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Publications (53)
Introduction:
Hypophysitis is reported in 8.5%-14% of patients receiving combination immune checkpoint inhibition (cICI) but can be a diagnostic challenge. This study aimed to assess the role of routine diagnostic imaging performed during therapeutic monitoring of combination anti-CTLA-4/anti-PD-1 treatment in the identification of hypophysitis an...
Introduction
Cyclin E1 amplification and over-expression is associated with platinum resistance in high grade serous ovarian cancer (HGSC), and may predict response to WEE1 inhibition. Adavosertib, a WEE1 inhibitor, has activity in unselected women with recurrent ovarian and endometrial cancer. We aimed to evaluate the efficacy of adavosertib in wo...
9525
Background: Denosumab (deno) is an antibody directed against Receptor Activator of NF Kappa-b ligand (RANKL) with established indications as a bone anti-resorptive agent in several cancers. Pre-clinical studies and several case series suggest anti-RANKL can enhance the anti-tumor effect of immune checkpoint inhibitors possibly via modulation o...
Aim:
To catalogue and compare the pattern of metastatic disease in germline BRCA1/2 pathogenic mutation carriers and non-carriers with breast, ovarian and prostate cancer from a rapid autopsy programme.
Methods and results:
The number of metastases in the major body systems and the proportion of participants with metastases were documented in 50...
High-grade serous ovarian cancer (HGSC) is frequently characterized by homologous recombination (HR) DNA repair deficiency and, while most such tumors are sensitive to initial treatment, acquired resistance is common. We undertook a multiomics approach to interrogate molecular diversity in end-stage disease, using multiple autopsy samples collected...
Fewer than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSCs) survive more than five years after diagnosis, but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage HGSC who survived more than 10 years after dia...
5515
Background: Cyclin E1 gene amplification and protein over-expression is a marker of platinum resistance in high grade serous ovarian, fallopian tube or primary peritoneal cancer (HGSC), and may predict response to WEE1 inhibition. Adavosertib, a WEE1 inhibitor, has demonstrated activity in unselected women with recurrent ovarian and serous end...
9503
Background: Combination anti-PD(L)1 and BRAF/MEK-targeted therapy (TT) improves PFS in stage IV melanoma vs TT. In stage IV melanoma recent data suggest immunotherapy 1st until progression, rather than BRAF-TT, improves OS, and induction TT upfront adds little benefit. NeoTrio explored the optimal combination of BRAF-TT and anti-PD1 using the...
Background:
Vaginal melanoma (VM) is a rare cancer and has a poor response to immune checkpoint blockade (ICB). CD8+Tissue Resident Memory (TRM) T cells proliferate in response to ICB and correlate with longer survival in metastatic cutaneous melanoma. However, their capacity to respond to VM and their neoantigens is not known.
Methods:
Using lo...
Background
Patients with BRAF -mutant and wild-type melanoma have different response rates to immune checkpoint blockade therapy. However, the reasons for this remain unknown. To address this issue, we investigated the precise immune composition resulting from BRAF mutation in treatment-naive melanoma to determine whether this may be a driver for d...
Objectives
The primary objective of this study was to describe treatment patterns after poly-ADP ribose polymerase (PARP) inhibitor in patients with epithelial ovarian cancer. Secondary objectives were to evaluate duration of response, time to first subsequent therapy, progression-free survival and overall survival.
Methods
This was a retrospectiv...
BRCA1 and BRCA2 tumor suppressor genes are central components of the homologous recombination (HR) DNA repair pathway, a high-fidelity process required to maintain genome integrity in the presence of DNA damaging agents. Germline or somatic mutation in BRCA1 or BRCA2, and methylation of BRCA1 therefore strongly influence response of patients with h...
Purpose:
We aimed to investigate the role of FDG-PET/CT in monitoring of response and immune-related adverse events (irAEs) following first-line combination-immune checkpoint inhibitor (combination-ICI) therapy for advanced melanoma.
Methods:
We retrospectively reviewed outcomes in patients who had (1) first-line nivolumab plus ipilimumab; (2) p...
Background
Mucosal melanoma is a rare subtype of melanoma originating from mucosal tissues (1), metastases are very aggressive and respond poorly to therapy, including immune checkpoint inhibitors (ICI) such as anti-CTLA4 and anti-PD1 antibodies (2–5). CD8+ T cells constitute the most abundant immune infiltrate in metastatic melanoma, of which the...
Background
Metastatic Merkel cell carcinoma (mMCC) is an aggressive neuroendocrine malignancy of the skin with a poor prognosis. Immune checkpoint inhibitors (ICIs) have shown substantial efficacy and favorable safety in clinical trials.
Methods
Medical records of patients (pts) with mMCC treated with ICIs from August 2015 to December 2018 at Pete...
Ovarian clear cell adenocarcinoma (OCCA) is characterized by a particularly poor response to conventional chemotherapy and a short overall survival time in women with established disease. The development of targeted treatments for OCCA relies on a better understanding of its molecular characteristics. IL6 is strongly expressed in OCCA and may there...
Background: Acquired drug resistance is the major obstacle in controlling high-grade serous ovarian cancer (HGSC) and leads to poor overall survival. Comparatively little massively parallel sequencing data exist from HGSC patients with recurrent or end-stage disease who have been extensively treated with chemotherapy or newer targeted agents, such...
Introduction: The development of chemotherapy resistance is common in relapsed high-grade serous ovarian cancer (HGSOC). An understanding of mechanisms that are associated with the development of chemotherapy resistance in the clinical setting is needed to improve treatment outcomes. In this study, cell lines newly derived from patients with relaps...
10041
Background: Predictors of outcomes of immune checkpoint inhibitors (ICI) are desirable. We aim to investigate the prognostic value of ¹⁸ F-fluorodeoxyglucose-PET/CT (FDG-PET) parameters at baseline and response monitoring of patients (pts) with advanced melanoma receiving ipi/nivo. Methods: From 2016-2019, melanoma pts who received ipi/nivo a...
Background:
Health economic studies of anti-cancer systemic treatments typically make strong assumptions regarding the number of drug lines received after initial therapy. This may have a substantial effect on health economic outcomes and impact drug reimbursement and uptake in practice. This study aims to quantify the real-world systemic treatment...
Background: Immune checkpoint blockade is now established as standard of care in several malignancies. Trials involving combined cytotoxic T lymphocyte associated protein 4 (CTLA4) and programmed cell death protein 1 (PD1) blockade demonstrate improved tumour responses in melanoma but at the cost of severe grade 3-4 immune related adverse events (i...
Background: Hypophysitis is one of the commonly reported adverse events related to immune checkpoint inhibitors (ICI), and the incidence is expected to rise with increased use of combined programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte associated protein 4 (CTLA4) blockade. The clinical diagnosis can be delayed due to non-specific...
Background
The efficacy of immune checkpoint inhibitors (ICI) in metastatic melanoma is well established. However, there are limited data regarding their efficacy in in-transit melanoma (ITM). This study assessed the efficacy of ICI in patients with ITM.
Methods
A retrospective review of patients with ITM commenced on an ICI between March 2013 and...
Introduction
There is increasing evidence demonstrating the benefits of exercise in counteracting cancer treatment-related fatigue. Immunotherapy is an established treatment for advanced melanoma, and is associated with fatigue in a third of patients. The safety and efficacy of exercise in counteracting treatment-related fatigue in patients with ad...
9540
Background: mMCC is a rare, highly aggressive neuroendocrine cancer with a poor prognosis. ICIs have favourable efficacy and safety in clinical trials. We outline single centre experience utilising ICIs in mMCC. Methods: Medical records of patients (pts) with mMCC treated with ICIs from Aug 2015 to Dec 2018 at Peter MacCallum Cancer Centre in...
Introduction:
Recent trials have established ipilimumab-nivolumab (I-N) as a robust first line (IL) treatment for patients (pts) with asymptomatic melanoma brain metastases (MBM). However, the efficacy of I-N for symptomatic MBM or after intracranial progression on either a BRAF-MEK inhibitor (BRAF-MEKi) or anti-PD1 is unknown. We performed a sing...
Immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) have transformed the management of many malignancies. Although rare, immune-mediated myocarditis presents unique clinical challenges due to heterogenous presentation, potential life-threatening consequences, and the time-critical need to differentiate it from other causes of ca...
Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across...
PURPOSE
The ALLOCATE study was designed as a pilot to demonstrate the feasibility and clinical utility of real-time targeted molecular profiling of patients with recurrent or advanced ovarian cancer for identification of potential targeted therapies.
PATIENTS AND METHODS
A total of 113 patients with ovarian cancer of varying histologies were recru...
9583
Background: The efficacy of ICIs in metastatic melanoma is well-established. However, there is limited data regarding their efficacy in in-transit melanoma metastases (ITM). This study assessed the efficacy of ICI in patients with ITM. Methods: A multisite, retrospective review of patients with ITM treated with ICI from 2004-2018. Demographic...
Objectives:
Readily apparent cyclin E1 expression occurs in 50% of HGSOC, but only half are linked to 19q12 locus amplification. The amplified/cyclin E1hi subset has intact BRCA1/2, unfavorable outcome, and is potentially therapeutically targetable. We studied whether non-amplified/cyclin E1hi HGSOC has similar characteristics. We also assessed th...
Background: The Australian Ovarian Cancer Assortment Trial (ALLOCATE) was designed as a pilot study to demonstrate feasibility of molecularly profiling patients with recurrent ovarian cancer with the aim of allocating patients to targeted therapies based on the genomic profile of their tumors.
Materials and Methods: Two next-generation sequencing (...
Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing we identified recurrent mutations in the protein translational regulator and in NF1, USP9X, KRAS, BRAF and NRAS. RAS pathway mutations were mutually exclu...
Purpose:
Cyclin E1 (CCNE1) amplification is associated with primary treatment resistance and poor outcome in high grade serous ovarian cancer (HGSC). Here, we explore approaches to target CCNE1 amplified cancers and potential strategies to overcome resistance to targeted agents.
Experiment design:
To examine dependency on CDK2 in CCNE1 amplified...
Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA sampl...
Objectives:
Obesity is an increasing health problem that is reported to influence chemotherapy dosing. The extent to which this occurs and whether this affects outcomes in ovarian cancer was unclear. To describe chemotherapy dosing practices in normal, overweight and obese patients treated for FIGO Stage III/IV serous ovarian cancer in the Austral...
Significance
Women with high-grade serous ovarian cancer (HGSC) harboring Cyclin E1 ( CCNE1 ) gene amplification generally face a poor clinical outcome. These tumors comprise a significant group of ∼20% of HGSCs that are not associated with BRCA1/2 mutation and are unlikely to respond to standard cytotoxic or poly-ADP-ribose polymerase inhibitors....
Amplification of Cyclin E1 (CCNE1) is associated with poor outcome in breast, lung and other solid cancers, and is the most prominent structural variant associated with primary treatment failure in high-grade serous ovarian cancer (HGSC). We have previously shown that CCNE1 amplified tumors show amplicon-dependent sensitivity to CCNE1 suppression....
Definitive treatment with concurrent cisplatin and radiation is the standard of care for locally advanced cervix cancer. The optimal management of patients with a contraindication to cisplatin has not been established. We conducted a retrospective audit of concurrent chemotherapy in a cohort of patients with locally advanced cervix cancer.
All pati...
e15541
Background: Definitive treatment with concurrent cisplatin and radiation is the standard of care for locally advanced cervical cancer. The optimal management of patients with a contraindication to cisplatin has not been established. We conducted a retrospective audit of the impact of concurrent chemoradiation in a cohort of patients (pts) wi...
Urothelial carcinoma (transitional cell carcinoma) is the most common malignancy of the urinary tract. Urothelial carcinoma of the bladder is a common disease but has traditionally been underrepresented in both public awareness and cancer research. The purpose of this review is to provide an outline of the recent updates in understanding of urothel...
