Germline Tyms Genotype is Highly Predictive in Patients with Advanced Colorectal and Gastroesophageal Cancer Independent of Fluoropyrimidine Pharmacology: Results from Two Prospective Translational Studies

Abstract

ABSTRACT Aim: Germline gene polymorphisms may impact clinical outcome in patients with gastrointestinal malignancies, but there are no data on the interaction between chemotherapy pharmacokinetics (PK) and gene polymorphisms, to assess their independent predictive value. Methods: Two studies prospectively assessed 44 gene polymorphisms in 16 genes (TYMS, MTHFR, GSTP1, -M1, -T1, DPYD, XRCC1, XRCC3, XPD, ERCC1, RECQ1, RAD54L, ABCB1, ABCC2, ABCG2, UGT2B7) by Sanger sequencing in 64 patients with advanced colorectal cancer (CRC) receiving capecitabine/oxaliplatin chemotherapy, and 76 patients with advanced gastroesophageal (GE) cancer receiving epirubicin/cisplatin/capecitabine (ECC) chemotherapy, respectively. Plasma concentrations of all anticancer drugs were sampled for up to 24 hours, analyzed using validated LC-MS/MS (capecitabine), HPLC (epirubicin) and flameless atomic absorption spectrometry (platinum), and results submitted to population PK analysis using non-linear mixed effects modeling. We calculated the association between gene polymorphisms, anticancer drug exposure, radiological tumor response, progression-free survival (PFS), overall survival (OS) and chemotherapy-related toxicity using appropriate statistical tests. Results: Patients with a low clearance of the active metabolite 5FU had an increased risk of neutropenia in both groups (p A and A2846T were associated with diarrhea (p Conclusions: Carriers of the TYMS high-expression genotype have a markedly inferior outcome when receiving capecitabine-based chemotherapy for advanced colorectal or gastroesophageal cancer. Therapeutic targeting of this molecularly-defined subgroup of patients should be explored to improve their prognosis. Disclosure: All authors have declared no conflicts of interest.