Medical Biology - Research Publications
Permanent URI for this collection
Search Results
1 - 10 of 10
-
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.
-
ItemUse and outcomes of chemotherapy for metastatic pancreatic cancer in Australia(WILEY, 2022-01)BACKGROUND: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is highly lethal. Combination chemotherapy regimens improve overall survival (OS). Historically, only one-third of mPDAC patients in Victoria received chemotherapy. AIM: To describe current Australian chemotherapy utilisation and outcomes in patients with mPDAC using the multi-site PURPLE (Pancreatic cancer: Understanding Routine Practice and Lifting End Results) registry. METHODS: PURPLE collects longitudinal data on consecutive patients with pancreatic cancer seen since January 2016. Data were collated for patients with mPDAC from six Victorian sites, and analysed descriptively. RESULTS: Three hundred and sixty-three patients with mPDAC were identified. Median age was 70 years (range 20-94 years). First-line chemotherapy was administered in 195 (54%) patients. Prevalent regimens included gemcitabine-nab-paclitaxel (71%), gemcitabine alone (10%) and FOLFIRINOX (6%). Sixty-two of 195 (32%) patients who received first line treatment have proceeded to second-line chemotherapy. Chemotherapy-treated patients were younger (69 versus 73 years; P < 0.01), with better Eastern Cooperative Oncology Group (ECOG) performance status (ECOG 0-1 89 vs 66%; P < 0.01) and lower median Charlson comorbidity index (3 vs 4; P < 0.01) compared with untreated patients. Median OS of the entire cohort from diagnosis of metastases was 5.1 months. Median OS was 9.3 months in the chemotherapy treated patients, and 2.5 months in chemotherapy-untreated patients (P < 0.01). CONCLUSIONS: A substantial proportion of patients with mPDAC still do not receive active treatment, which may in part by explained by age, poor performance status and comorbidity. Gemcitabine-nab-paclitaxel was the preferred first-line chemotherapy regimen. Median OS for treated patients in this cohort was comparable to that of recent published clinical trials.
-
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.
-
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.
-
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.
-
ItemRight versus left sided metastatic colorectal cancer: Teasing out clinicopathologic drivers of disparity in survival(WILEY, 2019-06)BACKGROUND: Metastatic colorectal cancer (mCRC) patients with a right-sided primary (RC) have an inferior survival to mCRC arising from a left-sided primary (LC). Previous analyses have suggested multiple factors contribute. METHODS: The Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Registry prospectively captured data on consecutive mCRC patients. RC were defined as tumors proximal to the splenic flexure; LC were those at and distal to the splenic flexure and included rectal cancers. Patient, tumor, treatment, and survival data were analyzed stratified by side. RESULTS: Of 2306 patients enrolled from July 2009-March 2018, 747 (32%) had an RC. Patients with RC were older, more likely to be female and have a Charlson score ≥3. RC were more frequently BRAF mutated, deficient in mismatch repair, associated with peritoneal metastases, and less likely to receive chemotherapy. Progression-free survival on first-line systemic therapy was inferior for RC patients (8.1 vs. 10.8 months, hazard ratio [HR] for progression in RC 1.38, P < 0.001). Median overall survival for all RC patients was inferior (19.6 vs. 27.5 months, HR for death in RC 1.44, P < 0.001), and inferior within the treated (21 vs. 29.5 months, HR 1.52, P < 0.001) and untreated subgroups (5.9 vs. 10.3 months, HR 1.38, P = 0.009). Primary side remained a significant factor for overall survival in multivariate analysis. CONCLUSION: Our data from a real-world population confirms the poorer prognosis associated with RC. Primary tumor location remains significantly associated with overall survival even when adjusting for multiple factors, indicating the existence of further side-based differences that are as yet undefined.
-
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.
-
ItemCART-WHEEL.org: An Ethically Approved Online Database for Patient-Entered Data to Facilitate Rare Cancer Research(LIPPINCOTT WILLIAMS & WILKINS, 2020-02-21)PURPOSE: Rare cancers are challenging for researchers, as clinicians and scientists have difficulty recruiting sufficient patient cases to power studies appropriately. Likewise, patients often are frustrated by a lack of specific information or evidence base for their cancer and, although eager to participate in research, have limited opportunities. We established CART-WHEEL.org, an online patient-entered database, to directly engage patients in the research process, collect rare cancer data, and facilitate their entry into additional research. PATIENTS AND METHODS: Patients access CART-WHEEL.org directly online. Clinical information is collected from users via a streamlined questionnaire developed collaboratively with consumer groups to ensure accessibility and relevance. Data collected include the following: patient demographics, comorbidities, and risk factors and tumor diagnostic, biomarker, and treatment history. Patients can download a medical summary for personal use; consent for research use of data; and indicate willingness to be contacted about other research or clinical trials. We describe data collected to date and its validation, and we provide examples of how CART-WHEEL.org can facilitate rare cancer research. RESULTS: From January 2010 to March 2018, 558 patients provided consent and entered their rare cancer data. One hundred distinct rare tumor types and patients from 22 countries were included. Validation of data entered by 21 patients with sarcoma against a hospital database demonstrated accuracy sufficient to facilitate future research in key fields, such as tumor site (95%) and histopathologic diagnosis (90%). Examples of CART-WHEEL-based disease-specific projects, subsequent recruitment to other rare cancer projects, and rare cancer patient cases of interest are described. CONCLUSIONS: Online platforms like CART-WHEEL.org can engage consumers directly, facilitating collection of patient-entered rare cancer data for hypothesis generation, and connect patients with researchers to enable specific rare cancer research and clinical trials.
-
ItemGuesstimates are not good enough for determining what is happening in routine care(NATURE PUBLISHING GROUP, 2010-12-07)
-
ItemMethylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma(NATURE PUBLISHING GROUP, 2018-09-28)Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.