About the Project
Lacking effective targeted therapies, patients with triple negative breast cancer (TNBC) have relatively poorer prognosis with higher likelihood of distant recurrence within 5 years of diagnosis than patients with hormone receptor positive breast cancer. Approximately 34% of TNBC achieve a pathological complete response (pCR) to surgery after the use of neoadjuvant (i.e. prior surgery) multi-agent chemotherapy, and are associated with improved outcomes. The poor prognosis of TNBC is, therefore, derived largely from the fraction of patients with significant residual disease in the breast after neoadjuvant chemotherapy (NACT).
There is a range of emerging therapeutic options for advanced TNBC recurring after anthracycline and taxane therapy, for example, carboplatin and novel therapies such as, immunotherapy and Poly (ADP-ribose) polymerases (PARP) inhibitors. Platinum-based chemotherapy is a common treatment option for patients with metastatic TNBC (mTNBC). Studies had shown that patients who have inherited breast cancer with germline BRCA1/2 mutations, they may actually do better longer with platinum drugs first. Results from our TNT trial (a randomized Phase III trial of carboplatin compared to docetaxel for patients with metastatic or recurrent locally advanced ER–, PR– and HER2– breast cancer) have also suggested that mTNBC with BRCA1/2 mutation may have greater benefit from carboplatin than standard of care. On the other hand, the OlympiAD (Phase III) trial showed that olaparib, one kind of PARP inhibitor, delayed progression of HER2-negative BRCA-mutation advanced breast cancer, compared to chemotherapy.
Developing predictive biomarkers for patient response to additional therapeutic targets is critical in metastatic setting. Using the genomic data (RNA-sequencing data) collected in TNT trial, we aim to develop accurate transcriptional measure of aberrant DNA repair deficiency. TNT clinical trial design: TNT was a phase III, parallel group, randomised controlled trial conducted in 74 UK centres (ISRCTN97330959, NCT00532727) (Chief Investigator: Professor Andrew Tutt). Patients provided written informed consent. 376 patients with advanced germline BRCA1/2 mutation or TNBC suitable for taxanes were randomly assigned to docetaxel or carboplatin. The primary endpoint was objective response (ORR). Secondary endpoints included progression-free survival (PFS), overall survival, and safety. We would also evaluate the expression patterns of these transcriptional BRCAness signatures in our newly developed trial, PHOENIX, of high-risk metastatic risk TNBC. PHOENIX (Chief investigator: Professor Andrew Tutt) is a peer reviewed and Cancer Research UK endorsed clinical trial platform initiative involving post neoadjuvant pre-surgical disease profiling and novel therapy “window of opportunity” (WOP) biomarker endpoint trial. This WOP trial provides an opportunity to answer key biological hypotheses and more rapidly inform and refine combination therapy treatment approaches in a biologically assessable chemotherapy resistant treatment site within a subgroup of TNBC patients who are at high risk of metastatic relapse. The clinical impact of this proposed study is to develop predictive biomarkers and address the clinical challenge of identifying patients who are likely to benefit from standard and emerging therapies for mTNBC.
Candidate profile
Candidates must have a first class or upper second class honours BSc Honours/MSc or equivalent in statistics, computer science, computational biology or bioinformatics
How to apply
Full details about these studentship projects, and the online application form, are available on our website, at: www.icr.ac.uk/phds Applications for all projects should be made online. Please ensure that you read and follow the application instructions very carefully.
Closing date: Monday 20th November 2017
Applicants should be available for interview 29h and 30th January 2018.
Please apply via the ICR vacancies web portal https://studentapps.icr.ac.uk/
Download a PDF of the complete project proposal:
https://d1ijoxngr27nfi.cloudfront.net/default-document-library/cheang-icr-studentship-proposal-form-2016-updated-web.pdf
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