Background: Non-response to neoadjuvant therapy is a significant challenge for clinicians managing solid cancers. This thesis aimed to determine whether Epithelial Mesenchymal Transition (EMT) was associated with non-response to neoadjuvant therapy in patients with locally advanced rectal cancer.
Methods: Representative tissue specimens from the tumour invasive front of consecutive patients undergoing resection of rectal cancer from 2009-2011 were used. Patients with marked regression to neoadjuvant therapy were classified as responders with the remainder as non-responders. Markers of EMT included: reduced immunohistochemical expression of membranous E-cadherin, increased nuclear beta-catenin expression and tumour budding. In-situ-hybridisation was used to assess the expression of microRNA-200c (mir200c), an upstream master-regulator of EMT. Real-time polymerase chain reaction was used to quantitate expression of the gene for E-cadherin.
Results: From 103 patients undergoing resection of rectal cancer, 69 received neoadjuvant chemoradiotherapy; 65% of these were non-responders. Reduced mir200c expression was significantly associated with higher T grade. Reduced membranous E-cadherin, increased nuclear beta-catenin and tumour budding individually predicted the presence of extra-mural vascular invasion. Reduced E-cadherin, nucleic beta-catenin, reduced mir200c and tumour budding were all significantly associated with non-response to neoadjuvant therapy (all p<0.001). Reduced E-cadherin and mir200c expression were both associated with reduced cancer specific survival (log-rank p-value 0.036 and 0.009 respectively). E-cadherin gene expression was not related to radiotherapy response or tumour budding.
Conclusion: Targeted biomarkers of EMT were associated with non-response to neoadjuvant therapy and reduced survival in advanced rectal cancer. EMT may provide a practical clinical biomarker and novel therapeutic target, to improve the proportion of patients who respond to neoadjuvant therapy.