1. Lung Cancer in Never-Smokers from the Princess Margaret Cancer Centre 1 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; 2 Laboratory Genetics, University Health Network, Toronto, ON, Canada; 3 Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada Grzegorz J. Korpanty 1, Suzanne Kamel-Reid 2, Ming-Sound Tsao 3, Alona Zer 1, Geoffrey Liu 1, Natasha Leighl 1, Ronald Feld 1, Melania Pintilie 1, Frances A. Shepherd 1 Results Methods Conclusions The study population consisted of 634 patients with histologically confirmed lung cancer of all TNM stages treated in Princess Margaret Hospital, Toronto from 1988 to 2014. Clinico-pathological and treatment data were extracted from the patients’ medical records. Variables included in the univariate analysis of overall survival (OS) included: age, sex, ethnicity, BMI, ECOG performance status, TNM stage at diagnosis, presence of mutations, targeted treatments and their duration, radiation therapy and participation in clinical trials. Lung cancer in never-smokers represents a distinct clinical and molecular entity characterized by a high incidence of targetable mutations and long survival. Tissue analysis for mutations Updated abstract Background: Lung cancer in never smokers accounts for ~15-20% of cases, and globally is a growing clinical problem. Methods: We identified 634 never-smokers with lung cancer diagnosed/treated at the Princess Margaret Cancer Centre from 1988-2014. Clinical and demographic data were retrieved from the patient record with the aim of characterizing the epidemiology, demographics, pathology, molecular profile, treatment, and survival in these patients. Results: There were 457 females (72%) and 177 males (28%), median age 62.1 years (18–94) with median follow-up of 31 months. Most patients were Caucasian (47%) followed by Asian (41%), Black (5%), South Asian (4%) and other (3%). Environmental tobacco exposure was identified in 17%. A history of prior, non-lung malignancy was present in 101 (16%) patients (1 malignancy – 89; multiple cancers – 12 patients). Most patients had adenocarcinoma (88%) and most presented in stage IV (57%), followed by I – 25%, III – 12% and II – 6. Among 397 patients with molecular results to date 280 had a mutation (71%), 267 (95%) had one mutation and 13 (5%) had multiple mutations. EGFR mutations were the most common single mutations (80%), followed by ALK (10%), KRAS (3%), HER2 (1%), BRAF (1%), other (2%) and multiple (3%). Median overall survival (mOS) was 48 months (mo) for the entire cohort, 75 mo for all patients with EGFR mutation positive tumours, not reached for all ALK fusion positive (3 year OS – 90%), 66 mo for patients with tumours harboring other mutations (p=0.32) and 27 mo for patients with tumours with unknown mutation status (p<0.0001). Early TNM stage (p<0.0001), adenocarcinoma histology (p=0.013), ECOG PS 0-1 (p<0.0001), presence of EGFR mutation (p=0.0048) and use of targeted therapy (p<0.0001) were associated with longer survival, but not Asian ethnicity (p=0.81), female sex (p=0.27) or number of treatment lines (p=0.39). Among 125 patients with tumours harboring EGFR mutation, 53 (42%) presented with brain metastases at diagnosis. There was no significant difference in mOS for patients with EGFR mutation positive tumours and brain metastases at presentation vs. those without CNS disease at presentation - 27 vs. 33 mo, respectively (p=0.42). Among patients with EGFR mutation positive tumours, there was no difference in mOS in patients with Exon 19 deletions (75 mo) vs. Exon 21 insertions (82 mo) (p=0.19) and in Asians (97 mo) vs. Caucasians (82 mo) (p=0.13). Stage IV patients with EGFR and ALK mutation positive tumours received targeted treatment in 93% (152/163) and 85% (23/27) cases, respectively. Conclusions Lung cancer in never-smokers represents a distinct clinical and molecular entity characterized by a high incidence of targetable mutations and long survival. CharacteristicN (%) Age – yrs Median Range 62.1 18-94 Sex Male Female 177 (28) 457 (72) Race Caucasian Asian Black South Asian Other 299 (47) 258 (40) 34 (6) 24 (4) 19 (3) ECOG 0-1 2-3 423 (90) 47 (10) Second-hand smoke 109 (17) Previous non-lung cancers All One prior Multiple prior 101 (16) 89 (88) 12 (12) TNM stage at diagnosis 12341234 155 (25) 39 (6) 77 (12) 363 (57) Histopathology Adenocarcinoma Squamous Cell Large Cell Adenosquamous Small Cell Other (NSCLC, Mixed tumour, Carcinoid, Lymphoepithelioma) 553 (88) 29 (4) 15 (2.2) 11 (2) 5 (0.8) 21 (3) TTF-1 IHC positive (N=410)367 (89) Number of mutations (N=279) 0 1 2 3 Driver mutations (EGFR, ALK, BRAF, HER-2) 27 (9) 267 (87) 10 (3) 2 (1) 266 (87) Lines of systemic therapy (N=391) 1 2 3 +3 151 (39) 98 (25) 77 (20) 65 (16) Targeted treatment EGFR mutation positive (N=163) ALK fusion positive (N=27) 152 (95) 23 (85) Brain metastases at diagnosis (N=77) EGFR mutation positive EGFR WT ALK fusion positive Other Unknown 53 (68) 14 (18) 6 (8) 2 (3) Patients characteristics Results – mutations Mutation rate (280/397 = 71%) CovariateLevelsN 3 year survival (%) Logrank p-value 1.Sex Female 45758 0.27 Male 17752 2. Age ≤65 36755 0.4 >65 26758 3.BMI* ≤18.5 42 0.017 18.5-24.9 30155 >25 23659 4.ECOG 0 and 1 42349 <0.0001 2 and 3 4710 5.TNM stage at diagnosis 1 and 2 19493 <0.0001 3 7770 4 36330 6. Histology Adenocarcinoma 55358 0.013 Other 8143 7.Mutation status No mutation # 11754 0.00069 Any mutation 28074 8.EGFR Mutation positive 22972 0.0048 Wild type 11754 9.ALK Mutation positive 3190 0.12 Wild type 9567 10.Ethnicity Caucasian 29958 0.39 Asian 25858 Other 7747 11. Ethnicity/EGFR mutation positive Caucasian 8480 0.097 Asian 11969 Other 2659 12. Targeted treatment No 29334 <0.0001 Yes 17761 13.Treatment lines 0-2 30942 0.39 3-8 14250 14.Clinical trial No 33643 0.78 Yes 13445 15.Brain metastases at diagnosis No 28828 0.068 Yes 7746 16. Brain metastases at diagnosis and during follow-up No 38041 0.049 Yes 90 55 Univariate survival analysis Full cohort: OS by TNM stage OS by mutation OS in EGFR-mutant cohort by mutation type* OS in EGFR-mutant cohort by TNM stage EGFR + other mutations = 5 ALK + other mutations = 2 KRAS + other mutation = 1 * Because of low likelihood of multiple mutations, no further testing was performed when EGFR or ALK mutation was detected All patients N=634 Tissue available for molecular testing N=437 (69%) EGFR ONLY status* N=27 (6%) EGFR and ALK ONLY status* N=215 (49%) Multiple gene testing N=195 (45%) Sequenom N=120 (62%) Mi-Seq** N=75 (38%) No tissue available for molecular testing N=197 (31%) * - Data are missing for 55 patients # - No mutations detected using Sequenom/MiSeq methods (27 pts) and EGFR/ALK WT (90 pts) Stage 1,2 N=194 Median OS = Not reached Stage 3 N=77 Median OS = 65 months Stage 4 N=363 Median OS = 22 months Overall N=634 Median OS = 48 months Log-rank p<0.0001 EGFR N=229 Median OS = 75 months ALK N=31 Median OS = Not reached Other N=20 Median OS = 66 months Log-rank p=0.32 Stage 1,2 N=80 Median OS = Not reached Stage 3 N=24 Median OS = 116 months Stage 4 (No CNS mets at diagnosis) N=72 Median OS = 31 months Stage 4 (CNS mets at diagnosis) N=53 Median OS = 27 months Log-rank p<0.0001 Exon 19 del N=141 Median OS = 75 months Exon 21 ins N=87 Median OS = 87 months HR=1.4, 95% CI: 0.85 – 2.23 Log-rank p=0.19 * 1 patient with EGFR Exon 20 insertion excluded from analysis Log-rank p=0.097 Asian N=119 Median OS = 97 months Caucasian N=84 Median OS = 82 months Other N=26 Median OS = 40 months Overall survival Time to death (months) Overall survival Time to death (months) Overall survival Time to death (months) OS in EGFR-mutant cohort by mutation type and ethnicity OS in EGFR-mutant cohort by ethnicity Asian; Exon 19 del N=71 Median OS = Not reached Non-Asian; Exon 19 del N=70 Median OS = 75 months Asian; Exon 21 ins N=48 Median OS = 56 months Non-Asian; Exon 21 ins N=39 Median OS = 82 months Log-rank p=0.28 * 1 patient with EGFR Exon 20 insertion excluded from analysis Overall survival Time to death (months) ** Results are pending for 64 samples