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dc.contributor.authorMapagu, Maria Cristina
dc.date.accessioned2019-03-20T21:24:59Z
dc.date.available2019-03-20T21:24:59Z
dc.date.issued2018-06-29
dc.identifier.urihttp://hdl.handle.net/2123/20181
dc.description.abstractMost women with advanced epithelial ovarian cancers (EOC) will relapse. Currently, there are no predictive tests to guide clinicians when treating relapsed EOC. The aim of the work described in this thesis was to identify genomic markers that predict response to treatments commonly used in relapsed EOC: platinum chemotherapy, pegylated liposomal doxorubicin (PLD) and endocrine therapy. We identified women treated with platinum, PLD or endocrine therapy, performed molecular tests on primary tumour and associated these with response. In platinum-treated patients, we confirmed that homologous recombination (HR) deficiency, either HR pathway gene mutations or an overall ‘HRD score’, was associated with higher response rates. CCNE1 gain/amplification was associated with non-response to platinum (p=0.03). In PLD treated patients,BRCA mutations were associated with increased response (p=0.04). We examined HGSOC expression subtypes (C1, C2, C4, C5) in relation to platinum and PLD response, and although no significant associations were found there was an over-representation of the C4 subtype in platinum non-responders and an under-representation of the C2 subtype in PLD responders. Using RNA-Seq, we identified 41 differentially expressed genes (DEGs)between PLD-sensitive and -resistant, newly established HGSOC cell lines; 4 of these genes were also differentially expressed in tumours from PLD complete responders and non-responders. In patients treated with endocrine therapy, increasing ERa histoscores in HGSOC tumours may be associated with response (p=0.07). Using RNA-Seq, we identified oestrogen (E2)-regulated genes in ER+ HGSOC cell lines with differential E2growth response. We identified 27 DEGs between HGSOC tumours from endocrine therapy responders and non-responders, and found that most of these genes were E2-regulated. This E2-regulated signature may identify patients with ER+ HGSOC that respond to endocrine therapy. Taken together, we found that molecular markers in primary tumour could potentially predict treatment outcome in relapsed EOC. Our data provide a rationale for testing primary tumour for specific predictive molecular markers. If validated, these predictive markers could be used to personalise treatment of relapsed EOC.en_AU
dc.publisherUniversity of Sydneyen_AU
dc.publisherFaculty of Medicine and Healthen_AU
dc.publisherSydney Medical Schoolen_AU
dc.rightsThe author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.en_AU
dc.subjectovarian Canceren_AU
dc.subjectpredictive markersen_AU
dc.subjectcarboplatinen_AU
dc.subjectliposomal doxorubicinen_AU
dc.subjectendocrine therapyen_AU
dc.titleMolecular and Genetic Features Underlying Treatment Response in Relapsed Ovarian Canceren_AU
dc.typePhD Doctorateen_AU
dc.type.pubtypeDoctor of Philosophy Ph.D.en_AU


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