Papers by Geraldine Laven-Law
Faecal immunochemical tests can improve colonoscopy triage in patients with iron deficiency: a systematic review and meta-analysis
Critical reviews in oncology/hematology, Jul 1, 2024
Digestive diseases and sciences, May 16, 2024
Background The fecal immunochemical test (FIT) is widely used in colorectal cancer (CRC) screenin... more Background The fecal immunochemical test (FIT) is widely used in colorectal cancer (CRC) screening, but limited data exist for its application in individuals at above-average risk for CRC who complete surveillance colonoscopies. Aim To assess the accuracy, acceptability, and effectiveness of FIT in the interval between surveillance colonoscopies, for predicting advanced neoplasia (advanced adenoma or CRC) at the next colonoscopy. Methods Individuals enrolled in an Australian surveillance program were included. Diagnostic accuracy was determined for 614 individuals completing a two-sample FIT (OC-Sensor) ≤ 3 months preceding surveillance colonoscopy. 386 Individuals were surveyed to assess acceptability of interval FIT. Additionally, a retrospective analysis was performed on 7331 individuals offered interval FIT between colonoscopies, where a positive FIT (≥ 20 µg hemoglobin/g feces) triggered an early colonoscopy. Associations between interval FIT results and advanced neoplasia were determined using regression analysis. Results FIT detected CRC and advanced adenoma with sensitivities of 60.0% (3/5) and 27.1% (35/129), respectively. Most (89.1%, 344/386) survey respondents preferred completing interval FIT every 1-2 years. The detection rate of interval FIT for advanced neoplasia decreased with increasing FIT completion. Individuals returning a positive FIT had a higher risk of advanced neoplasia than those who did not complete FIT. Positive interval FIT reduced time-to-diagnosis for CRC and advanced adenoma by a median of 30 and 20 months, respectively. Conclusion Interval FIT was well accepted and enabled earlier detection of advanced neoplasia in individuals at aboveaverage risk of CRC. Given that interval FIT predicts advanced neoplasia, it may be used to personalize surveillance colonoscopy intervals.
<i>BCAT1</i> , <i>IKZF1</i> and <i>SEPT9</i> : methylated DNA biomarkers for detection of pan-gastrointestinal adenocarcinomas
Biomarkers, Apr 22, 2024
Comparing a fecal immunochemical test and circulating tumor DNA blood test for colorectal cancer screening adherence
Journal of gastroenterology and hepatology, Mar 2, 2024
Genome biology, Feb 5, 2024
Background: The androgen receptor (AR) is a tumor suppressor in estrogen receptor (ER) positive b... more Background: The androgen receptor (AR) is a tumor suppressor in estrogen receptor (ER) positive breast cancer, a role sustained in some ER negative breast cancers. Key factors dictating AR genomic activity in a breast context are largely unknown. Herein, we employ an unbiased chromatin immunoprecipitation-based proteomic technique to identify endogenous AR interacting co-regulatory proteins in ER positive and negative models of breast cancer to gain new insight into mechanisms of AR signaling in this disease. The DNA-binding factor GATA3 is identified and validated as a novel AR interacting protein in breast cancer cells irrespective of ER status. AR activation by the natural ligand 5α-dihydrotestosterone (DHT) increases nuclear AR-GATA3 interactions, resulting in AR-dependent enrichment of GATA3 chromatin binding at a subset of genomic loci. Silencing GATA3 reduces but does not prevent AR DNA binding and transactivation of genes associated with AR/GATA3 co-occupied loci, indicating a co-regulatory role for GATA3 in AR signaling. DHT-induced AR/GATA3 binding coincides with upregulation of luminal differentiation genes, including EHF and KDM4B, established master regulators of a breast epithelial cell lineage. These findings are validated in a patient-derived xenograft model of breast cancer. Interaction between AR and GATA3 is also associated with AR-mediated growth inhibition in ER positive and ER negative breast cancer. Conclusions: AR and GATA3 interact to transcriptionally regulate luminal epithelial cell differentiation in breast cancer regardless of ER status. This interaction facilitates the tumor suppressor function of AR and mechanistically explains why AR expression is associated with less proliferative, more differentiated breast tumors and better overall survival in breast cancer.
Peak calling parameters Peaks were called with MACS2 (v2.2.6
The Diagnostic Accuracy of a Fecal Immunochemical Test in Detecting Colorectal Cancer and Advanced Precancerous Colorectal Neoplasia in Patients with Iron Deficiency: A Protocol for Systematic Review and Meta-Analysis
Gastroenterology Research and Practice, Dec 7, 2023
Oncogene
Targeted therapy for triple-negative breast cancers (TNBC) remains a clinical challenge due to tu... more Targeted therapy for triple-negative breast cancers (TNBC) remains a clinical challenge due to tumour heterogeneity. Since TNBC have key features of transcriptionally addicted cancers, targeting transcription via regulators such as cyclin-dependent kinase 9 (CDK9) has potential as a therapeutic strategy. Herein, we preclinically tested a new selective CDK9 inhibitor (CDDD11-8) in TNBC using cell line, patient-derived organoid, and patient-derived explant models. In vitro, CDDD11-8 dose-dependently inhibited proliferation (IC50 range: 281–734 nM), induced cell cycle arrest, and increased apoptosis of cell lines, which encompassed the three major molecular subtypes of TNBC. On target inhibition of CDK9 activity was demonstrated by reduced RNAPII phosphorylation at a CDK9 target peptide and down-regulation of the MYC and MCL1 oncogenes at the mRNA and protein levels in all cell line models. Drug induced RNAPII pausing was evident at gene promoters, with strongest pausing at MYC target ...
Tu1131 USE OF METHYLATED CTDNA IN SURVEILLANCE AFTER TREATMENT FOR COLORECTAL CANCER
Gastroenterology
Faecal Immunochemical Test Plus Colonoscopy for Early Detection of Advanced Neoplasia in Individuals at Increased Risk of Colorectal Cancer: A Diagnostic Accuracy and Program Evaluation Study
Gastrointestinal Endoscopy
Clinical Chemistry
Background Fecal immunochemical tests (FITs) are widely used for colorectal cancer (CRC) screenin... more Background Fecal immunochemical tests (FITs) are widely used for colorectal cancer (CRC) screening; however, high ambient temperatures were found to reduce test accuracy. More recently, proprietary globin stabilizers were added to FIT sample buffers to prevent temperature-associated hemoglobin (Hb) degradation, but their effectiveness remains uncertain. We aimed to determine the impact of high temperature (>30°C) on OC-Sensor FIT Hb concentration with current FITs, characterize FIT temperatures during mail transit, and determine impact of ambient temperature on FIT Hb concentration using data from a CRC screening program. Methods FITs were analyzed for Hb concentration after in vitro incubation at different temperatures. Data loggers packaged alongside FITs measured temperatures during mail transit. Separately, screening program participants completed and mailed FITs to the laboratory for Hb analysis. Regression analyses compared the impact of environmental variables on FIT tempe...
Abstract P4-08-16: Selective Androgen Receptor Modulators in combination with CDK4/6 inhibitors demonstrate anti-cancer activity in preclinical treatment resistant ER+AR+ breast cancer models
Cancer Research
Background: The Androgen Receptor (AR) is expressed in up to 90% of all ER+ breast cancers and ha... more Background: The Androgen Receptor (AR) is expressed in up to 90% of all ER+ breast cancers and has been associated with better patient outcome. While androgens were used at a high dose as an anticancer therapy historically, this was discontinued with the advent of Tamoxifen due to virilising effects. Non-steroidal, tissue selective AR modulators (SARMs) represent an attractive alternative, offering a targeted approach to AR activation. Recent compelling pre-clinical data has established that the AR is a tumour suppressor in ER+ breast cancers and that AR activation with a natural androgen or a SARM suppressed ER-driven tumour growth, in preclinical models of endocrine-sensitive and -resistant ER+ breast cancer. Here, we evaluate the efficacy of a SARM (enobosarm) and a natural AR ligand (dihydrotestosterone, DHT) in the context of metastatic, CDK4/6 inhibitor (CDK4/6i) resistant breast cancer. Methods: Enobosarm and palbociclib treatments were evaluated in vitro by colony forming as...
Antagonistic sex hormone activity occurs in mammary gland development, whereby estrogen stimulate... more Antagonistic sex hormone activity occurs in mammary gland development, whereby estrogen stimulates and androgen inhibits post-pubertal growth, but the mechanistic basis of this is largely unknown. Whether sex hormone antagonism occurs in the context of breast cancer is also unclear. The estrogen receptor alpha (ER) unequivocally drives the majority of breast malignancies, but the role of the androgen receptor (AR) is controversial, particularly in the context of ER-positive (ER+) tumours resistant to standard-of-care ER targeting therapies. The controversy has constrained clinical implementation of new drugs that influence AR activity for treatment of this disease. Using a diverse panel of cell line and patient-derived models of ER+ breast cancer, we demonstrate that activation, not suppression, of AR activity exerts potent anti-tumour activity in multiple clinically relevant contexts, including tumours resistant to ER targeting therapy. We also show that AR agonists can be combined...
Abstract PD2-02: Combination CDK4/6 inhibition and AR agonism suppresses the growth of CDK4/6 inhibitor resistant breast cancers
Cancer Research, 2022
Resistance to standard-of care-therapies is a significant clinical challenge in estrogen receptor... more Resistance to standard-of care-therapies is a significant clinical challenge in estrogen receptor positive (ER+) breast cancer. Cyclin dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapies (ET) is the current standard-of-care for advanced metastatic ER+ breast cancer; however, resistance to this combination is considered inevitable, leading to disease progression. The androgen receptor (AR) is expressed in up to 90% of all ER+ breast cancers, and has been associated with better patient outcome. Compelling recent pre-clinical data demonstrates that selective androgen receptor AR modulators (SARMs) act to suppress ER-driven tumour growth of endocrine-sensitive and -resistant models of ER+ breast cancer. Furthermore, a recent clinical trial evaluating the efficacy of SARMs has shown clinical benefit in patients with ER+/AR+ metastatic breast cancer (NCT02463032). We hypothesise that the SARMS, either alone or in combination with a CDK4/6i, would be an effect...
Abstract GS2-03: The androgen receptor is a tumour suppressor in estrogen receptor positive breast cancer
Cancer Research, 2020
The Androgen receptor (AR) is expressed in up to 90% of primary ER-positive (ER+) breast cancer a... more The Androgen receptor (AR) is expressed in up to 90% of primary ER-positive (ER+) breast cancer and high expression of AR is an independent prognostic factor associated with good outcome. Its role in the context of ER+ breast cancer is very controversial and has constrained clinical implementation of new drugs that influence AR activity for treatment of women with this disease, resulting in concurrent clinical trials of opposite AR agonist and antagonist strategies. Herein, using RNA-seq and Chip-seq approaches, we demonstrate that therapeutic activation of AR for treatment of breast cancer leverages a natural regulatory mechanism that inhibits estrogen-stimulated proliferation and induction of cell cycle genes in patient-derived explants (PDE) of primary ER+ breast cancers, and in contemporary in vivo patient-derived xenograft (PDX) and cell line xenograft models of ER+ breast cancer resistant to standard-of-care ER targeting agents, including those harbouring genomic aberrations o...
Unraveling an identity for the androgen receptor-expressing mammary epithelial cell
Abstracts of the Endocrine Society of Australia Annual Scientific Meeting 2015, 23–26 August 2015
Three-dimensional (3D) epigenome remodelling is an important mechanism of gene deregulation in ca... more Three-dimensional (3D) epigenome remodelling is an important mechanism of gene deregulation in cancer. However, its potential as a target to overcome therapy resistance remains largely unaddressed.Here we show that FDA-approved epigenetic therapy Decitabine (5-Aza-mC) suppresses tumour growth in preclinical metastatic ER+ breast tumour xenograft models. Decitabine-induced genome-wide DNA hypomethylation results in large-scale 3D epigenome deregulation, including de-compaction of higher order chromatin structure and loss of topologically associated domain boundary insulation. Significant DNA hypomethylation at ER-enhancer elements was associated with gain in ER binding, creation of ectopic 3D enhancer-promoter interactions and concordant activation of ER-mediated transcription pathways. Importantly long-term withdrawal of epigenetic therapy partially restores methylation at ER-enhancer elements, resulting in loss of ectopic 3D enhancer-promoter interactions and associated gene repres...
Journal of the Endocrine Society, 2020
There is strong interest in targeting the androgen receptor (AR) in estrogen receptor (ER) positi... more There is strong interest in targeting the androgen receptor (AR) in estrogen receptor (ER) positive breast cancer, but widespread confusion exits as to what therapeutic strategy - agonism or antagonism - is appropriate. Current understanding of AR predominantly stems from the field of prostate cancer, where AR is the key oncogenic driver and therapeutic target. An ensuing assumption is that AR promotes malignancy in breast cancer and should be therapeutically antagonised. However, compelling pre-clinical data to support this assumption is lacking. Since estrogen stimulates and androgen inhibits the development of normal breast tissue, we hypothesized that AR acts as a tumour suppressor in the breast and that AR agonism is the appropriate therapeutic strategy for ER-driven breast cancer. We tested this hypothesis using a large suite of cell line and patient-derived explant (PDE) and xenograft (PDX) models of breast cancer, including those that were resistant to current therapies and ...
Targeting AR in endocrine-resistant breast cancer
Oncology Abstracts, 2019
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Papers by Geraldine Laven-Law