title: High expression of organic anion transporter 2 and organic cation transporter 2 is an independent predictor of good outcomes in patients with metastatic colorectal cancer treated with FOLFOX-based chemotherapy.
abstract: Although metastatic colorectal cancer (mCRC) is commonly treated with 5-fluorouracil (5-FU)/leucovorin/oxaliplatin (FOLFOX), their response to FOLFOX varies, and no biomarkers predictive of treatment outcome have been validated. Organic anion transporter 2 (OAT2) and organic cation transporter 2 (OCT2) are critical determinants in uptake of 5-FU and oxaliplatin, respectively. In this study, we evaluated whether OAT2 and OCT2 levels can predict effectiveness of FOLFOX-based therapy. We retrospectively assessed 90 patients with mCRC who were treated with first-line FOLFOX with or without bevacizumab. We immunohistochemically determined OAT2 and OCT2 expression levels at invasion fronts of their tumors and correlated the levels to clinicopathological parameters, including objective tumor response (OTR) and progression-free survival (PFS). High expression of OAT2 (OAT2(High)) and OCT2 (OCT2(High)) were detected in 36% and 60% of the tumors, respectively. OCT2(High) was significantly associated with invasion depth (P=0.03), whereas OAT2(High) was not associated with any clinicopathological parameters. In univariate analysis, OAT2(High) was significantly correlated with good OTR (P=0.02), and OCT2(High) with long PFS (P=0.03). Multivariate analyses showed that OAT2(High) and OCT2(High), respectively, were the sole independent predictors of good OTR (P=0.02) and long PFS (P=0.03). We found that patients with OAT2(High)/OCT2(High) showed the best treatment outcomes (good OTR and long PFS) with significantly higher frequency than patients with other expression patterns (P=0.003). OAT2(High)/OCT2(High) status was also the only independent predictive factor in multivariate analysis. This study suggests that OAT2(High) and OCT2(High) are important independent predictors of good outcomes in FOLFOX-treated mCRC.
authors.affiliation: Laboratory of Pathology, Department of Medical Biophysics, Kobe University Graduate School of Health Sciences 7-10-2 Tomogaoka, Suma, Kobe, Hyogo 654-0142, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Tashiro
authors.affiliation: Laboratory of Pathology, Department of Medical Biophysics, Kobe University Graduate School of Health Sciences 7-10-2 Tomogaoka, Suma, Kobe, Hyogo 654-0142, Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Tatsumi
authors.affiliation: Laboratory of Pathology, Department of Medical Biophysics, Kobe University Graduate School of Health Sciences 7-10-2 Tomogaoka, Suma, Kobe, Hyogo 654-0142, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Takeda
authors.affiliation: Laboratory of Pathology, Department of Medical Biophysics, Kobe University Graduate School of Health Sciences 7-10-2 Tomogaoka, Suma, Kobe, Hyogo 654-0142, Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Naka
authors.affiliation: Department of Surgery, Fujita Health University School of Medicine 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuoka
authors.affiliation: Laboratory of Pathology, Department of Medical Biophysics, Kobe University Graduate School of Health Sciences 7-10-2 Tomogaoka, Suma, Kobe, Hyogo 654-0142, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Department of Surgery, Fujita Health University School of Medicine 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Hatta
authors.affiliation: Department of Surgery, Fujita Health University School of Medicine 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Laboratory of Pathology, Department of Medical Biophysics, Kobe University Graduate School of Health Sciences 7-10-2 Tomogaoka, Suma, Kobe, Hyogo 654-0142, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kamoshida
keywords: 5-fluorouracil; Organic anion transporter 2; colorectal cancer; objective tumor response; organic cation transporter 2; oxaliplatin; progression-free survival