Imaging, Diagnosis, Prognosis PIK3CA Mutations Predict Local Recurrences in Rectal Cancer Patients

Purpose: 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. Experimental Design: 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. Results: 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. Conclusion: 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. (Clin Cancer Res 2009;15(22):6956–62) Colorectal cancer is the third most common cancer and the fourth most frequent cause of cancer deaths worldwide. WHO estimates that 945,000 new cases occur yearly, with 492,000 deaths (1). Approximately 25% of these cases are rectal cancer. In the treatment of rectal cancer patients, local and distant recurrences are a major problem because they are associated with both high morbidity and mortality. The introduction of total mesorectal excision (TME) surgery (2) in combination with preoperative radiotherapy resulted in a reduction of local recurrences (3) and has been recently accepted as standard treatment for rectal cancer in many countries. Although preoperative radiotherapy can prevent local recurrences in certain patients, the majority of patients will not develop a local recurrence without radiotherapy; furthermore, still more than 25% of the patients will develop distant metastases within 5 years of surgery, irrespective of preoperative radiotherapy (3, 4). Moreover, radiotherapy has several substantial negative side effects (5, 6). Therefore, identifying prognostic markers for refinement of personalized treatment is clinically relevant. Recently, Samuels et al. (7) identified somatic mutations in the PIK3CA gene in various human tumors, including colorectal cancer. PIK3CA mutations have been found in 10% to 30% colorectal cancers (7–12), with most activating mutations clustering in hotspots of exons 9 and 20, affecting the functionally important helical and kinase domains (7, 9, 13). Because there is a close interaction between RAS and phosphoinositide 3-kinases (PI3K; refs. 14–16), activation of the PI3K/AKT signaling pathway through PIK3CA mutations or the RAS–RAF– mitogen-activated protein kinase (MAPK) signaling was considered to be one of the most common mechanisms involved Authors' Affiliations: Departmentsof Experimental Therapy, Pathology, and Radiotherapy, Netherlands Cancer Institute, Amsterdam, the Netherlands; Departments of Surgical Oncology and Radiotherapy, Leiden University Medical Center, Leiden, the Netherlands; and Department of Pathology, University Medical Center St. Radboud, Nijmegen, the Netherlands Received 5/7/09; revised 7/22/09; accepted 8/10/09; published OnlineFirst