Impact of Smoking and Brain Metastasis on Outcomes of Advanced <i>EGFR</i> Mutation Lung Adenocarcinoma Patients Treated with First Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

<div><p>Objectives</p><p>This purpose of this study was to examine clinical-pathologic factors – particularly smoking and brain metastases – in <i>EGFR</i> mutation positive (M+) lung adenocarcinoma (ADC) to determine their impact on survival in patients treated with first line EGFR TKI.</p><p>Methods</p><p>A retrospective review of <i>EGFR</i> mutation reflex testing experience for all ADC diagnosed at a tertiary Asian cancer centre from January 2009 to April 2013. Amongst this cohort, patients with advanced <i>EGFR</i> M+ ADC treated with first line EGFR TKI were identified to determine factors that influence progression free and overall survival.</p><p>Results</p><p>444/742 (59.8%) ADC reflex tested for <i>EGFR</i> mutations were <i>EGFR</i> M+. Amongst never-smokers (n=468), <i>EGFR</i> M+ were found in 74.5% of females and 76.3% of males, and amongst ever smokers (n=283), in 53.3% of females and 35.6% of males. Exon 20 mutations were found more commonly amongst heavy smokers (> 50 pack years and > 20 pack years, Pearson’s chi square p=0.044, and p=0.038 respectively). 211 patients treated with palliative first line TKI had a median PFS and OS of 9.2 and 19.6 months respectively. 26% of patients had brain metastasis at diagnosis. This was significantly detrimental to overall survival (HR 1.85, CI 1.09-3.16, p=0.024) on multivariate analysis. There was no evidence that smoking status had a significant impact on survival.</p><p>Conclusions</p><p>The high prevalence of <i>EGFR</i> M+ in our patient population warrants reflex testing regardless of gender and smoking status. Smoking status and dosage did not impact progression free or overall survival in patients treated with first line EGFR TKI. The presence of brain metastasis at diagnosis negatively impacts overall survival.</p></div

Kaplan-Meier plots of cohort of 211 patients treated with 1^st line EGFR TKI; (a) PFS by brain metastasis in ECOG 0–1 patients, (b) PFS by brain metastasis in ECOG 2–4 patients, (c) OS by brain metastasis in ECOG 0–1 patients, and (d) OS by brain metastasis in ECOG 2–4 patients.

<p>Kaplan-Meier plots of cohort of 211 patients treated with 1^st line EGFR TKI; (a) PFS by brain metastasis in ECOG 0–1 patients, (b) PFS by brain metastasis in ECOG 2–4 patients, (c) OS by brain metastasis in ECOG 0–1 patients, and (d) OS by brain metastasis in ECOG 2–4 patients.</p

Sites of EGFR mutations amongst 461 patients.

<p>Sites of EGFR mutations amongst 461 patients.</p

Univariate analysis of progression free survival and overall survival.

<p>Univariate analysis of progression free survival and overall survival.</p

Clinical characteristics and <i>EGFR</i> mutation status rates categorised by smoking status and sex.

<p>11 patients with unknown smoking status, and 6 who had samples indeterminate for <i>EGFR</i> mutational status were excluded. 464/762 (60.9%) tested positive for <i>EGFR</i> mutations (<i>EGFR</i> M+). The number of patients needed to test in order to pick up 1 <i>EGFR</i> mutant lung adenocarcinoma in any sub-population stratified by sex and smoking status, was less than 3 patients (male ES; 1/0.357 = 2.8).</p

Multivariate analysis of progression free survival and overall survival.

<p>Multivariate analysis of progression free survival and overall survival.</p

Multivariate analysis of progression free survival and overall survival in female never-smokers aged ≤ 65 with ECOG PS 0–1 at diagnosis.

<p>Multivariate analysis of progression free survival and overall survival in female never-smokers aged ≤ 65 with ECOG PS 0–1 at diagnosis.</p

<i>EGFR</i> mutation rates amongst ever smokers classified by pack years.

<p><i>EGFR</i> mutation rates amongst ever smokers classified by pack years.</p

Hazards for survival from univariate analysis of populations with smoking characteristics as indicated across 3 studies do not show any significant differences in survival outcomes, while those from a more recent Korean study show that smoking has a significant impact, especially smoking dosage greater than 30 pack years.

<p>Hazards for survival from univariate analysis of populations with smoking characteristics as indicated across 3 studies do not show any significant differences in survival outcomes, while those from a more recent Korean study show that smoking has a significant impact, especially smoking dosage greater than 30 pack years.</p

Demographics of 211 patients treated with 1^st line TKI.

<p>Demographics of 211 patients treated with 1^st line TKI.</p