4111 - Comparison of molecular profiles between primary tumour and matched metastasis in non-small cell lung cancer

Background

Molecular heterogeneity drives tumour evolution and resistance to therapies. Because of biopsy challenges in non-small cell lung cancer (NSCLC), few studies compared the molecular profile between primary tumour (PT) and metastasis (Met). Here, we compare somatic single-nucleotide variants (SNVs), tumour mutational burden (TMB) and expression profiles between PT and matched metachronous Met in NSCLC patients (pts).

Methods

DNA and RNA were extracted from 14 matched fresh-frozen samples and PBMCs from 7 pts treated at the Institut d’Oncologie Thoracique (Gustave Roussy, GR) between 2011 and 2015. GATK4 Mutect2 were used for SNV calling and TMB on whole exome sequencing. Salmon was used for expression counts from RNAseq; Z-scores were computed by comparing data to 158 other NSCLC RNAseq from GR molecular profiling trials; GSVA R package was use to assess single sample gene set enrichment score (ssGSEA).

Results

Median age was 67 yo (62-78); 4/7 metastases were biopsied after chemotherapy; histology was adenocarcinoma (6) or large cell carcinoma (1). The median number of SNVs unique to PT or Met was 50 (10-143) or 79 (36-324), respectively; it was 65 (0-110) for shared SNVs; 6/7 pts had known driver alterations (TP53, KRAS, PIK3CA) in both lesions; one Met acquired a pathogenic KRAS G35C mutation. Median TMB was 3.9 (0.3-4.3) in PT and 4.1 (2.2-8.4) in Met. Genes with top negative Z-scores (MRFAP1, EP400, RIOX1, DDX27) were shared between PT and Met in 6/7 pts; genes with top positive Z-score were unique. ssGSEA-enriched genesets were shared between PT and Met; top enriched hallmarks included Myc targets, Mitotic Spindle, DNA repair, oxidative phosphorylation and TGFb signaling.

Conclusions

Matched comparison of molecular profiles between PT and Met evidence shared and unique alterations; this informs on tumor evolution and may help guiding treatment choice.

Clinical trial identification

Editorial acknowledgement

AK: AK was funded by the DUERTECC Gustave Roussy program

LCD: LCD was funded by the INSERM ATIP-Avenir grant from SPV

Legal entity responsible for the study

Sophie Postel-Vinay.

Funding

Cancéropole d’Ile de France.

Disclosure

A Kawachi: Funded by the DUERTECC Gustave Roussy program. L. Colmet-Daage: Funded by the INSERM ATIP-Avenir grant from SPV. L. Verlingue: Honoraria (self): Adaptherapy; Research grant / Funding (self): Bristol-Myers Squibb. D. Planchard: Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Celgene; Honoraria (self): Eli Lilly; Honoraria (self): Merck; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): prIME Oncology; Honoraria (self): Peer CME; Honoraria (self): Roche; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Boehringer Ingelheim ; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: prIME Oncology; Travel / Accommodation / Expenses: Pfizer. A. Hollebecque: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi. C. Massard: Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): BMS; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Janssen Cilag; Research grant / Funding (self): Merck, Novartis; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Roche; Research grant / Funding (self): Sanofi; Advisory / Consultancy: Amgen; Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BeiGene; Advisory / Consultancy: BMS; Advisory / Consultancy: Celgene; Advisory / Consultancy: Debiopharm; Advisory / Consultancy: Genentech; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Janssen; Advisory / Consultancy: Lilly. B. Besse: Research grant / Funding (self): Abbvie; Research grant / Funding (self): Amgen; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Biogen; Research grant / Funding (self): Blueprint Medicines; Research grant / Funding (self): BMS; Research grant / Funding (self): Celgene; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): GSK; Research grant / Funding (self): Ignyta; Research grant / Funding (self): IPSEN; Research grant / Funding (self): Merck KGaA; Research grant / Funding (self): MSD; Research grant / Funding (self): Nektar; Research grant / Funding (self): Onxeo; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Pharma Mar; Research grant / Funding (self): Sanofi; Research grant / Funding (self): Spectrum Pharmaceuticals; Research grant / Funding (self): Takeda. J. Soria: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Astex; Advisory / Consultancy: Clovis; Advisory / Consultancy: GSK; Advisory / Consultancy: GamaMabs; Advisory / Consultancy: Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: Mission Therapeutics; Advisory / Consultancy: Merus; Advisory / Consultancy: Pfizer; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Takeda; Full / Part-time employment: AstraZeneca. S. Postel Vinay: Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): BMS; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Janssen Cilag; Research grant / Funding (self): Merck; Research grant / Funding (self): Novartis; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Roche; Research grant / Funding (self): Sanofi. All other authors have declared no conflicts of interest.