Abstract 476P
Background
Next-generation sequencing (NGS) provides a molecular rationale to guide personalized treatment and follow-up of cancer patients. The aim of this study is to evaluate the potential of mutational testing on survival prediction in metastatic colorectal cancer (mCRC).
Methods
The Oncomine Solid Tumor DNA kit was used to sequence a panel of 22 gens in 296 patients. To homogenize the cohort, only patients treated with first-line doublets alone or plus approved targeted agents (200/296, 67%) were included. Univariate and multivariate Cox regression models with proportional hazards were fitted to assess risks of each mutated gene (individually or in combination) on Progression Free Survival (PFS)/ Overall Survival (OS), adjusting for baseline clinical variables (sex, age, ECOG, LDH, MSI status, ALP, PCR, leukocytes, number of affected organs and primary site). Log-Rank and Chi-squared tests were used to evaluate statistical significance.
Results
The most frequently mutated genes identified by targeted NGS included TP53 (66%), RAS (51%), SMAD4 (14%), PIK3CA (13%), BRAF (11%) and FBXW7 (11%). As univariate factors, PIK3CA mutations were associated with poor PFS (P=0.01), and PIK3CA and FBXW7 were prognostic factors for worse OS (P=0.007 and P=0.04, respectively). Coexisting mutations of BRAF and TP53 predicted PFS (P=0.01; HR 2.24) and OS (P=0.001; HR 3.18). Likewise, TP53-mutated patients with mutations in SMAD4 showed poor performance (P=0.019; HR 1.94), and with mutated PIK3CA predicted worse OS (P=0.005; HR 2.78). In a multivariate analysis, data showed that concurrent mutations of TP53 and FBXW7 predicted poor PFS (P=0.02; HR 2.65) and OS (P=0.02; HR 3.31), respectively. Additionally, simultaneous mutations in TP53 and SMAD4 were also associated with worse PFS (P=0.0001; HR 4.32) and OS (P=0.03; HR 2.91).
Conclusions
Mutations in SMAD4 or FBXW7 in a TP53-mutated background have prognostic value in mCRC patients independently of baseline clinical variables. These data might be useful for patient risk stratification.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Hospital Clinic of Barcelona.
Funding
Hospital Clinic of Barcelona.
Disclosure
A. Prat: Speaker Bureau/Expert testimony: Pfizer ; Speaker Bureau/Expert testimony: Novartis; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: BMS; Speaker Bureau/Expert testimony: Daiichi Sankyo; Advisory/Consultancy: Puma; Advisory/Consultancy: Oncolytics Biotech; Advisory/Consultancy: Lilly; Advisory/Consultancy: MSD. All other authors have declared no conflicts of interest.