Effect of preoperative radiotherapy on local recurrences in rectal cancer patients with PIK3CA mutation.

Abstract

3639 Background: Preoperative (chemo) radiation has a significant reducing effect on local recurrence rates in rectal cancer. Identifying rectal cancer patients who are at risk for local recurrence (LR) would allow for refinement in selection of patients who would benefit from preoperative radiotherapy (PRT). PIK3CA mutations have been demonstrated to correlate with poor prognosis among patients with resectable stage I to III colon cancer. In non-PRT stage I-III rectal cancer patients, we demonstrated a 5-year LR risk of 28% for mutated patients vs. 9% (p = 0.006) for nonmutated patients (He, CCR 2009). In this study, we evaluate whether PIK3CA mutant rectal cancer patients benefit from PRT in preventing LR. Methods: Patients were derived from the Total Mesorectal Excision (TME) trial, in which stage I-III rectal cancer patients were randomized for PRT (5x5 Gy) followed by TME surgery, or TME surgery only (median follow-up 7.2 years). A case-only design was used to evaluate the frequency of PIK3CA mutations in both irradiated and nonirradiated patients with a LR. Tumor-tissue of 24 out of 74 nonirradiated and 30 out of 32 irradiated patients with a LR was available. PIK3CA mutations in exon 9 and 20 were evaluated by PCR and sequencing. Results: We previously demonstrated a PIK3CA mutation frequency of 7.9% in 240 nonirradiated patients. In nonirradiated patients with a LR, the frequency of PIK3CA mutations was 20.8% (5/24), whereas in irradiated LR patients only 6.7% (2/30) PIK3CA mutations were found (OR = 0.27; 95% CI 0.05-1.56, p = 0.14). Due to the overall small number of mutations (∼8%), 29 cases (PIK3CA mutants) and 190 controls (wild-type patients) with a LR would be required to increase the power to a 90% level, which is 69 irradiated and 150 nonirradiated patients. Conclusions: PIK3CA mutations can be used as a prognosticator to identify rectal cancer patients with an increased risk for local recurrences. The odds ratio evaluating the beneficial effect of PRT on PIK3CA mutant patients suggests that PIK3CA mutations may also be used as a predictor for PRT benefit. This finding supports our suggestion that prospective evaluation of PIK3CA mutation status can reduce overtreatment for low-risk rectal cancer patients. No significant financial relationships to disclose.