Profiling mucinous ovarian cancer and comparisons with tumours of the gastro-intestinal tract: identification of markers for diagnosis, prognosis, and treatment targets.
Mucinous Ovarian Carcinoma (MOC) is a rare histological subtype, comprising 3-4% of all epithelial ovarian cancers. The majority (~80%) of patients are diagnosed at early stage, International Federation of Gynecology and Obstetrics (FIGO I/II), with a good prognosis after primary surgery. The key clinical challenges in MOC are: 1) identifying which patients with Stage I MOC are at risk of relapse and require adjuvant chemotherapy; 2) accurately diagnosing primary MOC from a cancer that has started elsewhere and spread to the ovary, most commonly from a gastrointestinal (GI) site; and 3) finding better treatment options for patients with advanced stage (III/IV) MOC. Using the international Ovarian Tumor Tissue Analysis consortium, this thesis sought to address these issues. Samples and data were pooled through the consortium for 3 projects: an immunohistochemistry (IHC) study on tissue microarrays examining the role of SATB2 in improving diagnosis of MOC (n=314) from colorectal and appendiceal tumours (n=230); a NanoString mRNA gene expression profiling study of mucinous ovarian borderline tumours (n=151), primary MOC (n=333), and upper (pancreatic/gastric, n=65)) and lower (colorectal/appendiceal, n=55) tumours to look for prognostic and diagnostic markers; thirdly a multicolour IHC and immune fluorescence project to quantify the immune infiltrate in MOC (n=124), assessing whether immune therapies are worth exploring for patients. In addition, an international commercial tumour profiling dataset was analysed with IHC and mutation data to examine profiles of MOC (n=295) and compare with publicly available GI profiles to look for shared treatment targets. I found that the addition of SATB2 in combination with CK7 was highly sensitive and specific in differentiating primary MOC from colorectal and appendiceal metastases, and made recommendations for clinical diagnostic practice. I confirmed that an infiltrative pattern of invasion in Stage I MOC is prognostic within the first two years of diagnosis and warrants consideration of adjuvant chemotherapy for those women. I identified that high expression of 2 genes, THBS2 and TAGLN were associated with poorer overall survival, suggesting a possible relationship with the infiltrative subtype and more aggressive disease. I confirmed prior suggestions that MOC are immunologically ‘cold’, with only 12 out of 66 early stage, and 1 out of 12 advanced stage tumours showing a T cell/PD-L1 phenotype potentially suitable for current immune based therapies. I confirmed the mutation profile of MOC with high rates of KRAS, TP53 mutations, and argued that clinical trial criteria for patients with advanced stage mucinous cancer involving the ovary should focus less on the site of origin, and more on molecular targets for basket trials with GI cancers sharing molecular features. This comprehensive body of work covers diagnosis through to treatment, with translational potential using SATB2, an infiltrative pattern of invasion in Stage I clinical decision making, targets such as THBS2 and TAGLN to be further explored and suggests a shift towards basket clinical trials with upper GI cancers due to phenotypic similarities with MOC.
Ovarian Cancer, Biomarkers, Tumour profiling, anzsrc-for: 3211 Oncology and carcinogenesis, anzsrc-for: 321502 Obstetrics and gynaecology, anzsrc-for: 4202 Epidemiology
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