Prognostic significance of tumor genotypes and CD8+ infiltrates in stage I-III colorectal cancer.

Abstract

BACKGROUND:

We explored the clinical significance of tumor genotypes and immunophenotypes in non-metastatic colorectal cancer (CRC).

METHODS:

In primary tumors (paraffin blocks) from 412 CRC patients treated with adjuvant chemotherapy, we examined pathogenic mutations (panel NGS; 347 informative); mismatch repair (MMR) immunophenotype (360 informative); and CD8+ lymphocyte density (high - low; 412 informative). The primary outcome measure was disease-free survival (DFS).

RESULTS:

We evaluated 1713 pathogenic mutations (median: 3 per tumor; range 0-49); 118/412 (28.6%) tumors exhibited high CD8+ density; and, 40/360 (11.1%) were MMR-deficient. Compared to MMR-proficient, MMR-deficient tumors exhibited higher CD8+ density (chi-square, p<0.001) and higher pathogenic mutation numbers (p=0.003). High CD8+ density was an independent favorable prognosticator (HR=0.49, 95%CI 0.29-0.84, Wald's p=0.010). Pathogenic BRCA1 and ARID1A mutations were inversely associated with each other (p<0.001), were not associated with MMR-deficiency or CD8+ density, but both independently predicted for unfavorable DFS (HR=1.98, 95%CI 1.12-3.48, p=0.018 and HR=1.99, 95%CI 1.11-3.54, p=0.020, respectively).

CONCLUSION:

In non-metastatic CRC, high CD8+ lymphocyte density confers a favorable prognosis and may be developed as a single marker in routine diagnostics. The unfavorable prognostic effect of pathogenic BRCA1 and ARID1A mutations is a novel observation that, if further validated, may improve treatment selection.

• Authors: Elena Fountzilas, Vassiliki Kotoula, Ioannis Tikas, Kyriaki Manousou, Kyriaki Papadopoulou, Christos Poulios, Vasilios Karavasilis, Ioannis Efstratiou, Dimitrios Pectasides, Kleo Papaparaskeva, Ioannis Varthalitis, Christos Christodoulou, George Papatsibas, Sofia Chrisafi, Georgios K Glantzounis, Amanda Psyrri, Gerasimos Aravantinos, Georgia-Angeliki Koliou, George K Koukoulis, George E Pentheroudakis, George Fountzilas
• Journal: Oncotarget (Oncotarget) Vol. 9 Issue 86 Pg. 35623-35638 (Nov 02 2018) ISSN: 1949-2553 [Electronic] United States
• PMID: 30479693 (Publication Type: Journal Article)