Prognostic significance of tumor genotypes and CD8+ infiltrates in stage I-III colorectal cancer
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Elena Fountzilas1, Vassiliki Kotoula2,3, Ioannis Tikas3, Kyriaki Manousou4, Kyriaki Papadopoulou3, Christos Poulios2, Vasilios Karavasilis5, Ioannis Efstratiou6, Dimitrios Pectasides7, Kleo Papaparaskeva8, Ioannis Varthalitis9, Christos Christodoulou10, George Papatsibas11, Sofia Chrisafi3, Georgios K. Glantzounis12, Amanda Psyrri13, Gerasimos Aravantinos14, Georgia-Angeliki Koliou4, George K. Koukoulis15, George E. Pentheroudakis16 and George Fountzilas3,17
1Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2Department of Pathology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
3Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece
4Section of Biostatistics, Hellenic Cooperative Oncology Group, Athens, Greece
5Department of Medical Oncology, Papageorgiou Hospital, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
6Department of Pathology, Papageorgiou Hospital, Thessaloniki, Greece
7Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens, Greece
8Department of Pathology, Konstantopouleio Agia Olga General Hospital, Athens, Greece
9Oncology Department, General Hospital of Chania, Crete, Greece
10Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece
11Oncology Department, University General Hospital of Larissa, Larissa, Greece
12Department of Surgery, University Hospital of Ioannina and School of Medicine, University of Ioannina, Greece
13Division of Oncology, Second Department of Internal Medicine, Attikon University Hospital, Athens, Greece
14Second Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece
15Department of Pathology, Faculty of Medicine, University of Thessaly, Larissa, Greece
16Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece
17Aristotle University of Thessaloniki, Thessaloniki, Greece
Elena Fountzilas, email: [email protected]
Keywords: targeted NGS; CD8; MMR; BRCA1; ARID1A
Received: June 29, 2018 Accepted: October 08, 2018 Published: November 02, 2018
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.
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