Association of beclin 1 expression with response to neoadjuvant chemoradiation therapy in patients with locally advanced rectal carcinoma

Abstract

Beclin 1 is an essential regulator of autophagy that is induced in response to cellular stress and serves to maintain cell survival in established tumors. We recently demonstrated that Beclin 1 suppression can sensitize colorectal cancer cells to radiation-induced DNA damage and apoptosis. Therefore, we hypothesized that the level of Beclin 1 expression may be associated with radiation sensitivity in vivo. We determined the association of Beclin 1 expression in pretreatment rectal cancer tissues with response to neoadjuvant chemoradiation in surgical resection specimens. Stages II and III (n=96) rectal adenocarcinoma patients were treated with neoadjuvant chemoradiation followed by surgical resection with curative intent. Beclin 1 was analyzed by immunohistochemistry and the expression level was dichotomized at the median value with categorization into low and high groups. We identified 56 (58.3%) and 40 (41.7%) patients whose tumors had high- versus low-level Beclin 1 expression, respectively. Rectal cancers with high versus low Beclin 1 expression were significantly less likely to be downstaged after chemoradiation treatment (45% [25/55] vs. 58% [22/38]; p=0.02). In a multivariable analysis adjusted for age, sex, histological grade and baseline tumor node metastasis (TNM) stage, the impact of Beclin 1 expression on tumor downstaging remained statistically significant (p=0.03). The association of the level of Beclin 1 expression with the rate of tumor downstaging after chemoradiation is consistent with in vitro data, and suggests that Beclin 1 may be a predictive biomarker for the efficacy of chemoradiation in patients with rectal cancer. What's new? Patients with nonmetastatic rectal cancer routinely receive chemotherapy and radiation before surgery. However, a predictive marker for the efficacy of chemoradiation is lacking. Here, the authors show that the essential autophagy protein Beclin 1 -known to protect against radiation-induced DNA damage- could be such a predictive marker. In locally advanced rectal cancer patients, high-level Beclin 1 expression in pretreatment tumor tissues was associated with a significantly reduced rate of tumor downstaging after chemoradiation and vice versa, supporting a new role of Beclin 1 as a clinical biomarker.