA1, BRCA2). MCPH1 contains 3 BRCT domains which are conserved in important molecules involved in DNA damage signaling, including BRCA1, MDC1 and 53BP1. MCPH1 binds to BRCA2 and regulates the localization of BRCA2 and Rad51 at sites of DNA damage. MCPH1 also regulates the ATP-dependent SWI-SNF chromatin remodeling complex during DNA repair. Methods: We used the NanoString nCounter gene expression system, which captures and counts individual mRNA transcripts, to analyze the expression of 44 selected genes, many of which are involved in DNA damage response, in 55 erlotinib-treated NSCLC p. We identified MCPH1 and correlated expression levels with clinical outcomes. Results: p characteristics: 16 males, 39 females (70.9%); 39 never-smokers (70.9%), 12 former smokers, 4 current smokers; 34 with EGFR deletion in exon 19 (61.8%), 21 with L858R mutation (38.2%). PFS was not reached for patients with high MCPH1, while it was 19 m for those with intermediate levels and 9 m for those with low levels (P=0.01). Median survival was 31 m for p with high levels, not reached for p with intermediate levels and 17 m for p with low levels (P=0.004). Conclusions: The enhanced effect of erlotinib in the presence of elevated MCPH1 could be due to the fact that MCPH1 can interfere with the function of MDC1 and 53BP1. The role of MCPH1 merits validation as a predictive marker of erlotinib response.