• single nucleotide polymorphism
• metastatic colrectal cancer
• TAS-102

As survival has improved for patients with metastatic colorectal cancer (mCRC), there is an increasing need for effective and well-tolerated therapies in third-line and subsequent-lines of treatment. The options for treating refractory mCRC have expanded with the recent introduction of regorafenib and TAS-102, both of which demonstrated improved survival in placebo-controlled phase III trials. TAS-102 is an oral agent consisting of trifluridine combined with tipiracil hydrochloride to improve bioavailability. This agent is currently approved for the treatment of patients who previously received fluoropyrimidine, oxaliplatin- and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) biological therapy, and if RAS wildtype, an anti-epidermal growth factor receptor (EGFR) therapy.
In the present work we analyzed pharmacogenetic markers involved in TAS-102 cellular uptake (hENT1, CNT1), metabolism (TK1) and elimination (MATE1, MATE2, OCT2) in order to identify functional polymorphisms contributing to the differences between patients in terms of disease severity, treatment efficacy and toxicity.
This study investigated 8 SNPs of the 6 above specified genes in three independents cohorts of refractory mCRC patients:
1) an evaluation cohort of 52 patients receiving TAS-102 referred at Cancer Institute Hospital in Japan; 2) a control cohort of 52 patients treated with regorafenib referred at Azienda Ospedaliero-Universitaria Pisana and; 3) a validation cohort of 129 patients receiving TAS-102 referred at Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy, Istituto Oncologico Veneto, Padova, Italy and Istituto Nazionale Tumori, Milano, Italy.
In the evaluation cohort, patients with hENT1 rs760370 G/- (N= 25) allelic variant had significant longer PFS [3.5 vs. 2.1 months, hazard ratio (HR) 0.44, 95%CI: 0.23-0.83, P=0.004] (Figure 2) and OS (8.7 vs. 5.3 months, HR 0.27, 95%CI: 0.10-0.70, P =0.003) compared to those with the A/A variant (N=27). This association was maintained in multivariate analyses (HR for PFS 0.44, P=0.023; HR for OS 0.17, P=0.008). In the control cohort of patients receiving regorafenib and no previous treatment with TAS-102, uni- and multivariate analyses showed no significant differences in hENT1 rs760370. Interaction between hENT1 rs760370 G/A variants and treatment suggested that the relation of hENT1 rs760370 AA variant with shorter PFS and OS was caused by the effect of TAS-102 treatment (p for PFS=0.069, p for OS=0.024). No other associations in terms of treatment efficacy and toxicity were identified.
A further validation of these findings has been obtained in the validation cohort of 129 patients treated with TAS-102 in Italy. At the univariate analysis, patients with hENT1 rs760370 G/- (N=83) had statistical improvement of PFS [2.1 vs. 1.9 months, HR 0.64, 95%CI: 0.43-0.95, P=0.021] and OS (9.0 vs. 3.9 months, HR 0.50, 95%CI: 0.29-0.86, P =0.009) than those with the A/A variant (N=46). The association was maintained in the multivariate model both for PFS (HR 0.65, 95%CI: 0.43-0.98, P=0.038) and OS (HR 0.54, 95%CI: 0.31-0.93, P=0.027).
These data suggest a possible role for hENT1 rs760370 variants in predicting the efficacy of TAS-102 in chemorefractory mCRC. Patients’ selection based on molecular factors is one of the most important challenges in modern oncology. In general, our results represent a step forward in the knowledge of TAS-102 mechanisms of action and if further validated might represent an useful tool for clinical decision making in chemorefractory mCRC patients.