Most patients who undergo surgery (oesophagectomy) for this cancer are treated pre-operatively with combined chemotherapy and radiotherapy, or chemotherapy alone (neoadjuvant therapy). Moreover, many patients who are unsuitable for oesophagectomy are managed definitively with combined chemotherapy and radiotherapy. Typically, chemotherapy entails cisplatin (CDDP) and 5-fluorouracil (5-FU). However, this is associated with significant treatment-related toxicity in up to 43% of the patients, while around 25-30% of tumours fail to respond to the treatment. This project will identify and investigate novel molecular biomarkers detectable in blood that can be used to predict the response of oesophageal cancer to chemotherapy and radiotherapy, as well as the risk of treatment toxicity. In collaboration with researchers and clinicians at Shanxi Cancer Hospital/Institute in China, where the incidence of oesophageal cancer is the highest in the world, we have found in pilot studies that members of the microRNA (miRNA)-200 family and mRNAs of cytokines of pro-inflammatory pathways in patient blood may be associated with toxicity and treatment response in oesophageal squamous cell carcinoma and adenocarcinoma. To further this work, panels of molecular biomarkers will be generated from pre-therapy blood samples collected from oesophageal cancer patients who attend Newcastle Calvary Mater Hospital and Shanxi Cancer Hospital, as well as Newcastle and Lake Macquarie Private Hospitals, and evaluated to identify predictors of treatment-associated toxicity and response to chemotherapy and radiotherapy.
The hypothesis to be tested is: Distinct miRNAs and mRNA expression profiles in blood can be used to predict the response of oesophageal cancers to chemotherapy and radiotherapy, and the risk of treatment-related toxicity.
Specific aims are:
- Identify circultaing miRNA expression profiles that predict response to chemotherapy and radiotherapy
- Rationale: Tumour miRNAs control cell survival, proliferation and response to treatment. miRNAs released by oesophageal cancer cells to blood are readily accessible sources of information relating to likely treatment response.
- Plan: Circulating miRNA expression profile will be examined in plasma by Affymetrix microarray before treatment. Tumour response will be determined and correlations between response and miRNA expression will be identified.
- Identify mRNA expression profiles that predict toxicity to chemotherapy and radiotherapy.
- Rationale: Expression of peripheral blood leukocyte-derived mRNAs has been shown to predict risk of toxicity, however, no previous studies have screened pre-therapy blood to identify novel predictive markers
- Plan: Blood-derived mRNA expression profiles will be examined by Affymetrix microarray in patients before treatment. Toxicity will be determined by Common Toxicity Criteria Adverse Event reporting. Correlations between toxicity and mRNA expression will be identified.
- Confirm differential expression of predictive miRNAs and mRNAs and develop predictive assays for chemotherapy and radiotherapy response and toxicity.
- Rationale: Molecular biomarkers discovered as above must be validated in a larger cohort of patients prospectively.
- Plan: Panels of miRNAs and mRNAs will be investigated with quantitative PCR (qPCR). Profiles that provide the best correlation statistics will be determined with specialised software.