Sir Peter MacCallum Department of Oncology - Research Publications

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    Small-scale mutations are infrequent as mechanisms of resistance in post-PARP inhibitor tumour samples in high grade serous ovarian cancer
    Burdett, NL ; Willis, MO ; Pandey, A ; Fereday, S ; DeFazio, A ; Bowtell, DDL ; Christie, EL (NATURE PORTFOLIO, 2023-12-10)
    While the introduction of poly-(ADP)-ribose polymerase (PARP) inhibitors in homologous recombination DNA repair (HR) deficient high grade serous ovarian, fallopian tube and primary peritoneal cancers (HGSC) has improved patient survival, resistance to PARP inhibitors frequently occurs. Preclinical and translational studies have identified multiple mechanisms of resistance; here we examined tumour samples collected from 26 women following treatment with PARP inhibitors as part of standard of care or their enrolment in clinical trials. Twenty-one had a germline or somatic BRCA1/2 mutation. We performed targeted sequencing of 63 genes involved in DNA repair processes or implicated in ovarian cancer resistance. We found that just three individuals had a small-scale mutation as a definitive resistance mechanism detected, having reversion mutations, while six had potential mechanisms of resistance detected, with alterations related to BRCA1 function and mutations in SHLD2. This study indicates that mutations in genes related to DNA repair are detected in a minority of HGSC patients as genetic mechanisms of resistance. Future research into resistance in HGSC should focus on copy number, transcriptional and epigenetic aberrations, and the contribution of the tumour microenvironment.
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    Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer
    Burdett, NL ; Willis, MO ; Alsop, K ; Hunt, AL ; Pandey, A ; Hamilton, PT ; Abulez, T ; Liu, X ; Hoang, T ; Craig, S ; Fereday, S ; Hendley, J ; Garsed, DW ; Milne, K ; Kalaria, S ; Marshall, A ; Hood, BL ; Wilson, KN ; Conrads, KA ; Pishas, K ; Ananda, S ; Scott, CL ; Antill, Y ; McNally, O ; Mileshkin, L ; Hamilton, A ; Au-Yeung, G ; Devereux, L ; Thorne, H ; Bild, A ; Bateman, NW ; Maxwell, GL ; Chang, JT ; Conrads, TPP ; Nelson, BH ; Bowtell, DDL ; Christie, ELL (NATURE PORTFOLIO, 2023-03)
    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 from 15 women with HR-deficient HGSC. Patients had polyclonal disease, and several resistance mechanisms were identified within most patients, including reversion mutations and HR restoration by other means. We also observed frequent whole-genome duplication and global changes in immune composition with evidence of immune escape. This analysis highlights diverse evolutionary changes within HGSC that evade therapy and ultimately overwhelm individual patients.
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    The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer
    Garsed, DW ; Pandey, A ; Fereday, S ; Kennedy, CJ ; Takahashi, K ; Alsop, K ; Hamilton, PT ; Hendley, J ; Chiew, Y-E ; Traficante, N ; Provan, P ; Ariyaratne, D ; Au-Yeung, G ; Bateman, NW ; Bowes, L ; Brand, A ; Christie, EL ; Cunningham, JM ; Friedlander, M ; Grout, B ; Harnett, P ; Hung, J ; McCauley, B ; McNally, O ; Piskorz, AM ; Saner, FAM ; Vierkant, RA ; Wang, C ; Winham, SJ ; Pharoah, PDP ; Brenton, JD ; Conrads, TP ; Maxwell, GL ; Ramus, SJ ; Pearce, CL ; Pike, MC ; Nelson, BH ; Goode, EL ; DeFazio, A ; Bowtell, DDL (NATURE PORTFOLIO, 2022-12)
    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 diagnosis using whole-genome sequencing, transcriptome and methylome profiling of their primary tumor samples, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes and differential immune responses appear to contribute to long-term survival in HGSC.
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    Estrogen receptor beta expression in triple negative breast cancers is not associated with recurrence or survival
    Takano, EA ; Younes, MM ; Meehan, K ; Spalding, L ; Yan, M ; Allan, P ; Fox, SB ; Redfern, A ; Clouston, D ; Giles, GG ; Christie, EL ; Anderson, RL ; Zethoven, M ; Phillips, K-A ; Gorringe, K ; Britt, KL (BMC, 2023-05-19)
    BACKGROUND: Triple negative BCa (TNBC) is defined by a lack of expression of estrogen (ERα), progesterone (PgR) receptors and human epidermal growth factor receptor 2 (HER2) as assessed by protein expression and/or gene amplification. It makes up ~ 15% of all BCa and often has a poor prognosis. TNBC is not treated with endocrine therapies as ERα and PR negative tumors in general do not show benefit. However, a small fraction of the true TNBC tumors do show tamoxifen sensitivity, with those expressing the most common isoform of ERβ1 having the most benefit. Recently, the antibodies commonly used to assess ERβ1 in TNBC have been found to lack specificity, which calls into question available data regarding the proportion of TNBC that express ERβ1 and any relationship to clinical outcome. METHODS: To confirm the true frequency of ERβ1 in TNBC we performed robust ERβ1 immunohistochemistry using the specific antibody CWK-F12 ERβ1 on 156 primary TNBC cancers from patients with a median of 78 months (range 0.2-155 months) follow up. RESULTS: We found that high expression of ERβ1 was not associated with increased recurrence or survival when assessed as percentage of ERβ1 positive tumor cells or as Allred > 5. In contrast, the non-specific PPG5-10 antibody did show an association with recurrence and survival. CONCLUSIONS: Our data indicate that ERβ1 expression in TNBC tumours does not associate with prognosis.
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    Evolution of core archetypal phenotypes in progressive high grade serous ovarian cancer
    Nath, A ; Cosgrove, PA ; Mirsafian, H ; Christie, EL ; Pflieger, L ; Copeland, B ; Majumdar, S ; Cristea, MC ; Han, ES ; Lee, SJ ; Wang, EW ; Fereday, S ; Traficante, N ; Salgia, R ; Werner, T ; Cohen, AL ; Moos, P ; Chang, JT ; Bowtell, DDL ; Bild, AH (NATURE PORTFOLIO, 2021-05-24)
    The evolution of resistance in high-grade serous ovarian cancer (HGSOC) cells following chemotherapy is only partially understood. To understand the selection of factors driving heterogeneity before and through adaptation to treatment, we profile single-cell RNA-sequencing (scRNA-seq) transcriptomes of HGSOC tumors collected longitudinally during therapy. We analyze scRNA-seq data from two independent patient cohorts to reveal that HGSOC is driven by three archetypal phenotypes, defined as oncogenic states that describe the majority of the transcriptome variation. Using a multi-task learning approach to identify the biological tasks of each archetype, we identify metabolism and proliferation, cellular defense response, and DNA repair signaling as consistent cell states found across patients. Our analysis demonstrates a shift in favor of the metabolism and proliferation archetype versus cellular defense response archetype in cancer cells that received multiple lines of treatment. While archetypes are not consistently associated with specific whole-genome driver mutations, they are closely associated with subclonal populations at the single-cell level, indicating that subclones within a tumor often specialize in unique biological tasks. Our study reveals the core archetypes found in progressive HGSOC and shows consistent enrichment of subclones with the metabolism and proliferation archetype as resistance is acquired to multiple lines of therapy.
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    TRACEBACK: Testing of Historical Tubo-Ovarian Cancer Patients for Hereditary Risk Genes as a Cancer Prevention Strategy in Family Members
    Delahunty, R ; Nguyen, L ; Craig, S ; Creighton, B ; Ariyaratne, D ; Garsed, DW ; Christie, E ; Fereday, S ; Andrews, L ; Lewis, A ; Limb, S ; Pandey, A ; Hendley, J ; Traficante, N ; Carvajal, N ; Spurdle, AB ; Thompson, B ; Parsons, MT ; Beshay, V ; Volcheck, M ; Semple, T ; Lupat, R ; Doig, K ; Yu, J ; Chen, XQ ; Marsh, A ; Love, C ; Bilic, S ; Beilin, M ; Nichols, CB ; Greer, C ; Lee, YC ; Gerty, S ; Gill, L ; Newton, E ; Howard, J ; Williams, R ; Norris, C ; Stephens, AN ; Tutty, E ; Smyth, C ; O'Connell, S ; Jobling, T ; Stewart, CJR ; Tan, A ; Fox, SB ; Pachter, N ; Li, J ; Ellul, J ; Mir Arnau, G ; Young, M-A ; Gordon, L ; Forrest, L ; Harris, M ; Livingstone, K ; Hill, J ; Chenevix-Trench, G ; Cohen, PA ; Webb, PM ; Friedlander, M ; James, P ; Bowtell, D ; Alsop, K (LIPPINCOTT WILLIAMS & WILKINS, 2022-06-20)
    PURPOSE: Tubo-ovarian cancer (TOC) is a sentinel cancer for BRCA1 and BRCA2 pathogenic variants (PVs). Identification of a PV in the first member of a family at increased genetic risk (the proband) provides opportunities for cancer prevention in other at-risk family members. Although Australian testing rates are now high, PVs in patients with TOC whose diagnosis predated revised testing guidelines might have been missed. We assessed the feasibility of detecting PVs in this population to enable genetic risk reduction in relatives. PATIENTS AND METHODS: In this pilot study, deceased probands were ascertained from research cohort studies, identification by a relative, and gynecologic oncology clinics. DNA was extracted from archival tissue or stored blood for panel sequencing of 10 risk-associated genes. Testing of deceased probands ascertained through clinic records was performed with a consent waiver. RESULTS: We identified 85 PVs in 84 of 787 (11%) probands. Familial contacts of 39 of 60 (65%) deceased probands with an identified recipient (60 of 84; 71%) have received a written notification of results, with follow-up verbal contact made in 85% (33 of 39). A minority of families (n = 4) were already aware of the PV. For many (29 of 33; 88%), the genetic result provided new information and referral to a genetic service was accepted in most cases (66%; 19 of 29). Those who declined referral (4 of 29) were all male next of kin whose family member had died more than 10 years before. CONCLUSION: We overcame ethical and logistic challenges to demonstrate that retrospective genetic testing to identify PVs in previously untested deceased probands with TOC is feasible. Understanding reasons for a family member's decision to accept or decline a referral will be important for guiding future TRACEBACK projects.
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    Phenotypic Consequences of SLC25A40-ABCB1 Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer
    Pishas, K ; Cowley, KJ ; Pandey, A ; Hoang, T ; Beach, JA ; Luu, J ; Vary, R ; Smith, LK ; Shembrey, CE ; Rashoo, N ; White, MO ; Simpson, KJ ; Bild, A ; Griffiths, J ; Cheasley, D ; Campbell, I ; Bowtell, DDL ; Christie, EL (MDPI, 2021-11)
    Despite high response rates to initial chemotherapy, the majority of women diagnosed with High-Grade Serous Ovarian Cancer (HGSOC) ultimately develop drug resistance within 1-2 years of treatment. We previously identified the most common mechanism of acquired resistance in HGSOC to date, transcriptional fusions involving the ATP-binding cassette (ABC) transporter ABCB1, which has well established roles in multidrug resistance. However, the underlying biology of fusion-positive cells, as well as how clonal interactions between fusion-negative and positive populations influences proliferative fitness and therapeutic response remains unknown. Using a panel of fusion-negative and positive HGSOC single-cell clones, we demonstrate that in addition to mediating drug resistance, ABCB1 fusion-positive cells display impaired proliferative capacity, elevated oxidative metabolism, altered actin cellular morphology and an extracellular matrix/inflammatory enriched transcriptional profile. The co-culture of fusion-negative and positive populations had no effect on cellular proliferation but markedly altered drug sensitivity to doxorubicin, paclitaxel and cisplatin. Finally, high-throughput screening of 2907 FDA-approved compounds revealed 36 agents that induce equal cytotoxicity in both pure and mixed ABCB1 fusion populations. Collectively, our findings have unraveled the underlying biology of ABCB1 fusion-positive cells beyond drug resistance and identified novel therapeutic agents that may significantly improve the prognosis of relapsed HGSOC patients.
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    Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer
    Rinne, N ; Christie, EL ; Ardasheva, A ; Kwok, CH ; Demchenko, N ; Low, C ; Tralau-Stewart, C ; Fotopoulou, C ; Cunnea, P (OAE PUBLISHING INC, 2021)
    The survival rates for women with ovarian cancer have shown scant improvement in recent years, with a 5-year survival rate of less than 40% for women diagnosed with advanced ovarian cancer. High-grade serous ovarian cancer (HGSOC) is the most lethal subtype where the majority of women develop recurrent disease and chemotherapy resistance, despite over 70%-80% of patients initially responding to platinum-based chemotherapy. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates many vital processes such as cell growth, survival and metabolism. However, this pathway is frequently dysregulated in cancers including different subtypes of ovarian cancer, through amplification or somatic mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), amplification of AKT isoforms, or deletion or inactivation of PTEN. Further evidence indicates a role for the PI3K/AKT/mTOR pathway in the development of chemotherapy resistance in ovarian cancer. Thus, targeting key nodes of the PI3K/AKT/mTOR pathway is a potential therapeutic prospect. In this review, we outline dysregulation of PI3K signaling in ovarian cancer, with a particular emphasis on HGSOC and platinum-resistant disease. We review pre-clinical evidence for inhibitors of the main components of the PI3K pathway and highlight past, current and upcoming trials in ovarian cancers for different inhibitors of the pathway. Whilst no inhibitors of the PI3K/AKT/mTOR pathway have thus far advanced to the clinic for the treatment of ovarian cancer, several promising compounds which have the potential to restore platinum sensitivity and improve clinical outcomes for patients are under evaluation and in various phases of clinical trials.
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    Evolution of core archetypal phenotypes in progressive high grade serous ovarian cancer.
    Nath, A ; Cosgrove, P ; Copeland, B ; Mirsafian, H ; Christie, E ; Pflieger, L ; Majumdar, S ; Cristea, M ; Han, E ; Lee, S ; Wang, E ; Fereday, S ; Traficante, N ; Salgia, R ; Werner, T ; Cohen, A ; Moos, P ; Chang, J ; Bowtell, D ; Bild, A (AMER ASSOC CANCER RESEARCH, 2021-07-01)
    Abstract The evolution of resistance in high-grade serous ovarian cancer (HGSOC) cells following chemotherapy is only partially understood. To uncover phenotypic changes associated with chemotherapy resistance, we profiled single-cell RNA-sequencing (scRNA-seq) transcriptomes of HGSOC tumors collected longitudinally during patient treatment. Analysis of scRNA-seq data from two independent patient cohorts revealed that HGSOC is driven by three core archetypal phenotypes, defined as oncogenic tasks that describe the majority of the transcriptome variation. A multi-task learning approach to identify the biological tasks of each archetype identified metabolism and proliferation, cellular defense response, and DNA repair signaling. The metabolism and proliferation archetype evolved during treatment and was enriched in cancer cells from patients that received multiple-lines of treatment and had elevated tumor burden indicated by CA-125 levels. The emergence of archetypes was not consistently associated with specific whole-genome driver mutations. However, archetypes were closely associated with subclonal populations at the single-cell level, indicating that subclones within a tumor often specialize in unique biological tasks. Our study reveals the core archetypes found in progressive HGSOC and shows consistent enrichment of subclones with the metabolism archetype as resistance is acquired to multiple lines of therapy. Citation Format: Aritro Nath, Patrick Cosgrove, Benjamin Copeland, Hoda Mirsafian, Elizabeth Christie, Lance Pflieger, Sumana Majumdar, Mihaela Cristea, Ernest Han, Stephen Lee, Edward Wang, Sian Fereday, Nadia Traficante, Ravi Salgia, Theresa Werner, Adam Cohen, Phillip Moos, Jeffrey Chang, David Bowtell, Andrea Bild. Evolution of core archetypal phenotypes in progressive high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3141.
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    Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes
    Dentro, SC ; Leshchiner, I ; Haase, K ; Tarabichi, M ; Wintersinger, J ; Deshwar, AG ; Yu, K ; Rubanova, Y ; Macintyre, G ; Demeulemeester, J ; Vazquez-Garcia, I ; Kleinheinz, K ; Livitz, DG ; Malikic, S ; Donmez, N ; Sengupta, S ; Anur, P ; Jolly, C ; Cmero, M ; Rosebrock, D ; Schumacher, SE ; Fan, Y ; Fittall, M ; Drews, RM ; Yao, X ; Watkins, TBK ; Lee, J ; Schlesner, M ; Zhu, H ; Adams, DJ ; McGranahan, N ; Swanton, C ; Getz, G ; Boutros, PC ; Imielinski, M ; Beroukhim, R ; Sahinalp, SC ; Ji, Y ; Peifer, M ; Martincorena, I ; Markowetz, F ; Mustonen, V ; Yuan, K ; Gerstung, M ; Spellman, PT ; Wang, W ; Morris, QD ; Wedge, DC ; Van Loo, P (CELL PRESS, 2021-04-15)
    Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.