Abstract IA010: Meeting the challenge of pancreatic cancer

Abstract

Abstract Approximately one third of patients (pts) with pancreatic adenocarcinoma (PDA) present with locally advanced unresectable disease (LAPC). Majority of pts with LAPC have micrometastatic disease at presentation. However, median survival times exceed those of pts with radiologically visible metastases and is currently around 14-16 months (versus less than 1 year). Initial treatment strategies in LAPC focused on radiation that did not improve survival. With improvements in systemic therapies, current treatments of LAPC are based on cytotoxic combinations similar to ones used in metastatic PDA. However, benefits of cytotoxic therapy remain very modest. Unfortunately, the development of systemic therapy for PDA was plagued by repeated failures of randomized clinical trials of a range of targeted and other agents. In recent years, we exponentially advanced knowledge of PDA’s molecular biology and are attempting to learn from our clinical failures. One thing that stood out, with very few exceptions, is lack of success in single target/pathway strategies, especially in the absence of predictive biomarkers and lack of targetable “driver” mutations. Immune checkpoint inhibitors were ineffective unlike successes in other cancers. Focus has therefore shifted to rational strategies based on biology that defines phenotype along with ongoing attempts to refine molecular characterizations of PDA. Major research strategies include targeting the stroma to enhance drug delivery (e.g., CEND-1), reversing the immune suppressive microenvironment (combinatorial immunotherapy), exploiting DNA repair defects (e.g., BRCA mutations), and most importantly tackling KRAS oncogene. KRASG12C, KRASwt, BRCAmutated, and microsatellite instability provide additional treatment opportunities in up to 10% of PDA patients. The goal of new therapy developments in LAPC must address the locoregional morbidity of the primary tumor with the ultimate goal of prolonging survival. Examples of ongoing research in locoregionally directed therapy include ablative radiation and tumor treating fields (TTF) that attempt to control its growth, reduce the tumor bulk, and improve possibilities of tumor resection. As our systemic therapies improve, locoregional therapy becomes more relevant. Improvements in molecular classifications of PDA, refinements in the use of organoids to predict drug and radiation effect, and use of liquid biopsies are examples of measures that will provide foundations for personalized treatment approaches. Collectively, we have endless opportunities for translational research based on advances in PDA’s basic science and our experiences from the many “negative” clinical trials. Citation Format: Philip A. Philip. Meeting the challenge of pancreatic cancer [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 IA010.