CRC continues to be a leading cause of cancer-related deaths, with 5-year 5% survival rate in metastatic patients. In early disease, adjuvant chemotherapy is becoming common practice to improve cure rates for patients with high-risk (hr) stage II primary disease as per the AJCC/UICC-TNM classification. However, the specificity of risk assessment is suboptimal, as all HR pts receive aggressive chemotherapy but only a minority of them are expected to have recurrences. Here, we aimed to explore biological pathways in stage II/III CRC associated with recurrence and outcome.
1062 FFPE archival tumors from the AVANT phase III trial were profiled by nanostring, Avant was a prospective 3-arm randomized phase 3 clinical trial, in histologically confirmed stage 3 or hr (as defined by AJCC) stage 2 CRC, with DFS as a primary endpoint. Results were all validated in TCGA and GSE39582.
Retrospective analysis of the AVANT trial uncovered a prognostic signature containing 3 biological axes: stromal, proliferative, and immune. This signature outperformed published signatures such as CMS subtypes and diagnostic signatures like OncotypeDx in an independent data set. High GZMB expression alone had a significant prognostic impact in AVANT and GSE39582 (OS Cox model HR 0.46 and p-value 0.000201) while other individual T-effector genes were not prognostic or less prognostic. Tumor FACS experiments identified immune-cell types expressing GZMB that are low for PD1 and could drive the-effector independent prognostic role for GZMB in CRC.
The results described herein furthers our understanding of the biological bases underlying stage II/III CRC disease progression and provide scientific rationale for future HR stratification and targeted treatment evaluation in biomarker defined subpopulations of resectable hr CRC patients.
Clinical trial identification
Legal entity responsible for the study
M. Das Thakur: Employee: Genentech. A. Udyavar, C. Li, W. O’Gorman, Y. Li, A. Au-Yeung, C. Takahashi, R. Bourgon, A. Daemen, P. Hegde, C. Bais: Employee: Hoffmann-La Roche. T. Sandmann, L.J.W. Bosch: Past employee: Hoffmann-La Roche.