Sir Peter MacCallum Department of Oncology - Research Publications

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    Gata-3 Negatively Regulates the Tumor-Initiating Capacity of Mammary Luminal Progenitor Cells and Targets the Putative Tumor Suppressor Caspase-14
    Asselin-Labat, M-L ; Sutherland, KD ; Vaillant, F ; Gyorki, DE ; Wu, D ; Holroyd, S ; Breslin, K ; Ward, T ; Shi, W ; Bath, ML ; Deb, S ; Fox, SB ; Smyth, GK ; Lindeman, GJ ; Visvader, JE (AMER SOC MICROBIOLOGY, 2011-11)
    The transcription factor Gata-3 is a definitive marker of luminal breast cancers and a key regulator of mammary morphogenesis. Here we have explored a role for Gata-3 in tumor initiation and the underlying cellular mechanisms using a mouse model of "luminal-like" cancer. Loss of a single Gata-3 allele markedly accelerated tumor progression in mice carrying the mouse mammary tumor virus promoter-driven polyomavirus middle T antigen (MMTV-PyMT mice), while overexpression of Gata-3 curtailed tumorigenesis. Through the identification of two distinct luminal progenitor cells in the mammary gland, we demonstrate that Gata-3 haplo-insufficiency increases the tumor-initiating capacity of these progenitors but not the stem cell-enriched population. Overexpression of a conditional Gata-3 transgene in the PyMT model promoted cellular differentiation and led to reduced tumor-initiating capacity as well as diminished angiogenesis. Transcript profiling studies identified caspase-14 as a novel downstream target of Gata-3, in keeping with its roles in differentiation and tumorigenesis. A strong association was evident between GATA-3 and caspase-14 expression in preinvasive ductal carcinoma in situ samples, where GATA-3 also displayed prognostic significance. Overall, these studies identify GATA-3 as an important regulator of tumor initiation through its ability to promote the differentiation of committed luminal progenitor cells.
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    Precision oncology using a clinician-directed, tailored approach to molecular profiling
    Lam, M ; Tran, B ; Beck, S ; Tie, J ; Herath, D ; Whittle, J ; Kwan, EM ; Fox, SB ; Fellowes, A ; Ananda, S ; Lipton, L ; Gibbs, P ; Rosenthal, MA ; Desai, J (WILEY, 2018-02)
    AIM: Precision oncology involves molecularly matching patients to targeted agents usually in early drug development (EDD) programs. Molecular profiling (MP) identifies actionable targets. Comprehensive commercial MP platforms are costly and in resource limited environments, a more practical approach to MP is necessary to support EDD and precision oncology. We adopted a clinician-directed, tailored approach to MP to enrol patients onto molecularly targeted trials. We report the feasibility of this approach. METHODS: All patients referred to the Royal Melbourne Hospital (RMH) EDD between September 2013 and September 2015 were identified in a prospective database. Key captured data included clinicopathological data, MP platform ordered (if any), molecular targets identified and subsequent enrolment onto clinical trials. EDD-clinician decisions to order MP and the platform utilized was guided by patient consultation, tumor type, trial availability and requirement for molecular information. RESULTS: We identified 377 patients referred to RMH EDD. A total of 216 (57%) had MP ordered. The remainder had known actionable targets (19%), or were inappropriate for clinical trials (24%). In those undergoing MP, 187 genetic aberrations were found in 113 patients with 98 considered actionable targets in 86 patients. Ninety-eight (25%) patients were enrolled onto a clinical trial, including 40 (11%) receiving molecularly matched treatments. Median progression-free survival was improved in patients enrolled onto molecularly matched trials compared to those on unmatched trials (3.6 months vs 1.9 months, HR 0.58 [0.38-0.89], P  =  0.013). CONCLUSION: A clinician-directed, tailored approach to the use of MP is feasible, resulting in 11% of patients enrolled onto molecularly matched trials.
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    Australian recommendations for EGFR T790M testing in advanced non-small cell lung cancer
    John, T ; Bowden, JJ ; Clarke, S ; Fox, SB ; Garrett, K ; Horwood, K ; Karapetis, CS (WILEY, 2017-08)
    First-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used as first-line therapy in patients with non-small cell lung cancer (NSCLC) harboring a sensitizing mutation in the EGFR gene. Unfortunately, resistance to these therapies often occurs within 10 months of commencing treatment and is mostly commonly due to the development of the EGFR T790M mutation. Treatment with the third-generation EGFR TKI, osimertinib can prolong progression free survival in patients with the T790M mutation, so it is important to determine the resistance mechanism in order to plan ongoing therapeutic strategies. Here we review the evidence and make recommendations for the timing of T790M mutation testing, the most appropriate specimens to test and the available testing methods in patients progressing during treatment with first line EGFR TKIs for NSCLC.
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    Cousins not twins: intratumoural and intertumoural heterogeneity in syndromic neuroendocrine tumours
    Flynn, A ; Dwight, T ; Benn, D ; Deb, S ; Colebatch, AJ ; Fox, S ; Harris, J ; Duncan, EL ; Robinson, B ; Hogg, A ; Ellul, J ; To, H ; Cuong, D ; Miller, JA ; Yates, C ; James, P ; Trainer, A ; Gill, AJ ; Clifton-Bligh, R ; Hicks, RJ ; Tothill, RW (WILEY, 2017-07)
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    GATA3 expression in triple-negative breast cancers
    Byrne, DJ ; Deb, S ; Takano, EA ; Fox, SB (WILEY, 2017-07)
    AIMS: GATA-binding protein 3 (GATA3) is a well-studied transcription factor found to be essential in the development of luminal breast epithelium and has been identified in a variety of tumour types, including breast and urothelial carcinomas, making it a useful immunohistochemistry marker in the diagnosis of both primary and metastatic disease. METHODS AND RESULTS: We investigated GATA3 protein expression in a 106 primary triple-negative breast carcinomas (100 basal-like, six non-basal-like) using Cell Marque mouse monoclonal anti-GATA3 (L50-823). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to quantify mRNA expression in 22 triple-negative breast cancers (TNBCs) (20 primary and two cell lines), four luminal (three primary and one cell line) and five human epidermal growth factor receptor 2 (HER2) (four primary and one cell line) amplified tumours. In 98 TNBCs where IHC was assessable, 47 (48%) had a 1+ or greater staining with 20 (21%) having high GATA3 expression when using a weighted scoring. CONCLUSION: Our study has demonstrated that GATA3 expression is common in primary triple-negative breast carcinomas. It also suggests that although GATA3 is an oestrogen receptor (ER) regulated gene, it still proves useful in differentiating between primary and metastatic tumours in patients with a history of breast cancer regardless of its molecular subtype.
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    MDM4 is a rational target for treating breast cancers with mutant p53
    Miranda, PJ ; Buckley, D ; Raghu, D ; Pang, J-MB ; Takano, EA ; Vijayakumaran, R ; Teunisse, AFAS ; Posner, A ; Procter, T ; Herold, MJ ; Gamell, C ; Marine, J-C ; Fox, SB ; Jochemsen, A ; Haupt, S ; Haupt, Y (WILEY, 2017-04)
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    Reply to the Baader-Meinhof phenomenon in ductal carcinoma in situ of the breast
    Pang, J-MB ; Gorringe, KL ; Fox, SB (WILEY-BLACKWELL, 2016-09)
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    Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma
    Kader, T ; Hill, P ; Zethoven, M ; Goode, DL ; Elder, K ; Thio, N ; Doyle, M ; Semple, T ; Sufyan, W ; Byrne, DJ ; Pang, J-MB ; Murugasu, A ; Miligy, IM ; Green, AR ; Rakha, EA ; Fox, SB ; Mann, GB ; Campbell, IG ; Gorringe, KL (WILEY, 2019-07)
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    Molecular comparison of interval and screen-detected breast cancers
    Cheasley, D ; Li, N ; Rowley, SM ; Elder, K ; Mann, GB ; Loi, S ; Savas, P ; Goode, DL ; Kader, T ; Zethoven, M ; Semple, T ; Fox, SB ; Pang, J-M ; Byrne, D ; Devereux, L ; Nickson, C ; Procopio, P ; Lee, G ; Hughes, S ; Saunders, H ; Fujihara, KM ; Kuykhoven, K ; Connaughton, J ; James, PA ; Gorringe, KL ; Campbell, IG (WILEY, 2019-06)
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    Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications
    McCart Reed, AE ; Kalaw, E ; Nones, K ; Bettington, M ; Lim, M ; Bennett, J ; Johnstone, K ; Kutasovic, JR ; Saunus, JM ; Kazakoff, S ; Xu, Q ; Wood, S ; Holmes, O ; Leonard, C ; Reid, LE ; Black, D ; Niland, C ; Ferguson, K ; Gresshoff, I ; Raghavendra, A ; Harvey, K ; Cooper, C ; Liu, C ; Kalinowski, L ; Reid, AS ; Davidson, M ; Pearson, JV ; Pathmanathan, N ; Tse, G ; Papadimos, D ; Pathmanathan, R ; Harris, G ; Yamaguchi, R ; Tan, PH ; Fox, SB ; O'Toole, SA ; Simpson, PT ; Waddell, N ; Lakhani, SR (WILEY, 2019-02)