ORCID Profile
0000-0001-6872-1021
Current Organisation
Peter MacCallum Cancer Centre
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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: 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: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.YDBIO.2017.01.015
Abstract: In mice, implantation always occurs towards the antimesometrial side of the uterus, while the placenta develops at the mesometrial side. What determines this particular orientation of the implanting blastocyst remains unclear. Uterine glands are critical for implantation and pregnancy. In this study, we showed that uterine gland development and active Wnt signaling activity is limited to the antimesometrial side of the uterus. Dkk2, a known antagonist of Wnt signaling, is only present at the mesometrial side of the uterus. Imaging of whole uterus, thick uterine sections (100-1000µm), and in idual glands revealed that uterine glands are simple tubes with branches that are directly connected to the luminal epithelium and are only present towards the antimesometrial side of the uterus. By developing a unique mouse model targeting the uterine epithelium, we demonstrated that Wnt/β-catenin signaling is essential for prepubertal gland formation and normal implantation, but dispensable for postpartum gland development and regeneration. Our results for the first time have provided a probable explanation for the antimesometrial bias for implantation.
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 Society of Clinical Oncology (ASCO)
Date: 12-2019
DOI: 10.1200/PO.19.00019
Abstract: 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. A total of 113 patients with ovarian cancer of varying histologies were recruited from two tertiary hospitals, with 99 patient cases suitable for prospective analysis. Targeted molecular and methylation profiling of fresh biopsy and archived tumor s les were performed by screening for mutations or copy-number variations in 44 genes and for promoter methylation of BRCA1 and RAD51C. Somatic genomic or methylation events were identified in 85% of all patient cases, with potentially actionable events with defined targeted therapies (including four resistance events) detected in 60% of all patient cases. On the basis of these findings, six patients received molecularly guided therapy, three patients had unsuspected germline cancer–associated BRCA1/ 2 mutations and were referred for genetic counseling, and two intermediate differentiated (grade 2) serous ovarian carcinomas were reclassified as low grade, leading to changes in clinical management. Additionally, secondary reversion mutations in BRCA1/ 2 were identified in fresh biopsy s les of two patients, consistent with clinical platinum oly (ADP-ribose) polymerase inhibitor resistance. Timely reporting of results if molecular testing is done at disease recurrence, as well as early referral for patients with platinum-resistant cancers, were identified as factors that could improve the clinical utility of molecular profiling. ALLOCATE molecular profiling identified known genomic and methylation alterations of the different ovarian cancer subtypes and was deemed feasible and useful in routine clinical practice. Better patient selection and access to a wider range of targeted therapies or clinical trials will further enhance the clinical utility of molecular profiling.
Publisher: Elsevier BV
Date: 06-2017
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: 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: Oxford University Press (OUP)
Date: 15-06-2018
Abstract: Unopposed oestrogen is responsible for approximately 80% of all the endometrial cancers. The relationship between unopposed oestrogen and endometrial cancer was indicated by the increase in the number of endometrial cancer cases due to the widespread use of oestrogen replacement therapy. Approximately 30% of the endometrial cancer patients have mutations in the Wnt signalling pathway. How the unbalanced ratios of ovarian hormones and the mutations in Wnt signalling pathway interact to cause endometrial cancer is currently unclear. To study this, we have developed a uterine epithelial cell-specific inducible cre mouse model and used 3D in vitro culture of human endometrial cancer cell lines. We showed that activating mutations in the Wnt signalling pathway for a prolonged period leads to endometrial hyperplasia but not endometrial cancer. Interestingly, unopposed oestrogen and activating mutations in Wnt signalling together drive the progression of endometrial hyperplasia to endometrial cancer. We have provided evidence that progesterone can be used as a targeted therapy against endometrial cancer cases presented with the activating mutations in Wnt signalling pathway.
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: Bioscientifica
Date: 07-2017
DOI: 10.1530/REP-17-0339
Abstract: κΩΨ¥–€™±≈‰ greater than less than Recent studies showed that genetic aberrations in the MED12 gene, probably through the canonical WNT/β-catenin pathway, lead to the pathogenesis of uterine fibroids. However, a comprehensive analysis of the WNT pathway in MED12-mutated and MED12-wild type fibroids has not been performed. The objective of this study was to determine the status of the WNT pathway in human fibroids. We performed Sanger sequencing to define the MED12 mutational status of fibroids and normal myometrium s les. qPCR arrays were carried out to determine the status of the WNT signaling pathway in MED12-mutated and MED12-wild type fibroids. Liquid chromatography-mass spectrometry (LC-MS), western blotting, and immunohistochemistry were used to monitor the expression of β-catenin. We showed that β-catenin expression was increased in fibroids compared to the adjacent myometrium s les. However, β-catenin expression showed no correlation with MED12 mutation status. Of all the WNT signaling components, WNT inhibitors showed the greatest differences in expression between fibroids and controls. WIF1, a WNT inhibitor, was identified as the most significantly upregulated gene in fibroids. We cultured primary fibroid cells on hydrogels of known stiffness to decipher the influence of biomechanical cues on β-catenin expression and revealed increased levels of β-catenin when cells were cultured on a stiffer surface. In conclusion, our data showed tha t β-catenin expression in fibroids occurs independently of MED12 mutations. Biomechanical changes upregulate β-catenin expression in fibroids, pro viding an attractive avenue for developing new treatments for this disease.
Publisher: The Endocrine Society
Date: 13-12-2018
Abstract: The central characteristic of uterine fibroids is excessive deposition of extracellular matrix (ECM), which contributes to fibroid growth and bulk-type symptoms. Despite this, very little is known about patterns of ECM protein expression in fibroids and whether these are influenced by the most common genetic anomalies, which relate to MED12. We performed extensive genetic and proteomic analyses of clinically annotated fibroids and adjacent normal myometrium to identify the composition and expression patterns of ECM proteins in MED12 mutation–positive and mutation–negative uterine fibroids. Genetic sequencing of tissue s les revealed MED12 alterations in 39 of 65 fibroids (60%) from 14 patients. Using isobaric tagged–based quantitative mass spectrometry on three selected patients (n = 9 fibroids), we observed a common set of upregulated (& .5-fold) and downregulated (& .66-fold) proteins in small, medium, and large fibroid s les of annotated MED12 status. These two sets of upregulated and downregulated proteins were the same in all patients, regardless of variations in fibroid size and MED12 status. We then focused on one of the significant upregulated ECM proteins and confirmed the differential expression of periostin using western blotting and immunohistochemical analysis. Our study defined the proteome of uterine fibroids and identified that increased ECM protein expression, in particular periostin, is a hallmark of uterine fibroids regardless of MED12 mutation status. This study sets the foundation for further investigations to analyze the mechanisms regulating ECM overexpression and the functional role of upregulated ECM proteins in leiomyogenesis.
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 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
No related grants have been discovered for Yi-An Ko.