Germline polymorphisms may act as predictors of response to preoperative chemoradiation in locally advanced T3 rectal tumors.

PURPOSE

Patients with locally advanced T3 rectal tumors who present with complete pathologic response to preoperative chemoradiation have a low rate of local recurrence and an excellent prognosis. Predictive markers for complete pathologic response are needed with the perspective of improving individualized treatment of these patients. This study was designed to investigate the predictive value of a new combination of three gene polymorphisms: thymidylate synthase, epidermal growth factor receptor Sp1-216, and epidermal growth factor A61G.

METHODS

Pretreatment blood samples from 60 patients with locally advanced T3 rectal tumors were analyzed for thymidylate synthase, epidermal growth factor receptor Sp1-216, and epidermal growth factor A61G gene polymorphisms by polymerase chain reaction. Treatment consisted of preoperative radiotherapy (total dose 65 Gy) and concomitant chemotherapy (Uftoral) followed by total mesorectal excision eight weeks after treatment. Pathologic response was evaluated according to the tumor regression grade system.

RESULTS

Thirty percent (18/60) of patients presented with complete pathologic response. Patients with thymidylate synthase genotype 2/2 had a significantly higher rate of complete pathologic response with 53 percent (8/15) compared with 22 percent in the 2/3 or 3/3 group. When combining thymidylate synthase and epidermal growth factor A61G genotype analysis, a small subgroup with a complete pathologic response rate of 100 percent was identified. Only a minor proportion of the complete responders were identified by this combination. Adding the epidermal growth factor receptor Sp1-216 genotype analysis, a complete pathologic response rate of 64 percent in the combination group was found compared with 21 percent and an 87 percent risk of being a noncomplete responder in the noncombination group.

CONCLUSIONS

A promising new combination of predictive markers for complete pathologic response was presented and warrants further investigation in prospective clinical trials.