Tumor Immunogenomic Features Determine Outcomes in Patients with Metastatic Colorectal Cancer Treated with Standard-of-Care Combinations of Bevacizumab and Cetuximab.

PURPOSE

CALGB/SWOG 80405 was a randomized phase III trial in first-line patients with metastatic colorectal cancer treated with bevacizumab, cetuximab, or both, plus chemotherapy. We tested the effect of tumor immune features on overall survival (OS).

EXPERIMENTAL DESIGN

Primary tumors (N = 554) were profiled by RNA sequencing. Immune signatures of macrophages, lymphocytes, TGFβ, IFNγ, wound healing, and cytotoxicity were measured. CIBERSORTx scores of naive and memory B cells, plasma cells, CD8+ T cells, resting and activated memory CD4+ T cells, M0 and M2 macrophages, and activated mast cells were measured.

RESULTS

Increased M2 macrophage score [HR, 6.30; 95% confidence interval (CI), 3.0-12.15] and TGFβ signature expression (HR, 1.35; 95% CI, 1.05-1.77) were associated with shorter OS. Increased scores of plasma cells (HR, 0.55; 95% CI, 0.38-0.87) and activated memory CD4+ T cells (HR, 0.34; 95% CI, 0.16-0.65) were associated with longer OS. Using optimal cutoffs from these four features, patients were categorized as having either 4, 3, 2, or 0-1 beneficial features associated with longer OS, and the median (95% CI) OS decreased from 42.5 (35.8-47.8) to 31.0 (28.8-34.4), 25.2 (20.6-27.9), and 17.7 (13.5-20.4) months respectively (P = 3.48e-11).

CONCLUSIONS

New immune features can be further evaluated to improve patient response. They provide the rationale for more effective immunotherapy strategies.