Sir Peter MacCallum Department of Oncology - Research Publications

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    Antiglitches in accreting pulsars from superfluid vortex avalanches
    Howitt, G ; Melatos, A (Oxford University Press (OUP), 2022-07-01)
    ABSTRACT Three sudden spin-down events, termed ‘antiglitches’, were recently discovered in the accreting pulsar NGC 300 ULX-1 by the Neutron Star Interior Composition Explorer mission. Unlike previous antiglitches detected in decelerating magnetars, these are the first antiglitches recorded in an accelerating pulsar. One standard theory is that pulsar spin-up glitches are caused by avalanches of collectively unpinning vortices that transfer angular momentum from the superfluid interior to the crust of a neutron star. Here, we test whether vortex avalanches are also consistent with the antiglitches in NGC 300 ULX-1, with the angular momentum transfer reversed. We perform N-body simulations of up to 5 × 103 pinned vortices in two dimensions in secularly accelerating and decelerating containers. Vortex avalanches routinely occur in both scenarios, propagating inwards and outwards, respectively. The implications for observables, such as size and waiting time statistics, are considered briefly.
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    Cancer-related cognitive impairment in patients with newly diagnosed aggressive lymphoma undergoing standard chemotherapy: a longitudinal feasibility study
    Gates, P ; Krishnasamy, M ; Wilson, C ; Hawkes, EA ; Dore, V ; Perchyonok, Y ; Rowe, CC ; Walker, AK ; Vardy, JL ; de Ruiter, MB ; Cushion, T ; Dhillon, HM ; Gough, K (SPRINGER, 2022-06-14)
    PURPOSE: Cancer-related cognitive impairment (CRCI) is a recognised adverse consequence of cancer and its treatment. This study assessed the feasibility of collecting longitudinal data on cognition in patients with newly diagnosed, aggressive lymphoma undergoing standard therapy with curative intent via self-report, neuropsychological assessment, peripheral markers of inflammation, and neuroimaging. An exploration and description of patterns of cancer-related cognitive impairment over the course of treatment and recovery was also undertaken and will be reported separately. METHODS: Eligible participants completed repeated measures of cognition including self-report and neuropsychological assessment, and correlates of cognition including blood cell-based inflammatory markers, and neuroimaging at three pre-specified timepoints, time 1 (T1) - pre-treatment (treatment naïve), time 2 (T2) - mid-treatment, and time 3 (T3) - 6 to 8 weeks post-completion of treatment. RESULTS: 30/33 eligible patients (91%, 95% CI: 76%, 97%) were recruited over 10 months. The recruitment rate was 3 patients/month (95% CI: 2.0, 4.3 patients/month). Reasons for declining included feeling overwhelmed and rapid treatment commencement. Mean age was 57 years (SD = 17 years) and 16/30 (53%) were male. Most patients (20/30, 67%) had diffuse large B cell lymphoma or Hodgkin lymphoma (4/30, 13%). The neuroimaging sub-study was optional, 11/30 participants (37%) were eligible to take part, and all agreed. The remaining 19 participants were ineligible as their diagnostic PET/CT scan was completed prior. Retention and compliance with all assessments were 89 to 100% at all timepoints. Only one participant was withdrawn due to disease progression. CONCLUSIONS: Findings from this study including excellent recruitment, retention, and compliance rates demonstrate it is feasible to longitudinally assess cognition in people with newly diagnosed aggressive lymphoma during their initial treatment and recovery to inform the development of future research to improve patient experiences and cognitive outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12619001649101.
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    Post Hoc Analysis of Lorlatinib Intracranial Efficacy and Safety in Patients With ALK-Positive Advanced Non-Small-Cell Lung Cancer From the Phase III CROWN Study.
    Solomon, BJ ; Bauer, TM ; Ignatius Ou, S-H ; Liu, G ; Hayashi, H ; Bearz, A ; Penkov, K ; Wu, Y-L ; Arrieta, O ; Jassem, J ; Calella, AM ; Peltz, G ; Polli, A ; Thurm, H ; Mok, T (American Society of Clinical Oncology (ASCO), 2022-11-01)
    PURPOSE: Lorlatinib significantly improved progression-free survival (PFS) versus crizotinib and showed robust intracranial activity in patients with previously untreated advanced ALK-positive non-small-cell lung cancer (NSCLC) in the phase III CROWN trial. Here, we report post hoc efficacy outcomes in patients with and without brain metastases at baseline, and present data on the incidence and management of CNS adverse events (AEs) in CROWN. METHODS: Eligible patients were randomly assigned 1:1 to first-line lorlatinib (100 mg once daily) or crizotinib (250 mg twice a day); no crossover between treatment arms was permitted. Tumor assessments, including CNS magnetic resonance imaging, were performed at screening and then at 8-week intervals. Regular assessments of patient-reported outcomes were conducted. RESULTS: PFS by blinded independent central review was improved with lorlatinib versus crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% v 22% and 78% v 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression versus crizotinib in patients with (7% v 72%) and without (1% v 18%) brain metastases at baseline. In total, 35% of patients had CNS AEs with lorlatinib, most of grade 1 severity. Occurrence of CNS AEs did not result in a clinically meaningful difference in patient-reported quality of life. At analysis, 56% of CNS AEs had resolved (33% without intervention; 17% with lorlatinib dose modification), and 38% were unresolved; most required no intervention. Lorlatinib dose modification did not notably influence PFS. CONCLUSION: First-line lorlatinib improved PFS outcomes and reduced CNS progression versus crizotinib in patients with advanced ALK-positive non-small-cell lung cancer with or without brain metastases at baseline. Half of all CNS AEs resolved without intervention or with lorlatinib dose modification.
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    Survey of brachytherapy training experience among radiation oncology trainees and fellows in the Royal Australian and New Zealand College of Radiologists (RANZCR)
    Ong, WL ; Byrne, A ; Chelvarajah, R ; Chong, C ; Gallo, J ; Kain, M ; Khong, J ; O'Reilly, E ; Udovicich, C ; Weeransinghe, C ; Zhong Hu, T-C ; Bece, A (WILEY, 2022-05-11)
    INTRODUCTION: To evaluate brachytherapy training experience among trainees and fellows trained through the Royal Australian and New Zealand College of Radiologists (RANZCR). METHODS: All current trainees and fellows (who obtained fellowship from 2015 onwards) were sent an online anonymous questionnaire on various aspects of brachytherapy training, including number of cases observed/ performed, opinions on brachytherapy assessment during training, barriers to brachytherapy training and future role of brachytherapy. RESULTS: The overall survey response rate was 24% (40/161 trainees, 30/126 fellows). Of the 70 respondents, 50 (71%), 38 (54%) and 43 (61%) reported to have received formal brachytherapy teaching from radiation oncologists, radiation therapists and medical physicists respectively. Most respondents had exposure to gynaecology brachytherapy - two-thirds of trainees and all fellows have performed at least one gynaecology brachytherapy procedure. Prostate brachytherapy exposure was more limited - by the end of training, 27% and 13% of fellows did not have exposure to LDR and HDR prostate brachytherapy. More than two-thirds indicated there should be a minimum number of brachytherapy case requirements during training, and half indicated that trainees should be involved in ≥6 gynaecology brachytherapy procedures. Barriers affecting training include lack of caseload (70%) and perceived decreasing role of brachytherapy (66%). Forty-three percent of respondents were concerned about the decline in brachytherapy utilisation. CONCLUSION: This is the first survey on brachytherapy training experience among RANZCR trainees and fellows. It highlighted limited brachytherapy exposure during RANZCR training, and the need to revisit brachytherapy training requirement in the current training programme, along with long-term brachytherapy workforce planning.
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    Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With NTRK Fusion-Positive Solid Tumors
    Demetri, GD ; De Braud, F ; Drilon, A ; Siena, S ; Patel, MR ; Cho, BC ; Liu, S ; Ahn, M-J ; Chiu, C-H ; Lin, JJ ; Goto, K ; Lee, J ; Bazhenova, L ; John, T ; Fakih, M ; Chawla, SP ; Dziadziuszko, R ; Seto, T ; Heinzmann, S ; Pitcher, B ; Chen, D ; Wilson, TR ; Rolfo, C (AMER ASSOC CANCER RESEARCH, 2022-04-01)
    PURPOSE: Entrectinib potently inhibits tropomyosin receptor kinases (TRKAs)/B/C and ROS1, and previously induced deep [objective response rate (ORR) 57.4%] and durable [median duration of response (DoR) 10.4 months] responses in adults with NTRK fusion-positive solid tumors from three phase I/II trials. This article expands prior reports with additional patients and longer follow-up. PATIENTS AND METHODS: Patients with locally advanced/metastatic NTRK fusion-positive solid tumors and ≥12 months' follow-up were included. Primary endpoints were ORR and DoR by blinded independent central review (BICR); secondary endpoints included progression-free survival (PFS), intracranial efficacy, and safety. The safety-evaluable populations included all patients who had received ≥1 entrectinib dose. RESULTS: At clinical cut-off (August 31, 2020), the efficacy-evaluable population comprised 121 adults with 14 tumor types and ≥30 histologies. Median follow-up was 25.8 months; 61.2% of patients had a complete (n = 19) or partial response (n = 55). Median DoR was 20.0 months [95% confidence interval (CI), 13.0-38.2]; median PFS was 13.8 months (95% CI, 10.1-19.9). In 11 patients with BICR-assessed measurable central nervous system (CNS) disease, intracranial ORR was 63.6% (95% CI, 30.8-89.1) and median intracranial DoR was 22.1 (95% CI, 7.4-not estimable) months. The safety profile of entrectinib in adults and pediatric patients was aligned with previous reports. Most treatment-related adverse events (TRAEs) were grade 1/2 and manageable/reversible with dose modifications. TRAE-related discontinuations occurred in 8.3% of patients. CONCLUSIONS: With additional clinical experience, entrectinib continues to demonstrate durable systemic and intracranial responses and can address the unmet need of a CNS-active treatment in patients with NTRK fusion-positive solid tumors.
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    Managing advanced prostate cancer in the Asia Pacific region: "Real-world" application of Advanced Prostate Cancer Consensus Conference 2019 statements
    Chiong, E ; Murphy, DG ; Buchan, NC ; Chua, MLK ; Hakim, L ; Hamid, AR ; Hong, SK ; Horvath, LG ; Kanesvaran, R ; Khochikar, M ; Letran, J ; Lojanapiwat, B ; Malek, R ; Ng, ACF ; Nguyen, TV ; Pang, S-T ; Poon, DMC ; Ong, TA ; Saad, M ; Schubach, K ; Shiroki, R ; Turkeri, L ; Williams, S ; Wong, A ; Ye, D ; Davis, ID (WILEY, 2022-02-08)
    AIM: The second Asia-Pacific Advanced Prostate Cancer Consensus Conference (APAC APCCC 2020) gathered insights into the real-world application in the Asia-Pacific (APAC) region of consensus statements from the 3rd Advanced Prostate Cancer Consensus Conference (APCCC 2019). METHODS: The 4-h our virtual meeting in October 2020 brought together 26 experts from 14 APAC countries to discuss APCCC 2019 recommendations. Presentations were prerecorded and viewed prior to the meeting. A postmeeting survey gathered views on current practice. RESULTS: The meeting and survey highlighted several developments since APAC APCCC 2018. Increased access and use in the region of PSMA PET/CT imaging is providing additional diagnostic and staging information for advanced prostate cancer and influencing local and systemic therapy choices. Awareness of oligometastatic disease, although not clearly defined, is increasing. Novel androgen receptor pathway antagonists are expanding treatment options. Cost and access to contemporary treatments and technologies continue to be a significant factor influencing therapeutic decisions in the region. With treatment options increasing, multidisciplinary treatment planning, shared decision making, and informed choice remain critical. A discussion on the COVID-19 pandemic highlighted challenges for diagnosis, treatment, and clinical trials and new service delivery models that will continue beyond the pandemic. CONCLUSION: APAC-specific prostate cancer research and data are important to ensure that treatment guidelines and recommendations reflect local populations and resources. Facilitated approaches to collaboration across the region such as that achieved through APAC APCCC meetings continue to be a valuable mechanism to ensure the relevance of consensus guidelines within the region.
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    Weight is More Informative than Body Mass Index for Predicting Postmenopausal Breast Cancer Risk: Prospective Family Study Cohort (ProF-SC)
    Ye, Z ; Li, S ; Dite, GS ; Nguyen, TL ; MacInnis, RJ ; Andrulis, IL ; Buys, SS ; Daly, MB ; John, EM ; Kurian, AW ; Genkinger, JM ; Chung, WK ; Phillips, K-A ; Thorne, H ; Winship, IM ; Milne, RL ; Dugue, P-A ; Southey, MC ; Giles, GG ; Terry, MB ; Hopper, JL (AMER ASSOC CANCER RESEARCH, 2022-03-01)
    UNLABELLED: We considered whether weight is more informative than body mass index (BMI) = weight/height2 when predicting breast cancer risk for postmenopausal women, and if the weight association differs by underlying familial risk. We studied 6,761 women postmenopausal at baseline with a wide range of familial risk from 2,364 families in the Prospective Family Study Cohort. Participants were followed for on average 11.45 years and there were 416 incident breast cancers. We used Cox regression to estimate risk associations with log-transformed weight and BMI after adjusting for underlying familial risk. We compared model fits using the Akaike information criterion (AIC) and nested models using the likelihood ratio test. The AIC for the weight-only model was 6.22 units lower than for the BMI-only model, and the log risk gradient was 23% greater. Adding BMI or height to weight did not improve fit (ΔAIC = 0.90 and 0.83, respectively; both P = 0.3). Conversely, adding weight to BMI or height gave better fits (ΔAIC = 5.32 and 11.64; P = 0.007 and 0.0002, respectively). Adding height improved only the BMI model (ΔAIC = 5.47; P = 0.006). There was no evidence that the BMI or weight associations differed by underlying familial risk (P > 0.2). Weight is more informative than BMI for predicting breast cancer risk, consistent with nonadipose as well as adipose tissue being etiologically relevant. The independent but multiplicative associations of weight and familial risk suggest that, in terms of absolute breast cancer risk, the association with weight is more important the greater a woman's underlying familial risk. PREVENTION RELEVANCE: Our results suggest that the relationship between BMI and breast cancer could be due to a relationship between weight and breast cancer, downgraded by inappropriately adjusting for height; potential importance of anthropometric measures other than total body fat; breast cancer risk associations with BMI and weight are across a continuum.
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    Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial
    Majem, M ; Goldman, JW ; John, T ; Grohe, C ; Laktionov, K ; Kim, S-W ; Kato, T ; Vu, HV ; Lu, S ; Li, S ; Lee, KY ; Akewanlop, C ; Yu, C-J ; de Marinis, F ; Bonanno, L ; Domine, M ; Shepherd, FA ; Atagi, S ; Zeng, L ; Kulkarni, D ; Medic, N ; Tsuboi, M ; Herbst, RS ; Wu, Y-L (AMER ASSOC CANCER RESEARCH, 2022-06-01)
    PURPOSE: In the phase III ADAURA trial, adjuvant treatment with osimertinib versus placebo, with/without prior adjuvant chemotherapy, resulted in a statistically significant and clinically meaningful disease-free survival benefit in completely resected stage IB-IIIA EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). We report health-related quality of life (HRQoL) outcomes from ADAURA. PATIENTS AND METHODS: Patients randomized 1:1 received oral osimertinib 80 mg or placebo for 3 years or until recurrence/discontinuation. HRQoL (secondary endpoint) was measured using the Short Form-36 (SF-36) health survey at baseline, 12, and 24 weeks, then every 24 weeks until recurrence or treatment completion/discontinuation. Exploratory analyses of SF-36 score changes from baseline until week 96 and time to deterioration (TTD) were performed in the overall population (stage IB-IIIA; N = 682). Clinically meaningful changes were defined using the SF-36 manual. RESULTS: Baseline physical/mental component summary (PCS/MCS) scores were comparable between osimertinib and placebo (range, 46-47) and maintained to Week 96, with no clinically meaningful differences between arms; difference in adjusted least squares (LS) mean [95% confidence intervals (CI), -1.18 (-2.02 to -0.34) and -1.34 (-2.40 to -0.28), for PCS and MCS, respectively. There were no differences between arms for TTD of PCS and MCS; HR, 1.17 (95% CI, 0.82-1.67) and HR, 0.98 (95% CI, 0.70-1.39), respectively. CONCLUSIONS: HRQoL was maintained with adjuvant osimertinib in patients with stage IB-IIIA EGFRm NSCLC, who were disease-free after complete resection, with no clinically meaningful differences versus placebo, further supporting adjuvant osimertinib as a new treatment in this setting. See related commentary by Patil and Bunn, p. 2204.
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    Mitochondrial Dysfunction Is a Driver of SP-2509 Drug Resistance in Ewing Sarcoma.
    Tokarsky, EJ ; Crow, JC ; Guenther, LM ; Sherman, J ; Taslim, C ; Alexe, G ; Pishas, KI ; Rask, G ; Justis, BS ; Kasumova, A ; Stegmaier, K ; Lessnick, SL ; Theisen, ER (American Association for Cancer Research (AACR), 2022-07-06)
    UNLABELLED: Expression of the fusion oncoprotein EWS/FLI causes Ewing sarcoma, an aggressive pediatric tumor characterized by widespread epigenetic deregulation. These epigenetic changes are targeted by novel lysine-specific demethylase-1 (LSD1) inhibitors, which are currently in early-phase clinical trials. Single-agent-targeted therapy often induces resistance, and successful clinical development requires knowledge of resistance mechanisms, enabling the design of effective combination strategies. Here, we used a genome-scale CRISPR-Cas9 loss-of-function screen to identify genes whose knockout (KO) conferred resistance to the LSD1 inhibitor SP-2509 in Ewing sarcoma cell lines. Multiple genes required for mitochondrial electron transport chain (ETC) complexes III and IV function were hits in our screen. We validated this finding using genetic and chemical approaches, including CRISPR KO, ETC inhibitors, and mitochondrial depletion. Further global transcriptional profiling revealed that altered complex III/IV function disrupted the oncogenic program mediated by EWS/FLI and LSD1 and blunted the transcriptomic response to SP-2509. IMPLICATIONS: These findings demonstrate that mitochondrial dysfunction modulates SP-2509 efficacy and suggest that new therapeutic strategies combining LSD1 with agents that prevent mitochondrial dysfunction may benefit patients with this aggressive malignancy.
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    The Tumor Microenvironment of Clear-Cell Ovarian Cancer.
    Devlin, M-J ; Miller, R ; Laforets, F ; Kotantaki, P ; Garsed, DW ; Kristeleit, R ; Bowtell, DD ; McDermott, J ; Maniati, E ; Balkwill, FR (American Association for Cancer Research (AACR), 2022-11-02)
    Some patients with advanced clear-cell ovarian cancer (CCOC) respond to immunotherapy; however, little is known about the tumor microenvironment (TME) of this relatively rare disease. Here, we describe a comprehensive quantitative and topographical analysis of biopsies from 45 patients, 9 with Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage I/II (early CCOC) and 36 with FIGO stage III/IV (advanced CCOC). We investigated 14 immune cell phenotype markers, PD-1 and ligands, and collagen structure and texture. We interrogated a microarray data set from a second cohort of 29 patients and compared the TMEs of ARID1A-wildtype (ARID1Awt) versus ARID1A-mutant (ARID1Amut) disease. We found significant variations in immune cell frequency and phenotype, checkpoint expression, and collagen matrix between the malignant cell area (MCA), leading edge (LE), and stroma. The MCA had the largest population of CD138+ plasma cells, the LE had more CD20+ B cells and T cells, whereas the stroma had more mast cells and αSMA+ fibroblasts. PD-L2 was expressed predominantly on malignant cells and was the dominant PD-1 ligand. Compared with early CCOC, advanced-stage disease had significantly more fibroblasts and a more complex collagen matrix, with microarray analysis indicating "TGFβ remodeling of the extracellular matrix" as the most significantly enriched pathway. Data showed significant differences in immune cell populations, collagen matrix, and cytokine expression between ARID1Awt and ARID1Amut CCOC, which may reflect different paths of tumorigenesis and the relationship to endometriosis. Increased infiltration of CD8+ T cells within the MCA and CD4+ T cells at the LE and stroma significantly associated with decreased overall survival.