Abstract 352P
Background
Next-generation sequencing (NGS) provides a molecular rationale to inform prognostic stratification and guide personalized treatment in cancer patients. Here, we aimed at determining the prognostic and predictive value of actionable mutated genes in metastatic colorectal cancer (mCRC).
Methods
A total of 294 mCRC patients that underwent targeted NGS-based testing were selected, of whom 200 receiving first-line treatments were included for prognostic analyses. Cox proportional hazards models were fitted to assess risks of individual and coexistent mutated genes on progression-free and overall survival (PFS and OS), adjusting for baseline clinical variables. Discriminative performance of biomarkers was assessed by time-dependent estimates of the area under the curve (AUC).
Results
The most recurrently mutated genes were TP53 (64%), KRAS or NRAS (49%), PIK3CA (15%), SMAD4 (14%), BRAF (13%) and FBXW7 (9.5%). Mutations in FBXW7 correlated with worse OS rates (P = 0.036; HR, 2.24) and SMAD4 mutations predicted negative PFS (P = 0.0015; HR, 2.63) independently of clinical factors. Concurrent mutations in TP53 and FBXW7 were associated with increased risk of death (P = 0.02; HR, 3.31) as well as double mutated TP53 and SMAD4 (P = 0.03; HR, 2.91). These associations showed a trend towards statistical significance in a second cohort of 1095 patients sequenced with the MSK-IMPACT gene-panel. Addition of the previous three mutated genes upon clinical factors discriminated those patients at high risk with an AUC of 0.87. Gene set enrichment analysis revealed specific functions associated with SMAD4 and FBXW7 mutated tumors in samples with altered TP53.
Conclusions
Mutated SMAD4 and FBXW7 in TP53-driven tumors predict a negative prognostic outcome in mCRC, which could be useful for patient clinical management.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
A. Prat: Other, Personal, Full or part-time Employment, An Immediate Family Member: Novartis; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Personal, Other, Fees: Pfizer, Novartis, Roche, MSD Oncology, Lilly, Daiichi Sankyo, Amgen, Guardant Healt; Financial Interests, Personal, Advisory Board: Amgen, Roche, Novartis, Pfizer, Bristol-Myers Squibb, Boehringer, PUMA, Oncoloytics Biotech, Daiichi Sankyo, AbbVie, AstraZeneca; Financial Interests, Institutional, Advisory Role: NanoString Technologies; Financial Interests, Institutional, Other, Research Funding: Roche, Novartis, Incyte, Puma Biotechnology. J. Maurel: Financial Interests, Personal, Advisory Board: Advance Medical, Roche, Cancer Expert Now, Sirtex, Pierre-Fabre, Shire, AstraZeneca, Bayer, Sanofi; Financial Interests, Institutional, Funding: Amgen, Merck, Incyte, Roche; Financial Interests, Institutional, Invited Speaker: Merck; Non-Financial Interests, Leadership Role: GEMCAD (Grupo Español Multidisciplinar en Cancer Digestivo). All other authors have declared no conflicts of interest.