Abstract B87: Co-expression of GLUT1 and MCT4 is a poor prognostic marker and predicts response to adjuvant chemotherapy in PDAC

Abstract

Abstract Background: Mutant KRAS stimulates glucose uptake and lactate production in pancreatic ductal adenocarcinoma (PDAC), contributing to metabolic pathway reprogramming and tumor progression. A prognostic effect for glucose transporter GLUT1 and lactate transporter MCT4 expression in PDAC has been demonstrated but it is not known if the expression of markers of glycolytic and lactate metabolism pathways is predictive of treatment response. We aimed to validate the prognostic and assess the predictive effects of GLUT1 and MCT4 protein levels in resectable PDAC. Methods: Immunohistochemical analysis for GLUT1 and MCT4 was performed on a tissue microarray (TMA) comprising 261 resected PDAC tumors with associated clinical outcome data. The expression of GLUT1 and MCT4 in the epithelial compartment of PDAC was quantified and patient samples were scored as low (negative and weak staining) and high (moderate and strong staining) expression groups. Univariable disease-specific survival (DSS) was assessed using the Kaplan-Meier method. Results: 70% (182) of the patients included in the TMA had high GLUT1 staining and 58% had high MCT4 staining. GLUT1high patients had reduced median DSS compared to GLUT1low patients (1.34 vs. 2.05 years, p=0.0136). Median DSS was also reduced in the MCT4high group (1.33 vs. 1.91 years in MCT4low, p=0.0153). There was a significant co-occurrence of high GLUT1 with high MCT4 expression (70%, p<0.0001). GLUT1highMCT4high patients had reduced DSS (N=124, 1.21 years, p=0.0114) compared to GLUT1lowMCT4low (N=55, 2.04 years), GLUT1lowMCT4high (N=27, 2.12 years) and GLUT1highMCT4low (N=61, 1.85 years). 31% of all patients received adjuvant single agent chemotherapy with a pyrimidine analog. Two of the combined GLUT1/MCT4 phenotypes were found to be predictive biomarkers for adjuvant chemotherapy. GLUT1lowMCT4low showed a treatment associated two year increase in median DSS (3.32 vs. 1.38 years, p=0.0020) and GLUT1highMCT4high demonstrated a treatment associated 10 month increase in median DSS (1.68 vs. 0.89 years, p=0.0071) compared to no adjuvant therapy. No significant treatment related differences were observed in either the GLUT1lowMCT4high (p=0.24) or GLUT1highMCT4low groups (p=0.95). Conclusions: GLUT1 and MCT4 expression are poor prognostic markers in PDAC and co-expression of these biomarkers enhances this effect. Neither GLUT1 nor MCT4 were found to be of predictive relevance when considered individually. Patients with low tumor GLUT1 and MCT4 expression had the best outcomes with chemotherapy with a pyrimidine analog. Hence, immunohistochemical analysis of GLUT1 and MCT4 in resected PDAC defines patient subgroups with different survival prognosis and predicted sensitivity to pyrimidine analog chemotherapy. The combined effect of GLUT1 and MCT4 expression on PDAC outcome suggests that therapeutic agents which can alter the glycolytic/lactate pathway may have potential for increasing sensitivity to treatment. Citation Format: Joanna M. Karasinska, Steve E. Kalloger, Hui-li Wong, Taixiang Wang, Daniel J. Renouf, David F. Schaeffer.{Authors}. Co-expression of GLUT1 and MCT4 is a poor prognostic marker and predicts response to adjuvant chemotherapy in PDAC. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B87.