ORCID Profile
0000-0003-3399-5342
Current Organisation
Peter MacCallum Cancer Centre
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: American Association for Cancer Research (AACR)
Date: 2011
DOI: 10.1158/1078-0432.CCR-10-2224
Abstract: Purpose: Primary tumor xenografts (PTXG) established directly from patients' primary tumors in immunosuppressed animals might represent the spectrum of histologic complexity of lung cancers better than xenografts derived from established cell lines. These models are important in the study of aberrant biological pathways in cancers and as preclinical models for testing new therapeutic agents. However, not all primary tumors engraft when implanted into immunosuppressed mice. We have investigated factors that may influence the ability of primary non–small cell lung cancer (NSCLC) to form xenografts and their association with clinical outcome. Experimental Design: Tumor fragments from patients undergoing curative surgery were implanted into NOD-SCID (nonobese diabetic-severely combined immunodeficient) mice within 24 hours of surgery. Patient characteristics for tumors that engrafted (XG) and did not engraft (no-XG) were compared. Patient tumor DNA was profiled for the presence of 238 known mutations in 19 cancer-associated genes by using the MassARRAY platform. Results: Xenografts were established and passaged successfully from 63 of 157 (40%) implanted NSCLCs. Tumor factors associated with engraftment included squamous histology, poor differentiation, and larger tumor size. Significantly fewer EGFR (epidermal growth factor receptor)-mutated tumors engrafted (P = 0.03) conversely, more K-RAS–mutated tumors engrafted (P = 0.05). In multivariate analysis including age, sex, stage, and mutation, patients with XG tumors had significantly shorter disease-free survival compared with no-XG patients (hazard ratio: 7.0, 95% CI: 3.1–15.81 P & 0.000003). Conclusion: PTXGs closely mirror the histology and molecular profiles of primary tumors and therefore may serve as important preclinical models. Tumors that engraft are biologically more aggressive and may be more representative of cancers with a higher propensity to relapse after surgery. Clin Cancer Res 17(1) 134–41. ©2010 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 2022
DOI: 10.1158/1078-0432.CCR-21-3530
Abstract: In the phase III ADAURA trial, adjuvant treatment with osimertinib versus placebo, with/without prior adjuvant chemotherapy, resulted in a statistically significant and clinically meaningful disease-free survival benefit in completely resected stage IB–IIIA EGFR-mutated (EGFRm) non–small cell lung cancer (NSCLC). We report health-related quality of life (HRQoL) outcomes from ADAURA. Patients randomized 1:1 received oral osimertinib 80 mg or placebo for 3 years or until recurrence/discontinuation. HRQoL (secondary endpoint) was measured using the Short Form-36 (SF-36) health survey at baseline, 12, and 24 weeks, then every 24 weeks until recurrence or treatment completion/discontinuation. Exploratory analyses of SF-36 score changes from baseline until week 96 and time to deterioration (TTD) were performed in the overall population (stage IB–IIIA N = 682). Clinically meaningful changes were defined using the SF-36 manual. Baseline physical/mental component summary (PCS/MCS) scores were comparable between osimertinib and placebo (range, 46–47) and maintained to Week 96, with no clinically meaningful differences between arms difference in adjusted least squares (LS) mean [95% confidence intervals (CI), −1.18 (−2.02 to −0.34) and −1.34 (−2.40 to −0.28), for PCS and MCS, respectively. There were no differences between arms for TTD of PCS and MCS HR, 1.17 (95% CI, 0.82–1.67) and HR, 0.98 (95% CI, 0.70–1.39), respectively. HRQoL was maintained with adjuvant osimertinib in patients with stage IB–IIIA EGFRm NSCLC, who were disease-free after complete resection, with no clinically meaningful differences versus placebo, further supporting adjuvant osimertinib as a new treatment in this setting. See related commentary by Patil and Bunn, p. 2204
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487226.V1
Abstract: Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487232.V1
Abstract: Supplementary Data from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: Impact Journals, LLC
Date: 23-05-2017
Publisher: AME Publishing Company
Date: 04-2019
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-03-2018
Abstract: The AURA study ( ClinicalTrials.gov identifier: NCT01802632) included two cohorts of treatment-naïve patients to examine clinical activity and safety of osimertinib (an epidermal growth factor receptor [EGFR] –tyrosine kinase inhibitor selective for EGFR–tyrosine kinase inhibitor sensitizing [ EGFRm] and EGFR T790M resistance mutations) as first-line treatment of EGFR-mutated advanced non–small-cell lung cancer (NSCLC). Sixty treatment-naïve patients with locally advanced or metastatic EGFRm NSCLC received osimertinib 80 or 160 mg once daily (30 patients per cohort). End points included investigator-assessed objective response rate (ORR), progression-free survival (PFS), and safety evaluation. Plasma s les were collected at or after patients experienced disease progression, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), to investigate osimertinib resistance mechanisms. At data cutoff (November 1, 2016), median follow-up was 19.1 months. Overall ORR was 67% (95% CI, 47% to 83%) in the 80-mg group, 87% (95% CI, 69% to 96%) in the 160-mg group, and 77% (95% CI, 64% to 87%) across doses. Median PFS time was 22.1 months (95% CI, 13.7 to 30.2 months) in the 80-mg group, 19.3 months (95% CI, 13.7 to 26.0 months) in the 160-mg group, and 20.5 months (95% CI, 15.0 to 26.1 months) across doses. Of 38 patients with postprogression plasma s les, 50% had no detectable circulating tumor DNA. Nine of 19 patients had putative resistance mechanisms, including lification of MET (n = 1) lification of EGFR and KRAS (n = 1) MEK1, KRAS, or PIK3CA mutation (n = 1 each) EGFR C797S mutation (n = 2) JAK2 mutation (n = 1) and HER2 exon 20 insertion (n = 1). Acquired EGFR T790M was not detected. Osimertinib demonstrated a robust ORR and prolonged PFS in treatment-naïve patients with EGFRm advanced NSCLC. There was no evidence of acquired EGFR T790M mutation in postprogression plasma s les.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22488177.V1
Abstract: Supplementary Figure from Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor–Mutated Non–Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial
Publisher: American Society of Clinical Oncology (ASCO)
Date: 08-2015
Abstract: Although epidermal growth factor receptor (EGFR) –mutated adenocarcinomas initially have high response rates to EGFR tyrosine kinase inhibitors (TKIs), most patients eventually develop resistance. Patient-derived xenografts (PDXs) are considered preferred preclinical models to study the biology of patient tumors. EGFR-mutant PDX models may be valuable tools to study the biology of these tumors and to elucidate mechanisms of resistance to EGFR-targeted therapies. Surgically resected early-stage non–small-cell lung carcinoma (NSCLC) tumors were implanted into nonobese diabetic severe combined immune deficient (NOD-SCID) mice. EGFR TKI treatment was initiated at tumor volumes of 150 μL. Gene expression analysis was performed using a microarray platform. Of 33 lung adenocarcinomas with EGFR activating mutations, only 6 (18%) engrafted and could be propagated beyond passage one. Engraftment was associated with upregulation of genes involved in mitotic checkpoint and cell proliferation. A differentially expressed gene set between engrafting and nonengrafting patients could identify patients harboring EGFR-mutant tumor with significantly different prognoses in The Cancer Genome Atlas Lung Adenocarcinoma datasets. The PDXs included models with variable sensitivity to first- and second-generation EGFR TKIs and the monoclonal antibody cetuximab. All EGFR-mutant NSCLC PDXs studied closely recapitulated their corresponding patient tumor phenotype and clinical course, including response pattern to EGFR TKIs. PDX models closely recapitulate primary tumor biology and clinical outcome. They may serve as important laboratory models to investigate mechanisms of resistance to targeted therapies, and for preclinical testing of novel treatment strategies.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2020
DOI: 10.1158/1535-7163.MCT-20-0149
Abstract: ABBV-321 (serclutamab talirine), a next-generation EGFR-targeted antibody–drug conjugate (ADC) incorporates a potent pyrrolobenzodiazepine (PBD) dimer toxin conjugated to the EGFR-targeting ABT-806 affinity-matured AM1 antibody. ABBV-321 follows the development of related EGFR-targeted ADCs including depatuxizumab mafodotin (depatux-m, ABT-414), ABT-806 conjugated to monomethyl auristatin F (MMAF), and ABBV-221 (losatuxizumab vedotin), AM1 antibody conjugated to monomethyl auristatin E (MMAE). The distinct tumor selectivity of ABBV-321 differentiates it from many previous highly active antibody PBD conjugates that lack a therapeutic window. Potency of the PBD dimer, combined with increased binding of AM1 to EGFR-positive tumor cells, opens the possibility to target a wide array of tumors beyond those with high levels of EGFR overexpression or lification, including those insensitive to auristatin-based ADCs. ABBV-321 exhibits potent antitumor activity in cellular and in vivo studies including xenograft cell line and patient-derived xenograft glioblastoma, colorectal, lung, head and neck, and malignant mesothelioma tumor models that are less sensitive to depatux-m or ABBV-221. Combination studies with ABBV-321 and depatux-m suggest a promising treatment option permitting suboptimal, and potentially better tolerated, doses of both ADCs while providing improved potency. Collectively, these data suggest that ABBV-321 may offer an extended breadth of efficacy relative to other EGFR ADCs while extending utility to multiple EGFR-expressing tumor indications. Despite its highly potent PBD dimer payload, the tumor selectivity of ABBV-321, coupled with its pharmacology, toxicology, and pharmacokinetic profiles, support continuation of ongoing phase I clinical trials in patients with advanced EGFR-expressing malignancies.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487217.V1
Abstract: Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: Informa UK Limited
Date: 11-2014
DOI: 10.2147/CLEP.S69718
Publisher: Springer Science and Business Media LLC
Date: 07-11-2016
DOI: 10.1007/S40273-015-0343-2
Abstract: There is a growing appetite for large complex databases that integrate a range of personal, socio-demographic, health, genetic and financial information on in iduals. It has been argued that 'Big Data' will provide the necessary catalyst to advance both biomedical research and health economics and outcomes research. However, it is important that we do not succumb to being data rich but information poor. This paper discusses the benefits and challenges of building Big Data, analysing Big Data and making appropriate inferences in order to advance cancer care, using Cancer 2015 (a prospective, longitudinal, genomic cohort study in Victoria, Australia) as a case study. Cancer 2015 has been linked to State and Commonwealth reimbursement databases that have known limitations. This partly reflects the funding arrangements in Australia, a country with both public and private provision, including public funding of private healthcare, and partly the legislative frameworks that govern data linkage. Additionally, linkage is not without time delays and, as such, achieving a contemporaneous database is challenging. Despite these limitations, there is clear value in using linked data and creating Big Data. This paper describes the linked Cancer 2015 dataset, discusses estimation issues given the nature of the data and presents panel regression results that allow us to make possible inferences regarding which patient, disease, genomic and treatment characteristics explain variation in health expenditure.
Publisher: S. Karger AG
Date: 2019
DOI: 10.1159/000501211
Abstract: b i Introduction: /i /b The cancer research community increasingly question the rigidity of eligibility criteria in clinical trials. Common reasons for “screen failure” (RFSF) are well documented however, their effect on subsequent standard therapy (SST) and outcomes is unclear. b i Methods: /i /b This retrospective study evaluated patients aged ≥18 years with solid malignancy who were listed as ineligible on a screening log between February 2011 and March 2018. Patients screen-failed for biomarker results or incorrect cancer stage rior treatment profile were excluded. Data were collected from electronic hospital records, including demographics, cancer history, RFSF, subsequent therapy, and outcomes. b i Results: /i /b Overall, 217 patients were eligible. The most common histologies were lung (28%), melanoma, colon, and pancreatic (all 11%) 90% were metastatic. The most common RFSF were rapid disease progression (PD 16%), performance status (PS) ≥2 (12%), and abnormal liver function tests (aLFT 12%). After screen failure, 129/217 (59%) had SST 9 were dose-reduced. Treatment-naïve or phase III trial-ineligible patients were more likely to receive SST than those pre-treated or phase I trial-ineligible (72/104 vs. 52/113, i /i = 0.0006 71/109 vs. 15/42, i /i = 0.00013), respectively. RFSF stabilised/improved in 104/217 (48%) the main RFSF was co-morbidity (19/104). The most common RFSF to deteriorate were rapid PD (27/72), PS ≥2 (20/72), and aLFT with liver metastases (LM 13/72). b i Conclusions: /i /b RFSF related to organ function rarely deteriorate unless directly involved with underlying malignancy. Most RFSF do not prevent patients from having SST, nor increase dose reductions, especially in treatment-naïve hase III trial-ineligible patients. Those with RFSF of poor PS, rapid PD, and aLFT from LM are less suitable for SST. Careful broadening of trial eligibility is warranted.
Publisher: Wiley
Date: 16-10-2013
DOI: 10.1002/CAM4.142
Publisher: Elsevier BV
Date: 10-2023
Publisher: Impact Journals, LLC
Date: 22-03-2014
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22488168.V1
Abstract: Supplementary Figure from Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor–Mutated Non–Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.JTHO.2017.02.013
Abstract: Results of recent clinical studies of immune checkpoint inhibitors in malignant pleural mesothelioma (MPM) have d ened initial enthusiasm. However, the immune environment and targets of these treatments such as programmed cell death protein 1 and its ligand programmed death ligand 1 (PD-L1) have not been well characterized in MPM. Using a large cohort of patients, we investigated PD-L1 expression, immune infiltrates, and genome-wide copy number status and correlated them to clinicopathological features. Tissue microarrays were constructed and stained with PD-L1(clone E1L3N [Cell Signaling Technology, Danvers, MA]), cluster of differentiation 4, cluster of differentiation 8, and forkhead box P3 antibodies. PD-L1 positivity was defined as at least 5% membranous staining regardless of intensity, and high PD-L1 positivity was defined as at least 50%. Genomic DNA from a representative subset of 113 patients was used for genome-wide copy number analysis. The percent genome alteration was computed as a proxy for genomic instability, and statistical analyses were used to relate copy number aberrations to other variables. Among 329 patients evaluated, PD-L1 positivity was detected in 130 of 311 (41.7%), but high PD-L1 positivity was seen in only 30 of 311 (9.6%). PD-L1 positivity correlated with nonepithelioid histological subtype and increased infiltration with cluster of differentiation 4-positive, cluster of differentiation 8-positive, and forkhead box P3-positive lymphocytes. High PD-L1-positive expression correlated with worse prognosis (hazard ratio = 2.37, 95% confidence interval: 1.57-3.56, p < 0.001) in univariate analysis but not in multivariate analysis. Higher percent genome alteration was associated with epithelioid histological subtype and poorer survival (hazard ratio = 1.59, 95% confidence interval: 1.01-2.5, p = 0.04) but not PD-L1 expression. PD-L1 expression was associated with nonepithelioid MPM, poor clinical outcome, and increased immunological infiltrates. Increased genomic instability did not correlate with PD-L1 expression but was associated with poorer survival.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2018
DOI: 10.1158/1078-0432.CCR-17-3493
Abstract: Cell lines formed from an in idual's tumor can be used to predict response to specific therapies and determine genomic predictors. For mesothelioma, where chemotherapy remains the backbone of current therapeutic paradigms, such assays could be used to treat patients with the most effective agents specific to their “chemical profile.” Clin Cancer Res 24(7) 1513–5. ©2018 AACR. See related article by Schunselaar et al., p. 1761
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22488165.V1
Abstract: Supplementary Table from Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor–Mutated Non–Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial
Publisher: Informa UK Limited
Date: 03-2017
Publisher: Springer Science and Business Media LLC
Date: 27-02-2023
DOI: 10.1038/S41467-023-35962-X
Abstract: Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. This analysis evaluates acquired resistance mechanisms to second-line osimertinib (n = 78) in patients with EGFR T790M advanced non-small cell lung cancer (NSCLC) from AURA3 (NCT02151981), a randomized phase 3 study comparing osimertinib with chemotherapy. Plasma s les collected at baseline and disease progression/treatment discontinuation are analyzed using next-generation sequencing. Half (50%) of patients have undetectable plasma EGFR T790M at disease progression and/or treatment discontinuation. Fifteen patients (19%) have resistance-related genomic alteration MET lification (14/78, 18%) and EGFR C797X mutation (14/78, 18%).
Publisher: Springer Science and Business Media LLC
Date: 17-02-2009
DOI: 10.1007/S00262-009-0672-0
Abstract: "Cancer stem cells" that resist conventional treatments may be a cause of therapeutic failure in melanoma. We report a subpopulation of clonogenic melanoma cells that are characterized by high prominin-1/CD133 expression in melanoma and melanoma cell lines. These cells have enhanced clonogenicity and self-renewal in vitro, and serve as a limited in vitro model for melanoma stem cells. In some cases clonogenic CD133(+) melanoma cells show increased expression of some cancer/testis (CT) antigens. The expression of NY-ESO-1 in an HLA-A2 expressing cell line allowed CD133(+) clonogenic melanoma cells to be targeted for killing in vitro by NY-ESO-1-specific CD8(+) T-lymphocytes. Our in vitro findings raise the hypothesis that if melanoma stem cells express CT antigens in vivo that immune targeting of these antigens may be a viable clinical strategy for the adjuvant treatment of melanoma.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487229.V1
Abstract: Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22488171.V1
Abstract: Supplementary Figure from Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor–Mutated Non–Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487208.V1
Abstract: Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487214.V1
Abstract: Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2016
DOI: 10.1097/CJI.0000000000000121
Abstract: Immunomodulatory agents that target PD-1 and its ligand (PD-L1) are being increasingly used in the management of lung cancer. Potential immune-related adverse events include dermatological complications which mostly are of low grade severity. The use of immune checkpoint inhibitors may lead to the exacerbation of autoimmune conditions. We report a case of a documented psoriasis flare with anti-PD-1 treatment for lung cancer.
Publisher: Elsevier BV
Date: 02-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2017
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.LUNGCAN.2016.05.024
Abstract: To identify parameters that drive the cost-effectiveness of precision medicine by comparing the use of multiplex targeted sequencing (MTS) to select targeted therapy based on tumour genomic profiles to either no further testing with chemotherapy or no further testing with best supportive care in the fourth-line treatment of metastatic lung adenocarcinoma. A combined decision tree and Markov model to compare costs, life-years, and quality-adjusted life-years over a ten-year time horizon from an Australian healthcare payer perspective. Data sources included the published literature and a population-based molecular cohort study (Cancer 2015). Uncertainty was assessed using deterministic sensitivity analyses and quantified by estimating expected value of perfect artial perfect information. Uncertainty due to technological/scientific advancement was assessed through a number of plausible future scenario analyses. Point estimate incremental cost-effective ratios indicate that MTS is not cost-effective for selecting fourth-line treatment of metastatic lung adenocarcinoma. Lower mortality rates during testing and for true positive patients, lower health state utility values for progressive disease, and targeted therapy resulting in reductions in inpatient visits, however, all resulted in more favourable cost-effectiveness estimates for MTS. The expected value to decision makers of removing all current decision uncertainty was estimated to be between AUD 5,962,843 and AUD 13,196,451, indicating that additional research to reduce uncertainty may be a worthwhile investment. Plausible future scenarios analyses revealed limited improvements in cost-effectiveness under scenarios of improved test performance, decreased costs of testing/interpretation, and no biopsy costs/adverse events. Reductions in off-label targeted therapy costs, when considered together with the other scenarios did, however, indicate more favourable cost-effectiveness of MTS. As more clinical evidence is generated for MTS, the model developed should be revisited and cost-effectiveness re-estimated under different testing scenarios to further understand the value of precision medicine and its potential impact on the overall health budget.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.PATHOL.2019.08.006
Abstract: Lung cancer is the most commonly diagnosed malignancy and the leading cause of death from cancer globally. Diagnosis of advanced non-small cell lung cancer (NSCLC) is associated with 5-year relative survival of 3.2%. ROS proto-oncogene 1 (ROS1) is an oncogenic driver of NSCLC occurring in up to 2% of cases and commonly associated with younger age and a history of never or light smoking. Results of an early trial with the tyrosine kinase inhibitor (TKI) crizotinib that inhibits tumours that harbour ROS1 rearrangements have shown an objective response rate (ORR) of 72% (95% CI 58-83%), median progression free survival (PFS) of 19.3 months (95% CI 15.2-39.1 months) and median overall survival (OS) of 51.4 months (95% CI 29.3 months to not reached). Therefore, with the availability of highly effective ROS1-targeted TKI therapy, upfront molecular testing for ROS1 status alongside EGFR and ALK testing is recommended for all patients with NSCLC. We review the tissue requirements for ROS1 testing by immunohistochemistry (IHC) and fluorescent in situ hybridisation (FISH) and we present a testing algorithm for advanced NSCLC and consider how the future of pathology testing for ROS1 may evolve.
Publisher: Wiley
Date: 10-2019
DOI: 10.1111/IMJ.14230
Abstract: Current guidelines recommend a step-wise screening algorithm for all colorectal carcinomas (CRC) to identify patients with Lynch syndrome (LS). To describe the frequencies of mismatch repair deficiency (dMMR), BRAFV600E mutations and MLH1 methylation in resected CRC, and evaluate the impact of universal screening on LS detection. Retrospectively, 1171 consecutive cases of resected CRC were identified between 2010 and 2017 from a large multi-centre pathology service. Testing for dMMR by immunohistochemistry (IHC) was initiated by the reporting pathologist from 2010, until universal testing was introduced in 2015. Patients with dMMR were referred to the Family Cancer Clinic (FCC) for consideration of germline mutation analysis. IHC was performed on 680 tumours, with abnormal expression in 124 (18%). Referral to FCC was made for 44 of the 88 patients with abnormal IHC (excluding those with BRAFV600E mutations). Of the 29 who attended, 16 underwent germline genetic testing, and LS was diagnosed in 7 with a germline mutation. After implementation of universal testing, there was a greater incidence of dMMR (17% vs 10%, P = 0.02), rate of BRAFV600E testing (79% vs 25%, P < 0.0001), and referral to FCC (61% vs 33%, P < 0.0001), but no difference in FCC attendance rate (65% vs 67%, P = 0.59) or new LS diagnoses (1.6% vs 0%, P = 0.06). Universal IHC testing may increase the detection of LS, and should be implemented where possible. However, the full benefit was limited by low referral to and uptake of genetic testing, and further strategies are needed to overcome these barriers.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.PATHOL.2016.08.003
Abstract: Malignant mesothelioma (MM) continues to be a disease with poor prognosis and limited treatment options. Calretinin and caveolin-1 expression by tumour in MM have recently been described to be associated with tumour histology, differentiation and consequently survival. In a large, well annotated cohort, we studied both of these biomarkers and explored their association with clinicopathological parameters and survival. A retrospective search of patients with MM who underwent surgery at the Austin Hospital in Melbourne, Australia, was conducted. Clinical history and outcome data were retrieved from patient records. Tissue microarrays (TMAs) were constructed and stained for calretinin and caveolin-1. 'H scores' were derived, taking intensity and distribution of staining, and the cohort was dichotomised using median values for both markers. In the 329 patients evaluated, median age was 67 years. Males outnumbered females by 5:1. Epithelioid histology 202/319 (62.9%) was the most common, followed by biphasic 72/319 (21.8%) and sarcomatoid 45/319 (13.6%) histology could not be confirmed in 10 patients. Calretinin expression was detected in 246 of the 324 (76%) evaluable patients and high expression was associated with epithelioid histology (p < 0.0001). Caveolin-1 was expressed in 298 (94%) of 317 evaluable patients which was much higher compared to its expression in a cohort of lung adenocarcinomas (8/58, 13.7%). However, no association with histology was found (p = 0.409). When taken as a continuous variable, calretinin expression was found to be an independent predictor of survival, alongside histology, neutrophil-lymphocyte ratio, weight loss and stage. No prognostic value was demonstrable for caveolin-1 expression and calretinin/caveolin-1 ratio. There was no relationship between calretinin and caveolin-1 expression. In MM, increased calretinin expression is associated with epithelioid histology and better survival. Caveolin-1 is a sensitive MM marker and is expressed in a high proportion of cases but lacks association with histology and survival.
Publisher: American Association for Cancer Research (AACR)
Date: 10-02-2022
DOI: 10.1158/1078-0432.CCR-21-3597
Abstract: Entrectinib potently inhibits tropomyosin receptor kinases (TRKAs)/B/C and ROS1, and previously induced deep [objective response rate (ORR) 57.4%] and durable [median duration of response (DoR) 10.4 months] responses in adults with NTRK fusion-positive solid tumors from three phase I/II trials. This article expands prior reports with additional patients and longer follow-up. Patients with locally advanced/metastatic NTRK fusion-positive solid tumors and ≥12 months' follow-up were included. Primary endpoints were ORR and DoR by blinded independent central review (BICR) secondary endpoints included progression-free survival (PFS), intracranial efficacy, and safety. The safety-evaluable populations included all patients who had received ≥1 entrectinib dose. At clinical cut-off (August 31, 2020), the efficacy-evaluable population comprised 121 adults with 14 tumor types and ≥30 histologies. Median follow-up was 25.8 months 61.2% of patients had a complete (n = 19) or partial response (n = 55). Median DoR was 20.0 months [95% confidence interval (CI), 13.0–38.2] median PFS was 13.8 months (95% CI, 10.1–19.9). In 11 patients with BICR-assessed measurable central nervous system (CNS) disease, intracranial ORR was 63.6% (95% CI, 30.8–89.1) and median intracranial DoR was 22.1 (95% CI, 7.4–not estimable) months. The safety profile of entrectinib in adults and pediatric patients was aligned with previous reports. Most treatment-related adverse events (TRAEs) were grade 1/2 and manageable/reversible with dose modifications. TRAE-related discontinuations occurred in 8.3% of patients. With additional clinical experience, entrectinib continues to demonstrate durable systemic and intracranial responses and can address the unmet need of a CNS-active treatment in patients with NTRK fusion-positive solid tumors.
Publisher: Springer Science and Business Media LLC
Date: 26-12-2022
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487217
Abstract: Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: Springer Science and Business Media LLC
Date: 26-02-2014
DOI: 10.1038/SREP04186
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487226
Abstract: Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.CCR.2013.03.013
Abstract: Nearly 90% of human melanomas contain inactivated wild-type p53, the underlying mechanisms for which are not fully understood. Here, we identify that cyclin B1/CDK1-phosphorylates iASPP, which leads to the inhibition of iASPP dimerization, promotion of iASPP monomer nuclear entry, and exposure of its p53 binding sites, leading to increased p53 inhibition. Nuclear iASPP is enriched in melanoma metastasis and associates with poor patient survival. Most wild-type p53-expressing melanoma cell lines coexpress high levels of phosphorylated nuclear iASPP, MDM2, and cyclin B1. Inhibition of MDM2 and iASPP phosphorylation with small molecules induced p53-dependent apoptosis and growth suppression. Concurrent p53 reactivation and BRAFV600E inhibition achieved additive suppression in vivo, presenting an alternative for melanoma therapy.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487223
Abstract: Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487211.V1
Abstract: Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487220
Abstract: Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: Wiley
Date: 09-2017
DOI: 10.1111/IMJ.13531
Abstract: In Australia, mutations in epidermal growth factor mutations (EGFR) occur in 15% of patients diagnosed with non-small-cell lung cancer and are found with higher frequency in female, non-smokers of Asian ethnicity. Activating mutations in the EGFR gene are rarely described in SCLC. We present two cases of de novo EGFR mutations in patients with SCLC detected in tissue and in plasma cell free DNA, both of whom were of Asian ethnicity and never-smokers. These two cases add to the growing body of evidence suggesting that screening for EGFR mutations in SCLC should be considered in patients with specific clinical features.
Publisher: American Association for Cancer Research (AACR)
Date: 12-08-2008
DOI: 10.1158/1078-0432.CCR-07-4170
Abstract: Purpose: Patients with macroscopic stage III melanoma represent a heterogeneous cohort with average 5-year overall survival rates of & %. With current algorithms, it is not possible to predict which patients will achieve longer-term survival. We hypothesized that molecular profiling could be used to identify prognostic groups within patients with stage III melanoma while also providing a greater understanding of the biological programs underpinning these differences. Experimental Design: Lymph node sections from 29 patients with stage IIIB and IIIC melanoma, with ergent clinical outcome including 16 “poor-prognosis” and 13 “good-prognosis” patients as defined by time to tumor progression, were subjected to molecular profiling using oligonucleotide arrays as an initial training set. Twenty-one differentially expressed genes were validated using quantitative PCR and the 15 genes with strongest cross-platform correlation were used to develop two predictive scores, which were applied to two independent validation sets of 10 and 14 stage III tumor s les. Results: Supervised analysis using differentially expressed genes was able to differentiate the prognostic groups in the training set. The developed predictive scores correlated directly with clinical outcome. When the predictive scores were applied to the two independent validation sets, clinical outcome was accurately predicted in 90% and 85% of patients, respectively. Conclusion: We describe a gene expression profile that is capable of distinguishing clinical outcomes in a previously homogeneous group of stage III melanoma patients.
Publisher: Elsevier BV
Date: 09-2009
Publisher: Springer Science and Business Media LLC
Date: 24-05-2005
Abstract: Disseminated Intravascular Coagulation (DIC) complicates up to 7% of malignancies, the commonest solid organ association being adenocarcinoma. Transitional Cell Carcinoma (TCC) has rarely been associated with DIC. A 74-year-old woman with TCC bladder and DIC was found to have a cardiac lesion suspicious for metastatic disease. The DIC improved with infusion of plasma and administration of Vitamin K, however the cardiac lesion was deemed inoperable and chemotherapy inappropriate given the patients functional status. We postulate that direct activation of the coagulation cascade by the intraventricular metastasis probably triggered the coagulopathy in this patient. Cardiac metastases should be considered in cancer patients with otherwise unexplained DIC. This may influence treatment choices.
Publisher: Elsevier BV
Date: 12-2016
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487208
Abstract: Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: Springer Science and Business Media LLC
Date: 09-11-2016
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.C.6542049
Abstract: Abstract ABBV-321 (serclutamab talirine), a next-generation EGFR-targeted antibody–drug conjugate (ADC) incorporates a potent pyrrolobenzodiazepine (PBD) dimer toxin conjugated to the EGFR-targeting ABT-806 affinity-matured AM1 antibody. ABBV-321 follows the development of related EGFR-targeted ADCs including depatuxizumab mafodotin (depatux-m, ABT-414), ABT-806 conjugated to monomethyl auristatin F (MMAF), and ABBV-221 (losatuxizumab vedotin), AM1 antibody conjugated to monomethyl auristatin E (MMAE). The distinct tumor selectivity of ABBV-321 differentiates it from many previous highly active antibody PBD conjugates that lack a therapeutic window. Potency of the PBD dimer, combined with increased binding of AM1 to EGFR-positive tumor cells, opens the possibility to target a wide array of tumors beyond those with high levels of EGFR overexpression or lification, including those insensitive to auristatin-based ADCs. ABBV-321 exhibits potent antitumor activity in cellular and i in vivo /i studies including xenograft cell line and patient-derived xenograft glioblastoma, colorectal, lung, head and neck, and malignant mesothelioma tumor models that are less sensitive to depatux-m or ABBV-221. Combination studies with ABBV-321 and depatux-m suggest a promising treatment option permitting suboptimal, and potentially better tolerated, doses of both ADCs while providing improved potency. Collectively, these data suggest that ABBV-321 may offer an extended breadth of efficacy relative to other EGFR ADCs while extending utility to multiple EGFR-expressing tumor indications. Despite its highly potent PBD dimer payload, the tumor selectivity of ABBV-321, coupled with its pharmacology, toxicology, and pharmacokinetic profiles, support continuation of ongoing phase I clinical trials in patients with advanced EGFR-expressing malignancies. /
Publisher: Oxford University Press (OUP)
Date: 31-05-2016
DOI: 10.1093/JNCI/DJW031
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487214
Abstract: Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532467.V1
Abstract: AbstractPurpose: Entrectinib potently inhibits tropomyosin receptor kinases (TRKAs)/B/C and ROS1, and previously induced deep [objective response rate (ORR) 57.4%] and durable [median duration of response (DoR) 10.4 months] responses in adults with i NTRK /i fusion-positive solid tumors from three phase I/II trials. This article expands prior reports with additional patients and longer follow-up. Patients and Methods: Patients with locally advanced/metastatic i NTRK /i fusion-positive solid tumors and ≥12 months' follow-up were included. Primary endpoints were ORR and DoR by blinded independent central review (BICR) secondary endpoints included progression-free survival (PFS), intracranial efficacy, and safety. The safety-evaluable populations included all patients who had received ≥1 entrectinib dose. Results: At clinical cut-off (August 31, 2020), the efficacy-evaluable population comprised 121 adults with 14 tumor types and ≥30 histologies. Median follow-up was 25.8 months 61.2% of patients had a complete ( i n /i = 19) or partial response ( i n /i = 55). Median DoR was 20.0 months [95% confidence interval (CI), 13.0–38.2] median PFS was 13.8 months (95% CI, 10.1–19.9). In 11 patients with BICR-assessed measurable central nervous system (CNS) disease, intracranial ORR was 63.6% (95% CI, 30.8–89.1) and median intracranial DoR was 22.1 (95% CI, 7.4–not estimable) months. The safety profile of entrectinib in adults and pediatric patients was aligned with previous reports. Most treatment-related adverse events (TRAEs) were grade 1/2 and manageable/reversible with dose modifications. TRAE-related discontinuations occurred in 8.3% of patients. Conclusions: With additional clinical experience, entrectinib continues to demonstrate durable systemic and intracranial responses and can address the unmet need of a CNS-active treatment in patients with i NTRK /i fusion-positive solid tumors. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532467
Abstract: AbstractPurpose: Entrectinib potently inhibits tropomyosin receptor kinases (TRKAs)/B/C and ROS1, and previously induced deep [objective response rate (ORR) 57.4%] and durable [median duration of response (DoR) 10.4 months] responses in adults with i NTRK /i fusion-positive solid tumors from three phase I/II trials. This article expands prior reports with additional patients and longer follow-up. Patients and Methods: Patients with locally advanced/metastatic i NTRK /i fusion-positive solid tumors and ≥12 months' follow-up were included. Primary endpoints were ORR and DoR by blinded independent central review (BICR) secondary endpoints included progression-free survival (PFS), intracranial efficacy, and safety. The safety-evaluable populations included all patients who had received ≥1 entrectinib dose. Results: At clinical cut-off (August 31, 2020), the efficacy-evaluable population comprised 121 adults with 14 tumor types and ≥30 histologies. Median follow-up was 25.8 months 61.2% of patients had a complete ( i n /i = 19) or partial response ( i n /i = 55). Median DoR was 20.0 months [95% confidence interval (CI), 13.0–38.2] median PFS was 13.8 months (95% CI, 10.1–19.9). In 11 patients with BICR-assessed measurable central nervous system (CNS) disease, intracranial ORR was 63.6% (95% CI, 30.8–89.1) and median intracranial DoR was 22.1 (95% CI, 7.4–not estimable) months. The safety profile of entrectinib in adults and pediatric patients was aligned with previous reports. Most treatment-related adverse events (TRAEs) were grade 1/2 and manageable/reversible with dose modifications. TRAE-related discontinuations occurred in 8.3% of patients. Conclusions: With additional clinical experience, entrectinib continues to demonstrate durable systemic and intracranial responses and can address the unmet need of a CNS-active treatment in patients with i NTRK /i fusion-positive solid tumors. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487211
Abstract: Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: Elsevier BV
Date: 04-2017
Publisher: Elsevier BV
Date: 09-2019
Publisher: Springer Science and Business Media LLC
Date: 2012
DOI: 10.1186/GM385
Publisher: Elsevier BV
Date: 04-2021
Publisher: Wiley
Date: 07-06-2017
DOI: 10.1002/HED.24751
Abstract: Not-infrequently patients with head and neck cancer are also diagnosed with synchronous lung cancer or metachronous primary lung cancer, which complicates the treatment decisions and prognosis. Patients were identified from a database of patients with head and neck cancer with second primary non-small cell lung cancer (NSCLC). Thirty-four eligible patients (15 with synchronous lung cancer and 19 with metachronous lung cancer) were identified. Thirteen of 15 patients with synchronous lung cancer received curative intent treatment for head and neck cancer first. Six of 15 patients were in complete remission, 5 of 15 patients had died, and 4 were alive with progressive disease. Median time between 2 diagnoses was 47 months in the metachronous lung cancer group. Twelve patients had died, 3 were alive with disease, and 4 were lost to follow-up. Median survival from the time of lung cancer diagnosis was 13 months with a trend to better survival with synchronous lung cancer (15 vs 11 months p = .11). Aggressive multidisciplinary management of second primary lung malignancies in patients with head and neck cancer can result in respectable long-term disease control particularly in patients with synchronous lung cancer. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1544-1549, 2017.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22488171
Abstract: Supplementary Figure from Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor–Mutated Non–Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22488174
Abstract: Supplementary Figure from Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor–Mutated Non–Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.LUNGCAN.2016.05.003
Abstract: AZD9291, a T790M specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has demonstrated impressive response rates in tumours harbouring the EGFR T790M resistance mutation. Emergence of resistance to AZD9291 has been shown to occur through several different mechanisms including the development of new mutations (e.g. C797S) in the EGFR tyrosine kinase domain. We studied two patients with paired tumour biopsies and blood s les pre- and post-progression on AZD9291 to explore possible resistance mechanisms. Pre- and Post-AZD9291 tumour biopsies as well as serial plasma s les were collected from two patients on the AURA clinical study (AZD9291 First Time in Patients Ascending Dose study). Droplet digital PCR (ddPCR) assays were used to quantify T790M, the driver EGFR mutation, and the C797S mutation in genomic DNA from paired tumour biopsies and plasma cell-free DNA. In the first patient, both EGFR T790M and L858R became undetectable in the plasma within 1 month after treatment with AZD9291. However, the T790M and the original L858R mutation re-emerged with radiologically confirmed resistance to AZD9291. In patient two, the levels of T790M were undetectable at the time of radiological resistance to AZD9291 but increasing levels of the original EGFR exon 19 deletion was detected. MET lification was detected in a biopsy performed on progression. The EGFR C797S mutation was not detected in either patient at the time of relapse. ddPCR of cell free DNA enables real time monitoring of patients on 3rd generation TKIs. As resistance mechanisms are variable, monitoring levels of the initial activating EGFR mutation may facilitate more reliable detection of progression.
Publisher: Elsevier BV
Date: 10-2009
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22488177
Abstract: Supplementary Figure from Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor–Mutated Non–Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial
Publisher: American Association for Cancer Research (AACR)
Date: 14-02-2017
DOI: 10.1158/1078-0432.CCR-16-0844
Abstract: Purpose: Malignant pleural mesothelioma (MPM) is a rare but aggressive disease with few therapeutic options. The tumor–stromal interface is important in MPM, but this is lost in cell lines, the main model used for preclinical studies. We sought to characterize MPM patient-derived xenografts (PDX) to determine their suitability as preclinical models and whether tumors that engraft reflect a more aggressive biological phenotype. Experimental Design: Fresh tumors were harvested from extrapleural pneumonectomy, decortication, or biopsy s les of 50 MPM patients and implanted subcutaneously into immunodeficient mice and serially passaged for up to five generations. We correlated selected mesothelioma biomarkers between PDX and patient tumors, and PDX establishment with the clinical pathologic features of the patients, including their survival. DNA of nine PDXs was profiled using the OncoScan FFPE Express platform. Ten PDXs were treated with cisplatin and pemetrexed. Results: A PDX was formed in 20 of 50 (40%) tumors implanted. Histologically, PDX models closely resembled the parent tumor. PDX models formed despite preoperative chemotherapy and radiotherapy. In multivariable analysis, patients whose tumors formed a PDX had significantly poorer survival when the model was adjusted for preoperative treatment (HR, 2.46 95% confidence interval, 1.1–5.52 P = 0.028). Among 10 models treated with cisplatin, seven demonstrated growth inhibition. Genomic abnormalities seen in nine PDX models were similar to that previously reported. Conclusions: Patients whose tumors form PDX models have poorer clinical outcomes. MPM PDX tumors closely resemble the genotype and phenotype of parent tumors, making them valuable models for preclinical studies. Clin Cancer Res 23(4) 1060–7. ©2016 AACR.
Publisher: Springer International Publishing
Date: 2016
DOI: 10.1007/978-3-319-42044-8_27
Abstract: Identifying circulating tumour DNA (ctDNA) for monitoring of cancer therapy is dependent on the development of readily designed, sensitive cancer-specific DNA markers. Genomic rearrangements that are present in the vast majority of cancers provide such markers.Tumour DNA isolated from two fresh-frozen lung tumours underwent whole genome sequencing. Genomic rearrangements were detected using a new computational algorithm, GRIDSS. Four genomic rearrangements from each tumour were chosen for further study using rearrangement-specific primers. Six of the eight rearrangements tested were identified as tumour-specific, the remaining two were present in the germline. ctDNA was quantified using digital PCR for the tumour genomic rearrangements in patient blood. Interestingly, one of the patients had no detectable ctDNA either prior to or post surgery although the rearrangements were readily detectable in the tumour DNA.This study demonstrates the feasibility of using digital PCR based on genomic rearrangements for the monitoring of minimal residual disease. In addition, whole genome sequencing provided further information enabling therapeutic choices including the identification of a cryptic EGFR exon 19 deletion in one patient and the identification of a high somatic mutation load in the other patient. This approach can be used as a model for all cancers with rearranged genomes.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532659.V1
Abstract: AbstractPurpose: In the phase III ADAURA trial, adjuvant treatment with osimertinib versus placebo, with/without prior adjuvant chemotherapy, resulted in a statistically significant and clinically meaningful disease-free survival benefit in completely resected stage IB–IIIA EGFR-mutated ( i EGFR /i m) non–small cell lung cancer (NSCLC). We report health-related quality of life (HRQoL) outcomes from ADAURA. Patients and Methods: Patients randomized 1:1 received oral osimertinib 80 mg or placebo for 3 years or until recurrence/discontinuation. HRQoL (secondary endpoint) was measured using the Short Form-36 (SF-36) health survey at baseline, 12, and 24 weeks, then every 24 weeks until recurrence or treatment completion/discontinuation. Exploratory analyses of SF-36 score changes from baseline until week 96 and time to deterioration (TTD) were performed in the overall population (stage IB–IIIA i N /i = 682). Clinically meaningful changes were defined using the SF-36 manual. Results: Baseline physical/mental component summary (PCS/MCS) scores were comparable between osimertinib and placebo (range, 46–47) and maintained to Week 96, with no clinically meaningful differences between arms difference in adjusted least squares (LS) mean [95% confidence intervals (CI), −1.18 (−2.02 to −0.34) and −1.34 (−2.40 to −0.28), for PCS and MCS, respectively. There were no differences between arms for TTD of PCS and MCS HR, 1.17 (95% CI, 0.82–1.67) and HR, 0.98 (95% CI, 0.70–1.39), respectively. Conclusions: HRQoL was maintained with adjuvant osimertinib in patients with stage IB–IIIA i EGFR /i m NSCLC, who were disease-free after complete resection, with no clinically meaningful differences versus placebo, further supporting adjuvant osimertinib as a new treatment in this setting. i See related commentary by Patil and Bunn, p. 2204 /i /
Publisher: Elsevier BV
Date: 2016
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22518654
Abstract: In vivo Efficacy of ABBV-321 tumor targeting.
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.JTHO.2018.08.007
Abstract: There is no approved second-line treatment for malignant pleural mesothelioma (MPM). On the basis of promising early results, pembrolizumab was used off-label in Switzerland and Australia. We investigated outcomes in association with clinicopathological features and expression of programmed death ligand 1 (PD-L1). Registry data in Australia and Switzerland were pooled. Patient characteristics, including age, sex, histological subtype, and previous treatments were captured. Outcomes were assessed locally. PD-L1 expression was categorized as negative (<5%), intermediate (5%-49%), and high (≥50%). A total of 93 patients (48 from Switzerland and 45 from Australia) were treated 68 patients (73%) had epithelioid MPM, and 67 (72%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Pembrolizumab was the second-line treatment in 48 of 93 patients (52%). PD-L1 expression results were available for 66 patients (71%). Most (68%) were negative, 18% were intermediate, and 14% were high for PD-L1 expression. In the full cohort, the overall response rate (ORR) was 18%, the median progression-free survival (mPFS) was 3.1 months, and the median overall survival was 7.2 months. In patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and only one previous systemic treatment (n = 35), the ORR was 37%, the mPFS was 3.7 months, and the median overall survival was 10.2 months. The nonepitheloid histological subtype showed an improved ORR (24% versus 16% [p = 0.54) and mPFS (5.6 versus 2.8 months [p = 0.02]). Compared with intermediate and negative PD-L1 expression, high PD-L1 expression was associated with an improved ORR (44% versus 42% versus 11% [p = 0.01]) and mPFS (6.2 versus 3.9 versus 2.7 months [p = 0.04]). Toxicity was as expected. These real-world data demonstrate similar response rates but inferior survival compared with those in early-phase trials. High PD-L1 expression and nonepitheloid histological subtype were associated with greater activity. Anti-PD-L1 immunotherapy is a reasonable second-line therapy in patients with MPM.
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.JTHO.2017.08.006
Abstract: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has demonstrated efficacy in tumors harboring the EGFR T790M resistance mutation. Inevitably, resistance to third-generation inhibitors results in disease progression, with the EGFR C797S mutation being one of several resistance pathways identified to date. On the basis of preclinical data, we report what is the first known case of a patient harboring the T790M and C797S mutations in trans treated with combination gefitinib and osimertinib. On development of progressive disease after multiple therapies, the patient's plasma was sequenced using the Oncomine Lung cfDNA Assay (Thermo Fisher Scientific, Waltham, MA). Subsequent monitoring of circulating tumor DNA in plasma was performed by droplet digital polymerase chain reaction. Sequencing showed that the T790M and C797S mutations were in trans. Within 2 weeks of commencement of combination therapy, rapid clinical improvement occurred. Accompanying this, a rapid decline in the C797S mutation subclone in plasma was detected. However, the levels of the EGFR exon 19 deletion driver mutation and the T790M resistance mutation in the circulating tumor DNA continued to rise and the patient died from progressive disease 6 weeks after commencement of combination therapy. There were no adverse events seen with the combination therapy. This is, to the best of our knowledge, the first reported case of combination EGFR tyrosine kinase inhibitor therapy tailored to the allelic conformation of T790M and C797S mutation that resulted in brief clinical improvement without toxicity.
Publisher: Elsevier BV
Date: 10-2011
Publisher: AMPCo
Date: 11-2013
DOI: 10.5694/MJA13.11144
Publisher: Wiley
Date: 24-03-2014
DOI: 10.1002/IJC.28832
Abstract: The cancer-testis antigens are a group of unrelated proteins aberrantly expressed in various cancers in adult somatic tissues. This aberrant expression can trigger spontaneous immune responses, a phenomenon exploited for the development of disease markers and therapeutic vaccines. However, expression levels often vary amongst patients presenting the same cancer type, and these antigens are therefore unlikely to be in idually viable as diagnostic or prognostic markers. Nevertheless, patterns of antigen expression may provide correlates of specific cancer types and disease progression. Herein, we describe the development of a novel, readily customizable cancer-testis antigen microarray platform together with robust bioinformatics tools, with which to quantify anti-cancer testis antigen autoantibody profiles in patient sera. By exploiting the high affinity between autoantibodies and tumor antigens, we achieved linearity of response and an autoantibody quantitation limit in the pg/mL range-equating to a million-fold serum dilution. By using oriented attachment of folded, recombinant antigens and a polyethylene glycol microarray surface coating, we attained minimal non-specific antibody binding. Unlike other proteomics methods, which typically use lower affinity interactions between monoclonal antibodies and tumor antigens for detection, the high sensitivity and specificity realized using our autoantibody-based approach may facilitate the development of better cancer biomarkers, as well as potentially enabling pre-symptomatic diagnosis. We illustrated the usage of our platform by monitoring the response of a melanoma patient cohort to an experimental therapeutic NY-ESO-1-based cancer vaccine inter alia, we found evidence of determinant spreading in in idual patients, as well as differential CT antigen expression and epitope usage.
Publisher: Future Medicine Ltd
Date: 05-2022
Abstract: Background: In metastatic non-small-cell lung cancer (mNSCLC), PD-L1 expression is associated with benefit from immune checkpoint inhibitor (ICI) therapy. However, the significance of PD-L1 expression in chemotherapy-treated patients is uncertain. Methods: Using the chemotherapy control arm of first-line randomized trials, a meta-analysis of the association between efficacy outcomes and PD-L1 status was performed, stratified by assay due to inter-assay differences. Results: Across 12 trials and 4378 patients, overall survival (OS) was superior in high PD-L1 versus negative tumors and low versus negative according to 22C3/28-8 assays. When classified by SP142 assay, no significant difference in response or survival was seen between PD-L1 groups. Conclusion: In mNSCLC, high PD-L1-expressing tumors are associated with longer OS and improved objective rate when treated with chemotherapy. Inter-assay variability impacts outcome results.
Publisher: Oxford University Press (OUP)
Date: 04-10-2010
DOI: 10.1093/JNCI/DJQ385
Publisher: American Society of Clinical Oncology (ASCO)
Date: 06-2013
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22488165
Abstract: Supplementary Table from Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor–Mutated Non–Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial
Publisher: American Medical Association (AMA)
Date: 2017
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22488168
Abstract: Supplementary Figure from Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor–Mutated Non–Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.LUNGCAN.2018.10.027
Abstract: In AURA3 (NCT02151981), osimertinib treatment provided significant clinical benefit compared with platinum-pemetrexed in patients with epidermal growth factor receptor (EGFR) T790M-positive advanced non-small-cell lung cancer (NSCLC), whose tumors had progressed on previous EGFR-tyrosine kinase inhibitor therapy. This retrospective analysis investigated detection rates for T790M, common (exon 19 deletion and L858R), and rare EGFR mutations in tissue s les from the screened population of AURA3. In AURA3, eligible patients were randomized 2:1 to receive oral osimertinib 80 mg once daily or intravenous platinum-pemetrexed every 3 weeks for up to six cycles. Tumor tissue s les were centrally tested for EGFR mutations using the cobas A total of 820 screened patients had a valid EGFR mutation test result, of whom 452 (55%) were T790M-positive. Detection rates were similar by ethnicity (Asian versus non-Asian) for T790M (53% versus 58%) and exon 19 deletions (56% versus 63%). Conversely, the L858R rate was higher among Asian patients versus non-Asian patients (39% versus 28% p = 0.0017). In the overall population, a higher proportion of patients had T790M detected against a background of exon 19 deletion versus L858R mutations (64% versus 47% p < 0.0001). Rare EGFR mutations were detected in 28 (3%) patients, including G719X (2%), exon 20 insertion (1%), and S768I (<1%). Among AURA3 screened patients with EGFR mutation-positive advanced NSCLC, approximately half had detectable T790M in their tumor tissue, a rate unaffected by ethnicity. Results are consistent with previous reports of T790M detection rate in this patient population.
Publisher: Wiley
Date: 12-07-2017
DOI: 10.1111/AJCO.12699
Abstract: 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.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487229
Abstract: Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: Public Library of Science (PLoS)
Date: 23-07-2013
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-09-2023
DOI: 10.1200/JCO.23.01476
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487232
Abstract: Supplementary Data from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: American Association for Cancer Research (AACR)
Date: 06-2008
DOI: 10.1158/1078-0432.CCR-07-1322
Abstract: Purpose: Cancer cells recapitulate many behaviors of pluripotent embryonic cells such as unlimited proliferation, and the capacity to self-renew and to migrate. Embryo-cancer sequence A (ECSA), later named developmental pluripotency associated-2 (DPPA2), is an embryonic gene initially isolated from pluripotent human preimplantation embryos. We hypothesized that ECSA/DPPA2 would be quiescent in most normal tissues but expressed in cancers and may therefore be a useful target for immunotherapy. Experimental Design: ECSA/DPPA2 expression was examined in a panel of normal and tumor tissue by reverse transcription PCR, quantitative real-time PCR, and immunohistochemistry. A panel of 110 non–small cell lung cancers (NSCLC) were further investigated for the presence of ECSA/DPPA2 transcripts and several cancer testis antigens (CTA). Sera from 104 patients were analyzed for spontaneous ECSA/DPPA2 antibody production by ELISA and Western blot. Results: ECSA/DPPA2 transcripts were limited to normal testis, placenta, bone marrow, thymus, and kidney but expressed in a variety of tumors most notably in 30% of NSCLC. Enrichment for CTAs in ECSA/DPPA2-positive NSCLC was observed. Immunohistochemistry confirmed nuclear and cytoplasmic localization in subpopulations of cells with coexpression of the CTA MAGE-A3. Antibodies to recombinant ECSA/DPPA2 protein were detected in the sera of 4 of 104 patients with NSCLC but not in healthy controls. Conclusions: The restricted expression in normal tissues, expression in tumors with coexpression of CTAs, and spontaneous immunogenicity indicate that ECSA/DPPA2 is a promising target for antigen-specific immunotherapy in NSCLC.
Publisher: Springer Science and Business Media LLC
Date: 08-2009
DOI: 10.1038/ONC.2009.197
Abstract: Most patients with non-small-cell lung cancer (NSCLC) present with advanced disease. Current treatment paradigms are shifting from cytotoxic chemotherapies alone to single-agent and combination biological and targeted therapies. As patient responses to these therapies vary, predictive biomarkers will be an important facet of a patient's diagnostic workup in personalized medicine, as there is accumulating evidence that they may enable the prognostication and prediction of therapeutic response. Potential biomarkers for the selection of patients with NSCLC most likely to benefit from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, include mutations, gene copy number increase and single-nucleotide polymorphisms of the EGFR gene, EGFR protein expression and oncogenic mutation on the KRAS gene. Many techniques are available to assay for these biomarkers. In this review, we present the current weight of evidence for using these methods as biomarkers for anti-EGFR therapy in patients with NSCLC.
Publisher: Elsevier BV
Date: 04-2013
Publisher: American Society of Hematology
Date: 05-02-2009
DOI: 10.1182/BLOOD-2008-06-165266
Abstract: Professional antigen-presenting cells (APCs) are sentinel cells of the immune system that present antigen to T lymphocytes and mediate an appropriate immune response. It is therefore surprising that knowledge of the professional APCs in human lymph nodes is limited. Using 3-color immunohistochemistry, we have identified APCs in human lymph nodes, excluding plasmacytoid APCs, that fall into 2 nonoverlapping classes: (1) CD209+ APCs, coexpressing combinations of CD206, CD14, and CD68, that occupied the medullary cords, lined the capsule and trabeculae and were also scattered throughout the diffuse T-lymphocyte areas of the paracortex and (2) APCs expressing combinations of CD1a, CD207, and CD208, that were always restricted to the paracortex. Surprisingly, this second class of APCs was almost entirely absent from many lymph nodes. Our data suggest that most CD208+ cells, often referred to as “interdigitating cells,” derive from migratory APCs, and that the major APC subset consistently resident in the paracortex of human lymph nodes is the CD209+ subset. All APC subsets were demonstrated to be in close contact with the fibroreticular network. The identification of 2 distinct APC populations in the paracortex of human lymph nodes has important implications for understanding T-lymphocyte responses and optimizing vaccine design.
Publisher: AME Publishing Company
Date: 06-2018
Publisher: Wiley
Date: 07-2015
DOI: 10.1111/IMJ.12653
Abstract: Novel cancer immunotherapy antibodies are moving from clinical trials into routine practice, delivering sustained benefits and prolonged survival to patients with melanoma, lung, kidney and other cancers. These immunostimulatory antibodies non-specifically activate the patient's own immune system by inhibiting immune system checkpoint proteins. This mechanism of action is entirely different to traditional cancer treatments, such as chemotherapy. While there are virtually no immediate toxicities, serious life-threatening autoimmune side-effects such as colitis, dermatitis, hypophysitis, pneumonitis and hepatitis can occur, sometimes starting long after the treatment has been given. Recognition, referral and prompt treatment with immunosuppressive drugs like corticosteroids can control these immune-related side-effects without compromising efficacy. This exciting new class of drugs is defining a new paradigm in cancer therapy.
Publisher: AME Publishing Company
Date: 05-2019
Publisher: Wiley
Date: 04-2015
DOI: 10.1111/AJCO.12361
Abstract: The two dominant approaches to manipulating cancer immunotherapeutics are active, where the immune system is directly stimulated, and passive, where antitumor antibodies stimulate an indirect immune response. At this point, the active approach is receiving more attention in the arena of lung cancer, with ongoing vaccine clinical trials and studies investigating the role of immune checkpoint inhibitors, in particular those that block the programmed death 1(PD-1) receptor and its ligands. Early results from trials of PD-1/PD-L1 ligand inhibitors in nonsmall cell lung cancer are promising, with patients experiencing rapid and durable responses in the first-, second- and third-line setting as well as in combination with chemotherapy and other immune checkpoint inhibitors. Although the number of patients in these trials is small and the results are preliminary, lung cancer physicians are encouraged that they may soon have agents that confer benefits in excess of those seen with chemotherapy to offer their patients. Further results of ongoing trials are highly anticipated.
Publisher: Elsevier BV
Date: 12-2022
DOI: 10.1016/J.CLLC.2022.08.009
Abstract: The treatment paradigm of non-small-cell lung cancer without oncogenic drivers has varied dramatically in recent years and is constantly evolving. Immune- checkpoint inhibitors have demonstrated unprecedented durable efficacy in a subset of these patients, so these drugs have become the standard of care in most cases. There are different ways to deliver these agents, such as monotherapy and combinations of immunotherapy or chemotherapy plus immunotherapy. Treatment selection is complicated by an absence of head-to-head comparisons in randomized trials because these agents have gained approval by demonstrating superiority to platinum-doublet chemotherapy alone. Unfortunately, most patients will progress and die from their disease despite advances. Furthermore, after progression on these agents, there is a lack of randomized controlled data to support further management, constituting an unmet need. This review discusses the therapeutic alternatives after progression, summarizes mechanisms of resistance and progression patterns, and describes the main approaches under clinical investigation in the field.
Publisher: Informa UK Limited
Date: 03-04-2019
DOI: 10.1080/17425247.2019.1598374
Abstract: Malignant mesothelioma (MM) is an aggressive malignancy arising from the mesothelial cells lining the pleura and other serosal membranes. It is associated with an extremely poor prognosis and has limited therapeutic options. Epidermal growth factor receptor (EGFR) is known to be highly overexpressed in mesothelioma with reported EGFR overexpression between 44 to 97%. Given this, several anti-EGFR agents have been trialed in mesothelioma. In this review, we provide an overview of the current available data on anti-EGFR therapies in MM and future directions of investigation with these targeted agents in MM. While many anti-EGFR therapies have failed to show significant efficacy in the management of MM, the pathway is biologically active and its abrogation preclinically points toward it being a valid target. Toward targeting the pathway, many novel EGFR-based therapies are still being investigated. Current ongoing research of interest in MM include EGFR-targeted nanotechnology approach for drug delivery, antibodies targeting the extracellular EGFR and potentially anti-EGFR antibody drug conjugates.
Publisher: Springer Science and Business Media LLC
Date: 16-08-2021
DOI: 10.1186/S13053-021-00190-1
Abstract: The Australian Pancreatic Cancer Screening Program (APCSP) offers endoscopic ultrasound surveillance for in iduals at increased risk of pancreatic ductal adenocarcinoma (PDAC) with all participants requiring assessment by a Familial Cancer Service before or after study enrolment. In iduals aged 40–80 years (or 10 years younger than the earliest PDAC diagnosis) were eligible for APCSP study entry if they had 1) ≥ two blood relatives with PDAC (at least one of first-degree association) 2) a clinical or genetic diagnosis of Hereditary Pancreatitis or Peutz-Jeghers syndrome irrespective of PDAC family history or 3) a known PDAC predisposition germline pathogenic variant ( BRCA2, PALB2, CDKN2A, or Lynch syndrome) with ≥one PDAC-affected first- or second-degree relative. Retrospective medical record review was conducted for APCSP participants enrolled at the participating Australian hospitals from January 2011 to December 2019. We audited the genetic investigations offered by multiple Familial Cancer Services who assessed APCSP participants according to national guidelines, local clinical protocol and/or the availability of external research-funded testing, and the subsequent findings. Descriptive statistical analysis was performed using Microsoft Excel. Of 189 kindreds (285 participants), 50 kindreds (71 participants) had a known germline pathogenic variant at enrolment ( BRCA2 n = 35, PALB2 n = 6, CDKN2A n = 3, STK11 n = 3, PRSS1 n = 2, MLH1 n = 1). Forty-eight of 136 (35%) kindreds with no known germline pathogenic variant were offered mutation analysis 89% was clinic-funded, with increasing self-funded testing since 2016. The relatively low rates of genetic testing performed reflects initial strict criteria for clinic-funded genetic testing. New germline pathogenic variants were detected in five kindreds (10.4%) after study enrolment ( BRCA2 n = 3 kindreds, PALB2 n = 1, CDKN2A n = 1). Of note, only eight kindreds were reassessed by a Familial Cancer Service since enrolment, with a further 21 kindreds identified as being suitable for reassessment. Germline pathogenic variants associated with PDAC were seen in 29.1% of our high-risk cohort (55/189 kindreds 82/285 participants). Importantly, 10.4% of kindreds offered genetic testing were newly identified as having germline pathogenic variants, with majority being BRCA2 . As genetic testing standards evolve rapidly in PDAC, 5-yearly reassessment of high-risk in iduals by Familial Cancer Services is warranted.
Publisher: Informa UK Limited
Date: 06-10-2016
DOI: 10.1080/14737140.2016.1241149
Abstract: Initial data of immune based therapy showed promise for improving malignant mesothelioma (MM) treatment. However, the results of such treatments have neither been predictable nor consistent and recent clinical studies of immune checkpoint inhibitors in MM have d ened initial enthusiasm. Areas covered: We comprehensively discuss the basis, modalities and updated results of immunotherapy in MM. An online search was conducted for relevant literature and abstracts of recent meetings. Expert commentary: Although initial studies have demonstrated proof of principle that manipulating the immune checkpoint axis holds promise in MM, results of some recent large studies using checkpoint inhibitors have been disappointing. This is not surprising given the low mutational load in MM and suggests that single agent immunotherapy has limited benefit in this disease. We believe that in order to demonstrate durable survival benefits, they will need to be used in combination approaches with other immunotherapies, vaccines or chemotherapy.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.JTHO.2018.07.015
Abstract: Malignant pleural mesothelioma is an aggressive malignancy with limited systemic therapy options. Promising results have been reported with use of anti-programmed cell death 1 therapy however, its benefits appear to be confined to a subgroup of patients. Microsatellite instability (MSI) results from the inactivation of DNA mismatch repair genes and results in a high tumor mutational burden, a phenomenon that has not been seen with mesothelioma. MSI and protein absence have been shown to correlate in colorectal cancer, such that most centers have adopted immunohistochemistry (IHC) to screen for MSI-high colorectal cancers. We profiled a large cohort of patients with mesothelioma to determine the rate of negative IHC staining results the four common mismatch repair proteins. A tissue microarray comprising 335 patients with malignant pleural mesothelioma were used. IHC for the four common mismatch repair proteins (mutL homolog 1 PMS1 homolog 2, mismatch repair system component mutS homolog 2 and mutS homolog 6) was performed. Programmed death ligand 1 IHC staining with the E1L3N clone was also performed. DNA was isolated from IHC equivocal s les and analyzed for microsatellite instability by using the Promega MSI Analysis System (version 1.2, Promega, Madison, WI). Of the patients profiled, 329 had intact mismatch repair proteins by IHC. Six s les with IHC testing results indicating absent mismatch repair protein were analyzed for MSI and confirmed to be negative. Of the six IHC-negative s les, five were negative for programmed death ligand 1 staining and one s le had more than 5% staining. In this large retrospective series, we were unable to identify any patients with malignant pleural mesothelioma with microsatellite instability. Response to anti-programmed cell death 1-based immunotherapy may be driven by other mechanisms.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2019
DOI: 10.1038/S41419-019-1568-3
Abstract: Malignant melanoma is one of the most difficult cancers to treat due to its resistance to chemotherapy. Despite recent successes with BRAF inhibitors and immune checkpoint inhibitors, many patients do not respond or become resistant to these drugs. Hence, alternative treatments are still required. Due to the importance of the BCL-2-regulated apoptosis pathway in cancer development and drug resistance, it is of interest to establish which proteins are most important for melanoma cell survival, though the outcomes of previous studies have been conflicting. To conclusively address this question, we tested a panel of established and early passage patient-derived cell lines against several BH3-mimetic drugs designed to target in idual or subsets of pro-survival BCL-2 proteins, alone and in combination, in both 2D and 3D cell cultures. None of the drugs demonstrated significant activity as single agents, though combinations targeting MCL-1 plus BCL-XL, and to a lesser extent BCL-2, showed considerable synergistic killing activity that was elicited via both BAX and BAK. Genetic deletion of BFL-1 in cell lines that express it at relatively high levels only had minor impact on BH3-mimetic drug sensitivity, suggesting it is not a critical pro-survival protein in melanoma. Combinations of MCL-1 inhibitors with BRAF inhibitors also caused only minimal additional melanoma cell killing over each drug alone, whilst combinations with the proteasome inhibitor bortezomib was more effective in multiple cell lines. Our data show for the first time that therapies targeting specific combinations of BCL-2 pro-survival proteins, namely MCL-1 plus BCL-XL and MCL-1 plus BCL-2, could have significant benefit for the treatment of melanoma.
Publisher: Springer Science and Business Media LLC
Date: 31-08-2012
Abstract: Vasculitis has been associated with malignancies, more commonly hematological rather than solid malignancies. Due to the rarity of these conditions and the lack of a temporal association, the relationship between vasculitis and malignancy remains unclear. Paraneoplastic vasculitis as a phenomenon of lung cancer has been described in the literature. To the best of our knowledge, this is the first case report of leukocytoclastic vasculitis being an initial presentation of malignant pleural mesothelioma. We report the case of an 84-year old Greek man who presented to our facility with an erythematous, pruritic and purpuric rash affecting his limbs. This was biopsy-proven to be leukocytoclastic vasculitis and treated conservatively with topical corticosteroids as well as oral prednisolone, with good results. Six months later, he was diagnosed as having malignant pleural mesothelioma. As he remained asymptomatic from his malignancy, no systemic chemotherapy was instituted. He had a recurrence of biopsy-proven leukocytoclastic vasculitis two months after he was diagnosed as having mesothelioma, which again settled with conservative measures. It is important to remain vigilant with regard to the association between leukocytoclastic vasculitis and malignancies. A diagnosis of vasculitis requires a search for malignancies as well as other possible etiologies. This is particularly of relevance when the vasculitis becomes chronic, recurrent or treatment is no longer effective. Should our patient have experienced refractory vasculitis, we would have instituted systemic chemotherapy to treat the underlying malignancy.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532659
Abstract: AbstractPurpose: In the phase III ADAURA trial, adjuvant treatment with osimertinib versus placebo, with/without prior adjuvant chemotherapy, resulted in a statistically significant and clinically meaningful disease-free survival benefit in completely resected stage IB–IIIA EGFR-mutated ( i EGFR /i m) non–small cell lung cancer (NSCLC). We report health-related quality of life (HRQoL) outcomes from ADAURA. Patients and Methods: Patients randomized 1:1 received oral osimertinib 80 mg or placebo for 3 years or until recurrence/discontinuation. HRQoL (secondary endpoint) was measured using the Short Form-36 (SF-36) health survey at baseline, 12, and 24 weeks, then every 24 weeks until recurrence or treatment completion/discontinuation. Exploratory analyses of SF-36 score changes from baseline until week 96 and time to deterioration (TTD) were performed in the overall population (stage IB–IIIA i N /i = 682). Clinically meaningful changes were defined using the SF-36 manual. Results: Baseline physical/mental component summary (PCS/MCS) scores were comparable between osimertinib and placebo (range, 46–47) and maintained to Week 96, with no clinically meaningful differences between arms difference in adjusted least squares (LS) mean [95% confidence intervals (CI), −1.18 (−2.02 to −0.34) and −1.34 (−2.40 to −0.28), for PCS and MCS, respectively. There were no differences between arms for TTD of PCS and MCS HR, 1.17 (95% CI, 0.82–1.67) and HR, 0.98 (95% CI, 0.70–1.39), respectively. Conclusions: HRQoL was maintained with adjuvant osimertinib in patients with stage IB–IIIA i EGFR /i m NSCLC, who were disease-free after complete resection, with no clinically meaningful differences versus placebo, further supporting adjuvant osimertinib as a new treatment in this setting. i See related commentary by Patil and Bunn, p. 2204 /i /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487220.V1
Abstract: Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: Elsevier BV
Date: 11-2016
Publisher: Elsevier BV
Date: 10-2012
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487223.V1
Abstract: Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With i NTRK /i Fusion-Positive Solid Tumors
Publisher: Elsevier BV
Date: 04-2016
Publisher: Elsevier BV
Date: 11-2017
Publisher: Informa UK Limited
Date: 12-10-2016
DOI: 10.1080/14737140.2016.1244008
Abstract: Malignant mesothelioma (MM) is an aggressive malignancy of the pleura and other serosal membranes originating from mesothelial cells that, despite decades of research, continues to have limited therapeutic options and is associated with a poor prognosis. Areas covered: MMs induce a strong inflammatory response that is also associated with neoangiogenesis and activation of proangiogenic factors. Given this, several anti-angiogenic agents have been trialled in a variety of malignancies including mesothelioma. Herein we summarise the role of angiogenesis in MM and the current available data targeting these pathways. Expert commentary: The addition of bevacizumab to cisplatin emetrexed chemotherapy is currently a therapeutic option with a proven 2.7 month overall survival benefit in fit patients less than 75. Other antiangiogenics such as nintedinib show early promise, although the Phase III trial results are eagerly awaited before this therapy enters treatment paradigms. Beyond this, it is likely that combinations of antiangiogenics with immunotherapies will be investigated in future studies.
Publisher: Elsevier BV
Date: 12-2015
Publisher: BMJ
Date: 06-2023
DOI: 10.1136/BMJRESP-2022-001571
Abstract: With treatment-related improvements in survival, rehabilitation is essential to improve function and health-related quality of life and manage the high symptom burden associated with lung cancer. Despite this, significant heterogeneity exists in the outcomes and instruments used to evaluate lung cancer rehabilitation programme impact. This study aims to develop a core set of clinically relevant lung cancer rehabilitation outcomes for use in clinical practice. An international Delphi consensus study involving consumer, healthcare professional and researcher stakeholders to determine which outcomes to include and how to measure these. Stage 1 (preliminary): mixed methods to develop the potential list of outcomes (1) overview of systematic reviews of lung cancer exercise interventions and (2) focus groups and in idual interviews with people with lung cancer. Stage 2: outcomes were grouped according to the International Classification of Functioning, Disability and Health domains. Stage 3: to determine priority outcomes for core outcome set (COS) inclusion participants will rate each outcome’s importance (one-nine-point Likert scale) over two-three survey rounds. Stage 4: following review by the steering committee, a consensus meeting will be held if agreement on the COS has not been reached. Stage 5: recommendations will be made regarding a single instrument for measuring each COS outcome by reviewing existing resources where consensus has already been reached. Where resources do not exist the quality and feasibility of potential measurement instruments will be appraised, and the Delphi consensus survey and meeting process outlined in stages 3–4 will be repeated. This protocol adheres to the COS-Standardised Protocol statement and will be conducted and reported according to the COS-Standards for Development recommendations and the COS-Standards for Reporting. Ethics approval (20/9/22, University of Melbourne ID 2022-24839-32231-3). Dissemination in peer-reviewed journals and conference presentations.
Publisher: Public Library of Science (PLoS)
Date: 22-04-2016
Publisher: Wiley
Date: 08-2017
DOI: 10.1111/AJCO.12754
Abstract: Since the identification of anaplastic lymphoma kinase (ALK) gene rearrangements in non-small cell lung cancer (NSCLC) in 2005, the treatment of ALK-rearranged NSCLC (ALK+ NSCLC) has evolved at a rapid pace. This molecularly distinct subset of NSCLC has uniquely important biology, clinicopathologic features and mechanisms of drug resistance which impact on the choice of treatment for a patient with this disease. There are multiple ALK tyrosine kinase inhibitors now available in clinical practice with efficacy data continuing to emerge and guide the optimal treatment algorithm. A detailed search of medical databases and clinical trial registries was conducted to capture all relevant articles on this topic enabling an updated detailed overview of the landscape of management of ALK-rearranged NSCLC.
Publisher: Elsevier BV
Date: 07-2012
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2017
Abstract: LUME-Meso is a phase II/III randomized, double-blind trial designed to assess efficacy and safety of nintedanib plus chemotherapy as first-line treatment of malignant pleural mesothelioma (MPM). Phase II results are reported here. Chemotherapy-naïve patients with unresectable, nonsarcomatoid MPM (Eastern Cooperative Oncology Group performance status 0 to 1), stratified by histology (epithelioid or biphasic), were randomly assigned in a 1:1 ratio to up to six cycles of pemetrexed and cisplatin plus nintedanib (200 mg twice daily) or placebo followed by nintedanib plus placebo monotherapy until progression. The primary end point was progression-free survival (PFS). Eighty-seven patients were randomly assigned. The median number of pemetrexed and cisplatin cycles was six the median treatment duration for nintedanib was 7.8 months and 5.3 months for placebo. Primary PFS favored nintedanib (hazard ratio [HR], 0.56 95% CI, 0.34 to 0.91 P = .017), which was confirmed in updated PFS analyses (HR, 0.54 95% CI, 0.33 to 0.87 P = .010). A trend toward improved overall survival also favored nintedanib (HR, 0.77 95% CI, 0.46 to 1.29 P = .319). Benefit was evident in epithelioid histology, with a median overall survival gain of 5.4 months (HR, 0.70 95% CI, 0.40 to 1.21 P = .197 median [nintedanib v placebo], 20.6 months v 15.2 months) and median PFS gain of 4.0 months (HR, 0.49 95% CI, 0.30 to 0.82 P = .006 median [nintedanib v placebo], 9.7 v 5.7 months). Neutropenia was the most frequent grade ≥ 3 adverse event (AE nintedanib 43.2% v placebo 12.2%) rates of febrile neutropenia were low (4.5% in nintedanib group v 0% in placebo group). AEs leading to discontinuation were reported in 6.8% of those receiving nintedanib versus 17.1% of those in the placebo group. Addition of nintedanib to pemetrexed plus cisplatin resulted in PFS improvement. AEs were manageable. The clinical benefit was evident in patients with epithelioid histology. The confirmatory phase III part of the study is ongoing.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22488174.V1
Abstract: Supplementary Figure from Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor–Mutated Non–Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.C.6542049.V1
Abstract: Abstract ABBV-321 (serclutamab talirine), a next-generation EGFR-targeted antibody–drug conjugate (ADC) incorporates a potent pyrrolobenzodiazepine (PBD) dimer toxin conjugated to the EGFR-targeting ABT-806 affinity-matured AM1 antibody. ABBV-321 follows the development of related EGFR-targeted ADCs including depatuxizumab mafodotin (depatux-m, ABT-414), ABT-806 conjugated to monomethyl auristatin F (MMAF), and ABBV-221 (losatuxizumab vedotin), AM1 antibody conjugated to monomethyl auristatin E (MMAE). The distinct tumor selectivity of ABBV-321 differentiates it from many previous highly active antibody PBD conjugates that lack a therapeutic window. Potency of the PBD dimer, combined with increased binding of AM1 to EGFR-positive tumor cells, opens the possibility to target a wide array of tumors beyond those with high levels of EGFR overexpression or lification, including those insensitive to auristatin-based ADCs. ABBV-321 exhibits potent antitumor activity in cellular and i in vivo /i studies including xenograft cell line and patient-derived xenograft glioblastoma, colorectal, lung, head and neck, and malignant mesothelioma tumor models that are less sensitive to depatux-m or ABBV-221. Combination studies with ABBV-321 and depatux-m suggest a promising treatment option permitting suboptimal, and potentially better tolerated, doses of both ADCs while providing improved potency. Collectively, these data suggest that ABBV-321 may offer an extended breadth of efficacy relative to other EGFR ADCs while extending utility to multiple EGFR-expressing tumor indications. Despite its highly potent PBD dimer payload, the tumor selectivity of ABBV-321, coupled with its pharmacology, toxicology, and pharmacokinetic profiles, support continuation of ongoing phase I clinical trials in patients with advanced EGFR-expressing malignancies. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22518654.V1
Abstract: In vivo Efficacy of ABBV-321 tumor targeting.
No related grants have been discovered for Thomas John.