Sir Peter MacCallum Department of Oncology - Research Publications

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    Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.
    Morra, A ; Schreurs, MAC ; Andrulis, IL ; Anton-Culver, H ; Augustinsson, A ; Beckmann, MW ; Behrens, S ; Bojesen, SE ; Bolla, MK ; Brauch, H ; Broeks, A ; Buys, SS ; Camp, NJ ; Castelao, JE ; Cessna, MH ; Chang-Claude, J ; Chung, WK ; Collaborators, N ; Colonna, SV ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Dennis, J ; Devilee, P ; Dörk, T ; Dunning, AM ; Dwek, M ; Easton, DF ; Eccles, DM ; Eriksson, M ; Evans, DG ; Fasching, PA ; Fehm, TN ; Figueroa, JD ; Flyger, H ; Gabrielson, M ; Gago-Dominguez, M ; García-Closas, M ; García-Sáenz, JA ; Genkinger, J ; Grassmann, F ; Gündert, M ; Hahnen, E ; Haiman, CA ; Hamann, U ; Harrington, PA ; Hartikainen, JM ; Hoppe, R ; Hopper, JL ; Houlston, RS ; Howell, A ; Investigators, A ; Investigators, K ; Jakubowska, A ; Janni, W ; Jernström, H ; John, EM ; Johnson, N ; Jones, ME ; Kristensen, VN ; Kurian, AW ; Lambrechts, D ; Marchand, LL ; Lindblom, A ; Lubiński, J ; Lux, MP ; Mannermaa, A ; Mavroudis, D ; Mulligan, AM ; Muranen, TA ; Nevanlinna, H ; Nevelsteen, I ; Neven, P ; Newman, WG ; Obi, N ; Offit, K ; Olshan, AF ; Park-Simon, T-W ; Patel, AV ; Peterlongo, P ; Phillips, K-A ; Plaseska-Karanfilska, D ; Polley, EC ; Presneau, N ; Pylkäs, K ; Rack, B ; Radice, P ; Rashid, MU ; Rhenius, V ; Robson, M ; Romero, A ; Saloustros, E ; Sawyer, EJ ; Schmutzler, RK ; Schuetze, S ; Scott, C ; Shah, M ; Smichkoska, S ; Southey, MC ; Tapper, WJ ; Teras, LR ; Tollenaar, RAEM ; Tomczyk, K ; Tomlinson, I ; Troester, MA ; Vachon, CM ; van Veen, EM ; Wang, Q ; Wendt, C ; Wildiers, H ; Winqvist, R ; Ziogas, A ; Hall, P ; Pharoah, PDP ; Adank, MA ; Hollestelle, A ; Schmidt, MK ; Hooning, MJ ( 2023-02-13)
    Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09-1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words).
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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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    Evaluating the cost-effectiveness of [18F]FDG-PET/CT for investigation of persistent or recurrent neutropenic fever in high-risk haematology patients
    Tew, M ; Douglas, AP ; Szer, J ; Bajel, A ; Harrison, SJ ; Tio, SY ; Worth, LJ ; Hicks, RJ ; Ritchie, D ; Slavin, MA ; Thursky, KA ; Dalziel, K (BMC, 2023-12-15)
    BACKGROUND: A recent randomised trial demonstrated [18F]fluorodeoxyglucose positron-emission tomography in combination with low-dose CT (FDG-PET/CT), compared to standard of care computed tomography (CT) imaging, positively impacted antimicrobial management and outcomes of acute leukaemia and haematopoietic stem cell transplant recipients with persistent and recurrent neutropenic fever. We conducted an economic evaluation from a healthcare perspective alongside the clinical trial. METHODS: Unit costs in Australian dollars were applied to all resources used (antimicrobials, diagnostic tests, ICU and hospital bed days). Effectiveness was measured as number of patients with antimicrobial rationalisation, 6-month mortality and quality-adjusted life years (QALYs) derived from patient-reported trial-based health-related quality-of-life. Generalised linear models were used to analyse costs and outcomes. Incremental cost-effectiveness ratios (ICERs) for all outcomes and net monetary benefit (NMB) for QALYs were calculated. We performed bootstrapping with 1000 replications using the recycled predictions method. RESULTS: The adjusted healthcare costs were lower for FDG-PET/CT (mean $49,563; 95%CI 36,867, 65,133) compared to CT (mean $57,574; 95% CI 44,837, 73,347). The difference in QALYs between the two groups was small (0.001; 95% CI -0.001, 0.004). When simulated 1000 times, FDG-PET/CT was the dominant strategy as it was cheaper with better outcomes than the standard CT group in 74% of simulations. The estimated NMBs at willingness-to-pay thresholds of $50,000 and $100,000 per QALY were positive, thus FDG-PET/CT remained cost-effective at these thresholds. CONCLUSIONS: FDG-PET/CT is cost effective when compared to CT for investigation of persistent/recurrent neutropenic fever in high-risk patients, providing further support for incorporation of FDG-PET/CT into clinical guidelines and funding. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT03429387.
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    Evolution of Humoral and Cellular Immunity Post-Breakthrough Coronavirus Disease 2019 in Vaccinated Patients With Hematologic Malignancy Receiving Tixagevimab-Cilgavimab
    Hall, VG ; Nguyen, THO ; Allen, LF ; Rowntree, LC ; Kedzierski, L ; Chua, BY ; Lim, C ; Saunders, NR ; Klimevski, E ; Tennakoon, GS ; Seymour, JF ; Wadhwa, V ; Cain, N ; Vo, KL ; Nicholson, S ; Karapanagiotidis, T ; Williamson, DA ; Thursky, KA ; Spelman, T ; Yong, MK ; Slavin, MA ; Kedzierska, K ; Teh, BW (OXFORD UNIV PRESS INC, 2023-11-01)
    BACKGROUND: In-depth immunogenicity studies of tixagevimab-cilgavimab (T-C) are lacking, including following breakthrough coronavirus disease 2019 (COVID-19) in vaccinated patients with hematologic malignancy (HM) receiving T-C as pre-exposure prophylaxis. METHODS: We performed a prospective, observational cohort study and detailed immunological analyses of 93 patients with HM who received T-C from May 2022, with and without breakthrough infection, during a follow-up period of 6 months and dominant Omicron BA.5 variant. RESULTS: In 93 patients who received T-C, there was an increase in Omicron BA.4/5 receptor-binding domain (RBD) immunoglobulin G (IgG) antibody titers that persisted for 6 months and was equivalent to 3-dose-vaccinated uninfected healthy controls at 1 month postinjection. Omicron BA.4/5 neutralizing antibody was lower in patients receiving B-cell-depleting therapy within 12 months despite receipt of T-C. COVID-19 vaccination during T-C treatment did not incrementally improve RBD or neutralizing antibody levels. In 16 patients with predominantly mild breakthrough infection, no change in serum neutralization of Omicron BA.4/5 postinfection was detected. Activation-induced marker assay revealed an increase in CD4+ (but not CD8+) T cells post infection, comparable to previously infected healthy controls. CONCLUSIONS: Our study provides proof-of-principle for a pre-exposure prophylaxis strategy and highlights the importance of humoral and cellular immunity post-breakthrough COVID-19 in vaccinated patients with HM.
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    A CAF01-adjuvanted whole asexual blood-stage liposomal malaria vaccine induces a CD4+ T-cell-dependent strain-transcending protective immunity in rodent models
    Okoth, WA ; Ho, M-F ; Zaman, M ; Cooper, E ; Som, P ; Burgess, M ; Walton, M ; Nevagi, RJ ; Beattie, L ; Murphy, D ; Stanisic, DI ; Good, MF ; Miller, LH (AMER SOC MICROBIOLOGY, 2023-12-19)
    Malaria is a devastating disease that has claimed many lives, especially children <5 years of age in Sub-Saharan Africa, as documented in World Malaria Reports by WHO. Even though vector control and chemoprevention tools have helped with elimination efforts in some, if not all, endemic areas, these efforts have been hampered by serious issues (including drug and insecticide resistance and disruption to social cohesion caused by the COVID-19 pandemic). Development of an effective malaria vaccine is the alternative preventative tool in the fight against malaria. Vaccines save millions of lives each year and have helped in elimination and/or eradication of global diseases. Development of a highly efficacious malaria vaccine that will ensure long-lasting protective immunity will be a "game-changing" prevention strategy to finally eradicate the disease. Such a vaccine will need to counteract the significant obstacles that have been hampering subunit vaccine development to date, including antigenic polymorphism, sub-optimal immunogenicity, and waning vaccine efficacy.
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    Approach to diagnostic evaluation and prevention of invasive fungal disease in patients prior to allogeneic hematopoietic stem cell transplant
    O'Keeffe, JC ; Singh, N ; Slavin, MA (WILEY, 2023-11)
    In recent years, advancements in the treatment landscape for hematological malignancies, such as acute myeloid leukemia and acute lymphoblastic leukemia, have significantly improved disease prognosis and overall survival. However, the treatment landscape is changing and the emergence of targeted oral therapies and immune-based treatments has brought forth new challenges in evaluating and preventing invasive fungal diseases (IFDs). IFD disproportionately affects immunocompromised hosts, particularly those undergoing therapy for acute leukemia and allogeneic hematopoietic stem cell transplant. This review aims to provide a comprehensive overview of the pretransplant workup, identification, and prevention of IFD in patients with hematological malignancy. The pretransplant period offers a critical window to assess each patient's risk factors and implement appropriate prophylactic measures. Risk assessment includes evaluation of disease, host, prior treatments, and environmental factors, allowing a dynamic evaluation that considers disease progression and treatment course. Diagnostic screening, involving various biomarkers and radiological modalities, plays a crucial role in early detection of IFD. Antifungal prophylaxis choice is based on available evidence as well as individual risk assessment, potential for drug-drug interactions, toxicity, and patient adherence. Therapeutic drug monitoring ensures effective antifungal stewardship and optimal treatment. Patient education and counselling are vital in minimizing environmental exposures to fungal pathogens and promoting medication adherence. A well-structured and individualized approach, encompassing risk assessment, prophylaxis, surveillance, and patient education, is essential for effectively preventing IFD in hematological malignancies, ultimately leading to improved patient outcomes and overall survival.
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    Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.
    Saner, FAM ; Takahashi, K ; Budden, T ; Pandey, A ; Ariyaratne, D ; Zwimpfer, TA ; Meagher, NS ; Fereday, S ; Twomey, L ; Pishas, KI ; Hoang, T ; Bolithon, A ; Traficante, N ; Alsop, K ; Christie, EL ; Kang, E-Y ; Nelson, GS ; Ghatage, P ; Lee, C-H ; Riggan, MJ ; Alsop, J ; Beckmann, MW ; Boros, J ; Brand, AH ; Brooks-Wilson, A ; Carney, ME ; Coulson, P ; Courtney-Brooks, M ; Cushing-Haugen, KL ; Cybulski, C ; El-Bahrawy, MA ; Elishaev, E ; Erber, R ; Gayther, SA ; Gentry-Maharaj, A ; Blake Gilks, C ; Harnett, PR ; Harris, HR ; Hartmann, A ; Hein, A ; Hendley, J ; AOCS Group, ; Hernandez, BY ; Jakubowska, A ; Jimenez-Linan, M ; Jones, ME ; Kaufmann, SH ; Kennedy, CJ ; Kluz, T ; Koziak, JM ; Kristjansdottir, B ; Le, ND ; Lener, M ; Lester, J ; Lubiński, J ; Mateoiu, C ; Orsulic, S ; Ruebner, M ; Schoemaker, MJ ; Shah, M ; Sharma, R ; Sherman, ME ; Shvetsov, YB ; Singh, N ; Rinda Soong, T ; Steed, H ; Sukumvanich, P ; Talhouk, A ; Taylor, SE ; Vierkant, RA ; Wang, C ; Widschwendter, M ; Wilkens, LR ; Winham, SJ ; Anglesio, MS ; Berchuck, A ; Brenton, JD ; Campbell, I ; Cook, LS ; Doherty, JA ; Fasching, PA ; Fortner, RT ; Goodman, MT ; Gronwald, J ; Huntsman, DG ; Karlan, BY ; Kelemen, LE ; Menon, U ; Modugno, F ; Pharoah, PDP ; Schildkraut, JM ; Sundfeldt, K ; Swerdlow, AJ ; Goode, EL ; DeFazio, A ; Köbel, M ; Ramus, SJ ; Bowtell, DDL ; Garsed, DW (Cold Spring Harbor Laboratory, 2023-11-10)
    BACKGROUND: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 (BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC. PATIENTS AND METHODS: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss. RESULTS: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10-7), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC (P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10-6) compared to patients with either alteration alone, and their median OS was three times longer than non-carriers whose tumours retained RB1 expression (9.3 years vs. 3.1 years). Enhanced sensitivity to cisplatin (P < 0.01) and paclitaxel (P < 0.05) was seen in BRCA1 mutated cell lines with RB1 knockout. Among 126 patients with whole-genome and transcriptome sequence data, combined RB1 loss and genomic evidence of homologous recombination deficiency was correlated with transcriptional markers of enhanced interferon response, cell cycle deregulation, and reduced epithelial-mesenchymal transition in primary HGSC. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. CONCLUSIONS: Co-occurrence of RB1 loss and BRCA mutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.
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    The Feasibility of Quality Assurance in the TOPGEAR International Phase 3 Clinical Trial of Neoadjuvant Chemoradiation Therapy for Gastric Cancer (an Intergroup Trial of the AGITG/TROG/NHMRC CTC/EORTC/CCTG)
    Lukovic, J ; Moore, AJ ; Lee, MT ; Willis, D ; Ahmed, S ; Akra, M ; Hortobagyi, E ; Kron, T ; Joon, DL ; Liu, A ; Ryan, J ; Thomas, M ; Wall, K ; Ward, I ; Wiltshire, KL ; O'Callaghan, CJ ; Wong, RKS ; Ringash, JG ; Haustermans, K ; Leong, T (ELSEVIER SCIENCE INC, 2023-12-01)
    PURPOSE: The TOPGEAR phase 3 trial hypothesized that adding preoperative chemoradiation therapy (CRT) to perioperative chemotherapy will improve survival in patients with gastric cancer. Owing to the complexity of gastric irradiation, a comprehensive radiation therapy quality assurance (RTQA) program was implemented. Our objective is to describe the RTQA methods and outcomes. METHODS AND MATERIALS: RTQA was undertaken in real time before treatment for the first 5 patients randomized to CRT from each center. Once acceptable quality was achieved, RTQA was completed for one-third of subsequent cases. RTQA consisted of evaluating (1) clinical target volume and organ-at-risk contouring and (2) radiation therapy planning parameters. Protocol violations between high- (20+ patients enrolled) and low-volume centers were compared using the Fisher exact test. RESULTS: TOPGEAR enrolled 574 patients, of whom 286 were randomized to receive preoperative CRT and 203 (71%) were included for RTQA. Of these, 67 (33%) and 136 (67%) patients were from high- and low-volume centers, respectively. The initial RTQA pass rate was 72%. In total, 28% of cases required resubmission. In total, 200 of 203 cases (99%) passed RTQA before treatment. Cases from low-volume centers required resubmission more often (44/136 [33%] vs 13/67 [18%]; P = .078). There was no change in the proportion of cases requiring resubmission over time. Most cases requiring resubmission had multiple protocol violations. At least 1 aspect of the clinical target volume had to be adjusted in all cases. Inadequate coverage of the duodenum was most common (53% major violation, 25% minor violation). For the remaining cases, the resubmission process was triggered secondary to poor contour/plan quality. CONCLUSIONS: In a large multicenter trial, RTQA is feasible and effective in achieving high-quality treatment plans. Ongoing education should be performed to ensure consistent quality during the entire study period.
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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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    Vasculature is getting Hip(po): Hippo in vascular development and disease
    Kobayashi, S ; Cox, AG ; Harvey, KF ; Hogan, BM (CELL PRESS, 2023-12-04)
    The Hippo signaling pathway regulates developmental organ growth, regeneration, and cell fate decisions. Although the role of the Hippo pathway, and its transcriptional effectors YAP and TAZ, has been well documented in many cell types and species, only recently have the roles for this pathway come to light in vascular development and disease. Experiments in mice, zebrafish, and in vitro have uncovered roles for the Hippo pathway, YAP, and TAZ in vasculogenesis, angiogenesis, and lymphangiogenesis. In addition, the Hippo pathway has been implicated in vascular cancers and cardiovascular diseases, thus identifying it as a potential therapeutic target for the treatment of these conditions. However, despite recent advances, Hippo's role in the vasculature is still underappreciated compared with its role in epithelial tissues. In this review, we appraise our current understanding of the Hippo pathway in blood and lymphatic vessel development and highlight the current knowledge gaps and opportunities for further research.