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

Abstract

// Elena Fountzilas 1 , Vassiliki Kotoula 2, 3 , Ioannis Tikas 3 , Kyriaki Manousou 4 , Kyriaki Papadopoulou 3 , Christos Poulios 2 , Vasilios Karavasilis 5 , Ioannis Efstratiou 6 , Dimitrios Pectasides 7 , Kleo Papaparaskeva 8 , Ioannis Varthalitis 9 , Christos Christodoulou 10 , George Papatsibas 11 , Sofia Chrisafi 3 , Georgios K. Glantzounis 12 , Amanda Psyrri 13 , Gerasimos Aravantinos 14 , Georgia-Angeliki Koliou 4 , George K. Koukoulis 15 , George E. Pentheroudakis 16 and George Fountzilas 3, 17 1 Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 Department of Pathology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece 3 Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece 4 Section of Biostatistics, Hellenic Cooperative Oncology Group, Athens, Greece 5 Department of Medical Oncology, Papageorgiou Hospital, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece 6 Department of Pathology, Papageorgiou Hospital, Thessaloniki, Greece 7 Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens, Greece 8 Department of Pathology, Konstantopouleio Agia Olga General Hospital, Athens, Greece 9 Oncology Department, General Hospital of Chania, Crete, Greece 10 Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece 11 Oncology Department, University General Hospital of Larissa, Larissa, Greece 12 Department of Surgery, University Hospital of Ioannina and School of Medicine, University of Ioannina, Greece 13 Division of Oncology, Second Department of Internal Medicine, Attikon University Hospital, Athens, Greece 14 Second Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece 15 Department of Pathology, Faculty of Medicine, University of Thessaly, Larissa, Greece 16 Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece 17 Aristotle University of Thessaloniki, Thessaloniki, Greece Correspondence to: Elena Fountzilas, email: elenafou@gmail.com Keywords: targeted NGS; CD8; MMR; BRCA1; ARID1A Received: June 29, 2018      Accepted: October 08, 2018      Published: November 02, 2018 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.