Sir Peter MacCallum Department of Oncology - Research Publications

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    Metformin may offer no protective effect in men undergoing external beam radiation therapy for prostate cancer
    Ranasinghe, WKB ; Williams, S ; Ischia, J ; Wetherell, D ; Baldwin, G ; Shulkes, A ; Sengupta, S ; Bolton, D ; Patel, O (WILEY, 2019-05)
    OBJECTIVES: To assess whether metformin reduces radio-resistance and increases survival in men undergoing external beam radiation therapy (EBRT) for prostate cancer (PCa), and to determine its effect on hypoxia inducible factor 1-α (HIF1α). PATIENTS AND METHODS: All patients treated with curative intent with EBRT for PCa at a major cancer centre between 2000 and 2007 were included in this study. The outcome measures of time to biochemical failure (BF), metastasis, PCa-specific mortality and overall survival (OS) were analysed in those taking metformin vs those not, using competing risk and Cox regression models. To determine metformin's effect on HIF1α expression and survival in vitro, PC3 cells with high basal HIF1α levels were subjected to increasing doses of metformin after H2 O2 -induced oxidative stress. RESULTS: A total of 2055 eligible cases, including 113 who were on metformin, were identified, with a median follow-up of 95.7 months. There were no differences in age, initial prostate-specific antigen level, Gleason score, T-stage, D'Amico risk class or duration of androgen deprivation therapy (ADT) between patients who were or were not on metformin. Treatment with metformin did not result in any apparent improvement in time to BF, time to metastasis detection or OS, but there was a 1.5-fold increase in PCa-specific deaths (P = 0.045) in patients on metformin and ADT when adjusted for cancer risk and comorbidities. When comparing patients on high-dose metformin (>1 g/d) with those on low-dose metformin (≤1 g), there was no difference in either time to metastases or time to BF. In vitro metformin at a high concentration of 100 μM did not reduce HIF1α expression, nor did metformin affect the PC3 cell survival when exposed to oxidative stress (H2 O2 ). CONCLUSIONS: No association was found between the use of metformin and time to metastasis detection, time to BF or OS in patients undergoing radiation therapy with or without ADT for PCa. In vitro, low therapeutic concentrations of metformin had no effect on HIF1α, and this observation could explain the conflicting evidence for the effectiveness of metformin in men undergoing EBRT for PCa. Higher, more toxic doses of metformin may be required to inhibit the mammalian target of rapamycin-HIF1α pathway in this patient group.
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    An analysis of a multiple biomarker panel to better predict prostate cancer metastasis after radical prostatectomy
    Zhang, AY ; Chiam, K ; Haupt, Y ; Fox, S ; Birch, S ; Tilley, W ; Butler, LM ; Knudsen, K ; Comstock, C ; Rasiah, K ; Grogan, J ; Mahon, KL ; Bianco-Miotto, T ; Ricciardelli, C ; Bohm, M ; Henshall, S ; Delprado, W ; Stricker, P ; Horvath, LG ; Kench, JG (WILEY, 2019-03-01)
    A plethora of individual candidate biomarkers for predicting biochemical relapse in localized prostate cancer (PCa) have been proposed. Combined biomarkers may improve prognostication, and ensuring validation against more clinically relevant endpoints are required. The Australian PCa Research Centre NSW has contributed to numerous studies of molecular biomarkers associated with biochemical relapse. In the current study, these biomarkers were re-analyzed for biochemical relapse, metastatic relapse and PCa death with extended follow-up. Biomarkers of significance were then used to develop a combined prognostic model for clinical outcomes and validated in a large independent cohort. The discovery cohort (n = 324) was based on 12 biomarkers with a median follow-up of 16 years. Seven biomarkers were significantly associated with biochemical relapse. Three biomarkers were associated with metastases: AZGP1, Ki67 and PML. Only AZGP1 was associated with PCa death. In their individual and combinational forms, AZGP1 and Ki67 as a dual BM signature was the most robust predictor of metastatic relapse (AUC 0.762). The AZPG1 and Ki67 signature was validated in an independent cohort of 347 PCa patients. The dual BM signature of AZGP1 and Ki67 predicted metastasis in the univariable (HR 7.2, 95% CI, 1.6-32; p = 0.01) and multivariable analysis (HR 5.4, 95% CI, 1.2-25; p = 0.03). The dual biomarker signature marginally improved risk prediction compared to AZGP1 alone (AUC 0.758 versus 0.738, p < 0.001). Our findings indicate that biochemical relapse is not an adequate surrogate for metastasis or PCa death. The dual biomarker signature of AZGP1 and Ki67 offers a small benefit in predicting metastasis over AZGP1 alone.
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    Reproducible diagnosis of chronic lymphocytic leukemia by flow cytometry: An European Research Initiative on CLL (ERIC) & European Society for Clinical Cell Analysis (ESCCA) Harmonisation project
    Rawstron, AC ; Kreuzer, K-A ; Soosapilla, A ; Spacek, M ; Stehlikova, O ; Gambell, P ; McIver-Brown, N ; Villamor, N ; Psarra, K ; Arroz, M ; Milani, R ; de la Serna, J ; Teresa Cedena, M ; Jaksic, O ; Nomdedeu, J ; Moreno, C ; Rigolin, GM ; Cuneo, A ; Johansen, P ; Johnsen, HE ; Rosenquist, R ; Niemann, CU ; Kern, W ; Westerman, D ; Trneny, M ; Mulligan, S ; Doubek, M ; Pospisilova, S ; Hillmen, P ; Oscier, D ; Hallek, M ; Ghia, P ; Montserrat, E (WILEY, 2018-01)