PUB146 Prognostic Prediction of Pemetrexed-Platinum Chemotherapeutic Regimen by Serum Metabolomics

Abstract

Lung cancer is a leading cause of cancer deaths worldwide and chemotherapy is the major treatment for advanced stage patients. Currently, pemetrexed combined with platinum (PC regimen), due to its promising efficacy and a favorable toxicity profile, has become a standard schedule as the first-line treatment for advanced non-squamous NSCLC. Nevertheless, like all chemotherapeutic regimens, drug resistance inevitably limits the efficiency of this preferred cytotoxic drug combination. In virtually all initial responders rapidly develop acquired resistance. Besides, some cases are intrinsically resistant to this chemotherapy regimen, and the disease progressed at the first radiological assessment of response after one or two cycles of treatment. Metabolomics, by testing the holistic low-molecular-weight organism metabolites, offers an appropriate strategy to studies of pathophysiological processes, interaction of environment and genotype, drug toxicity and efficacy, biomarker discovery and so on. Metabolites play a substantial role in biological systems. Being the closest biological proximity to the phenotype of the system, metabolomics allows rapid observation of responses to system perturbations in the metabolome. In this work, we hypothesis that the metabolic characteristics of serum may associated with the inherent response (resistance or sensitivity) of patients to cytotoxic drugs. In this study, ultra performance liquid chromatography coupled to mass spectrometry (UPLC-MS) analytical platform was applied to perform the metabolic profiling studies of serum samples, aiming to find metabolic biomarkers which could predict the benchmark of pemetrexed and platinum treatment in adeno-NSCLC patients. In the retrospective study, serum samples were subjected to the untargeted metabolomic analysis. The results clearly indicated the different patterns of metabolomics profiles in accordance with the clinical outcomes of progressive disease (PD) or partial response (PR). We then established a prediction model consisting of a robust metabolites-pattern that can predict the response of chemotherapy-naive NSCLC patients before receiving PC chemotherapy regimen. And in prospective study, we employed this new method to select the patients who are more likely to benefit from PC regimen, and gave suggests to take an alternative chemotherapy regimen to the patients who might not sensitive to the PC regimen according to our investigation. The metabolic alterations in serum before pemetrexed and platinum chemotherapy regimen are associated with clinical benefit. This study offers a validated method to identify patients who are unlikely to respond to this treatment and thus can be offered alternative treatments or entry into clinical trials.