Abstract 101P
Background
Somatic alterations of the MET oncogene are emerging as an attractive target in human cancers, despite the challenge represented by the detection and annotation of the plethora of functional events. Thus, understanding the molecular epidemiology of MET alterations is essential. While the occurrence of MET exon 14 skipping mutations (METex14) in US lung cancer patients is well defined, it is not widely published for European patients. In addition, reports on the occurrence of METex14 outside lung cancer and other clinically relevant MET alterations across all cancers are limited. Finally, it becomes increasingly clear that co-occurring alterations (e.g. in KRAS) can drive resistance of MET oncogenic events, including in particular METex14 lung cancer resistance to MET inhibitors.
Methods
A retrospective study was conducted on a SOPHiA GENETICS (SG) proprietary genomics database of 36,645 European cancer patients. Genomic data were processed by our algorithm that supports the detection and annotation of multiple variant classes (gene fusions, exon skipping, amplifications, and point mutations) including the challenging METex14 detection from both RNA and DNA samples.
Results
Among the 13,150 patients with clearly annotated tumor lineage, 81% of all MET alterations occurred within the 5,854 lung cancer subjects, including 137 METex14 mutations (2.3%). Overall, we observed 670 MET variants of potential clinical relevance across all cancers, including 431 (1.2%) METex14 mutations, 116 (0.3%) kinase domain mutations, 91 (0.2%) high level amplifications, and 12 (< 0.1%) fusions. The SG algorithm was then used to re-analyze MET alteration frequencies in two US-centric cohorts, TCGA (∼9k patients) and GENIE (∼104k patients). Results were largely consistent with the SG cohort. We also annotated activating variants in the MAPK and RTK pathways, including RET, ROS1, ALK, KRAS and BRAF genes, and identified patterns of co-occurrence and mutual exclusivity.
Conclusions
This study brings new insights into the distribution of MET alterations in European cancer patients and demonstrates its consistency with US data. This extended understanding of the molecular epidemiology of MET variants holds the promise to further inform targeted therapy approaches.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Novartis Pharma AG.
Funding
Novartis Pharma AG.
Disclosure
J. Wolf: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Blueprint Medicines; Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Ignyta; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Loxo; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Seattle; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim Pharmaceuticals Inc; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer. L. Ventouras, P. Menu, A. Wójtowicz, M.Mina: Financial Interests, Personal, Full or part-time Employment: SOPHiA GENETICS. M. Zou, S. Diallo, A. Chassot Agostinho, R. Tiedt: Financial Interests, Personal, Full or part-time Employment: Novartis.