Abstract 1052P
Background
Comprehensive molecular profiling to identify genomic driver mutations is inconsistently performed for squamous (sq) non-small cell lung cancer (NSCLC). Thorough profiling of this, by smoking status, will help guide diagnostic and therapeutic decision-making.
Methods
Analyses included advanced sq-NSCLC tumors molecularly profiled by next-generation sequencing (NGS) using a 592 gene panel (NextSeq) with paired whole-exome and whole-transcriptome sequencing (NovaSeq). Smoking status was obtained from medical records. Genomic alterations and tumor mutation burden (TMB) were compared by smoking status. Gene set enrichment analyses (GSEA) were also assessed. Fisher’s exact, Chi-square, and Mann-Whitney U tests were used, where appropriate, to assess statistical significance. Significance = p < 0.05/q < 0.05 for all comparisons except GSEA, where significance = p<0.05/FDR < 0.25.
Results
2413 sq-NSCLC tumors with reported smoking status were assessed, of which 2347 (97.3%) and 66 (2.7%) were from ever- and never-smokers, respectively. A significantly higher median TMB (8.0 vs 5.0 mut/Mb) was seen in ever- vs never-smokers. Actionable mutations were detected in both groups as detailed in the table. A significantly higher prevalence of TP53 alterations was seen in ever-smokers (90.9% vs 61.4%), while never-smokers had a significantly higher prevalence of METex14 alterations (18.8% vs 0.3%) with a trend toward higher prevalence of actionable EGFR mutations (6.9% vs 0.6%; p<0.05, q = 0.052). GSEA identified significantly enriched expression of JAK-STAT signaling in never-smokers, with trend toward enriched interferon-gamma and interferon-alpha signaling in never-smokers (FDR 0.27). Table: 1052P
| Molecular Alteration | Never-smokers % (n) | Ever-smokers % (n) |
| METex14 | 18.8 (3) | 0.3 (4) |
| EGFR exon19del/L858R | 6.9 (4) | 0.6 (13) |
| BRAF V600E | 3.5 (2) | 0.2 (4) |
| ALK fusion | 3.2 (1) | 0.1 (1) |
| KRAS G12C | 0 (0) | 1.8 (39) |
| HER2 | 0 (0) | 0.2 (4) |
| NTRK fusion | 0 (0) | 0.08 (1) |
| NRG1 fusion | 0 (0) | 0.08 (1) |
Conclusions
Differences in the molecular and immunologic composition of sq-NSCLC by smoking status were observed, though clinically actionable mutations were seen in both groups. Relevant information can be gleaned from NGS to guide decision-making in sq-NSCLC regardless of smoking status.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
J. Reuss: Financial Interests, Personal, Advisory Board: Genentech/Roche, Sanofi/Genzyme, Personalis; Financial Interests, Institutional, Research Grant: Genentech/Roche, Verastem; Financial Interests, Personal, Invited Speaker: AstraZeneca. N. Gandhi: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences. P. Walker: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences. B. Halmos: Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Advaxis, Amgen, AbbVie, Daiichi Sankyo, Pfizer, GlaxoSmithKline, BeiGene, Janssen; Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, Veracyte, Janssen, Takeda, Merck, Bristol-Myers Squibb, Genentech, Pfizer, Eli-Lilly. C. Aggarwal: Financial Interests, Personal, Advisory Role: Genentech, Lilly, Celgene, Merck, AstraZeneca, Blueprint Genetics, Shionogi, Daiichi Sankyo, Regeneron/Sanofi, Eisai, BeiGene, Turning Point Therapeutics, Pfizer, Janssen, Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Genentech/Roche, Incyte, Macrogenics, Merck, AstraZeneca. J. Xiu: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences. S.P. Patel: Financial Interests, Personal, Advisory Role: Amgen, AstraZeneca, Bristol-Myers Squibb, Certis, Eli Lilly, Genentech, Illumina, Merck, Pfizer, Rakuten, Tempus; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Fate Therapeutics, Iovance, Merck, Pfizer, Genentech, SQZ Biotechnologies. A. VanderWalde: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences; Financial Interests, Personal, Advisory Role: West Clinic, George Clinic, Genentech, Mirati. S.S. Ramalingam: Financial Interests, Institutional, Other, Consultant: Amgen, BMS, Merck, AstraZeneca, Takeda, Eisai, Daiichi Sankyo, GSK; Financial Interests, Personal, Other, Editor in Chief, CANCER journal: American Cancer Society; Financial Interests, Research Grant: Merck, AstraZeneca, Advaxis, BMS, Amgen, Takeda, Genmab, GSK. S.V. Liu: Financial Interests, Personal, Advisory Role: Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Lilly, Merck, Novartis, Regeneron, Sanofi, Takeda, Turning Point Therapeutics; Financial Interests, Institutional, Research Grant: Alkermes, Bayer, Blueprint, Bristol-Myers Squibb, Elevation Oncology, Genentech/Roche, Gilead, Merck, Merus, Nuvalent, Pfizer, Rain Therapeutics, RAPT, Turning Point Therapeutics.