Abstract 5180: Pharmacodynamic biomarker analysis of gastrointestinal cancer patients treated with metronomic chemotherapy in the Italian COMET Trial
Authors: Manca Maria L. , Prospero Diana , Darvishi Saeedeh , Bandini Arianna , Banchi Marta , Orlandi Paola , Padilla Hector , Sanchez Alejandro , Perucho Claire E. , de Avila Nydia , Padilla Hazel , Ortega Brianna E. , Stewart Ryley D. , Santillan Magdiel , Lopez Valeria , Kirken Robert , Allegrini Giacomo , Bocci Guido , Francia Giulio 
Published: March 2024

Abstract
Metronomic, or continuous low-dose, chemotherapy produces antitumor effects through multiple mechanisms. These include inhibition of angiogenesis and activation of the immune system. At AACR 2017 we presented a small, proof-of-concept, multiplex analysis of 14 cytokines specifically chosen by their association with activation of the immune system. The 14 cytokines were evaluated in 31 out of 38 patients with advanced refractory gastrointestinal tumors, enrolled in a phase II clinical trial of metronomic UFT (a 5-fluorouracil prodrug; 100 mg/twice per day p.o.) and cyclophosphamide (500 mg/mq2 i.v. bolus on day 1 and then 50 mg/day p.o.) plus celecoxib (200 mg/twice a day p.o.); the Italian COMET trial (Clinical Trial ID NCT02926911; Allegrini et al. Angiogenesis 2012: 15(2):275-86). We evaluated baseline (day 0) plasma levels with levels at days 28 and 56, and tested for correlations with observed Progression Free Survival, which we then reported (Valenzuela et al. Clin Exp Med. 2021: 21(1):149-159). We now present a comprehensive analysis of 75 cytokines in 34 of the 38 patients. Furthermore we extend the analysis to include baseline (day 0), days 28 and 56, and days 84 and 112 of the COMET trial, and we also correlated specific cytokines levels with Overall Survival. After an estimation of optimal cut-off points of plasma levels of the cytokines, survival analysis was performed, and log-rank tests and cox regression analyses were applied. We show that pre-treatment plasma level &lt;435.46pg/ml of macrophage-derived chemokine (MDC), was a predictive marker for those patients with better progression-free survival at 3 and 6 months (log-rank test p=0.0046; Cox regression analysis p=0.016). Moreover, baseline plasma levels of three cytokines, including monocyte chemoattractant protein 2 (MCP-2), monocyte chemoattractant protein 4 (MCP-4) and TNF-related apoptosis-inducing ligand (TRAIL), were associated with an improved overall survival. MCP-2 values &gt;26.21pg/ml (log-rank test p=0.0012; Cox regression analysis p=0.007), MCP-4 &gt;72.97pg/ml (log-rank test p=0.012; Cox regression analysis p=0.019) and TRAIL &gt;60.73pg/ml (log-rank test p=0.0059; Cox regression analysis p=0.011) were predictive markers for subjects with a better overall survival at 6 and 9 months. These results indicate that a methodology based on the detection of optimal cut-off points and survival analysis allowed the selection of potential biomarkers, such as MDC or MCPs. We propose that the systematic use of these statistical strategies, aimed at detecting potential biomarkers, could help to identify those patients that are likely to benefit from metronomic chemotherapy schedules. This would allow the stratification of such patients for future metronomic chemotherapy trials, and the potential identification of patients that should instead be offered alternative therapeutic strategies.
Citation Format: Maria L. Manca, Diana Prospero, Saeedeh Darvishi, Arianna Bandini, Marta Banchi, Paola Orlandi, Hector Padilla, Alejandro Sanchez, Claire E. Perucho, Nydia de Avila, Hazel Padilla, Brianna E. Ortega, Ryley D. Stewart, Magdiel Santillan, Valeria Lopez, Robert Kirken, Giacomo Allegrini, Guido Bocci, Giulio Francia. Pharmacodynamic biomarker analysis of gastrointestinal cancer patients treated with metronomic chemotherapy in the Italian COMET Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5180.