Outcome to erlotinib in non-small cell lung cancer (NSCLC) patients (p) according to the presence of the EGFR T790M mutation and BRCA1 mRNA expression levels in pretreatment biopsies.

Abstract

7514 Background: The initial pr esence of double EGFR mutations (L858R or exon 19 deletion plus T790M) has been detected in the absence of drug selection and could explain the selection of the T790M mutation as the single drug-resistance mutation during therapy with gefitinib or erlotinib. Experimental evidence shows that the disruption of BRCA1 enhances erlotinib-mediated cytotoxicity. Methods: Pretreatment biopsi es from129 erlotinib-treated NSCLC p with EGFR mutations were re- examined for the presence of the T790M mutation using laser microdissection followed by TaqMan assay in the pr esence of a peptide-nucleic acid clamp. BRCA1 mRNA expression was examined by quantitative PCR. Results: Double mutations were found in 45 p (35%), with no differences between p with and those without T790M in characteristics or initial r esponse to erlotinib (63.6% vs 72.3%, respectively). Median progression-free survival (PFS) was 12 months (m) in p with T790M and 18 m in p without T790M (p = 0.05). PFS was 27 m in p with low BRCA1, 18 m in p with intermediate BRCA1 and 10 m in p with high BRCA1. PFS was also 27 m for p with T790M and low BRCA1, while it dropped to 3 m for p with T790M and intermediate or high BRCA1. The multivariate analysis showed an association between poor PFS and T790M (HR, 3.96; p = 0.001), male sex (HR, 3.18; p = 0.01), brain metastases (HR, 4.55; p = 0.006), intermediate BRCA1 (HR, 4.36; p = 0.008), and high BRCA1 (HR, 5.81; p = 0.001). Conclusions: The high frequency of pretreatment double mutations concurs with a previous report (Mah eswaran et al. NEJM 2008). The strong influence of T790M and BRCA1 levels on erlotinib outcome can lead to novel personalized treatment strategies. No significant financial relationships to disclose.