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

Abstract

Background: 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 polymorfisms (MTHFR, TSER and DPYD) on toxicity and response to pre-operative radio-chemotherapy. Materials and methods: We HAVE enrolled sixteen patients with locally advanced RC treated with pre-operative radiotherapy and fluoropyrimidines base 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 pyrosequensing of genomic DNA extracted from peripheral blood samples. Genetics markers were correlated with toxicity to treatment (chemotherapy and radio-chemotherapy) and clinical response. Results: Patients characteristics were: male 13 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 wilde type, DPYD A2846T, T/T homozygous wilde type and DPYD T1679 g, T/T homozygous wilde type in 100% of pts, homozygous wilde type MTHFR C677T in 10% of pts, MTHFR C677T homozygous mutated in 50% of pts, heterozygous MTHFR A1298C in 60% of pts and homozygous wilde type MTHFR A 1298C in 40% of pts. G3-G4 advers events (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 wilde type was not associated with severe toxicity. Rectal surgery with TME will be performed 8 weeks after the end of pre-operative chemo-radiotherapy. We obtained 7 patological complete response and nine partial patological response. Adjuvant chemotherapy was well tolerated without G3-G4 adverse events. Three pts with patological complete respose were treated with Transanal Endoscopic Microsurgery (TEM) and they are alive without recurrence to twelve months after surgery. Conclusion: Concomitant assesment of genetic polymorphisms of MTHFR and DPYD is promising to predict severe toxicity during preoperative chemo-radioterapy 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.