Biomarkers for Response to Neoadjuvant Chemoradiation for Rectal Cancer

Locally advanced rectal cancer (LARC) is currently treated with neoadjuvant chemoradiation. Although approximately 45% of patients respond to neoadjuvant therapy with T-level downstaging, there is no effective method of predicting which patients will respond. Molecular biomarkers have been investigated for their ability to predict outcome in LARC treated with neoadjuvant chemotherapy and radiation. A literature search using PubMed resulted in the initial assessment of 1,204 articles. Articles addressing the ability of a biomarker to predict outcome for LARC treated with neoadjuvant chemotherapy and radiation were included. Six biomarkers met the criteria for review: p53, epidermal growth factor receptor (EGFR), thymidylate synthase, Ki-67, p21, and bcl-2/bax. On the basis of composite data, p53 is unlikely to have utility as a predictor of response. Epidermal growth factor receptor has shown promise as a predictor when quantitatively evaluated in pretreatment biopsies or when EGFR polymorphisms are evaluated in germline DNA. Thymidylate synthase, when evaluated for polymorphisms in germline DNA, is promising as a predictive biomarker. Ki-67 and bcl-2 are not useful in predicting outcome. p21 needs to be further evaluated to determine its usefulness in predicting outcome. Bax requires more investigation to determine its usefulness. Epidermal growth factor receptor, thymidylate synthase, and p21 should be evaluated in larger prospective clinical trials for their ability to guide preoperative therapy choices in LARC.

Introduction

Colorectal cancer (CRC) is the third most common cancer diagnosis among both genders, with an estimated 148,810 new cases and approximately 49,960 deaths in the United States in 2008 (1). Of those colorectal diagnoses, approximately 40,740 will be distal to the rectosigmoid junction and designated as rectal cancers (1). The 5-year survival rate for CRC patients is 64%, with 90% 5-year survival in localized disease and 10% 5-year survival for patients with metastases (1). There can be significant morbidity associated with rectal cancer treatments, including diarrhea, dysuria, hematologic toxicity, and the need for a permanent colostomy.

The ideal treatment recommendations for rectal cancer are still being developed, with some suggesting that the TNM staging system should be expanded to include substages 2, 3. Studies have demonstrated that, for locally advanced rectal cancer (LARC) (Stage T3, T4, or node-positive disease), preoperative chemoradiation (CRT) significantly improves local control and reduces toxicity profiles compared with postoperative CRT but with similar survival rates 4, 5, 6, 7, 8, 9. Furthermore, the ability to achieve pathologic downstaging, or a complete pathologic response, after neoadjuvant CRT is correlated with improved survival, decreased local recurrence, and a higher rate of sphincter-preserving surgeries 10, 11, 12.

Approximately 40–60% of LARC patients treated with neoadjuvant CRT achieve some degree of pathologic downstaging. However, there is no effective method of predicting which patients will respond to neoadjuvant CRT. Prospective identification of patients who have a higher likelihood of responding to preoperative CRT could be important in deceasing treatment morbidity and improving survival and local control in LARC. In addition, patients who are unlikely to respond could be offered alternative approaches to therapy. Recent studies have evaluated the potential of genetic biomarkers to predict outcome in LARC treated with neoadjuvant CRT. The goal of this review is to examine the current literature for the most commonly researched biomarkers for predicting outcome to neoadjuvant CRT in LARC patients.