Abstract CT055: Microdose induced oxaliplatin-DNA adducts as a predictive biomarker of response in colorectal cancer

Abstract

Abstract Background Combination 5-FU and oxaliplatin (FOLFOX) is standard therapy for colorectal cancer (CRC) in neoadjuvant, adjuvant, and metastatic settings. However, oxaliplatin neuropathy is the main dose-limiting toxicity that often necessitates dose reduction or discontinuation before progression. Prediction of oxaliplatin sensitivity in tumor cells would be valuable for dose optimization to maximize anti-tumorigenic effect and limit sensory neuropathy. Oxaliplatin functions via the formation of covalent drug-DNA adducts which ultimately inhibit cell replication and promote apoptosis. Detection of these drug-DNA adducts could serve as a biomarker of oxaliplatin efficacy. We therefore hypothesized that drug-DNA adduct levels induced by sub-therapeutic "diagnostic microdoses" are proportional to those induced by therapeutic doses and are predictive of tumor responses. Methods The feasibility of this predictive diagnostic microdosing approach was assessed in CRC cell culture and a pilot clinical trial of six CRC patients. Four CRC cell lines were cultured with therapeutically relevant (100 µM) or diagnostic microdose (1 µM) concentrations of [14C]oxaliplatin. The C-14 label enabled quantification of oxaliplatin-DNA adduct levels with accelerator mass spectrometry, an ultrasensitive isotope analysis technique. Adduct formation was correlated with oxaliplatin cytotoxicity as measured by the MTT viability assay. In a pilot clinical trial (NCT02569723), six CRC patients received an intravenous diagnostic microdose containing [14C]oxaliplatin prior to treatment and a second [14C]oxaliplatin dose during FOLFOX chemotherapy. Adduct levels from peripheral blood mononuclear cells (PBMC), used as surrogates for tumor cells, were correlated to mean tumor volume change of evaluable target lesions. Results Drug-DNA adduct levels were linearly proportional between microdoses and therapeutically relevant concentrations in cell culture (R2 = 0.91, p < 0.0001) and patient samples (R2 = 0.63, p < 0.0001). Plasma pharmacokinetics of microdoses were consistent with those of therapeutic dosing. No microdose-associated toxicity was observed in this patient population. PBMC adduct levels significantly correlated with tumor shrinkage (microdose: R2 = 0.82, p = 0.033; therapeutic dose: R2=0.65, p = 0.099). Conclusion Diagnostic microdosing with oxaliplatin is feasible and is predictive of oxaliplatin sensitivity in CRC patients. Citation Format: Justin Chen, May Cho, Maike Zimmermann, Thomas Semrad, Chun-Yi Wu, Aiming Yu, Chong-Xian Pan, Paul T. Henderson, Edward J. Kim. Microdose induced oxaliplatin-DNA adducts as a predictive biomarker of response in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT055.