P-220 - MTHFR, TSER and DPYD gene mutation is associated with toxicity and response in pre-operative chemo-radiotherapy for local advanced rectal cancer

Abstract

Introduction: Radiotherapy and 5 FU based chemotherapy is the most common pre-operative regimen used for cT3-T4, N1 rectal cancer (RC). Evaluation of predictive markers of response and toxicity to radio-chemotherapy is a challenging approach for patients (pts) and drug selection. In the present experience we have analyzed the predictive role of the genetic polymorphisms (MTHFR, TSER and DPYD) on toxicity and response to pre-operative radio-chemotherapy. Methods: We have enrolled eighteen patients with locally advanced RC treated with pre-operative radiotherapy and fluoropyrimidines based chemotherapy. Genetic polymorphisms of MTHFR C677T, MTHFRA 1298C, DPYD IVS 14 + 1G>A, DPYDA 2846T, DPYD T 1679 G, TSER 28 bp VNTR were analyzed by PCR and pyrosequencing of genomic DNA extracted from peripheral blood samples. Genetic markers were correlated with toxicity to treatment (chemotherapy and radio-chemotherapy) and clinical response. Results: Patients characteristics were: male 15 pts, female 3 pts, median age 66 years, ECOG PS 0-1 all pts. We found DPYD IVS 14 + 1 G>A G/G homozygous wild type, DPYD A2846T, T/T homozygous wild type and DPYD T1679 g, T/T homozygous wild type in 100% of pts, homozygous wild type MTHFR C677T in 10% of pts, MTHFR C677T homozygous mutated in 50% of pts, heterozygous MTHFR A1298C in 60% of pts and homozygous wild type MTHFR A 1298C in 40% of pts. Adverse events G-3 (diarrhea, neutropenia, asthenia, mucositis) were observed in 60% of pts with heterozygous MTHFR A 1298C and in 10% of pts with homozygous mutated MTHFR C 677t treated with chemo radiotherapy combination. DPYD homozygous wild type was not associated with severe toxicity. Rectal surgery with TME/TEM will be performed 8 weeks after the end of pre-operative chemo-radiotherapy. We obtained 9 pathological complete response and 9 partial pathological response. Adjuvant chemotherapy was well tolerated without G3-G4 adverse events. Five pts with pathological complete response were treated with Transanal Endoscopic Microsurgery (TEM) and they are alive without recurrence to twelve months after surgery. Conclusion: Concomitant assessment of genetic polymorphisms of MTHFR and DPYD is promising to predict severe toxicity during preoperative chemo-radiotherapy approach for pts with locally advanced rectal cancer. This result does not exclude the need to consider other non-genetic factors that might influence the individual enzyme activities.