Sir Peter MacCallum Department of Oncology - Research Publications

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    A MXI1-NUTM1 fusion protein with MYC-like activity suggests a novel oncogenic mechanism in a subset ofNUTM1-rearranged tumors
    McEvoy, CR ; Holliday, H ; Thio, N ; Mitchell, C ; Choong, DY ; Yellapu, B ; Leong, HS ; Xu, H ; Lade, S ; Browning, J ; Takano, EA ; Byrne, DJ ; Gill, AJ ; Duong, CP ; Li, J ; Fellowes, AP ; Fox, SB ; Swarbrick, A ; Prall, OWJ (ELSEVIER SCIENCE INC, 2021-01)
    Most NUTM1-rearranged neoplasms (NRNs) have fusions between NUTM1 and BRD (bromodomain-containing) family members and are termed NUT carcinomas (NCs) because they show some squamous differentiation. However, some NRNs are associated with fusions between NUTM1 and members of the MAD (MAX dimerization) gene family of MYC antagonists. Here we describe a small round cell malignancy from the gastro-esophageal junction with a previously unreported fusion between NUTM1 and the MAD family member MXI1. In contrast to NCs, the MXI1-NUTM1 tumor did not show squamous differentiation and did not express MYC, TP63 or SOX2, genes known to be targets of BRD-NUTM1 proteins and critical for NC oncogenesis. Transcriptome analysis showed paradoxical enrichment of MYC target genes in the MXI1-NUTM1 tumor despite the lack of MYC expression. When expressed in vitro MXI1-NUTM1 partially phenocopied MYC, enhancing cell proliferation and cooperating with oncogenic HRAS to produce anchorage-independent cell growth. These data provide evidence that MAD family members, which are normally repressors of MYC activity, can be converted into MYC-like mimics by fusion to NUTM1. The pathological features and novel oncogenic mechanism of the MXI1-NUTM1 tumor show that identification of NUTM1 fusion partners can be important for accurate diagnostic classification of some NRN subtypes, and potentially may guide therapeutic options.
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    Survey of recurrent diagnostic challenges in breast phyllodes tumours
    Tan, BY ; Fox, SB ; Lakhani, SR ; Tan, PH (WILEY, 2023-01)
    BACKGROUND: Breast phyllodes tumours (PTs) are graded as benign, borderline, or malignant by analysis of multiple histological features. PT grading is often inconsistent, likely due to variation in the weighting of grading criteria by pathologists. DESIGN: The hierarchy of use of diagnostic criteria was identified using a 20-question survey. RESULTS: In all, 213 pathologists from 29 countries responded. 54% reported 10-50 PT cases per year. Criteria considered key to PT diagnosis were: increased stromal cellularity (84.3%), stromal overgrowth (76.6%), increased stromal mitoses (67.8%), stromal atypia (61.5%), stromal fronding (59.0%), periductal stromal condensation (58.0%), irregular tumour borders (46.3%), and/or lesional heterogeneity (33.7%). The importance of grading parameters were: mitotic activity (55.5%), stromal overgrowth (54.0%), stromal atypia (51.9%), increased stromal cellularity (41.7%), and nature of the tumour border (38.9%). 49% would diagnose malignant PT without a full array of adverse features. 89% used the term "cellular fibroepithelial lesion (FEL)" for difficult cases; 45% would diagnose an FEL with stromal fronding (but lacking other PT features) as fibroadenoma (FA), 35% FEL, and 17% PT. 59% deemed clinico-radiological findings diagnostically significant; 68% considered age (≥40 years) important in determining if an FEL was a FA or PT. In FELs from young patients, increased stromal cellularity (83%), fronding (52%), and mitoses (41%) were more common. 34% regarded differentiating cellular FA from PT as a specific challenge; 54% had issues assigning a borderline PT grade. CONCLUSION: Criteria for grading PT lie on a spectrum, leading to interpretive variability. The survey highlights the criteria most used by pathologists, which do not completely align with WHO recommendations.
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    A Matched Molecular and Clinical Analysis of the Epithelioid Haemangioendothelioma Cohort in the Stafford Fox Rare Cancer Program and Contextual Literature Review
    Abdelmogod, A ; Papadopoulos, L ; Riordan, S ; Wong, M ; Weltman, M ; Lim, R ; Mcevoy, C ; Fellowes, A ; Fox, S ; Bedo, J ; Penington, J ; Pham, K ; Hofmann, O ; Vissers, JHA ; Grimmond, S ; Ratnayake, G ; Christie, M ; Mitchell, C ; Murray, WK ; Mcclymont, K ; Luk, P ; Papenfuss, AT ; Kee, D ; Scott, CL ; Goldstein, D ; Barker, HE (MDPI, 2023-09)
    BACKGROUND: Epithelioid haemangioendothelioma (EHE) is an ultra-rare malignant vascular tumour with a prevalence of 1 per 1,000,000. It is typically molecularly characterised by a WWTR1::CAMTA1 gene fusion in approximately 90% of cases, or a YAP1::TFE3 gene fusion in approximately 10% of cases. EHE cases are typically refractory to therapies, and no anticancer agents are reimbursed for EHE in Australia. METHODS: We report a cohort of nine EHE cases with comprehensive histologic and molecular profiling from the Walter and Eliza Hall Institute of Medical Research Stafford Fox Rare Cancer Program (WEHI-SFRCP) collated via nation-wide referral to the Australian Rare Cancer (ARC) Portal. The diagnoses of EHE were confirmed by histopathological and immunohistochemical (IHC) examination. Molecular profiling was performed using the TruSight Oncology 500 assay, the TruSight RNA fusion panel, whole genome sequencing (WGS), or whole exome sequencing (WES). RESULTS: Molecular analysis of RNA, DNA or both was possible in seven of nine cases. The WWTR1::CAMTA1 fusion was identified in five cases. The YAP1::TFE3 fusion was identified in one case, demonstrating unique morphology compared to cases with the more common WWTR1::CAMTA1 fusion. All tumours expressed typical endothelial markers CD31, ERG, and CD34 and were negative for pan-cytokeratin. Cases with a WWTR1::CAMTA1 fusion displayed high expression of CAMTA1 and the single case with a YAP1::TFE3 fusion displayed high expression of TFE3. Survival was highly variable and unrelated to molecular profile. CONCLUSIONS: This cohort of EHE cases provides molecular and histopathological characterisation and matching clinical information that emphasises the molecular patterns and variable clinical outcomes and adds to our knowledge of this ultra-rare cancer. Such information from multiple studies will advance our understanding, potentially improving treatment options.
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    Predicting breast cancer-specific survival in metaplastic breast cancer patients using machine learning algorithms.
    Feng, Y ; McGuire, N ; Walton, A ; AP-MBC Consortium, ; Fox, S ; Papa, A ; Lakhani, SR ; McCart Reed, AE (Elsevier BV, 2023)
    Metaplastic breast cancer (MpBC) is a rare and aggressive subtype of breast cancer, with data emerging on prognostic factors and survival prediction. This study aimed to develop machine learning models to predict breast cancer-specific survival (BCSS) in MpBC patients, utilizing a dataset of 160 patients with clinical, pathological, and biological variables. An in-depth variable selection process was carried out using gain ratio and correlation-based methods, resulting in 10 variables for model estimation. Five models (decision tree with bagging; logistic regression; multilayer perceptron; naïve Bayes; and, random forest algorithms) were evaluated using 10-fold cross-validation. Despite the constraints posed by the absence of therapeutic information, the random forest model exhibited the highest performance in predicting BCSS, with an ROC area of 0.808. This study emphasizes the potential of machine learning algorithms in predicting prognosis for complex and heterogeneous cancer subtypes using clinical datasets, and their potential to contribute to patient management. Further research that incorporates additional variables, such as treatment response, and more advanced machine learning techniques will likely enhance the predictive power of MpBC prognostic models.
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    Pitfalls in machine learning-based assessment of tumor-infiltrating lymphocytes in breast cancer: a report of the international immuno-oncology biomarker working group
    Thagaard, J ; Broeckx, G ; Page, DB ; Jahangir, CA ; Verbandt, S ; Kos, Z ; Gupta, R ; Khiroya, R ; Abduljabbar, K ; Acosta Haab, G ; Acs, B ; Akturk, G ; Almeida, JS ; Alvarado-Cabrero, I ; Amgad, M ; Azmoudeh-Ardalan, F ; Badve, S ; Baharun, NB ; Balslev, E ; Bellolio, ER ; Bheemaraju, V ; Blenman, KRM ; Botinelly Mendonca Fujimoto, L ; Bouchmaa, N ; Burgues, O ; Chardas, A ; Cheang, MU ; Ciompi, F ; Cooper, LAD ; Coosemans, A ; Corredor, G ; Dahl, AB ; Dantas Portela, FL ; Deman, F ; Demaria, S ; Dore Hansen, J ; Dudgeon, SN ; Ebstrup, T ; Elghazawy, M ; Fernandez-Martin, C ; Fox, SB ; Gallagher, WM ; Giltnane, JM ; Gnjatic, S ; Gonzalez-Ericsson, P ; Grigoriadis, A ; Halama, N ; Hanna, MG ; Harbhajanka, A ; Hart, SN ; Hartman, J ; Hauberg, S ; Hewitt, S ; Hida, A ; Horlings, HM ; Husain, Z ; Hytopoulos, E ; Irshad, S ; Janssen, EAM ; Kahila, M ; Kataoka, TR ; Kawaguchi, K ; Kharidehal, D ; Khramtsov, A ; Kiraz, U ; Kirtani, P ; Kodach, LL ; Korski, K ; Kovacs, A ; Laenkholm, A-V ; Lang-Schwarz, C ; Larsimont, D ; Lennerz, JK ; Lerousseau, M ; Li, X ; Ly, A ; Madabhushi, A ; Maley, SK ; Manur Narasimhamurthy, V ; Marks, DK ; McDonald, ES ; Mehrotra, R ; Michiels, S ; Minhas, FUAA ; Mittal, S ; Moore, DA ; Mushtaq, S ; Nighat, H ; Papathomas, T ; Penault-Llorca, F ; Perera, RD ; Pinard, CJ ; Pinto-Cardenas, JC ; Pruneri, G ; Pusztai, L ; Rahman, A ; Rajpoot, NM ; Rapoport, BL ; Rau, TT ; Reis-Filho, JS ; Ribeiro, JM ; Rimm, D ; Roslind, A ; Vincent-Salomon, A ; Salto-Tellez, M ; Saltz, J ; Sayed, S ; Scott, E ; Siziopikou, KP ; Sotiriou, C ; Stenzinger, A ; Sughayer, MA ; Sur, D ; Fineberg, S ; Symmans, F ; Tanaka, S ; Taxter, T ; Tejpar, S ; Teuwen, J ; Thompson, EA ; Tramm, T ; Tran, WT ; van Der Laak, J ; van Diest, PJ ; Verghese, GE ; Viale, G ; Vieth, M ; Wahab, N ; Walter, T ; Waumans, Y ; Wen, HY ; Yang, W ; Yuan, Y ; Zin, RM ; Adams, S ; Bartlett, J ; Loibl, S ; Denkert, C ; Savas, P ; Loi, S ; Salgado, R ; Specht Stovgaard, E (WILEY, 2023-08)
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    Spatial analyses of immune cell infiltration in cancer: current methods and future directions. A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer
    Page, DB ; Broeckx, G ; Jahangir, CA ; Jahangir, C ; Verbandt, S ; Gupta, RR ; Thagaard, J ; Khiroya, R ; Kos, Z ; Abduljabbar, K ; Acosta Haab, G ; Acs, B ; Almeida, JS ; Alvarado-Cabrero, I ; Azmoudeh-Ardalan, F ; Badve, S ; Baharun, NB ; Bellolio, ER ; Bheemaraju, V ; Blenman, KRM ; Botinelly Mendonca Fujimoto, L ; Burgues, O ; Cheang, MCU ; Ciompi, F ; Cooper, LAD ; Coosemans, A ; Corredor, G ; Dantas Portela, FL ; Deman, F ; Demaria, S ; Dudgeon, SN ; Elghazawy, M ; Ely, S ; Fernandez-Martin, C ; Fineberg, S ; Fox, SB ; Gallagher, WM ; Giltnane, JM ; Gnjatic, S ; Gonzalez-Ericsson, P ; Grigoriadis, A ; Halama, N ; Hanna, MG ; Harbhajanka, A ; Hardas, A ; Hart, SN ; Hartman, J ; Hewitt, S ; Hida, A ; Horlings, HM ; Husain, Z ; Hytopoulos, E ; Irshad, S ; Janssen, EAM ; Kahila, M ; Kataoka, TR ; Kawaguchi, K ; Kharidehal, D ; Khramtsov, A ; Kiraz, U ; Kirtani, P ; Kodach, LL ; Korski, K ; Kovacs, A ; Laenkholm, A-V ; Lang-Schwarz, C ; Larsimont, D ; Lennerz, JK ; Lerousseau, M ; Li, X ; Ly, A ; Madabhushi, A ; Maley, SK ; Manur Narasimhamurthy, V ; Marks, DK ; McDonald, ES ; Mehrotra, R ; Michiels, S ; Minhas, FUAA ; Mittal, S ; Moore, DA ; Mushtaq, S ; Nighat, H ; Papathomas, T ; Penault-Llorca, F ; Perera, RD ; Pinard, CJ ; Pinto-Cardenas, JC ; Pruneri, G ; Pusztai, L ; Rahman, A ; Rajpoot, NM ; Rapoport, BL ; Rau, TT ; Reis-Filho, JS ; Ribeiro, JM ; Rimm, D ; Salomon, A-V ; Salto-Tellez, M ; Saltz, J ; Sayed, S ; Siziopikou, KP ; Sotiriou, C ; Stenzinger, A ; Sughayer, MA ; Sur, D ; Symmans, F ; Tanaka, S ; Taxter, T ; Tejpar, S ; Teuwen, J ; Thompson, EA ; Tramm, T ; Tran, WT ; van Der Laak, J ; van Diest, PJ ; Verghese, GE ; Viale, G ; Vieth, M ; Wahab, N ; Walter, T ; Waumans, Y ; Wen, HY ; Yang, W ; Yuan, Y ; Adams, S ; Bartlett, JMS ; Loibl, S ; Denkert, C ; Savas, P ; Loi, S ; Salgado, R ; Specht Stovgaard, E ; Akturk, G ; Bouchmaa, N (WILEY, 2023-08)
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    Dihydropyrimidine Dehydrogenase Deficiency and Implementation of Upfront DPYD Genotyping
    White, C ; Scott, RJ ; Paul, C ; Ziolkowski, A ; Mossman, D ; Fox, SB ; Michael, M ; Ackland, S (WILEY, 2022-10)
    Fluoropyrimidines (FP; 5-fluorouracil, capecitabine, and tegafur) are a commonly prescribed class of antimetabolite chemotherapies, used for various solid organ malignancies in over 2 million patients globally per annum. Dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is the critical enzyme implicated in FP metabolism. DPYD variant genotypes can result in decreased DPD production, leading to the development of severe toxicities resulting in hospitalization, intensive care admission, and even death. Management of toxicity incurs financial burden on both patients and healthcare systems alike. Upfront DPYD genotyping to identify variant carriers allows an opportunity to identify patients who are at high risk to suffer from serious toxicities and allow prospective dose adjustment of FP treatment. This approach has been shown to reduce patient morbidity, as well as improve the cost-effectiveness of managing FP treatment. Upfront DPYD genotyping has been recently endorsed by several countries in Europe and the United Kingdom. This review summarizes current knowledge about DPD deficiency and upfront DPYD genotyping, including clinical and cost-effectiveness outcomes, with the intent of supporting implementation of an upfront DPYD genotyping service with individualized dose-personalization.
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    ImmunoPET: IMaging of cancer imMUNOtherapy targets with positron Emission Tomography: a phase 0/1 study characterising PD-L1 with 89Zr-durvalumab (MEDI4736) PET/CT in stage III NSCLC patients receiving chemoradiation study protocol.
    Hegi-Johnson, F ; Rudd, SE ; Wichmann, C ; Akhurst, T ; Roselt, P ; Trinh, J ; John, T ; Devereux, L ; Donnelly, PS ; Hicks, R ; Scott, AM ; Steinfort, D ; Fox, S ; Blyth, B ; Parakh, S ; Hanna, GG ; Callahan, J ; Burbury, K ; MacManus, M (BMJ Publishing Group, 2022-11-18)
    BACKGROUND: ImmunoPET is a multicentre, single arm, phase 0-1 study that aims to establish if 89Zr-durvalumab PET/CT can be used to interrogate the expression of PD-L1 in larger, multicentre clinical trials. METHODS: The phase 0 study recruited 5 PD-L1+ patients with metastatic non-small cell lung cancer (NSCLC). Patients received 60MBq/70 kg 89Zr-durva up to a maximum of 74 MBq, with scan acquisition at days 0, 1, 3 or 5±1 day. Data on (1) Percentage of injected 89Zr-durva dose found in organs of interest (2) Absorbed organ doses (µSv/MBq of administered 89Zr-durva) and (3) whole-body dose expressed as mSv/100MBq of administered dose was collected to characterise biodistribution.The phase 1 study will recruit 20 patients undergoing concurrent chemoradiotherapy for stage III NSCLC. Patients will have 89Zr-durva and FDG-PET/CT before, during and after chemoradiation. In order to establish the feasibility of 89Zr-durva PET/CT for larger multicentre trials, we will collect both imaging and toxicity data. Feasibility will be deemed to have been met if more than 80% of patients are able complete all trial requirements with no significant toxicity. ETHICS AND DISSEMINATION: This phase 0 study has ethics approval (HREC/65450/PMCC 20/100) and is registered on the Australian Clinical Trials Network (ACTRN12621000171819). The protocol, technical and clinical data will be disseminated by conference presentations and publications. Any modifications to the protocol will be formally documented by administrative letters and must be submitted to the approving HREC for review and approval. TRIAL REGISTRATION NUMBER: Australian Clinical Trials Network ACTRN12621000171819.
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    A comparison of DNA sequencing and gene expression profiling to assist tissue of origin diagnosis in cancer of unknown primary
    Posner, A ; Prall, OW ; Sivakumaran, T ; Etemadamoghadam, D ; Thio, N ; Pattison, A ; Balachander, S ; Fisher, K ; Webb, S ; Wood, C ; DeFazio, A ; Wilcken, N ; Gao, B ; Karapetis, CS ; Singh, M ; Collins, IM ; Richardson, G ; Steer, C ; Warren, M ; Karanth, N ; Wright, G ; Williams, S ; George, J ; Hicks, RJ ; Boussioutas, A ; Gill, AJ ; Solomon, BJ ; Xu, H ; Fellowes, A ; Fox, SB ; Schofield, P ; Bowtell, D ; Mileshkin, L ; Tothill, RW (WILEY, 2023-01)
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    Identifying recurrences and metastasis after ductal carcinoma in situ (DCIS) of the breast
    Udayasiri, R ; Luo, T ; Gorringe, KL ; Fox, SB (WILEY, 2023-01)
    Ductal carcinoma in situ (DCIS) of the breast is a non-invasive tumour that has the potential to progress to invasive ductal carcinoma (IDC). Thus, it represents a treatment dilemma: alone it does not present a risk to life, however, left untreated it may progress to a life-threatening condition. Current clinico-pathological features cannot accurately predict which patients with DCIS have invasive potential, and therefore clinicians are unable to quantify the risk of progression for an individual patient. This leads to many women being over-treated, while others may not receive sufficient treatment to prevent invasive recurrence. A better understanding of the molecular features of DCIS, both tumour-intrinsic and the microenvironment, could offer the ability to better predict which women need aggressive treatment, and which can avoid therapies carrying significant side-effects and such as radiotherapy. In this review, we summarise the current knowledge of DCIS, and consider future research directions.