Prognostic implications of mismatch repair deficiency in patients with nonmetastatic colorectal and endometrial cancer

Elena Fountzilas; Vassiliki Kotoula; George Pentheroudakis; Kyriaki Manousou; Genovefa Polychronidou; Eleni Vrettou; Christos Poulios; Eirini Papadopoulou; Georgia Raptou; Eirini Pectasides; Georgia Karayannopoulou; Sofia Chrisafi; Pavlos Papakostas; Thomas Makatsoris; Ioannis Varthalitis; Amanda Psyrri; Epaminontas Samantas; Mattheos Bobos; Christos Christodoulou; Christos Papadimitriou; George Nasioulas; Dimitrios Pectasides; George Fountzilas

doi:10.1136/esmoopen-2018-000474

Prognostic implications of mismatch repair deficiency in patients with nonmetastatic colorectal and endometrial cancer

ESMO Open. 2019 Mar 12;4(2):e000474. doi: 10.1136/esmoopen-2018-000474. eCollection 2019.

Authors

Elena Fountzilas¹, Vassiliki Kotoula^{2

3}, George Pentheroudakis⁴, Kyriaki Manousou⁵, Genovefa Polychronidou⁶, Eleni Vrettou², Christos Poulios², Eirini Papadopoulou⁷, Georgia Raptou², Eirini Pectasides^{8

9}, Georgia Karayannopoulou², Sofia Chrisafi³, Pavlos Papakostas¹⁰, Thomas Makatsoris¹¹, Ioannis Varthalitis¹², Amanda Psyrri¹³, Epaminontas Samantas¹⁴, Mattheos Bobos³, Christos Christodoulou¹⁵, Christos Papadimitriou¹⁶, George Nasioulas⁷, Dimitrios Pectasides¹⁷, George Fountzilas¹⁸

Affiliations

¹ Department of Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
² Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece.
³ Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.
⁴ Department of Medical Oncology, University of Ioannina, Ioannina, Greece.
⁵ Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece, Athens, Greece.
⁶ Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece.
⁷ GeneKor Medical SA, Athens, Greece.
⁸ Department of Medicine, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
⁹ Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
¹⁰ Oncology Unit, Hippokration Hospital, Athens, Greece.
¹¹ Department of Medicine, Division of Oncology, University Hospital, University of Patras Medical School, Patras, Greece.
¹² Oncology Department, General Hospital of Chania, Chania, Greece.
¹³ Section of Medical Oncology, Department of Internal Medicine, Attikon University Hospital, Faculty of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
¹⁴ Third Department of Medical Oncology, AgiiAnargiri Cancer Hospital, Athens, Greece.
¹⁵ Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece.
¹⁶ Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
¹⁷ Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens, Greece.
¹⁸ Aristotle University of Thessaloniki, Thessaloniki, Greece.

Abstract

Background: The clinical relevance of mismatch repair (MMR) status in patients with nonmetastatic cancer across tumour types remains unclear. Our goal was to investigate the prognostic role of MMR deficiency in patients with stage I-III colorectal and endometrial cancer.

Methods: Patients with nonmetastatic colorectal and endometrial cancer with tumour tissue available for analysis were identified through the Hellenic Cooperative Oncology Group (HeCOG)'s tumour repository. Patients had been referred to Departments of Medical Oncology affiliated with HeCOG. MMR protein expression was evaluated by immunohistochemistry. The primary outcome measure was overall survival (OS).

Results: From May 1990 to September 2012, 1158 patients with nonmetastatic colorectal (N = 991) and endometrial cancer (N = 167) were identified (median age: 64 years, men: 544). All patients with colorectal and 109 (65%) with endometrial cancer had received adjuvant treatment. MMR deficiency was observed in 114 (11.5%) of colorectal and 80 (47.9%) of endometrial tumours. More commonly deficient proteins were PMS2 (69 patients, 7%) and MLH1 (63 patients, 6.5%) in colorectal cancer and MSH2 (58 patients, 34.7%) in endometrial cancer. Colorectal MMR-deficient (dMMR) tumours were more likely to be right sided (65 % dMMR vs 27 % proficient MMR, pMMR; p < 0.001), high grade (31% vs 15%, χ², p < 0.001) and with a mucinous component (64% vs 42%, p < 0.001). Endometrial dMMR tumours were more often of endometrioid histology (51.4 % endometrioid vs 20 % serous/clear cell, p = 0.020). Compared with MMR proficiency, MMR deficiency was associated with improved OS in patients with endometrial cancer (HR = 0.38, 95% CI 0.20 to 0.76, p = 0.006), but not in patients with colorectal cancer (HR = 0.73, 95% CI 0.49 to 1.09, p = 0.130). After adjusting for age, stage and grade, MMR deficiency maintained its favourable prognostic significance in patients with endometrial cancer (HR = 0.42, 95% CI 0.20 to 0.88, p = 0.021).

Conclusions: DMMR was associated with improved outcomes in patients with nonmetastatic endometrial cancer, but not in patients with nonmetastatic colorectal cancer who received adjuvant chemotherapy.

Keywords: Colorectal; MMR; early-stage; endometrial; prognosis.