Abstract
Identifying rectal cancer patients at risk for local recurrence would allow for refinement in the selection of patients who would benefit from preoperative radiotherapy. PIK3CA, KRAS, and BRAF mutations are commonly found in colon cancers, but their prevalence has not been clearly assessed in rectal cancer. In this study, we aim to determine the mutation frequencies of PIK3CA, KRAS, and BRAF and to investigate whether a mutation may be used as a prognostic parameter in rectal cancer patients. We evaluated DNA mutations in PIK3CA, KRAS, and BRAF in 240 stage I to III rectal tumors obtained from nonirradiated patients from the Dutch Total Mesorectal Excision trial. PIK3CA, KRAS, and BRAF mutations were identified in 19 (7.9%), 81 (33.9%), and 5 (2.1%) rectal cancers. Patients with PIK3CA mutations developed more local recurrences (5-year risks, 27.8% versus 9.4%; P = 0.006) and tended to develop these recurrences more rapidly after surgery (median local recurrence-free interval since surgery: 7.9 versus 19.6 months; P = 0.07) than patients without PIK3CA mutations. In multivariate analysis, PIK3CA mutations remained as an independent predictor for the development of local recurrences (hazard ratio, 3.4; 95% confidence interval, 1.2-9.2; P = 0.017), next to tumor-node-metastasis stage. PIK3CA mutations can be used as a biomarker in identifying rectal cancer patients with an increased risk for local recurrences. Currently, our findings suggest that prospective evaluation of PIK3CA mutation status could reduce overtreatment by preoperative radiotherapy for the low-risk patients who might otherwise only experience the side effects.
Highlights
Identifying rectal cancer patients at risk for local recurrence would allow for refinement in the selection of patients who would benefit from preoperative radiotherapy
Little is known regarding those mutation frequencies in rectal cancer because most of the mutation studies were done in colon cancer or colorectal cancer as a combined entity
Our large sample of rectal cancers, obtained from a prospective multicenter randomized trial (Dutch total mesorectal excision (TME) Trial), enabled us to make a precise estimate of the mutation frequency in rectal cancer
Summary
Identifying rectal cancer patients at risk for local recurrence would allow for refinement in the selection of patients who would benefit from preoperative radiotherapy. Conclusion: PIK3CA mutations can be used as a biomarker in identifying rectal cancer patients with an increased risk for local recurrences. We have identified the mutation pre‐ valence of PIK3CA, KRAS, and BRAF genes in rectal cancer and showed that PIK3CA mutations are strongly associated with a high risk of local recurrences in nonirradiated stage I to III rectal cancer patients. Our study indicates for the first time that PIK3CA mutations can be used as a biomarker in identifying rectal cancer patients with an increased risk for local recurrences. Our findings suggest that prospective evaluation of the PIK3CA mutation status could reduce overtreatment by preoperative radiotherapy for the low-risk rectal cancer patients who might otherwise only experience the side effects. Any available data that make this distinction largely focus on colon cancer, whereas the prevalence of these gene mutations remains unclear in rectal cancer
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