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Expression of p27 in Residual Rectal Cancer after Preoperative Chemoradiation Predicts Long-term Outcome

From the Departments of Surgery (HGM, LR, JGG), Pathology (JS, DSK), Epidemiology and Biostatistics (MM), Medicine (GKS, LS), and Radiation Oncology (BDM), Memorial Sloan-Kettering Cancer Center, New York, New York.

Correspondence: Address correspondence and reprint requests to: Jose G. Guillem, MD, MPH, 1275 York Avenue, Room C-1077, New York, NY 10021; Fax: 646-422-2318; E-mail: guillemj{at}mskcc.org

Background: Compared with surgery alone, preoperative radiotherapy and 5-fluorouracil–based chemotherapy (combined-modality therapy; CMT) improves outcomes in patients with locally advanced rectal cancer. Although numerous studies have focused on identifying molecular markers of prognosis in the primary rectal cancer before CMT, our aim was to identify markers of prognosis in residual rectal cancer after preoperative CMT.

Methods: Sixty-seven patients with locally advanced (T3–4 and/or N1) rectal cancer were treated with preoperative radiotherapy (median, 5040 cGy) with or without 5-fluorouracil–based chemotherapy. Residual tumor in the resected specimen, available for 52 patients, was analyzed for tumor-node-metastasis stage, lymphovascular and/or perineural invasion, and immunohistochemical expression of p27, p21, p53, Ki-67, retinoblastoma gene, cyclin D1, and bcl-2. Recurrence-free survival (RFS) was determined by the Kaplan-Meier method and compared by the log-rank test.

Results: With a median follow-up of 69 months, the overall 5-year RFS was 74%. RFS was significantly worse for patients with positive p27 expression (P = .005), T3–4 tumors (P = .02), and positive lymph nodes (P = .04) in the irradiated specimen. On multivariate analysis, positive p27 expression remained an independent negative prognostic factor for RFS (P = .04). None of the other proteins was significantly associated with RFS.

Conclusions: Our results indicate that positive p27 expression in rectal cancer after preoperative chemoradiation is an independent negative predictor of RFS. Expression of p27 in the residual rectal cancer may therefore identify patients with disease likely to be refractory to standard therapy and for whom investigational approaches should be strongly considered.

Key Words: p27 • Cyclin-dependent kinase inhibitor • Rectal neoplasms • Chemoradiation

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