Changes in expression levels of <i>ERCC1, DPYD,</i> and <i>VEGFA</i> mRNA after first-line chemotherapy of metastatic colorectal cancer: results of a multicenter study

Abstract

// Hideo Baba 1,* , Yoshifumi Baba 1,* , Shinji Uemoto 2 , Kazuhiro Yoshida 3 , Akio Saiura 4 , Masayuki Watanabe 4 , Yoshihiko Maehara 5 , Eiji Oki 5 , Yasuharu Ikeda 6 , Hiroyuki Matsuda 7 , Masakazu Yamamoto 8 , Mitsuo Shimada 9 , Akinobu Taketomi 10 , Michiaki Unno 11 , Kenichi Sugihara 12 , Yutaka Ogata 13 , Susumu Eguchi 14 , Seigo Kitano 15 , Kazuo Shirouzu 16 , Yasumitsu Saiki 17 , Hiroshi Takamori 18 , Masaki Mori 19 , Toshihiko Hirata 20 , Go Wakabayashi 21 and Norihiro Kokudo 22 1 Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan 2 Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan 3 Department of Surgical Oncology, Gifu Graduate School of Medicine, Gifu, Japan 4 Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan 5 Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan 6 Department of Gastroenterological Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan 7 Department of Surgery, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan 8 Department of Surgery, Tokyo Women&rsquo;s Medical University, Tokyo, Japan 9 Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan 10 Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan 11 Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan 12 Department of Surgical Oncology, Tokyo Medical and Dental University, Tokyo, Japan 13 Department of Surgery, Kurume University Medical Center, Kurume, Japan 14 Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan 15 Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Oita, Japan 16 Department of Surgery, Kurume University School of Medicine, Kurume, Japan 17 Coloproctology Center, Takano Hospital, Kumamoto, Japan 18 Department of Surgery, Saiseikai Kumamoto Hospital, Kumamoto, Japan 19 Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan 20 Department of Surgery, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan 21 Department of Surgery, Iwate Medical University, School of Medicine, Morioka, Japan 22 Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan * These authors have contributed equally to this work Correspondence to: Hideo Baba, email: // Keywords : ERCC1, DPYD, VEGFA, colorectal cancer, bevacizumab Received : July 18, 2015 Accepted : August 12, 2015 Published : August 19, 2015 Abstract Our previous study showed that administering oxaliplatin as first-line chemotherapy increased ERCC1 and DPD levels in liver colorectal cancers (CRCs) metastases. Second, whether the anti-VEGF monoclonal antibody bevacizumab alters tumoral VEGFA levels is unknown. We conducted this multicenter observational study to validate our previous findings on ERCC1 and DPD, and clarify the response of VEGFA expression to bavacizumab administration. 346 CRC patients with liver metastases were enrolled at 22 Japanese institutes. Resected liver metastases were available for 175 patients previously treated with oxaliplatin-based chemotherapy (chemotherapy group) and 171 receiving no previous chemotherapy (non-chemotherapy group). ERCC1 , DPYD , and VEGFA mRNA levels were measured by real-time RT-PCR. ERCC1 mRNA expression was significantly higher in the chemotherapy group than in the non-chemotherapy group ( P = 0.033), and were significantly correlated (Spearman&rsquo;s correlation coefficient = 0.42; P &lt; 0.0001). VEGFA expression level was higher in patients receiving bevacizumab ( n = 51) than in those who did not ( n = 251) ( P = 0.007). This study confirmed that first-line oxaliplatin-based chemotherapy increases ERCC1 and DPYD expression levels, potentially enhancing chemosensitivity to subsequent therapy. We also found that bevacizumab induces VEGFA expression in tumor cells, suggesting a biologic rationale for extending bevacizumab treatment beyond first progression.