Clinical impact of EGFR mutation fraction and tumor cellularity in EGFR mutation positive NSCLC.

Abstract

e19077 Background: We investigated the impact of mutation fraction, tumour sample cellularity, and diagnostic specimen type on EGFR TKI response, time to treatment failure (TTF) and overall survival in advanced EGFR mutation positive NSCLC patients. Methods: From March 2010 to May 2012, EGFR testing in the province of Ontario (Canada) was conducted at a single centre, using fragment analysis for exon 19 deletion and Sau961 restriction enzyme digest for exon 21 mutation. Patients with EGFR mutation positive samples were identified, tumour cellularity, mutation fraction (percent tumour cells mutated) and clinical outcome data collected. Regression analysis was undertaken to assess the association between demographic variables, mutation fraction, tumour cellularity and sample type on clinical outcomes. Results: Of 173 patients identified to date, 153 received EGFR TKI and are included in this analysis, with median follow up of 10.6 months (range 0-44). Most are female (73%), never smokers (65%), have exon 19 deletions (55%; 45% exon21 L858R), and median age 64 years (range 34 to 95). Tumour specimens tested include resection (36%), cytology (32%), and core biopsy samples (32%). Median EGFR mutation fraction is 30% (range 1% to 96%); 18% had a low (<10%) mutation fraction. Responses (any reduction) were seen in 66%, mixed response or stable disease in 28%, and progression in 7%. Median TTF of EGFR TKI therapy is 13.8 months. Median OS from TKI start is 24.1 months, with 1-, 2- and 3-year rates of 75%, 51% and 42%. In multivariable analysis, increasing mutation fraction was associated with EGFR TKI response (OR 2.5, p<0.01), but not TTF or OS. Female sex was associated with TTF (HR 0.49, p=0.007), and testing of larger samples (lobectomy, wedge, excision) was associated with TTF and OS (HR 0.45, p=0.007; HR 0.26, p=0.0002). Exon 19 deletions are associated with a higher risk of death (HR 2.41, p=0.02) and a lower probability of response than L858R (OR 0.31, p=0.004). Conclusions: Pathologic features may be relevant to clinical outcomes in EGFR mutation positive NSCLC, including mutation fraction, sample cellularity, specimen tested and mutation type. Validation of the use of EGFR mutation fraction in clinical decision-making is ongoing.