ORCID Profile
0000-0001-7292-1114
Current Organisations
National Cancer Centre Singapore
,
University of New South Wales
,
University of Sydney
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Publisher: American Association for Cancer Research (AACR)
Date: 24-09-2021
DOI: 10.1158/1078-0432.CCR-21-2681
Abstract: Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T-cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both preclinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.
Publisher: Informa UK Limited
Date: 14-04-2011
DOI: 10.1080/01635581.2011.538953
Abstract: Interest in dietary phytochemicals for potential cancer chemoprevention has increased substantially. Screening dietary compounds for chemopreventive activity however, requires a systematic and wide-ranging approach to encompass the complexity of carcinogenesis. We present some of the molecular pathways that underpin the broad biological processes involved in carcinogenesis. Oxidative stress, inflammation, and the evasion of apoptosis are important biological mechanisms by which carcinogenesis occurs. Subsequently, antioxidant, anti-inflammatory, and pro-apoptotic activity represent important activities for preventing, suppressing, or reversing the development of carcinogenesis. Ultimately, these mechanisms of action may provide a useful basis for screening novel phytochemicals for chemopreventive activity. In this review, we identify the important molecular processes that may be targeted in routine screenings of dietary phytochemicals to ultimately select the most effective potential candidates for cancer chemoprevention.
Publisher: Springer Science and Business Media LLC
Date: 10-04-2019
DOI: 10.1007/S00520-019-04781-6
Abstract: Patient-reported outcomes (PRO) are becoming increasingly recognised as essential to comprehensively collect chemotherapy-induced peripheral neuropathy (CIPN) symptom information. This study aimed to evaluate the utility and feasibility of CIPN PRO assessment tools in a real-world clinical setting through investigation of the correlation of PRO with NCI-CTCAE assessments particularly in relation to cumulative dose of chemotherapy. Patients receiving oxaliplatin or paclitaxel chemotherapy in Sydney, Australia, completed a questionnaire containing standardised CIPN PRO assessments (EORTC CIPN-20, PRO-CTCAE) via tablet device. PRO assessment scores were correlated with NCI-CTCAE grade determined by nursing assessment and analysed with respect to cumulative dose of chemotherapy. There were 87 patients who completed a total of 145 questionnaires, 68 in patients receiving oxaliplatin and 77 in patients receiving paclitaxel. CIPN PRO scores were associated with NCI-CTCAE grade, for EORTC CIPN-20 (r This study demonstrated that CIPN PRO may provide complementary information to nursing assessed NCI-CTCAE grade, particularly in earlier stages of chemotherapy and can be considered an important component in the comprehensive assessment of neuropathy.
Publisher: American Association for Cancer Research (AACR)
Date: 2022
DOI: 10.1158/1078-0432.CCR-21-1593
Abstract: Clinical trials that have a pharmacokinetic or a pharmacodynamic immunologic mechanism of action–based primary outcome could substantially improve the validity and efficiency of early development of immuno-oncology agents. Here, we outline different trial design options in this area, review ex les from the literature and their unique immunologic aspects, and highlight how these trials have been underutilized. We illustrate how new technologies and translationally focused approaches can be successfully used to develop different classes of immunotherapeutic agents.
Publisher: Elsevier BV
Date: 08-2011
Publisher: Elsevier BV
Date: 08-2011
Publisher: BMJ
Date: 07-2021
Abstract: With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel–novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel–novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel–novel combination of anti-programmed death 1 (PD-1) rogrammed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel–novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel–novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.
Publisher: Informa UK Limited
Date: 14-04-2019
Publisher: American Association for Cancer Research (AACR)
Date: 15-03-2023
DOI: 10.1158/1078-0432.CCR-23-0151
Abstract: For three years, COVID-19 has circulated among our communities and around the world, fundamentally changing social interactions, health care systems, and service delivery. For people living with (and receiving treatment for) cancer, pandemic conditions presented significant additional hurdles in an already unstable and shifting environment, including disrupted personal contact with care providers, interrupted access to clinical trials, distanced therapeutic encounters, multiple immune vulnerabilities, and new forms of financial precarity. In a 2020 perspective in this journal, we examined how COVID-19 was reshaping cancer care in the early stages of the pandemic and how these changes might endure into the future. Three years later, and in light of a series of interviews with patients and their caregivers from the United States and Australia conducted during the pandemic, we return to consider the potential legacy effects of the pandemic on cancer care. While some challenges to care provision and survivorship were unforeseen, others accentuated and lified existing problems experienced by patients, caregivers, and health care providers. Both are likely to have enduring effects in the “post-pandemic” world, raising the importance of focusing on lessons that can be learned for the future.
Publisher: Wiley
Date: 19-06-2013
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-2022
DOI: 10.1200/PO.22.00278
Abstract: HER2-altered non–small-cell lung cancer (NSCLC) represents a erse subgroup, including mutations, lifications, and overexpression. However, HER2 exon 20 insertion mutations are emerging as a distinct molecular subtype with expanding therapeutic options. We describe the molecular epidemiology and genomic features of HER2-altered NSCLC in an Asian tertiary cancer center. We identified patients with HER2-mutated NSCLC in our institutional database, collating clinicopathological features and treatment outcomes. The genomic landscape of human epidermal growth factor receptor 2 ( HER2)–mutated NSCLC was further evaluated using whole-exome sequencing (WES) data from combined local and publicly available data sets. HER2 lification and overexpression as selection biomarkers in NSCLC were further interrogated using HER2 immunohistochemistry and correlations with WES and RNA sequencing data. Among 1,252 patients with consecutive lung adenocarcinoma undergoing routine next-generation sequencing, the prevalence of HER2 mutations was 3.1%—exon 20 insertion mutations comprised 2.7%. We examined the clinicopathological features in 55 patients with HER2-mutated NSCLC comprising 40 exon 20 insertion and 15 nonexon 20 insertion mutations. The most common exon 20 insertion mutation was HER2 Y772_A775dup in 30 (75%), followed by HER2 G776delinsVC in five patients (13%). There were limited responses to HER2-directed therapies apart from trastuzumab-deruxtecan, and no responses were seen with immunotherapy monotherapy. Evaluating the genomics features of HER2 exon 20 insertion mutations using WES data revealed low tumor mutational burden (TMB), low incidence of cancer driver comutations, and a predominance of aging mutational signature—similar to EGFR-mutated tumors. In contrast, uncommon (or nonexon 20 insertion) HER2-mutated tumors resembled EGFR wild-type tumors with higher TMB, higher frequency of cancer driver comutations, and greater presence of smoking and APOBEC mutational signature. Finally, in evaluating HER2 immunohistochemistry in all lung adenocarcinoma, there was significant discordance comparing different scoring systems and poor correlation with HER2 RNA expression and HER2 lification. The incidence of HER2 mutations is 3.1% in East Asian nonsquamous NSCLC. HER2 exon 20 insertion–mutated tumors appear genomically distinct from uncommon (nonexon 20 insertion) HER2 mutations, the latter demonstrating higher TMB, co-occurring drivers, and predominant nonaging mutational signature. The therapeutic implications of the genomic and clinical features of HER2-mutated NSCLC warrant further investigation.
Publisher: Walter de Gruyter GmbH
Date: 10-01-2015
Abstract: : This study aims to further elucidate the demographic and diabetes characteristics of diabetic patients in Australia who use complementary and alternative medicines (CAM). : This was a prospective, cross-sectional questionnaire-based study of 149 patients with diabetes attending a general endocrine clinic in a tertiary referral hospital in Sydney, Australia. : Thirty-seven patients (25%) stated they had used CAM therapies within the past 5 years. Vitamins (53%) were the most common CAM therapy used. A greater number of CAM nonusers reported calf pain whilst walking (21% vs. 9%, : With the increasing burden of diabetes, health practitioners will need to be more vigilant and understanding of the potential impact of CAM use on diabetes management.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6530516.V1
Abstract: AbstractPurpose: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in i EGFR /i -mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in i EGFR /i sup T790M /sup -negative resistance. Experimental Design: We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic i EGFR /i -mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M sup + /sup ) and -negative (T790M sup − /sup ) disease. Results: Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M sup − /sup tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as i TP53 /i alterations, 3q chromosomal lifications, whole-genome doubling and nonaging mutational signatures in T790M sup − /sup tumors. Almost half of resistant tumors were further classified as immune sup hot /sup , with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M sup − /sup and T790M sup + /sup disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients. Conclusions: Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping ergent TKI resistance and outcome trajectories in i EGFR /i -mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential. /
Publisher: Informa UK Limited
Date: 04-2011
DOI: 10.1080/01635581.2011.535953
Abstract: Apoptosis is one of the most critical forms of defense against cancer, and the induction of apoptosis by dietary polyphenols represents significant potential for cancer preventive activity. The present study examined polyphenols extracted from selected native Australian fruits--Illawarra plum (Podocarpus elatus Endl., Podocarpaceae), Kakadu plum (Terminalia ferdinandiana Exell, Combretaceae), muntries (Kunzea pomifera F. Muell., Myrtaceae), and native currant (Acrotriche depressa R.Br., Epacridaceae)--for antiproliferative activity against a panel of cancer and normal cell lines. Each fruit selectively inhibited the growth of cancer cell lines in a dose-dependent manner. The mechanism of growth inhibition of the human promyelocytic leukaemia cells (HL-60) was determined to be apoptosis by morphological assessment, DNA fragmentation, flow cytometry, and caspase-3 induction. Furthermore, Kakadu plum was found to activate caspase-7, -9, and poly (ADP-ribose) polymerase (PARP), suggesting it acts via the intrinsic apoptosis pathway. The same fruit also caused direct DNA damage in colon adenocarcinoma cells (HT-29) as detected using the cytokinesis-block micronucleus cytome (CBMN Cyt) assay.
Publisher: Cold Spring Harbor Laboratory
Date: 02-01-2020
DOI: 10.1101/MCS.A004671
Abstract: We discuss the molecular evolution of gliosarcoma, a mesenchymal type of glioblastoma (GBM), using the case of a 37-yr-old woman who developed two recurrences and an extracranial metastasis. She was initially diagnosed with isocitrate dehydrogenase (IDH) wild-type gliosarcoma in the frontal lobe and treated with surgery followed by concurrent radiotherapy with temozolomide. Five months later the tumor recurred in the left frontal lobe, outside the initially resected area, and was treated with further surgery and radiotherapy. Six months later the patient developed a second left frontal recurrence and was again treated with surgery and radiotherapy. Six weeks later, further recurrence was observed in the brain and bone, and biopsy confirmed metastases in the pelvic bones. To understand the clonal relationships between the four tumor instances and the origin of metastasis, we performed whole-genome sequencing of the intracranial tumors and the tumor located in the right iliac bone. We compared their mutational and copy-number profiles and inferred the clonal phylogeny. The tumors harbored shared alterations in GBM driver genes, including mutations in TP53 , NF1 , and RB1 , and CDKN2A deletion. Whole-genome doubling was identified in the first recurrence and the extracranial metastasis. Comparisons of the metastatic to intracranial tumors highlighted a high similarity in molecular profile but contrasting evidence regarding the origin of the metastasis. Subclonal reconstruction suggested a parallel evolution of the recurrent tumors, and that the metastatic tumor was largely derived from the first recurrence. We conclude that metastasis in glioma can be a late event in tumorigenesis.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22480718
Abstract: Supplementary Data from Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities
Publisher: Mary Ann Liebert Inc
Date: 10-2008
DOI: 10.1089/ADT.2008.148
Abstract: There are substances that kill cancer cells, but induce T cell proliferation, like thalidomide. To find more of these, a new anticancer drug screening strategy is vital. In this study we report the development of a differential cytotoxicity screening or evaluation platform using the CellTiter-Glo (Promega, Annandale, NSW, Australia) luminescent cell viability assay (ATP assay) and also the CellTiter 96 AQueous (Promega) one solution cell proliferation assay [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay]. The results suggested the platform consisting of the combination of the ATP assay be used for quantifying peripheral blood mononuclear cells, while the more economic MTS colorimetric assay is well suited to be used detecting cell viability of cancer cells. In addition, we found paclitaxel (Taxol, MP Biomedicals Australasia Pty Ltd., Seven Hills, NSW, Australia) to be a useful control for this routine screening methodology. Taxol exhibits the desirable in vitro feature of differential cytotoxicity that spares the immunological cells, when used at a concentration that will kill the majority of the cancer cell population.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22480718.V1
Abstract: Supplementary Data from Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22480715
Abstract: Supplementary Data from Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities
Publisher: Wiley
Date: 06-2019
DOI: 10.1111/IMJ.14160
Abstract: Patients with advanced malignancies have historically been considered poor candidates for admission to the intensive care unit (ICU) however, prognosis is continually improving, and requirements for ICU access are increasing. To understand the characteristics and outcomes of oncology unit patients admitted to an Australian ICU and identify potential prognostic factors. A single-centre, retrospective, cohort study conducted at a tertiary public hospital with a quaternary ICU in Sydney, Australia. All patients admitted under the medical oncology team requiring ICU admission between June 2014 and June 2016 were evaluated. Clinical outcomes were determined including mortality, ICU requirements (ventilation, dialysis, vasopressors, infection) and prognostic scores (Acute Physiologic and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) score). There were 96 patients with mean age 61 years, 58% were male and 76% had metastatic disease. Most were receiving palliative treatment (89%), with recent chemotherapy (43%), immunotherapy (10%) and other therapies (5%). Of the 10 patients with recent immunotherapy, three (all with melanoma) required ICU admission due to immunotoxicity 13% were admitted due to an oncological emergency. Mean APACHE II score was 17 (standard deviation (SD) 5.33), mean SOFA score was 3.99 (SD 2.70), ICU mortality was 5% and hospital mortality was 22%. Using multivariate logistic regression analysis, cancer stage, infection during ICU admission, intracranial mass effect on ICU admission and SOFA score were associated with 30-day mortality. Our patient population had good short-term survival outcomes despite most receiving palliative treatment. Cancer patients can achieve positive outcomes after ICU admission, and appropriate selection of patients is crucial.
Publisher: Wiley
Date: 27-01-2020
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22480712
Abstract: Supplementary Data from Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities
Publisher: Wiley
Date: 29-09-2018
DOI: 10.1111/AJCO.12779
Publisher: Elsevier BV
Date: 10-2018
Abstract: Immune checkpoint inhibitor therapy has resulted in impressive and durable clinical activity for many cancers including melanoma however, there remain few reliable predictors for long-term response. This study investigated whether [18F]2-fluoro-2-deoxy-D-glucose (FDG-PET) imaging may better predict long-term outcomes compared with standard computed tomography (CT) response criteria. Retrospective analysis of metastatic melanoma patients treated with anti-PD-1-based immunotherapy with baseline and 1-year FDG-PET and CT imaging at Melanoma Institute Australia. One-year response was determined using RECIST for CT and EORTC criteria for PET, coded as complete response (CR or CMR), partial response (PR or PMR), stable disease (SD or SMD) or progressive disease (PD or PMD). Progression-free survival (PFS) was determined from the 1-year landmark. Patients (n = 104) were evaluated with median follow-up 30.1 months and 98% remain alive. Most received anti-PD-1 as monotherapy (67%) or combined with ipilimumab (31%). At 1 year, 28% had CR, 66% had PR and 6% had SD on CT, while 75% had CMR, 16% PMR and 9% SMD/PMD on PET. CMR was observed in 68% of patients with PR on CT. RECIST PFS post 1-year landmark was similar in patients with CR versus PR/SD, but improved in patients with CMR versus non-CMR {median not reached [NR] versus 12.8 month hazard ratio [HR] 0.06 [95% confidence interval (CI) 0.02-0.23] P < 0.01}. In patients with PR on CT, PFS was improved in patients with PR + CMR versus PR + non-CMR (median NR versus 12.8 months HR 0.07 [95% CI 0.02-0.27] P < 0.01). In the 78 CMR patients, 78% had discontinued treatment and 96% had ongoing response. Whilst only a small proportion of patients have a CR at 1 year, most patients with a PR have CMR on PET. Almost all patients with CMR at 1 year have ongoing response to therapy thereafter. PET may have utility in predicting long-term benefit and help guide discontinuation of therapy.
Publisher: BMJ
Date: 31-01-2018
Publisher: Elsevier BV
Date: 08-2023
Publisher: American Association for Cancer Research (AACR)
Date: 07-2020
DOI: 10.1158/1078-0432.CCR-20-1364
Abstract: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has necessitated changes in cancer care delivery as resources are reallocated. Clinical trials and other research activities are inevitably impacted. Start-up activities for new trials may be deferred and recruitment suspended. For patients already enrolled however, there are challenges in continuing treatment on trial. Regulatory bodies have issued guidance on managing clinical trials during the pandemic, including contingency measures for remote study visits, delivery of investigational product, and site monitoring visits. New cancer clinical trial practices during the SARS-CoV-2 pandemic include new risk assessment strategies, decentralized and remote trial coordination, data collection, and delegation of specific therapeutic activities. This experience could provide evidence of more feasible and cost-effective methods for future clinical trial conduct.
Publisher: Springer Science and Business Media LLC
Date: 16-03-2017
DOI: 10.1007/S11912-017-0586-5
Abstract: Malignant gliomas result in disproportionately high morbidity and mortality compared with other primary tumors, and progression of disease is inevitable. Novel therapies to improve outcomes are needed and immune checkpoint inhibitors hold significant promise. A limited body of preclinical evidence suggests that checkpoint inhibitors may be effective treatment for gliomas. Biomarkers to identify characteristics of gliomas responsive to these therapies will be essential. These may include mismatch repair deficiency and high mutational load that might be germline, somatic, or acquired after therapy. Evidence on the use of immune checkpoint inhibitors in gliomas is evolving. Clinical trials are underway and results are eagerly awaited. Understanding the role of immune checkpoint inhibitors in combination with other treatment modalities for gliomas is crucial to the improvement of outcomes. The design and conduct of future clinical trials need to account for increasingly complex treatment options.
Publisher: Springer Science and Business Media LLC
Date: 08-2014
DOI: 10.1038/SC.2014.82
Abstract: Case report. Subacute delayed ascending myelopathy (SDAM), also known as subacute post-traumatic ascending myelopathy, is a rare early neurological complication of spinal cord injury (SCI), and the aetiology, pathogenesis and optimal management of this condition are poorly understood. The radiological features together with the clinical picture appear to be the most useful. We aim to increase awareness and further characterise SDAM. Spinal Cord Injuries Unit, Royal North Shore Hospital, Sydney, Australia. We report two cases with radiological findings consistent with SDAM, and review the literature. Only a small number of cases have been reported and importantly, we report the first case occurring following a non-traumatic SCI. There are several hypotheses regarding pathogenesis, with several factors in our cases implicating a vascular mechanism. There is a lack of data characterising SDAM, and ascending myelopathy in a stable SCI should alert the clinician. Importantly, we propose that SDAM is the appropriate terminology.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22480715.V1
Abstract: Supplementary Data from Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities
Publisher: Elsevier BV
Date: 02-2022
Publisher: Wiley
Date: 06-2020
DOI: 10.3322/CAAC.21613
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22480712.V1
Abstract: Supplementary Data from Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities
Publisher: Informa UK Limited
Date: 30-11-2022
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2021
DOI: 10.1200/PO.20.00261
Abstract: Precision oncology has transformed the management of advanced cancers through implementation of advanced molecular profiling technologies to identify increasingly defined subsets of patients and match them to appropriate therapy. We report outcomes of a prospective molecular profiling study in a high-volume Asian tertiary cancer center. Patients with advanced cancer were enrolled onto a prospective protocol for genomic profiling, the In idualized Molecular Profiling for Allocation to Clinical Trials Singapore study, at the National Cancer Center Singapore. Primary objective was to identify molecular biomarkers in patient's tumors for allocation to clinical trials. The study commenced in February 2012 and is ongoing, with the results of all patients who underwent multiplex next-generation sequencing (NGS) testing until December 2018 presented here. The results were discussed at a molecular tumor board where recommendations for allocation to biomarker-directed trials or targeted therapies were made. One thousand fifteen patients were enrolled with a median age of 58 years (range 20-83 years). Most common tumor types were lung adenocarcinoma (26%), colorectal cancer (15%), and breast cancer (12%). A total of 1,064 NGS assays were performed, on fresh tumor tissue for 369 (35%) and archival tumor tissue for 687 (65%) assays. TP53 (39%) alterations were most common, followed by EGFR (21%), KRAS (14%), and PIK3CA (10%). Of 405 NGS assays with potentially actionable alterations, 111 (27%) were allocated to a clinical trial after molecular tumor board and 20 (4.9%) were enrolled on a molecularly matched clinical trial. Gene fusions were detected in 23 of 311 (7%) patients tested, including rare fusions in new tumor types and known fusions in rare tumors. In idualized Molecular Profiling for Allocation to Clinical Trials Singapore demonstrates the feasibility of a prospective broad molecular profiling program in an Asian tertiary cancer center, with the ability to develop and adapt to a dynamic landscape of precision oncology.
Publisher: Walter de Gruyter GmbH
Date: 2015
Abstract: : Five plants used traditionally by Australian Aboriginals and two edible native Australian fruits have been investigated for anticancer activity. The aim was to identify native Australian herbal medicines which displayed anticancer activity, with cytotoxicity to cancer cells but sparing or even proliferating normal immunological cells, and subsequently provide potentially new anticancer drug leads. : Extracts and derived fractions were assayed for cell viability against a multiple myeloma cell line, RPMI-8226, in comparison to the peripheral blood mononuclear cells (PBMC) representing normal human immunological cells. : None of the crude extracts exhibited the desirable differential activity however, following further fractionation of the : One fraction may potentially contain valuable compounds which may be useful for further investigation. This may focus on the identification of the bioavailable purified compounds present within these fractions or by detailed delineation of the related mechanisms of action.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6530516
Abstract: AbstractPurpose: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in i EGFR /i -mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in i EGFR /i sup T790M /sup -negative resistance. Experimental Design: We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic i EGFR /i -mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M sup + /sup ) and -negative (T790M sup − /sup ) disease. Results: Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M sup − /sup tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as i TP53 /i alterations, 3q chromosomal lifications, whole-genome doubling and nonaging mutational signatures in T790M sup − /sup tumors. Almost half of resistant tumors were further classified as immune sup hot /sup , with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M sup − /sup and T790M sup + /sup disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients. Conclusions: Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping ergent TKI resistance and outcome trajectories in i EGFR /i -mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential. /
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.EJCA.2022.10.012
Abstract: To determine the prognostic value of programmed death-ligand 1 (PD-L1) score in early-stage epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), contrasted against EGFR-wildtype NSCLC. Consecutive patients with Stage IA-IIIA NSCLC diagnosed 1st January 2010-31st December 2019 at National Cancer Centre Singapore with evaluable EGFR and PD-L1 status were included. Co-primary end-points were 2-year disease-free survival (DFS) and 5-year overall survival (OS) by Kaplan-Meier method. 455 patients were included (267 EGFR-mutated, EGFR-M+ 188 EGFR-wildtype, wt). Median age at diagnosis was 65 years, 52.3% (238/455) of patients were males, 62.9% (286/455) of patients were never-smokers and 92.5% (421/455) of patients had R0 resection. Stage IA comprised 42.4% (193/455) of patients, Stage IB comprised 23.1% (105/455) of patients, Stage IIA comprised 10.8% of patients (49/455), Stage IIB comprised 5.1% of patients (23/455) and Stage IIIA comprised 18.7% (85/455) of patients. Among EGFR-M+, 45.3% (121/267) were Ex19del and 41.9% (112/267) were L858R. PD-L1 ≥1% among EGFR-M+ and EGFR-wt was 45.3% (121/267) and 54.8% (103/188) respectively (p = 0.047). At median follow-up of 47 months, 178 patients had relapsed. Among EGFR-M+, 2-year DFS comparing PD-L1 <1% and PD-L1 ≥1% was 78.1% and 67.6% (p = 0.007) while 5-year OS was 59.5% and 42.8% (p = 0.001), respectively. Controlling for age, gender, lymphovascular invasion, adjuvant therapy and resection margin status, PD-L1 ≥1% (hazard ratio, HR 2.18, 95% CI 1.04-4.54, p = 0.038), stage IIB (HR 7.78, 95% CI 1.72-35.27, p = 0.008) and stage IIIA (HR 4.45, 95% CI 1.44-13.80, p = 0.01) emerged as independent predictors of inferior OS on multivariable analysis. In exploratory analysis, genomic analysis of 81 EGFR-M+ tumours was performed. PD-L1 ≥1% tumours had significantly higher rates of TP53 mutations (36.1% versus 15.6%, p = 0.04), with predominantly missense mutations. PD-L1 ≥1% is an independent predictor of worse OS among early-stage EGFR-mutated NSCLC and is associated with inferior DFS regardless of EGFR status. PD-L1 score as a risk stratification factor should be evaluated in prospective adjuvant studies among EGFR-mutated NSCLC.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-02-2022
DOI: 10.1200/JCO.21.01626
Abstract: Lung cancer has traditionally been classified by histology. However, a greater understanding of disease biology and the identification of oncogenic driver alterations has dramatically altered the therapeutic landscape. Consequently, the new classification paradigm of non–small-cell lung cancer is further characterized by molecularly defined subsets actionable with targeted therapies and the treatment landscape is becoming increasingly complex. This review encompasses the current standards of care for targeted therapies in lung cancer with driver molecular alterations. Targeted therapies for EGFR exon 19 deletion and L858R mutations, and ALK and ROS1 rearrangements are well established. However, there is an expanding list of approved targeted therapies including for BRAF V600E, EGFR exon 20 insertion, and KRAS G12C mutations, MET exon 14 alterations, and NTRK and RET rearrangements. In addition, there are numerous other oncogenic drivers, such as HER2 exon 20 insertion mutations, for which there are emerging efficacy data for targeted therapies. The importance of diagnostic molecular testing, intracranial efficacy of novel therapies, the optimal sequencing of therapies, role for targeted therapies in early-stage disease, and future directions for precision oncology approaches to understand tumor evolution and therapeutic resistance are also discussed.
Publisher: Springer Science and Business Media LLC
Date: 18-04-2017
DOI: 10.1007/S11912-017-0596-3
Abstract: Metastasis of cancer to the brain typically portends a poor prognosis and often results in significant morbidity, including from the side effects of treatment. More effective therapies for patients with brain metastases are needed. The current treatment paradigm uses multiple modalities, including surgery, radiation, and in some contexts, systemic chemotherapy and immunotherapy. Immune checkpoint inhibitors are increasingly being used to treat extracranial disease, and their effectiveness in the management of brain metastases needs to be understood. The evidence for immune checkpoint inhibitors in the management of brain metastases is largely limited to retrospective analyses of melanoma metastases and ipilimumab. Prospective clinical trials of more active agents are under way, and tentative results suggest activity. Immune checkpoint inhibitors have the potential to improve outcomes in patients with brain metastases. Results of current clinical trials will aid in determining the appropriate sequence or combination of local and systemic therapies.
Publisher: MDPI AG
Date: 19-02-2020
DOI: 10.3390/IJMS21041416
Abstract: The management of non-small cell lung cancer (NSCLC) has transformed with the discovery of therapeutically tractable oncogenic drivers. In addition to activating driver mutations, gene fusions or rearrangements form a unique sub-class, with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) targeted agents approved as the standard of care in the first-line setting for advanced disease. There are a number of emerging fusion drivers, however, including neurotrophin kinase (NTRK), rearrangement during transfection (RET), and neuregulin 1 (NRG1) for which there are evolving high-impact systemic treatment options. Brain metastases are highly prevalent in NSCLC patients, with molecularly selected populations such as epidermal growth factor receptor (EGFR) mutant and ALK-rearranged tumors particularly brain tropic. Accordingly, there exists a substantial body of research pertaining to the understanding of brain metastases in such populations. Little is known, however, on the molecular mechanisms of brain metastases in those with other targetable fusion drivers in NSCLC. This review encompasses key areas including the biological underpinnings of brain metastases in fusion-driven lung cancers, the intracranial efficacy of novel systemic therapies, and future directions required to optimize the control and prevention of brain metastases.
Publisher: American Association for Cancer Research (AACR)
Date: 13-11-2020
DOI: 10.1158/1078-0432.CCR-20-2989
Abstract: Coronavirus disease 2019 (COVID-19) has fundamentally disrupted the practice of oncology, shifting care onto virtual platforms, rearranging the logistics and economics of running a successful clinical practice and research, and in some contexts, redefining what treatments patients with cancer should and can receive. Since the start of the pandemic in early 2020, there has been considerable emphasis placed on the implications for patients with cancer in terms of their vulnerability to the virus and potential exposure in healthcare settings. But little emphasis has been placed on the significant, and potentially enduring, consequences of COVID-19 for how cancer care is delivered. In this article, we outline the importance of a focus on the effects of COVID-19 for oncology practice during and potentially after the pandemic, focusing on key shifts that are already evident, including: the pivot to online consultations, shifts in access to clinical trial and definitions of “essential care,” the changing economics of practice, and the potential legacy effects of rapidly implemented changes in cancer care. COVID-19 is reshaping oncology practice, clinical trials, and delivery of cancer care broadly, and these changes might endure well beyond the short- to mid-term of the active pandemic. Therefore, shifts in practice brought about by the pandemic must be accompanied by improved training and awareness, enhanced infrastructure, and evidence-based support if they are to harness the positives and offset the potential negative consequences of the impacts of COVID-19 on cancer care.
Publisher: SAGE Publications
Date: 2018
Abstract: Metastatic gastric cancer is associated with a poor prognosis and novel treatment options are desperately needed. The development of targeted therapies heralded a new era for the management of metastatic gastric cancer, however results from clinical trials of numerous targeted agents have been mixed. The advent of immune checkpoint inhibitors has yielded similar promise and results from early trials are encouraging. This review provides an overview of the systemic treatment options evaluated in metastatic gastric cancer, with a focus on recent evidence from clinical trials for targeted therapies and immune checkpoint inhibitors. The failure to identify appropriate predictive biomarkers has h ered the success of many targeted therapies in gastric cancer, and a deeper understanding of specific molecular subtypes and genomic alterations may allow for more precision in the application of novel therapies. Identifying appropriate biomarkers for patient selection is essential for future clinical trials, for the most effective use of novel agents and in combination approaches to account for growing complexity of treatment options.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2021
DOI: 10.1158/1078-0432.CCR-20-4607
Abstract: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in EGFRT790M-negative resistance. We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR-mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M+) and -negative (T790M−) disease. Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M− tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as TP53 alterations, 3q chromosomal lifications, whole-genome doubling and nonaging mutational signatures in T790M− tumors. Almost half of resistant tumors were further classified as immunehot, with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M− and T790M+ disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients. Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping ergent TKI resistance and outcome trajectories in EGFR-mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential.
Publisher: Informa UK Limited
Date: 03-2021
DOI: 10.2147/LCTT.S263610
Publisher: Elsevier BV
Date: 12-2020
Publisher: Springer Science and Business Media LLC
Date: 28-10-2022
DOI: 10.1038/S41467-022-33834-4
Abstract: Cancer vaccines as immunotherapy for solid tumours are currently in development with promising results. We report a phase 1 study of Ad-sig-hMUC1/ecdCD40L (NCT02140996), an adenoviral-vector vaccine encoding the tumour-associated antigen MUC1 linked to CD40 ligand, in patients with advanced adenocarcinoma. The primary objective of this study is safety and tolerability. We also study the immunome in vaccinated patients as a secondary outcome. This trial, while not designed to determine clinical efficacy, reports an exploratory endpoint of overall response rate. The study meets its pre-specified primary endpoint demonstrating safety and tolerability in a cohort of 21 patients with advanced adenocarcinomas (breast, lung and ovary). The maximal dose of the vaccine is 1 ×10 11 viral particles, with no dose limiting toxicities. All drug related adverse events are of low grades, most commonly injection site reactions in 15 (71%) patients. Using exploratory high-dimensional analyses, we find both quantitative and relational changes in the cancer immunome after vaccination. Our data highlights the utility of high-dimensional analyses in understanding and predicting effective immunotherapy, underscoring the importance of immune competency in cancer prognosis.
Publisher: MDPI AG
Date: 09-08-2022
DOI: 10.3390/IJMS23168863
Abstract: The management of advanced lung cancer has been transformed with the identification of targetable oncogenic driver alterations. This includes anaplastic lymphoma kinase (ALK) gene rearrangements. ALK tyrosine kinase inhibitors (TKI) are established first-line treatment options in advanced ALK rearranged non-small cell lung cancer (NSCLC), with several next-generation ALK TKIs (alectinib, brigatinib, ensartinib and lorlatinib) demonstrating survival benefit compared with the first-generation ALK TKI crizotinib. Still, despite high objective response rates and durable progression-free survival, drug resistance inevitably ensues, and treatment options beyond ALK TKI are predominantly limited to cytotoxic chemotherapy. Anti-angiogenic therapy targeting the vascular endothelial growth factor (VEGF) signaling pathway has shown efficacy in combination with platinum-doublet chemotherapy in advanced NSCLC without a driver alteration, and with EGFR TKI in advanced EGFR mutated NSCLC. The role for anti-angiogenic therapy in ALK rearranged NSCLC, however, remains to be elucidated. This review will discuss the pre-clinical rationale, clinical trial evidence to date, and future directions to evaluate anti-angiogenic therapy in ALK rearranged NSCLC.
Publisher: American Association for Cancer Research (AACR)
Date: 03-2021
DOI: 10.1158/1535-7163.MCT-20-0579
Abstract: Paget's “seed and soil” hypothesis of metastatic spread has acted as a foundation of the field for over a century, with continued evolution as mechanisms of the process have been elucidated. The central nervous system (CNS) presents a unique soil through this lens, relatively isolated from peripheral circulation and immune surveillance with distinct cellular and structural composition. Research in primary and metastatic brain tumors has demonstrated that this tumor microenvironment (TME) plays an essential role in the growth of CNS tumors. In each case, the cancerous cells develop complex and bidirectional relationships that reorganize the local TME and reprogram the CNS cells, including endothelial cells, pericytes, astrocytes, microglia, infiltrating monocytes, and lymphocytes. These interactions create a structurally and immunologically permissive TME with malignant processes promoting positive feedback loops and systemic consequences. Strategies to interrupt interactions with the native CNS components, on “salting the soil,” to create an inhospitable environment are promising in the preclinical setting. This review aims to examine the general and specific pathways thus far investigated in brain metastases and related work in glioma to identify targetable mechanisms that may have general application across the spectrum of intracranial tumors.
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.LUNGCAN.2019.11.022
Abstract: There is an expanding list of therapeutically relevant biomarkers for non-small cell lung cancer (NSCLC), and molecular profiling at diagnosis is paramount. Tissue attrition in scaling traditional single biomarker assays from small biopsies is an increasingly encountered problem. We sought to compare the performance of targeted next-generation sequencing (NGS) panels with traditional assays and correlate the mutational landscape with PD-L1 status in Singaporean patients. We identified consecutive patients diagnosed between Jan 2016 to Sep 2017 with residual tissue after standard molecular testing. Tissue s les were tested using a targeted NGS panel for DNA alterations (29 selected genes including BRAF, EGFR, ERBB2 and TP53) and an RNA fusion panel (ALK, ROS1 and RET). PD-L1 immunohistochemistry was also performed. A cost-effectiveness analysis of NGS compared to standard molecular testing was conducted. A total of 174 s les were evaluated: PD-L1 (n = 169), NGS DNA panel (n = 173) and RNA fusion (n = 119) testing. Median age was 68 years, 53 % were male, 58 % were never smokers, 85 % were Chinese, 66 % had stage IV disease and 95 % had adenocarcinoma histology. In patients profiled with NGS on DNA, EGFR (56 %), KRAS (14 %), BRAF (2 %) and ERBB2 (1 %) mutations were found. RNA fusion testing revealed fusions in ALK (6 %), RET (3 %) and ROS1 (1 %). Cost-effectiveness analysis demonstrated that compared to sequential testing in EGFR negative patients, upfront NGS testing would result in an additional 1 % of patients with actionable alterations for targeted therapy being identified without significant increases in testing cost or turnaround time. This study demonstrates that even in an EGFR mutant predominant population, upfront NGS represents a feasible, cost-effective method of diagnostic molecular profiling compared with sequential testing strategies. Our results support the implementation of diagnostic NGS in non-squamous NSCLC in Asia to allow patients access to the most appropriate personalized therapy.
Publisher: American Society for Clinical Investigation
Date: 07-2022
DOI: 10.1172/JCI145099
Publisher: Elsevier BV
Date: 12-2020
No related grants have been discovered for Aaron Tan.