Plasma microRNA biomarkers in rectal cancer patients undergoing neoadjuvant therapy

Abstract

Colorectal cancer (CRC) is the second most common cause of cancer related death worldwide with an expected 1.8 million new cases this year (1). CRC claims approximately 1200 New Zealand lives per year and rectal cancer patients account for approximately 25% of CRC cases (2). The mainstay of treatment for locally advanced rectal cancer is neoadjuvant therapy followed by surgical excision. The purpose of neoadjuvant therapy is to reduce rates of local recurrence, increase sphincter preservation and to improve tumour resectability (3), however the risk to patients is exposure to unnecessary toxins and their effects. Most importantly, patient response to neoadjuvant therapy is varied, and complete pathological response will occur in 15-27% of patients (4). Therefore, a significant proportion of patients undergoing therapy will suffer unnecessary delays to surgery and toxic exposure. There are currently no clinically utilised biomarkers to predict response to neo-adjuvant therapy. Development of predictive markers would enable optimal treatment of patients and avoid ineffective and potentially harmful treatments. miRNA are short regulatory transcripts that are stable in biofluids. Their dysregulation has been extensively reported in CRC and their usefulness in the detection of cancer and as predictors of prognosis and treatment response is a rapidly growing area of research. Whilst the majority of work has been on tissue biomarkers, blood biomarkers would be less invasive and expose patients to less risk.

This thesis has investigated changes in circulating miRNA levels in patients who have locally advanced rectal cancer and have undergone neoadjuvant therapy. The main aim of this study was to ascertain if miR-21, miR-29a, miR-143, and miR-145 levels in plasma prior to treatment can predict response to SCR and LCCR therapy. Plasma samples were taken prior to and after neoadjuvant therapy. RNA was extracted and miRNA levels were analysed using RT-qPCR. Relative expression was evaluated and compared to pathological specimen reports after surgery. In this pilot study we have found a significant increase in the relative expression miR-143 in plasma after SCR. There was no difference in expression of miR-21, miR-29a, miR-143 or miR-145 in patients with stage II and III rectal cancer compared to healthy controls. There was no difference in expression of target miRNA in patients who had a response to neoadjuvant therapy compared to those who did not respond.

This is the first study to use patients’ plasma to evaluate the expression of these miRNA and examine whether this can predict TRG. This is important because finding a predictive blood biomarker is a more accessible and potentially clinically useful tool than tumour biopsy. Findings from this study will contribute to the pool of research on the use of miRNA’s in CRC for diagnostic and predictive tests. As this is a pilot study, future samples being collected from these patients may also contribute to knowledge on recurrence.