Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Bowtell, David × Author: Gorringe, Kylie × Author: Scott, Clare × Start date: 2020 × Type: Journal Article ×

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    Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes
    Meagher, NS ; Gorringe, KL ; Wakefield, M ; Bolithon, A ; Pang, CNI ; Chiu, DS ; Anglesio, MS ; Mallitt, K-A ; Doherty, JA ; Harris, HR ; Schildkraut, JM ; Berchuck, A ; Cushing-Haugen, KL ; Chezar, K ; Chou, A ; Tan, A ; Alsop, J ; Barlow, E ; Beckmann, MW ; Boros, J ; Bowtell, DDL ; Brand, AH ; Brenton, JD ; Campbell, I ; Cheasley, D ; Cohen, J ; Cybulski, C ; Elishaev, E ; Erber, R ; Farrell, R ; Fischer, A ; Fu, Z ; Gilks, B ; Gill, AJ ; Gourley, C ; Grube, M ; Harnett, PR ; Hartmann, A ; Hettiaratchi, A ; Hogdall, CK ; Huzarski, T ; Jakubowska, A ; Jimenez-Linan, M ; Kennedy, CJ ; Kim, B-G ; Kim, J-W ; Kim, J-H ; Klett, K ; Koziak, JM ; Lai, T ; Laslavic, A ; Lester, J ; Leung, Y ; Li, N ; Liauw, W ; Lim, BWX ; Linder, A ; Lubinski, J ; Mahale, S ; Mateoiu, C ; McInerny, S ; Menkiszak, J ; Minoo, P ; Mittelstadt, S ; Morris, D ; Orsulic, S ; Park, S-Y ; Pearce, CL ; Pearson, J ; Pike, MC ; Quinn, CM ; Mohan, GR ; Rao, J ; Riggan, MJ ; Ruebner, M ; Salfinger, S ; Scott, CL ; Shah, M ; Steed, H ; Stewart, CJR ; Subramanian, D ; Sung, S ; Tang, K ; Timpson, P ; Ward, RL ; Wiedenhoefer, R ; Thorne, H ; Cohen, PA ; Crowe, P ; Fasching, PA ; Gronwald, J ; Hawkins, NJ ; Hogdall, E ; Huntsman, DG ; James, PA ; Karlan, BY ; Kelemen, LE ; Kommoss, S ; Konecny, GE ; Modugno, F ; Park, SK ; Staebler, A ; Sundfeldt, K ; Wu, AH ; Talhouk, A ; Pharoah, PDP ; Anderson, L ; DeFazio, A ; Kobel, M ; Friedlander, ML ; Ramus, SJ (AMER ASSOC CANCER RESEARCH, 2022-12-15)
    PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.
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    Therapeutic options for mucinous ovarian carcinoma
    Gorringe, KL ; Cheasley, D ; Wakefield, MJ ; Ryland, GL ; Allan, PE ; Alsop, K ; Amarasinghe, KC ; Ananda, S ; Bowtell, DDL ; Christie, M ; Chiew, Y-E ; Churchman, M ; DeFazio, A ; Fereday, S ; Gilks, CB ; Gourley, C ; Hadley, AM ; Hendley, J ; Hunter, SM ; Kaufmann, SH ; Kennedy, CJ ; Kobel, M ; Le Page, C ; Li, J ; Lupat, R ; McNally, OM ; McAlpine, JN ; Pyman, J ; Rowley, SM ; Salazar, C ; Saunders, H ; Semple, T ; Stephens, AN ; Thio, N ; Torres, MC ; Traficante, N ; Zethoven, M ; Antill, YC ; Campbell, IG ; Scott, CL (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2020-03)
    OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.