Somatic DNA mutations, MSI status, mutational load (ML): Association with overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) of CALGB/SWOG 80405 (Alliance).
Innocenti, F; Ou, F-S; Zemla, T; Niedzwiecki, D; Qu, X; Tam, R; Mahajan, S; Goldberg, RM; Mayer, RJ; Bertagnolli, MM; Sanoff, HK; Hochster, HS ...
Published in: Journal of Clinical Oncology
3504 Background: CALGB 80405 was a randomized phase III trial that found no difference in OS in first-line mCRC pts treated with either bevacizumab (Bev) or cetuximab (Cet). Primary tumor DNA from 361 pts, including KRAS mutant (mut) pts, has been profiled for somatic gene mutations/ML/MSI to discover molecular markers of OS. Methods: Mutations in 11 genes were determined by PCR, MSI by microsatellite analysis, and ML by next-generation sequencing (FoundationOne). Cox proportional hazard models are used, stratified by prior XRT and +/- adjuvant chemotherapy; adjusted by age, race, gender, synchronous vs. metachronous, liver metastases, sidedness, all RAS. Results: BRAF: Mut pts had shorter OS than wild-type (wt) pts (HR 1.92, 95% CI 1.34,2.75; p<0.001); HR 1.65 (1.09,2.50) after adjusting for sidedness (p 0.022). In mut pts longer OS is observed in Bev arm vs. Cet arm (p 0.041); in wt pts no arm difference is observed (p 0.291, table). MSI: OS does not differ between MSI-H and MSI-S pts (HR 0.78 [0.40, 1.52], p 0.450). In MSI-H pts longer OS is observed in Bev arm vs. Cet arm (p 0.002); in MSI-S pts no difference is observed (p 0.305, table). ML: Hypermutated MSI-H pts are excluded. In a subset of 205 pts, pts with ML>5 (N=93) have longer OS than pts with ML≤5 (N=112) (HR 0.65 [0.42,1.00], p 0.048). In Bev arm higher ML confers longer OS than lower ML (HR 0.85 [0.80,0.96], p 0.004); in Cet arm no difference is observed (HR 0.99 [0.90,1.09], p 0.862). Conclusions: BRAF is a strong negative prognostic factor in mCRC, even when sidedness is taken into account. ML is a novel marker for further evaluation. The effect of Bev and Cet in either BRAF mut or MSI-H pts should be tested in larger datasets. Updated results from more screened samples will be presented. [Table: see text]
