Abstract A042: Keratin 17 is a negative prognostic and predictive biomarker in pancreatic ductal adenocarcinoma

Abstract

Abstract Background: There is an urgent need to understand why patients with clinically and histologically identical pancreatic ductal adenocarcinomas (PDACs) differ in response to treatment, disease progression, and survival. Although two standard chemotherapies are available, predictive biomarkers to guide regimen selection have not been defined. We previously reported that keratin 17 (K17) expression is a hallmark of PDAC cases with shortest patient survival. Furthermore, K17, explored using in vitro and in vivo murine models, drives resistance to gemcitabine and 5-fluorouracil, the most common chemotherapeutic agents in the two chemotherapies. Here, we aimed to validate the prognostic value of K17 and to further explore its role as a predictive biomarker. Methods: We used a cohort of 305 cases, with localized disease and who had gone tumor resection. An indirect immunoperoxidase method was used to detect K17 expression on surgical specimens, as previously described. Survival was plotted using the Kaplan–Meier method and hazard ratios (HRs) were calculated using Cox proportional hazard regressions for both, overall survival (OS) and progression-free survival (PFS). Results: Patients in the high-K17 expression group had shorter overall survival [median=25 mo., HR=1.511, p=0.0338] than those in the low-K17 expression group (median=42 mo.). In addition, high K17 expression was associated with shorter median OS (p=0.0280) and PFS (p=0.0434) in patients who were treated with gemcitabine (GEM) or with Gemcitabine/nab-Paclitaxel (GEMTAX) therapy (OS p=0.1959, PFS p=0.0724), compared to low-K17 counterparts. When we further separated our cohort by K17 level of expression and compared GEM and GEMTAX responses, we found that patients with tumors with high K17 expression do not benefit from GEMTAX adjuvant therapy (p=0.0356). Of note, K17 expression within the responder group was significantly lower than in tumors within the non-responder group for both Gem and GEMTAX (p<0.001). Conclusions: K17 expression is confirmed as a robust prognostic biomarker, significantly correlated with poor OS and PFS in two independent cohorts of PDAC patients. More importantly, our results indicate that K17 expression predicts PDAC resistance to gemcitabine and poor response to GEMTAX. Collectively, our findings have implications could guide the development of K17 as a predictive biomarker for gemcitabine-based interventions in both adjuvant and palliative settings, to optimize therapeutic efficacy for PDAC. Citation Format: Lyanne Oblein, Lucia Roa-Peña, Sruthi Babu, Felicia D. Allard, Natalia D. Marchenko, Luisa F. Escobar-Hoyos, Kenneth R. Shroyer. Keratin 17 is a negative prognostic and predictive biomarker in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A042.