Abstract 1145: CXCR4-CXCL12-CXCR7 axis predicts prognosis in locally advanced-Chemo Radiotherapy (CRT) treated rectal cancer patients.

Abstract With optimized local treatment and the shift from a postoperative to a preoperative treatment approach, distant metastases have become the predominant mode of failure in locally advanced rectal cancer (LARC). Therefore, the intensification of chemotherapy appears today as an essential approach to improve distant control and survival in LARC. However, extensive evidence have indicated that the LARC presents a considerable heterogeneity in terms of prognostic and response to preoperative treatment. Thus a critical issue is the selection of patients for postoperative chemotherapy strongly favoring a risk-adapted strategy rather than “one size fits all” approach. The chemokine receptor CXCR4 is expressed in colorectal cancer (CRC) and correlates with reduced survival and disease-free interval. A novel receptor for CXCL12, CXCR7, was recently identified. Despite the signal transduction of CXCR7 is not defined it certainly regulates the activity of CXCR4. The aim of the present study is to evaluate the possible prognostic role of CXCR4-CXCL12-CXCR7 axis in LARC patients subjected to CRT neoadjuvant treatment and total mesorectal excision. Sixty-eight LARC patients treated with different scheme of CRT and with persistence of pathological tumor were evaluated for the expression of CXCR4, CXCR7, CXCL12 through immunohistochemistry. CXCR4 and CXCR7 were rated as negative (0-50%) CXCL12 was rated as low (50%). At a median follow up of 65 months, high CXCR4 expression (>50%) impacted significantly on 5- years-relapse free survival (RFS) and -cancer specific survival (CSS); high CXCR4 patients had a 5-year RFS of 51,5% versus 93,7% negative-low CXCR4 (HR 0.10; 95% CI, 0.07-0.44) (p = 0.0003), patients with high CXCR4 had a 5-year CSS of 69% versus the 100% of negative-low CXCR4 (HR 0.00; 95% CI, 0.03-0.43) (p = 0.001). The expression of CXCR7 and CXCL12 alone did not correlate with survival; concomitant expression of CXCR4/CXCR7 or CXCR4/CXCL12 improved the prediction of survival. High CXCR4 expression/ neg-low CXCR7 (< 50%) impacted on 5 years- RFS (p = 0.0001) as well as CSS (p = 0.0278); high CXCR4 expression plus neg-low CXCL12 (<50%) affected 5 years-RFS (p = 0.0166) and CSS (p = 0.0145). Interestingly evaluating CXCR4 categories (negative/low and high) versus the lymph nodal status (negative and positive) significantly improved the predictive power of CXCR4 and N status. High CXCR4 expression plus N+ identified patients with a worse 5 years RFS (p= 0.0001). The valuation of the CXCR4-CXCL12-CXCR7 axis is a valuable prognostic tool in rectal cancer patients treated with CRT neoadjuvant. Moreover CXCR4 inhibitors might be considered in the adjuvant treatment of rectal cancer. Citation Format: Crescenzo D'Alterio, Antonio Avallone, Paolo Delrio, Fabiana Tatangelo, Biagio Pecori, Elena Di Gennaro, Rosario Vincenzo Iaffaioli, Paolo Muto, Gerardo Botti, Stefania Scala. CXCR4-CXCL12-CXCR7 axis predicts prognosis in locally advanced-Chemo Radiotherapy (CRT) treated rectal cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1145. doi:10.1158/1538-7445.AM2013-1145