Sir Peter MacCallum Department of Oncology - Research Publications
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ItemPrecision oncology using a clinician-directed, tailored approach to molecular profiling(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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ItemAustralian recommendations for EGFR T790M testing in advanced non-small cell lung cancer(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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ItemGATA3 expression in triple-negative breast cancers(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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ItemMolecular comparison of interval and screen-detected breast cancers(WILEY, 2019-06)
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ItemCurrent mismatch repair deficiency tumor testing practices and capabilities: A survey of Australian pathology providers(WILEY, 2018-12)AIM & METHODS: An electronic survey of the Royal College of Pathologists of Australasia accredited pathology services was conducted to assess Lynch syndrome tumor screening practices and to identify barriers and capabilities to screen newly diagnosed colorectal and endometrial tumors in Australia. RESULTS: Australia lacks a national policy for universal mismatch repair-deficient (dMMR) testing of incident colorectal and endometrial tumors cases. Routine Lynch syndrome tumor screening program for colorectal and/or endometrial tumors was applied by 95% (37/39) of laboratories. Tumor dMMR screening methods varied; MMR protein immunohistochemistry (IHC) alone was undertaken by 77% of 39 laboratories, 18% performed both IHC and microsatellite instability testing, 5% did not have the capacity to perform in-house testing. For colorectal tumors, 47% (17/36) reported following a universal approach without age limit, 30% (11/36) tested only "red flag" cases; 6% (3/36) on clinician request only. For endometrial tumors, 37% (12/33) reported clinician request generated testing, 27% (9/33) were screening only "red flag" cases, and 12% (4/33) carried out universal screening without an age criteria. BRAF V600E mutation testing of colorectal tumors demonstrating aberrant MLH1 protein expression by IHC was the most common secondary tumor test, with 53% of laboratories performing the test; 15% of laboratories also applied the BRAF V600E test to endometrial tumors with aberrant MLH1 expression despite no evidence for its utility. Tumor testing for MLH1 promoter methylation was performed by less than 15% laboratories. CONCLUSION: Although use of tumor screening for evidence of dMMR is widely available, protocols for its use in Australia vary widely. This national survey provides a snapshot of the current availability and practice of tumor dMMR screening and identifies the need for a uniform national testing policy.
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ItemAn analysis of a multiple biomarker panel to better predict prostate cancer metastasis after radical prostatectomy(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.