ORCID Profile
0000-0002-8276-0374
Current Organisations
Peter MacCallum Cancer Institute
,
Royal Australasian College of Physicians
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Publisher: Springer Science and Business Media LLC
Date: 06-06-2016
DOI: 10.1038/NCOMMS11908
Abstract: Nature Communications 7 Article number:11479 (2016) Published: 10 May 2016 Updated: 6 June 2016. The original version of this Article contained an error in the spelling of ‘refine’ in the title of the paper. This has now been corrected in both the PDF and HTML.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540936
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540933
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: MDPI AG
Date: 11-01-2021
DOI: 10.3390/DIAGNOSTICS11010103
Abstract: Blood-based liquid biopsies are considered a new and promising diagnostic and monitoring tool for cancer. As liquid biopsies only require a blood draw, they are non-invasive, potentially more rapid and assumed to be a less costly alternative to genomic analysis of tissue biopsies. A multi-disciplinary workshop (n = 98 registrations) was organized to discuss routine implementation of liquid biopsies in cancer management. Real-time polls were used to engage with experts’ about the current evidence of clinical utility and the barriers to implementation of liquid biopsies. Clinical, laboratory and health economics presentations were given to illustrate the opportunities and current levels of evidence, followed by three moderated break-out sessions to discuss applications. The workshop concluded that tumor-informed assays using next-generation sequencing (NGS) or PCR-based genotyping assays will most likely provide better clinical utility than tumor-agnostic assays, yet at a higher cost. For routine application, it will be essential to determine clinical utility, to define the minimum quality standards and performance of testing platforms and to ensure their use is integrated into current clinical workflows including how they complement tissue biopsies and imaging. Early health economic models may help identifying the most viable application of liquid biopsies. Alternative funding models for the translation of complex molecular diagnostics, such as liquid biopsies, may also be explored if clinical utility has been demonstrated and when their use is recommended in multi-disciplinary consensus guidelines.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540939
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490194.V1
Abstract: Supplementary material
Publisher: Springer Science and Business Media LLC
Date: 23-11-2011
DOI: 10.1186/BCR3061
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540930
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Springer Science and Business Media LLC
Date: 02-2006
DOI: 10.1038/NCPONC0405
Abstract: A 70-year-old man presented with a smooth lump on his buccal mucosa and right-sided cervical lymphadenopathy. Staging investigations revealed extensive sclerotic bone metastases and the patient subsequently underwent palliative radiotherapy to the right face and cervical region. Seven months later he presented with a 4-day history of fatigue, muscle cr s, ataxia, paraesthesia, and blurred vision. Physical examination, biopsy of abnormal buccal mucosa, routine biochemistry, electrocardiogram, bone scan, CT scans of the chest, abdomen and pelvis, and MRI of the brain. Undifferentiated carcinoma of the salivary gland with sclerotic bone metastases and hypocalcemia. Palliative radiotherapy to the right face and cervical region, infusions of calcium gluconate and calcium chloride, oral calcium carbonate, vitamin D and magnesium, palliative chemotherapy (carboplatin and 5-fluorouracil), and whole brain radiotherapy.
Publisher: Elsevier BV
Date: 05-1995
DOI: 10.1016/S0968-0004(00)89007-6
Abstract: The discovery of structural and functional similarities between the product of the nematode cell-death gene ced-3 and mammalian interleukin-1 beta-converting enzyme (ICE) is providing important insights into the molecular mechanism of apoptosis. This article summarizes the current knowledge of ICE and its homologues, and how these may be involved in regulating apoptosis.
Publisher: Springer Science and Business Media LLC
Date: 22-09-2009
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540921.V1
Abstract: Supplementary movie from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.MEDJ.2021.11.001
Abstract: Detection of minimal residual disease in patients with cancer, who are in complete remission with no cancer cells detectable, has the potential to improve recurrence-free survival through treatment selection. Studies analyzing circulating tumor DNA (ctDNA) in patients with solid tumors suggest the potential to accurately predict and detect relapse, enabling treatment strategies that may improve clinical outcomes. Over the past decade, assays for ctDNA detection in plasma s les have steadily increased in sensitivity and specificity. These are applied for the detection of residual disease after treatment and for earlier detection of recurrence. Novel clinical trials are now assessing how assays for "residual disease and recurrence" (RDR) may influence current treatment paradigms and potentially change the landscape of risk classification for cancer recurrence. In this review, we appraise the progress of RDR detection using ctDNA and consider the emerging role of liquid biopsy in the monitoring and management of solid tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540945
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 13-01-2023
DOI: 10.1158/1078-0432.CCR-22-3094
Abstract: BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies. We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. Thirty-two patients with BRAF V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1 mutations, and MET lification. The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540948
Abstract: Supplementary Data from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Oxford University Press (OUP)
Date: 12-03-2022
Abstract: Despite the strong prognostic stratification of circulating tumor cells (CTCs) enumeration in metastatic breast cancer (MBC), current clinical trials usually do not include a baseline CTCs in their design. This study aimed to generate a classifier for CTCs prognostic simulation in existing datasets for hypothesis generation in patients with MBC. A K-nearest neighbor machine learning algorithm was trained on a pooled dataset comprising 2436 in idual MBC patients from the European Pooled Analysis Consortium and the MD Anderson Cancer Center to identify patients likely to have CTCs ≥ 5/7 mL blood (StageIVaggressive vs StageIVindolent). The model had a 65.1% accuracy and its prognostic impact resulted in a hazard ratio (HR) of 1.89 (Simulatedaggressive vs SimulatedindolentP & .001), similar to patients with actual CTCs enumeration (HR 2.76 P & .001). The classifier’s performance was then tested on an independent retrospective database comprising 446 consecutive hormone receptor (HR)-positive HER2-negative MBC patients. The model further stratified clinical subgroups usually considered prognostically homogeneous such as patients with bone-only or liver metastases. Bone-only disease classified as Simulatedaggressive had a significantly worse overall survival (OS P & .0001), while patients with liver metastases classified as Simulatedindolent had a significantly better prognosis (P & .0001). Consistent results were observed for patients who had undergone CTCs enumeration in the pooled population. The differential prognostic impact of endocrine- (ET) and chemotherapy (CT) was explored across the simulated subgroups. No significant differences were observed between ET and CT in the overall population, both in terms of progression-free survival (PFS) and OS. In contrast, a statistically significant difference, favoring CT over ET was observed among Simulatedaggressive patients (HR: 0.62 P = .030 and HR: 0.60 P = .037, respectively, for PFS and OS).
Publisher: Springer Science and Business Media LLC
Date: 08-12-2022
Publisher: Springer Science and Business Media LLC
Date: 04-03-2021
DOI: 10.1038/S41467-021-21576-8
Abstract: Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by s ling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour s les reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540942
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549547
Abstract: Abstract There is limited knowledge on the benefit of the α-subunit–specific PI3K inhibitor alpelisib in later lines of therapy for advanced estrogen receptor–positive (ER sup + /sup ) HER2 sup − /sup and triple-negative breast cancer (TNBC). We conducted a phase II multicohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER sup + /sup HER2 sup − /sup and TNBC. In the intention-to-treat ER sup + /sup cohort, the overall response rate was 30% and the clinical benefit rate was 36%. A decline in PI3K pathway mutant circulating tumor DNA (ctDNA) levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit, and improved progression-free-survival [HR 0.24 95% confidence interval (CI), 0.083–0.67, i P /i = 0.0065]. Detection of i ESR1 /i mutations at baseline in plasma was also associated with clinical benefit and improved progression-free survival (HR 0.22 95% CI, 0.078–0.60, i P /i = 0.003). Significance: Alpelisib monotherapy displayed efficacy in heavily pretreated ER sup + /sup breast cancer with i PIK3CA /i mutations. i PIK3CA /i mutation dynamics in plasma during treatment and i ESR1 /i mutations detected in plasma at baseline were candidate biomarkers predictive of benefit from alpelisib, highlighting the utility of ctDNA assays in this setting. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-12-9-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 2007 /a /i /
Publisher: Wiley
Date: 04-12-2014
DOI: 10.1002/CJP2.3
Publisher: Wiley
Date: 08-02-2013
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541074
Abstract: Supplementary Data from Alpelisib Monotherapy for PI3K-Altered, Pretreated Advanced Breast Cancer: A Phase II Study
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540915.V1
Abstract: Supplementary table from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541071
Abstract: Supplementary Figure from Alpelisib Monotherapy for PI3K-Altered, Pretreated Advanced Breast Cancer: A Phase II Study
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.CRITREVONC.2018.12.004
Abstract: The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease. In a retrospective, pooled analysis of in idual patient data from 18 cohorts, including 2436 MBC patients, a CTC threshold of 5 cells per 7.5 ml was used for stratification based on molecular subtypes, disease location, and prior treatments. Patients with ≥ 5 CTCs were classified as Stage IV For all patients, Stage IV We confirm the identification of two subgroups of MBC, Stage IV
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490194
Abstract: Supplementary material
Publisher: Wiley
Date: 26-09-2011
DOI: 10.1002/PATH.2976
Abstract: There is an urgent need to improve prognostic classifiers in breast cancer. Ki67 and B-cell lymphoma 2 protein (BCL2) are established prognostic markers which have traditionally been assessed separately, in a dichotomous manner. This study was conducted to test the hypothesis that combinatorial assessment of these markers would provide superior prognostic information and improve their clinical utility. Tissue microarrays were used to assess the expression of Ki67 and BCL2 in 2749 cases of invasive breast cancer. We devised a Ki67/BCL2 index representing the relative expression of each protein and assessed its association with breast cancer-specific survival (BCSS) using a Cox proportional-hazards model. Based on our findings, an independent cohort of 3992 cases was used to validate the prognostic significance of the Ki67/BCL2 index. All survival analyses were conducted on complete data as well as data where missing values were resolved using multiple imputation. This study complied with reporting recommendations for tumour marker prognostic studies (REMARK) criteria. The Ki67/BCL2 index showed a significant association with BCSS at 10 years in estrogen receptor (ER)-positive disease. In multivariate analysis, adjusting for major clinical and molecular markers, the Ki67/BCL2 index retained prognostic significance, robustly classifying cases into three risk groups [intermediate- versus low-risk hazard ratio (HR), 1.5 95% confidence interval (95% CI), 1.0-2.0 p = 0.031 high- versus low-risk HR, 2.6 95% CI, 1.3-5.0 p = 0.005]. This finding was validated in an independent cohort of 3992 tumours containing 2761 ER-positive tumours (intermediate- versus low-risk HR, 1.7 95% CI, 1.3-2.1 p < 0.001 high- versus low-risk HR, 2.0 95% CI, 1.4-2.9 p < 0.001). Ki67 and BCL2 can be effectively combined to produce an index which is an independent predictor of BCSS in ER-positive breast cancer, enhancing their potential prognostic utility.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-02-2018
Publisher: Public Library of Science (PLoS)
Date: 10-2020
Publisher: Wiley
Date: 02-2011
DOI: 10.1111/J.1445-5994.2009.02112.X
Abstract: Optimal delivery of intraperitoneal (i.p.) chemotherapy is dependent on adequate drug distribution. An accurate understanding of the limitations of i.p. distribution is critical if we are to improve cytotoxic delivery through this route. Using repeated scintigraphic peritoneography we investigated peritoneal fluid distribution in patients receiving i.p. therapy. Both early (1-6 h) and late (24-48 h) images were performed. The peritoneal cavity was ided into six regions pouch of Douglas, left and right paracolic gutters, left and right subphrenic spaces and the right subhepatic space. The distribution in each region was classified as absent (0), faint (1) or intense (2). A total distribution score was calculated from the summation of distribution values for each of the six regions. Distribution was then graded according to the total distribution score as follows: Grade 0 = 0-3 Grade 1 = 4-6 Grade 2 = 7-9 and Grade 3 = 10-12. Twenty-six participants were included in the study: all 26 patients had early imaging performed and 21 of these also had late imaging. Thirteen (50%) and 15 (71%) patients had grade 1 or 2 i.p. distribution on early and late imaging respectively. The most common abdominal regions to show maldistribution were the subphrenic spaces. This study highlights the deficiencies of distribution following i.p. drug delivery, with the majority of patients demonstrating multiple regions of faint or absent uptake on scintigraphic peritoneography imaging. Future large clinical studies investigating i.p. chemotherapy should include analyses of i.p. distribution to improve our understanding of optimal drug delivery through this route.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6533113.V1
Abstract: AbstractPurpose: BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies. Patients and Methods: We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. Results: Thirty-two patients with i BRAF /i V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal i KRAS /i , i NRAS /i , and i MAP2K1 /i mutations, and i MET /i lification. Conclusions: The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance. /
Publisher: American Society of Hematology
Date: 30-07-2020
Abstract: Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established, and the features that contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes and 34 genomes alongside previously published exome cohorts. To confirm our findings, we resequenced the genes identified in the exome cohort in 191 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations. Our sequencing revealed novel recurrent noncoding mutations surrounding a single exon of the HNRNPH1gene. In RNA-seq data from 103 of these cases, MCL tumors with these mutations had a distinct imbalance of HNRNPH1 isoforms. This altered splicing of HNRNPH1 was associated with inferior outcomes in MCL and showed a significant increase in protein expression by immunohistochemistry. We describe a functional role for these recurrent noncoding mutations in disrupting an autoregulatory feedback mechanism, thereby deregulating HNRNPH1 protein expression. Taken together, these data strongly imply a role for aberrant regulation of messenger RNA processing in MCL pathobiology.
Publisher: Springer Science and Business Media LLC
Date: 27-07-2010
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540942.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Wiley
Date: 24-05-2007
DOI: 10.1111/J.1445-5994.2007.01371.X
Abstract: Insulinomas are the most common hormone-producing pancreatic neuroendocrine tumours (NETs), and patients usually present with symptoms secondary to hypoglycaemia. Octreotide has been widely used in the symptomatic treatment of patients with pancreatic NETs, including insulinomas. We describe a case of a patient with a metastatic NET, subsequently identified as a malignant insulinoma, who developed severe hypoglycaemia after treatment with long-acting octreotide.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-0011
DOI: 10.1200/PO.16.00009
Abstract: Circulating tumor DNA (ctDNA) allows noninvasive disease monitoring across a range of malignancies. In metastatic melanoma, the extent to which ctDNA reflects changes in metabolic disease burden assessed by 18 F-labeled fluorodeoxyglucose positron emission tomography (FDG-PET) is unknown. We assessed the role of ctDNA analysis in combination with FDG-PET to monitor tumor burden and genomic heterogeneity throughout treatment. We performed a comprehensive analysis of serial ctDNA and FDG-PET in 52 patients who received systemic therapy for metastatic melanoma. Next-generation sequencing and digital polymerase chain reaction were used to analyze plasma s les from the cohort. ctDNA levels were monitored across patients with mutant BRAF, NRAS, and BRAF/NRAS wild type disease. Mutant BRAF and NRAS ctDNA levels correlated closely with changes in metabolic disease burden throughout treatment. TERT promoter mutant ctDNA levels also paralleled changes in tumor burden, which provide an alternative marker for disease monitoring. Of note, subcutaneous and cerebral disease sites were not well represented in plasma. Early changes in ctDNA and metabolic disease burden were important indicators of treatment response. Patients with an early decrease in ctDNA post-treatment had improved progression-free survival compared with patients in whom ctDNA levels remained unchanged or increased over time (hazard ratio, 2.6 P = .05). ctDNA analysis contributed key molecular information through the identification of putative resistance mechanisms to targeted therapy. A detailed comparison of the genomic architecture of plasma and multiregional tumor biopsy specimens at autopsy revealed the ability of ctDNA to comprehensively capture genomic heterogeneity across multiple disease sites. The findings highlight the powerful role of ctDNA in metastatic melanoma as a complementary modality to functional imaging that allows real-time monitoring of both tumor burden and genomic changes throughout therapy.
Publisher: Society of Nuclear Medicine
Date: 27-04-2017
Publisher: Springer Science and Business Media LLC
Date: 26-04-2012
DOI: 10.1038/BJC.2012.167
Publisher: Massachusetts Medical Society
Date: 29-03-2018
Publisher: Public Library of Science (PLoS)
Date: 27-12-2016
Publisher: American Association for the Advancement of Science (AAAS)
Date: 30-06-2017
Abstract: Drugs that show promise in preclinical models often fail in the clinic, in part because of limited information on drug localization within cells and across tissues. In a proof-of-concept study, Tyler et al. applied click chemistry methods to study the localization of bromodomain inhibitors. These are cancer drugs that alter chromatin structure and gene expression. Clickable derivatives of the drugs localized within chromatin and showed that the drugs exhibit distinct modes of binding at responsive and unresponsive genes. In a mouse leukemia model, the click-probes revealed that the drugs accumulate to different extents in the spleen and bone marrow, which are two tissue sources of leukemic cells. Science , this issue p. 1397
Publisher: Elsevier BV
Date: 08-2014
Abstract: T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date. Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 s les) and for FOXP3 from three studies (5239 s les)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival. In ER-negative tumours [triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive)], presence of CD8+ T cells within the tumour was associated with a 28% [95% confidence interval (CI) 16% to 38%] reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours [hazard ratio (HR) = 0.54 95% CI 0.37-0.79] versus CD8-negative tumours (HR = 0.87 95% CI 0.55-1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (P heterogeneity = 0.04) and approached significance in imputed data (P heterogeneity = 0.1). The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative [supplementary Figure S1, available at Annals of Oncology online] and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes. NEAT ClinicalTrials.gov: NCT00003577.
Publisher: Massachusetts Medical Society
Date: 28-03-2013
Publisher: Elsevier BV
Date: 10-2019
Publisher: Massachusetts Medical Society
Date: 20-10-2005
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540945.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Springer Science and Business Media LLC
Date: 06-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2008
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549508.V1
Abstract: Abstract Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked i in vitro /i and i in vivo /i synergy with venetoclax and overcomes venetoclax resistance in primary patient s les. Significance: Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. i This article is highlighted in the In This Issue feature, p. 587 /i /
Publisher: Springer Science and Business Media LLC
Date: 12-01-2023
Publisher: Springer Science and Business Media LLC
Date: 12-09-2016
DOI: 10.1038/NBT.3674
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541074.V1
Abstract: Supplementary Data from Alpelisib Monotherapy for PI3K-Altered, Pretreated Advanced Breast Cancer: A Phase II Study
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540948.V1
Abstract: Supplementary Data from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2015
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.PATHOL.2022.02.010
Abstract: Droplet digital PCR (ddPCR) has been demonstrated in many research studies to be a sensitive method in the analysis of circulating tumour DNA (ctDNA) for identifying mutations and tracking disease. The transition of ddPCR into the diagnostic setting requires a number of critical steps including the assessment of accuracy and precision and ultimately implementation into clinical use. Here we present the clinical validation of ddPCR for the detection of BRAF mutations (V600E and V600K) from plasma. We describe the performance characteristics assessed including the limit of blank, limit of detection, ruggedness, accuracy, precision and the effect of the matrix. Overall, each assay could achieve a limit of detection of 0.5% variant allele fraction and was highly accurate, with 100% concordance of results obtained from routine diagnostic testing of formalin fixed tumour s les or reference controls (n=36 for BRAF V600E and n=30 for BRAF V600K). Inter-laboratory reproducibility across 12 plasma s les for each assay was also assessed and results were 100% concordant. Overall, we report the successful validation and translation of a ddPCR assay into clinical routine practice.
Publisher: Springer Science and Business Media LLC
Date: 12-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540939.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Elsevier BV
Date: 04-2014
Publisher: Elsevier BV
Date: 12-2014
Abstract: Next-generation sequencing studies have provided further evidence to support the notion that cancer is a disease characterized by Darwinian evolution. Today, we often fail to capture this evolution and treatment decisions, even in the metastatic setting, are often based on analysis of primary tumor diagnosed years ago. Currently, this is considered a major reason for treatment failures in cancer care. Recent technological advances in the detection and characterization of circulating tumor cells and circulating tumor DNA might address this and allow for treatment tailoring based on real-time monitoring of tumor evolution. In this review, we summarize the most important recent findings in the field, focusing on challenges and opportunities in moving these tools forward in clinical practice.
Publisher: American Association for Cancer Research (AACR)
Date: 14-06-2019
DOI: 10.1158/1078-0432.CCR-18-2521
Abstract: In the neoadjuvant treatment (NAT) setting, dual HER2-targeted therapy is associated with increased pathologic complete response (pCR) rates compared with each therapy alone. Biomarkers allowing to predict treatment response during NAT are needed. We aim to evaluate whether circulating tumor DNA (ctDNA) is associated with response to anti-HER2–targeted therapy. Plasma DNA collected before NAT, at week 2, and before surgery from patients enrolled in the NeoALTTO trial was assessed using digital PCR for PIK3CA and TP53 mutation detection. A total of 69 of 455 (15.2%) patients had a PIK3CA and/or TP53 mutation detected in the baseline tumor s le and evaluable ctDNA results from baseline s les. CtDNA was detected in 41%, 20%, and 5% patients before NAT, at week 2, and before surgery, respectively. ctDNA detection before NAT was significantly associated with older age and ER-negative status. ctDNA detection before NAT was associated with decreased odds of achieving pCR (OR = 0.15 95% CI, 0.034–0.7 P = 0.0089), but not with event-free survival (EFS). Analyses for EFS were underpowered. Interestingly, the patients with HER2-enriched subtype tumors and undetectable ctDNA at baseline had the highest pCR rates. In contrast, patients with persistent ctDNA detection at baseline and week 2 had the lowest rate of pCR. ctDNA detection before neoadjuvant anti-HER2 therapies is associated with decreased pCR rates. Interestingly, patients with HER2-enriched tumors and undetectable ctDNA at baseline had the highest pCR rates, therefore appearing as the best candidates for treatment deescalation strategies.
Publisher: Springer Science and Business Media LLC
Date: 20-06-2019
DOI: 10.1038/S41467-019-10652-9
Abstract: Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient s les and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance.
Publisher: American Association for Cancer Research (AACR)
Date: 03-2019
DOI: 10.1158/2159-8290.CD-18-1151
Abstract: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL2-positive metastatic breast cancer. These findings support further investigation of combination therapy for patients with BCL2-positive tumors. See related commentary by Drago et al., p. 323. This article is highlighted in the In This Issue feature, p. 305
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549547.V1
Abstract: Abstract There is limited knowledge on the benefit of the α-subunit–specific PI3K inhibitor alpelisib in later lines of therapy for advanced estrogen receptor–positive (ER sup + /sup ) HER2 sup − /sup and triple-negative breast cancer (TNBC). We conducted a phase II multicohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER sup + /sup HER2 sup − /sup and TNBC. In the intention-to-treat ER sup + /sup cohort, the overall response rate was 30% and the clinical benefit rate was 36%. A decline in PI3K pathway mutant circulating tumor DNA (ctDNA) levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit, and improved progression-free-survival [HR 0.24 95% confidence interval (CI), 0.083–0.67, i P /i = 0.0065]. Detection of i ESR1 /i mutations at baseline in plasma was also associated with clinical benefit and improved progression-free survival (HR 0.22 95% CI, 0.078–0.60, i P /i = 0.003). Significance: Alpelisib monotherapy displayed efficacy in heavily pretreated ER sup + /sup breast cancer with i PIK3CA /i mutations. i PIK3CA /i mutation dynamics in plasma during treatment and i ESR1 /i mutations detected in plasma at baseline were candidate biomarkers predictive of benefit from alpelisib, highlighting the utility of ctDNA assays in this setting. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-12-9-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 2007 /a /i /
Publisher: American Association for the Advancement of Science (AAAS)
Date: 24-04-2020
Abstract: Bromodomain and extraterminal domain (BET) proteins contribute to the pathogenesis of cancer and immune diseases through their effects on transcriptional regulation. BET proteins contain two nearly identical bromodomains, BD1 and BD2, structural modules that have attracted great interest as targets for drug development. First-generation drugs that inhibited both BD1 and BD2 showed promising therapeutic activity in preclinical models but proved to be less efficacious in clinical trials. Gilan et al. took a different approach and designed drugs that selectively inhibited BD1 or BD2 (see the Perspective by Filippakopoulos and Knapp). They found that BD1 and BD2 inhibitors altered gene expression in different ways and that BD2 inhibitors had greater therapeutic activity than BD1 inhibitors in preclinical models of inflammation and autoimmune disease. Science , this issue p. 387 see also p. 367
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541071.V1
Abstract: Supplementary Figure from Alpelisib Monotherapy for PI3K-Altered, Pretreated Advanced Breast Cancer: A Phase II Study
Publisher: American Association for Cancer Research (AACR)
Date: 30-06-2022
DOI: 10.1158/2159-8290.CD-21-1696
Abstract: Alpelisib monotherapy displayed efficacy in heavily pretreated ER+ breast cancer with PIK3CA mutations. PIK3CA mutation dynamics in plasma during treatment and ESR1 mutations detected in plasma at baseline were candidate biomarkers predictive of benefit from alpelisib, highlighting the utility of ctDNA assays in this setting. This article is highlighted in the In This Issue feature, p. 2007
Publisher: Public Library of Science (PLoS)
Date: 21-04-2017
Publisher: Springer Science and Business Media LLC
Date: 08-10-2020
Publisher: Massachusetts Medical Society
Date: 04-07-2013
DOI: 10.1056/NEJMC1306040
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549508
Abstract: Abstract Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked i in vitro /i and i in vivo /i synergy with venetoclax and overcomes venetoclax resistance in primary patient s les. Significance: Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. i This article is highlighted in the In This Issue feature, p. 587 /i /
Publisher: American Society of Hematology
Date: 23-03-2017
DOI: 10.1182/BLOOD-2016-09-740308
Abstract: Circulating tumor DNA can monitor disease and predict treatment failure by tracking driver mutations and karyotypic abnormalities in MDS.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540936.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 13-11-2020
DOI: 10.1158/1078-0432.CCR-20-2251
Abstract: We evaluated the predictive value of pretreatment ctDNA to inform therapeutic outcomes in patients with metastatic melanoma relative to type and line of treatment. Plasma circulating tumor DNA (ctDNA) was quantified in 125 s les collected from 110 patients prior to commencing treatment with immune checkpoint inhibitors (ICIs), as first- (n = 32) or second-line (n = 27) regimens, or prior to commencing first-line BRAF/MEK inhibitor therapy (n = 66). An external validation cohort included 128 patients commencing ICI therapies in the first- (N = 77) or second-line (N = 51) settings. In the discovery cohort, low ctDNA (≤20 copies/mL) prior to commencing therapy predicted longer progression-free survival (PFS) in patients treated with first-line ICIs [HR, 0.20 95% confidence interval (CI) 0.07–0.53 P & 0.0001], but not in the second-line setting. An independent cohort validated that ctDNA is predictive of PFS in the first-line setting (HR, 0.42 95% CI, 0.22–0.83 P = 0.006), but not in the second-line ICI setting. Moreover, ctDNA prior to commencing ICI treatment was not predictive of PFS for patients pretreated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Reduced PFS and overall survival were observed in patients with high ctDNA receiving anti–PD-1 monotherapy, relative to those treated with combination anti–CTLA-4/anti–PD-1 inhibitors. Pretreatment ctDNA is a reliable indicator of patient outcome in the first-line ICI treatment setting, but not in the second-line ICI setting, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence indicated that treatment-naïve patients with high ctDNA may preferentially benefit from combined ICIs.
Publisher: Springer Science and Business Media LLC
Date: 17-01-2013
DOI: 10.1038/BJC.2012.558
Publisher: American Association for Cancer Research (AACR)
Date: 03-2022
DOI: 10.1158/2159-8290.CD-21-0522
Abstract: Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. This article is highlighted in the In This Issue feature, p. 587
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540927.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Elsevier BV
Date: 04-2020
Publisher: Springer Science and Business Media LLC
Date: 09-2015
DOI: 10.1038/NATURE14888
Publisher: Springer Science and Business Media LLC
Date: 18-08-2020
DOI: 10.1186/S13058-020-01328-0
Abstract: Metastatic breast cancer remains incurable. Next-generation sequencing (NGS) offers the ability to identify actionable genomic alterations in tumours which may then be matched with targeted therapies, but the implementation and utility of this approach is not well defined for patients with metastatic breast cancer. We recruited patients with advanced breast cancer of any subtype for prospective targeted NGS of their most recent tumour s les, using a panel of 108 breast cancer-specific genes. Genes were classified as actionable or non-actionable using the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) guidelines. Between February 2014 and May 2019, 322 patients were enrolled onto the study, with 72% ( n = 234) of patients successfully sequenced ( n = 357 s les). The majority (74%, n = 171) of sequenced patients were found to carry a potentially actionable alteration, the most common being a PIK3CA mutation. Forty-three percent ( n = 74) of patients with actionable alterations were referred for a clinical trial or referred for confirmatory germline testing or had a change in therapy outside of clinical trials. We found alterations in AKT1 , BRCA2 , CHEK2, ESR1 , FGFR1 , KMT2C , NCOR1 , PIK3CA and TSC2 to be significantly enriched in our metastatic population compared with primary breast cancers. Concordance between primary and metastatic s les for key driver genes ( TP53 , ERBB2 lification) was 75%. Additionally, we found that patients with a higher number of mutations had a significantly worse overall survival. Genomic profiling of patients with metastatic breast cancer can have clinical implications and should be considered in all suitable patients.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540918
Abstract: Supplementary table from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540915
Abstract: Supplementary table from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540933.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Springer Science and Business Media LLC
Date: 20-10-2006
DOI: 10.1007/S10637-006-9016-5
Abstract: The study's aim was to determine the maximum tolerated dose (MTD) of celecoxib combined with chemoradiotherapy (CRT) for locally advanced oesophageal cancer (OC). CRT comprised of 5FU (1000 mg/m(2)/day, days 1-4, weeks 1 & 5), cisplatin (75 mg/m(2), days 1 & 29) and radiotherapy (50 Gy in 25 fractions or 50.4 Gy in 28 fractions). Celecoxib was given daily during CRT at one of five doses (200 mg bd to 600 mg bd). Three to six patients were assigned per dose. Thirteen patients were recruited before trial closure due to external safety concerns regarding celecoxib. Median follow up was 17 months (95% CI 9 - >39). The highest administered dose was 400 mg bd (n=4) with one dose-limiting toxicity at this level: grade 3 rash. Five (38%) and 8(62%) patients had grade 3 non-haematological and haematological toxicities respectively. No grade 4 toxicities occurred. Radiological response rate was 54% (n=7: all CR). Six patients had resection with one pathological CR. Median progression-free and overall survival were 8.8 (95% CI 5.1 - >24.8) and 19.6 months (95% CI 7.3 - >39) respectively. A MTD was not reached. The regimen was tolerable, indicating that celecoxib can be safely administered with CRT for locally advanced OC.
Publisher: Elsevier BV
Date: 11-2018
Publisher: Springer Science and Business Media LLC
Date: 25-01-2011
Publisher: Elsevier BV
Date: 09-2009
Publisher: Elsevier BV
Date: 07-2015
Abstract: Expression of programmed death ligand 1 (PD-L1) in solid tumours has been shown to predict whether patients are likely to respond to anti-PD-L1 therapies. To estimate the therapeutic potential of PD-L1 inhibition in breast cancer, we evaluated the prevalence and significance of PD-L1 protein expression in a large collection of breast tumours. Correlations between CD274 (PD-L1) copy number, transcript and protein levels were evaluated in tumours from 418 patients recruited to the METABRIC genomic study. Immunohistochemistry was used to detect PD-L1 protein in breast tumours in tissue microarrays from 5763 patients recruited to the SEARCH population-based study (N = 4079) and the NEAT randomised, controlled trial (N = 1684). PD-L1 protein data was available for 3916 of the possible 5763 tumours from the SEARCH and NEAT studies. PD-L1 expression by immune cells was observed in 6% (235/3916) of tumours and expression by tumour cells was observed in just 1.7% (66/3916). PD-L1 was most frequently expressed in basal-like tumours. This was observed both where tumours were subtyped by combined copy number and expression profiling [39% (17/44) of IntClust 10 i.e. basal-like tumours were PD-L1 immune cell positive P < 0.001] and where a surrogate IHC-based classifier was used [19% (56/302) of basal-like tumours were PD-L1 immune cell positive P < 0.001]. Moreover, CD274 (PD-L1) lification was observed in five tumours of which four were IntClust 10. Expression of PD-L1 by either tumour cells or infiltrating immune cells was positively correlated with infiltration by both cytotoxic and regulatory T cells (P < 0.001). There was a nominally significant association between PD-L1 and improved disease-specific survival (hazard ratio 0.53, 95% confidence interval 0.26-1.07 P = 0.08) in ER-negative disease. Expression of PD-L1 is rare in breast cancer, markedly enriched in basal-like tumours and is correlated with infiltrating lymphocytes. PD-L1 inhibition may benefit the 19% of patients with basal-like tumours in which the protein is expressed. NCT00003577.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-04-2017
Abstract: Germline BRCA1 or BRCA2 mutations in patients with high-grade serous ovarian cancer (HGSC) are associated with favorable responses to chemotherapy. However, secondary intragenic (reversion) mutations that restore protein function lead to clinically significant rates of acquired resistance. The goal of this study was to determine whether reversion mutations could be found in an unbiased manner in circulating cell-free DNA (cfDNA) to predict treatment response in HGSC. Plasma and tumor s les were obtained from 30 patients with HGSC with either BRCA1 or BRCA2 germline mutation. Two cohorts were ascertained: patients with a malignancy before undergoing primary HGSC debulking surgery (n = 14) or patients at disease recurrence (n = 16). Paired tumor and plasma s les were available for most patients (24 of 30). Targeted licon, next-generation sequencing was performed using primers that flanked germline mutations, whose design did not rely on prior knowledge of reversion sequences. Five patients were identified with intragenic mutations predicted to restore BRCA1/2 open reading frames, including two patients with multiple independent reversion alleles. Reversion mutations were only detected in tumor s les from patients with recurrent disease (five of 16) and only in cfDNA from patients with a tumor-detected reversion (three of five). Findings from a rapid autopsy of a patient with multiple independent reversions indicated that reversion-allele frequency in metastatic sites is an important determinant of assay sensitivity. Abundance of tumor-derived DNA in total cell-free DNA, as measured by TP53 mutant allele frequency, also affected assay sensitivity. All patients with reversions detected in tumor-derived DNA were resistant to platin- or poly ADP ribose polymerase inhibitor-based chemotherapy. Reversion mutations can be detected in an unbiased analysis of cfDNA, suggesting clinical utility for predicting chemotherapy response in recurrent HGSC.
Publisher: Springer Science and Business Media LLC
Date: 07-12-2021
DOI: 10.1038/S41586-021-04278-5
Abstract: Breast cancers are complex ecosystems of malignant cells and the tumour microenvironment 1 . The composition of these tumour ecosystems and interactions within them contribute to responses to cytotoxic therapy 2 . Efforts to build response predictors have not incorporated this knowledge. We collected clinical, digital pathology, genomic and transcriptomic profiles of pre-treatment biopsies of breast tumours from 168 patients treated with chemotherapy with or without HER2 (encoded by ERBB2 )-targeted therapy before surgery. Pathology end points (complete response or residual disease) at surgery 3 were then correlated with multi-omic features in these diagnostic biopsies. Here we show that response to treatment is modulated by the pre-treated tumour ecosystem, and its multi-omics landscape can be integrated in predictive models using machine learning. The degree of residual disease following therapy is monotonically associated with pre-therapy features, including tumour mutational and copy number landscapes, tumour proliferation, immune infiltration and T cell dysfunction and exclusion. Combining these features into a multi-omic machine learning model predicted a pathological complete response in an external validation cohort (75 patients) with an area under the curve of 0.87. In conclusion, response to therapy is determined by the baseline characteristics of the totality of the tumour ecosystem captured through data integration and machine learning. This approach could be used to develop predictors for other cancers.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540918.V1
Abstract: Supplementary table from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Springer Science and Business Media LLC
Date: 16-08-2017
DOI: 10.1038/NATURE23643
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2008
DOI: 10.1158/1078-0432.CCR-07-5237
Abstract: Purpose: Prostate cancer risk is increased for men carrying a pathogenic germline mutation in BRCA2, and perhaps BRCA1. Our primary aim was to test for loss of heterozygosity (LOH) at the locus of the mutation in prostate cancers from men who a carry pathogenic germline mutation in BRCA1 or BRCA2, and to assess clinical and pathologic features of these tumors. Experimental Design: From 1,243 kConFab families: (a) 215 families carried a pathogenic BRCA1 mutation, whereas 188 families carried a pathogenic BRCA2 mutation (b) of the 158 men diagnosed with prostate cancer (from 137 families), 8 were confirmed to carry the family-specific BRCA1 mutation, whereas 20 were confirmed to carry the family-specific BRCA2 mutation and (c) 10 cases were eliminated from analysis because no archival material was available. The final cohort comprised 4 and 14 men with a BRCA1 and BRCA2 mutation, respectively. We examined LOH at the BRCA1 and BRCA2 genes using multiplex ligation-dependent probe lification of DNA from microdissected tumor. Results: LOH at BRCA2 was observed in 10 of 14 tumors from BRCA2 mutation carriers (71%), whereas no LOH at BRCA1 was observed in four tumors from BRCA1 mutation carriers (P = 0.02). Under the assumption that LOH occurs only because the cancer was caused by the germline mutation, carriers of BRCA2 mutations are at 3.5-fold (95% confidence interval, 1.8-12) increased risk of prostate cancer. A high Gleason was the only distinct clinical feature. Conclusions: These observations are consistent with the idea that BRCA2, but not BRCA1, is a tumor suppressor of prostate cancer.
Publisher: Wiley
Date: 08-05-2012
DOI: 10.1002/PATH.3983
Abstract: Micro-RNAs (miRNAs) are frequently dysregulated in a range of human malignancies, many have been shown to act either as tumour supressors or oncogenes and several have been implicated in breast cancer. However, breast cancer is a erse disease and little is known about the relationships between miRNA expression, clinical outcome and tumour subtype. We used locked nucleic acid probe in situ hybridization (LNA-ISH) to visualize, in tissue micro-arrays (TMAs) of 2919 formalin-fixed paraffin-embedded (FFPE) archival breast tumours, the expression of two key miRNAs that are frequently lost in a range of solid malignancies, let-7b and miR-205. These miRNAs were also quantified by quantitative reverse transcription PCR in cores of FFPE tissue from 40 of these cases, demonstrating that LNA-ISH is semi-quantitative. The tumours in the TMAs were assigned to subtypes based on their immunohistochemical (IHC) staining with ER, PR, HER2, CK5/6 and EGFR. let-7b expression was shown to be associated with luminal tumours and to have an independent significant positive prognostic value in this group. miR-205 is associated with tumours of ductal morphology and is of significant positive prognostic value within these tumours. We propose that the expression of miR-205 may contribute to ductal tumour morphology.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-01-2008
Abstract: Women from BRCA mutation–positive families who do not carry the family-specific mutation are generally at average cancer risk and therefore do not require intensive risk management. Participants were female noncarriers from BRCA mutation–positive families who had responded to 3 yearly follow-up questionnaires and had chosen to either receive or not receive their genetic test result. In the former group, undertaking mammography younger than age 40 years or more than once every 2 years, clinical breast examination (CBE) more than yearly, breast self-examination (BSE) more than monthly, or any transvaginal ultrasound (TVU) or CA-125 was considered overscreening. Screening behaviors of women who did and did not know their genetic test result were compared. Logistic regression and nonparametric analyses were performed to identify demographic and psychosocial factors (respectively) associated with overscreening. Of 325 eligible women, 116 knew their mutation status and 209 did not. For the first group, proportions overscreening were mammography, 53% CBE, 10% BSE, 11% TVU, 7% and CA-125, 10%. There were no significant differences in screening behaviors between the groups. In those aware of their mutation status, parous women were more likely to overuse mammography (odds ratio [OR] = 4.4 95% CI, 1.1 to 17 P = .03) and women with one or more first-degree relative with ovarian cancer (OC) were more likely to overuse OC screening (TVU: OR = 6.00 95% CI, 1.0 to 35.1 P = .047, and CA-125: OR = 6.50 95% CI, 1.49 to 28.4 P = .013). The reasons for overuse of screening (particularly mammography) by mutation noncarriers require additional elucidation given the potential for harm.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 30-05-2012
DOI: 10.1126/SCITRANSLMED.3003726
Abstract: Sizable genomic regions were screened and low-frequency mutations were identified in circulating DNA of cancer patients using tagged- licon deep sequencing (TAm-Seq).
Publisher: Springer Science and Business Media LLC
Date: 07-04-2013
DOI: 10.1038/NATURE12065
Abstract: Cancers acquire resistance to systemic treatment as a result of clonal evolution and selection. Repeat biopsies to study genomic evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumour heterogeneity. Recent studies have shown that genomic alterations in solid cancers can be characterized by massively parallel sequencing of circulating cell-free tumour DNA released from cancer cells into plasma, representing a non-invasive liquid biopsy. Here we report sequencing of cancer exomes in serial plasma s les to track genomic evolution of metastatic cancers in response to therapy. Six patients with advanced breast, ovarian and lung cancers were followed over 1-2 years. For each case, exome sequencing was performed on 2-5 plasma s les (19 in total) spanning multiple courses of treatment, at selected time points when the allele fraction of tumour mutations in plasma was high, allowing improved sensitivity. For two cases, synchronous biopsies were also analysed, confirming genome-wide representation of the tumour genome in plasma. Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance. These included an activating mutation in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) following treatment with paclitaxel a truncating mutation in RB1 (retinoblastoma 1) following treatment with cisplatin a truncating mutation in MED1 (mediator complex subunit 1) following treatment with tamoxifen and trastuzumab, and following subsequent treatment with lapatinib, a splicing mutation in GAS6 (growth arrest-specific 6) in the same patient and a resistance-conferring mutation in EGFR (epidermal growth factor receptor T790M) following treatment with gefitinib. These results establish proof of principle that exome-wide analysis of circulating tumour DNA could complement current invasive biopsy approaches to identify mutations associated with acquired drug resistance in advanced cancers. Serial analysis of cancer genomes in plasma constitutes a new paradigm for the study of clonal evolution in human cancers.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 06-2005
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540924
Abstract: Supplementary movie from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Oxford University Press (OUP)
Date: 09-2021
DOI: 10.1093/BIOINFORMATICS/BTAB606
Abstract: This work describes two novel workflows for variant calling that extend the widely used algorithms of Strelka2 and FreeBayes to call somatic mutations from multiple related tumour s les and one matched normal s le. We show that these workflows offer higher precision and recall than their single tumour-normal pair equivalents in both simulated and clinical sequencing data. Source code freely available at the following link: atlassian.petermac.org.au/bitbucket rojects/DAW/repos/multis levariantcalling and executable through Janis (github.com/PMCC-BioinformaticsCore/janis) under the GPLv3 licence. Supplementary data are available at Bioinformatics online.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540930.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540924.V1
Abstract: Supplementary movie from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Elsevier BV
Date: 05-2015
Publisher: Springer Science and Business Media LLC
Date: 19-11-2018
DOI: 10.1038/S41591-018-0243-Z
Abstract: Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and nonresponders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1-p24.3 loss and/or mutations in components of the SWI-SNF chromatin-remodeling complex were present in all patients with primary resistance and two-thirds of patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor evolution. Functional modeling demonstrated that compromise of the SWI-SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a model for real-time assessment of innovative targeted therapies.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540927
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Springer Science and Business Media LLC
Date: 10-05-2016
DOI: 10.1038/NCOMMS11479
Abstract: The genomic landscape of breast cancer is complex, and inter- and intra-tumour heterogeneity are important challenges in treating the disease. In this study, we sequence 173 genes in 2,433 primary breast tumours that have copy number aberration (CNA), gene expression and long-term clinical follow-up data. We identify 40 mutation-driver (Mut-driver) genes, and determine associations between mutations, driver CNA profiles, clinical-pathological parameters and survival. We assess the clonal states of Mut-driver mutations, and estimate levels of intra-tumour heterogeneity using mutant-allele fractions. Associations between PIK3CA mutations and reduced survival are identified in three subgroups of ER-positive cancer (defined by lification of 17q23, 11q13–14 or 8q24). High levels of intra-tumour heterogeneity are in general associated with a worse outcome, but highly aggressive tumours with 11q13–14 lification have low levels of intra-tumour heterogeneity. These results emphasize the importance of genome-based stratification of breast cancer, and have important implications for designing therapeutic strategies.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540921
Abstract: Supplementary movie from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6533113
Abstract: AbstractPurpose: BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies. Patients and Methods: We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. Results: Thirty-two patients with i BRAF /i V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal i KRAS /i , i NRAS /i , and i MAP2K1 /i mutations, and i MET /i lification. Conclusions: The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance. /
Publisher: Research Square Platform LLC
Date: 21-11-2020
DOI: 10.21203/RS.3.RS-106576/V1
Abstract: People with HIV have higher rates of certain comorbidities, particularly cardiovascular disease and some malignancies, than people without HIV. As somatic mutations associated with age related clonal haematopoiesis (CH) are linked to similar comorbidities in the general population, we hypothesized that CH may be more prevalent in people with HIV. To address this issue, we established a prospective cohort study recruiting 220 HIV-positive and 226 HIV negative participants aged 55 years or older in Australia. Demographic characteristics, clinical data and peripheral blood were collected to assess for the presence of CH mutations and identify potential risk factors for and clinical sequelae of CH. Investigators testing for CH were blinded to participants’ HIV status. In total, 132 CH mutations were identified in 99 (22.2%) of 446 participants. CH was more prevalent in HIV-positive participants than HIV-negative participants (27.7% vs. 16.8%, p =0.006), overall and across all age groups. HIV infection was associated with an increased odds of having CH (adjusted odds ratio 2.10, 95% confidence interval 1.30-3.38, p=0.002). The most common genes mutated were DNMT3A (48.5%), TET2(20.5%) and ASXL1 (11.4%). CH and HIV infection were independently associated with increases in blood parameters and biomarkers associated with inflammation. These data suggest a selective advantage for the emergence of CH in the context of chronic infection and inflammation related to HIV infection.
Publisher: Springer Science and Business Media LLC
Date: 30-11-2013
Publisher: Elsevier BV
Date: 05-2019
Publisher: Springer Science and Business Media LLC
Date: 25-07-0007
DOI: 10.1038/NCOMMS9760
Abstract: Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma s les collected over 1,193 days of clinical follow-up using exome and targeted licon sequencing. Mutation levels in the plasma s les reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma s les in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time s ling of multifocal clonal evolution.
Publisher: Informa UK Limited
Date: 20-08-2018
Publisher: Cold Spring Harbor Laboratory
Date: 29-05-2018
Publisher: Springer Science and Business Media LLC
Date: 29-06-2020
Publisher: Springer Science and Business Media LLC
Date: 23-06-2021
DOI: 10.1186/S13059-021-02401-3
Abstract: The human microbiome plays an important role in cancer. Accumulating evidence indicates that commensal microbiome-derived DNA may be represented in minute quantities in the cell-free DNA of human blood and could possibly be harnessed as a new cancer biomarker. However, there has been limited use of rigorous experimental controls to account for contamination, which invariably affects low-biomass microbiome studies. We apply a combination of 16S-rRNA-gene sequencing and droplet digital PCR to determine if the specific detection of cell-free microbial DNA (cfmDNA) is possible in metastatic melanoma patients. Compared to matched stool and saliva s les, the absolute concentration of cfmDNA is low but significantly above the levels detected from negative controls. The microbial community of plasma is strongly influenced by laboratory and reagent contaminants introduced during the DNA extraction and sequencing processes. Through the application of an in silico decontamination strategy including the filtering of licon sequence variants (ASVs) with batch dependent abundances and those with a higher prevalence in negative controls, we identify known gut commensal bacteria, such as Faecalibacterium , Bacteroides and Ruminococcus , and also other uncharacterised ASVs. We analyse additional plasma s les, highlighting the potential of this framework to identify differences in cfmDNA between healthy and cancer patients. Together, these observations indicate that plasma can harbour a low yet detectable level of cfmDNA. The results highlight the importance of accounting for contamination and provide an analytical decontamination framework to allow the accurate detection of cfmDNA for future biomarker studies in cancer and other diseases.
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2016
End Date: 2019
Funder: National Health and Medical Research Council
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