Medical Biology - Research Publications
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ItemImpact of the evolution in RAS mutation analysis in Australian patients with metastatic colorectal cancer(WILEY, 2022-10)BACKGROUND: RAS mutation testing now routinely informs the optimal management of metastatic colorectal cancer (mCRC), specifically the finding of a RAS mutation defines patients who will not benefit from treatment with an epidermal growth factor receptor inhibitor. Over time more RAS genes have been tested and more sensitive techniques used. AIMS: To review routine care RAS testing and results over time. METHODS: A retrospective analysis of the molecular data collected prospectively in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry from 2009 to 2018 was undertaken. Patients with RAS data were further analyzed. In parallel, the RAS mutation status of patients enrolled in the Test Tailor Treat (TTT) program was examined for 2011-2018. RESULTS: Of 2908 patients in the TRACC registry, 1892 (65%) were tested, with 898 (47%) of tested patients found to be RAS mutant (RASmt). RAS data were available for 5935 TTT patients. Of the tested TRACC patients diagnosed in 2009 and 2010, 38% were RASmt. For each 2-year period from 2011/2012 through to 2017/2018, the prevalence of RASmt in TRACC and TTT was 42% and 40% (2011/2012), 52% and 40% (2013/2014), 47% and 49% (2015/2016), and 47% and 49% (2017/2018). CONCLUSIONS: Based on both TRACC and TTT data, the proportion of patients reported to have a RAS mutation increased from 2009 to 2015 but has remained relatively stable in recent years. The increased proportion of RASmt patients observed over time is likely largely driven by the uptake of extended RAS testing.
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ItemBiology and Clinical Implications of Fecal Occult Blood Test Screen-Detected Colorectal Cancer(OXFORD UNIV PRESS, 2022-01-05)BACKGROUND: Fecal occult blood test (FOBT)-based screening for colorectal cancer (CRC) reduces mortality, with earlier stage at diagnosis a prominent feature. Other characteristics of FOBT screen-detected cancers and any implications for clinical management have not been well explored. METHODS: We examined a multisite clinical registry to compare the characteristics and outcomes of FOBT screen-detected CRC via the Australian National Bowel Cancer Screening Program (NBCSP), which is offered biennially to individuals aged 50-74 years, and age-matched non-screen-detected CRC in the same registry. All statistical tests were 2-sided. Odds ratios (ORs) were calculated using the Baptista-Pike method, and hazard ratios via the log-rank method. RESULTS: Of 7153 registry patients diagnosed June 1, 2006, to June 30, 2020, 4142 (57.9%) were aged between 50 and 74 years. Excluding 406 patients with non-NBCSP screen-detected cancers and 35 patients with unknown method of detection, 473 (12.8%) were screen detected via the NBCSP, and 3228 (87.2%) were non-screen detected. Screen-detected patients were younger (mean age = 62.4 vs 64.2 years; P < .001) and more medically fit (OR for ASA score 1-2 = 1.91, 95% confidence interval [CI] = 1.51 to 2.41; P < .001). Pathologic characteristics within each stage favored the screen-detected patients. Stage III screen-detected colon cancers were more likely to receive adjuvant therapy (OR = 3.58, 95% CI = 1.52 to 8.36; P = .002). Screen-detected patients had superior relapse-free (hazard ratio = 0.41, 95% CI = 0.29 to 0.60; P < .001) and overall survival (hazard ratio = 0.22, 95% CI = 0.15 to 0.35; P < .001), which was maintained in matched stage comparisons and multivariable analysis. CONCLUSIONS: Beyond stage at diagnosis, multiple other factors associated with a favorable outcome are observed in FOBT screen-detected CRC. Given the substantial stage-by-stage differences in survival outcomes, if independently confirmed, individualized adjuvant therapy and surveillance strategies could be warranted for FOBT screen-detected cancers.
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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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ItemThe impact of bevacizumab in metastatic colorectal cancer with an intact primary tumor: Results from a large prospective cohort study(WILEY, 2017-08)BACKGROUND: Debate continues regarding the benefits versus risks of initial resection of the primary tumor in metastatic colorectal cancer (mCRC) patients with an asymptomatic primary tumor. Although the benefit of the anti-vascular endothelial growth factor agent bevacizumab alongside first-line chemotherapy in mCRC is established, the impact of bevacizumab on the intact primary tumor (IPT) is less well understood. METHODS: Data from an Australian mCRC registry were used to assess the impact of bevacizumab-based regimens in the presence of an IPT, to see if this differs from effects in resected primary tumor (RPT) patients and to understand the safety profile of bevacizumab in patients with IPT. Progression-free survival (PFS), overall survival (OS) and safety endpoints were analyzed. RESULTS: Of 1204 mCRC patients, 826 (69%) were eligible for inclusion. Bevacizumab use was similar in both arms (IPT (64%) versus RPT (70%)); compared with chemotherapy alone, bevacizumab use was associated with significantly longer PFS (IPT: 8.5 months vs 4.7 months, P = 0.017; RPT: 10.8 months vs 5.8 months, P < 0.001) and OS (IPT: 20 months vs 14.8 months, P = 0.005; RPT: 24.4 months vs 17.3 months, P = 0.004)).1 Bevacizumab use in an IPT was associated with more GI perforations (4.5% vs 1.8%, P = 0.210) but less frequent bleeding (1.5% vs 5.3%, P = 0.050) and thrombosis (1.5% vs 2.7%, P = 0.470), versus chemotherapy alone. Median survival was equivalent between patients that did or did not experience bevacizumab-related adverse events - 20.0 months versus 19.9 months, hazard ratio = 0.98, P = 0.623.1 CONCLUSIONS: The addition of bevacizumab significantly improved survival outcomes in mCRC with an IPT. The occurrence of bevacizumab-related adverse events did not significantly impact survival outcomes.
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ItemGlucagonoma Masquerading as a Mucinous Cancer of the Ovary: Lessons from Cell Biology(IntechOpen, 2020-06-17)High-grade mucinous ovarian cancer (HGMOC) is often a misnomer as the majority of cases are metastatic disease with a gastro-intestinal origin. The standard platinum-based ovarian cancer (OC) chemotherapy regimens are often ineffective, and there are insufficient data to support the use of colorectal cancer (CRC) chemotherapy regimens due to the rarity of HGMOC. We described a cohort of four consecutive suspected HGMOC cases treated at the Royal Women’s Hospital, Melbourne in 2012. Two cases were treated as primary MOC, whereas the other two were considered to be metastatic CRC based on histopathological and clinical evidence. From the RNAseq analysis, we identified two cases of HGMOC whose gene expression profiles were consistent with mucinous epithelial OC, one case that was treated as metastatic CRC with gene expression profile correlated with CRC and one case with neuroendocrine (NET) gene expression features. Interestingly, glucagon was over-expressed in this tumor that was subsequently confirmed by immunohistochemistry. These findings suggest a rare glucagonoma-like NET appendiceal tumor that had metastasized to the surface of ovary and were unresponsive to CRC chemotherapy regimens. In summary, a carefully curated panel of expression markers and selected functional genomics could provide diagnosis and treatment guidance for patients with possible HGMOC.
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ItemGuesstimates are not good enough for determining what is happening in routine care(NATURE PUBLISHING GROUP, 2010-12-07)