Personalized Neoadjuvant Chemotherapy for Gastrointestinal Cancers: Shaping Imprecision to be Precise

Abstract Neoadjuvant chemotherapy can down-size or down-stage tumors, minimize post-surgical recurrence risk, or even replace surgery when deployed appropriately for patients with gastrointestinal cancers. However, accomplishing these goals is rate-limited by all-comer treatment protocols, median arm-based comparisons in clinical trials, and the persisting omission of precision approaches for cytotoxic agents. Despite heterogeneity in benefit from standard-of-care regimens, mounting biological data support the presence of actionable sensitivities or potentially targetable dependencies in most tumors. Conceptually, such tumor vulnerabilities could be a game changer. In treatment-resistant malignancies (biliary tract cancer and pancreatic ductal adenocarcinoma), individualized neoadjuvant treatment may increase the curative surgery frequencies that currently occur only in a minority of patients. For more treatment-sensitive gastrointestinal cancers, tailored chemotherapy strategies might reduce the need for high-intensity regimens, minimize post-surgical morbidity, and allow dose de-escalation for selected patients without compromising oncological outcomes. Personalizing chemotherapy strategies remains inferential from comparing outcomes of molecularly distinct patients receiving a single treatment or unselected patients (with comparable baseline characteristics) on different regimens. We discuss the critical importance of harnessing tumor biology to develop and implement predictive signatures for personalized neoadjuvant chemotherapy (alone or in combination with other modalities). This includes exploiting transcriptomics to retrospectively understand the molecular basis of treatment outcomes from patient biopsies, identifying existing agents to replace or supplement current standard of care for those unlikely to respond, and matching novel preclinical treatments to potential responder patients. Deploying mechanistically distinct cytotoxic regimens against gastrointestinal tumors with unique predispositions for DNA damage tolerance is a necessity for boosting neoadjuvant outcomes.