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

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

Oncotarget. 2018 Nov 02;9(86):35623-35638

Authors: Fountzilas E, Kotoula V, Tikas I, Manousou K, Papadopoulou K, Poulios C, Karavasilis V, Efstratiou I, Pectasides D, Papaparaskeva K, Varthalitis I, Christodoulou C, Papatsibas G, Chrisafi S, Glantzounis GK, Psyrri A, Aravantinos G, Koliou GA, Koukoulis GK, Pentheroudakis GE, Fountzilas G

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.

PMID: 30479693 [PubMed]

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