Publications

<p>MCC Patient characteristics (S1); Extension cohort of MCCs (S2); List of genes represented on the targeted sequencing panel (S3); Performance metrics for targeted sequencing and low coverage WGS (S4); Validation of mutations by orthogonal genotyping methods (S5); Immunohistochemistry scores for MCCs (S6); SNV and Indels called from targeted sequencing (S7); Mutational burden with respect to copy number changes through low coverage whole genome sequencing (S8); Gene level copy-number from LC-WGS (S9); Copies and viral integration sites for MCV positive MCCs (S10); Drug sensitivity data for 3 MCC cell lines (S11).</p>

Supplementary Figure from Tumor Genomic Testing for >4,000 Men with Metastatic Castration-resistant Prostate Cancer in the Phase III Trial PROfound (Olaparib)

Poster: 2018 ASM / R-0117 / The RAPPORT clinical trial: interim safety analysis of combination SABR with adjuvant anti-PD1 immunotherapy in oligometastatic renal cell carcinoma by: Siva1, M. Bressel1, M. Shaw1, S. Chander1, S. Loi1, D. Pryor2, S. Sandhu1, J. Mooi1, D. Jayamanne3, T. Eade3, N. Lawrentschuk 1, D. Murphy1, J. Lewin1, B. Tran1, F. Foroudi1; 1VIC/AU, 2QLD/AU, 3NSW/AU

Abstract Background There are few in-depth immunogenicity analyses of novel influenza vaccination strategies in high-risk patients with hematological malignancy (HM). Methods Participants receiving treatment for active HM (multiple myeloma [MM], chronic lymphocytic leukemia [CLL], or non-Hodgkin lymphoma [NHL]) in a randomized controlled trial of 2 doses of adjuvanted quadrivalent inactivated influenza vaccine (QIV) versus 2 doses of standard-dose QIV during 2022 were included. Hemagglutination (HA) inhibition assay and HA probe–specific B-cells were compared at baseline and 1, 2, and 6 months after the first vaccine dose (visits 1–4). A subset underwent ex vivo live virus infection of peripheral blood mononuclear cells at visits 1 and 3 with A/H1N1 and A/H3N2 to assess interferon (IFN) γ–producing CD4+ T cells, CD8+ T cells, natural killer cells, CD161+TRAV1-2+ mucosal-associated invariant T (MAIT)–like T cells and γδ T cells. Results In total, 62 patients with HM were analyzed (32 in the adjuvanted-dose and 30 in the standard-dose group), 13 (21.0%) with CLL, 24 (38.7%) MM, and 25 (40.3%) with NHL. Participants with MM had higher geometric mean antibody titers (P < .001) and influenza-specific B-cell responses for H1, H3, and B/Victoria at visits 2 and 3 than those with CLL or NHL (P < .05). The total CD19+ B-cell and HA probe–specific B-cell counts were found to significantly predict seroconversion at visits 2 and 3. Overall, with vaccination, there was an increase in the percentage frequency of B/Victoria influenza–specific B-cells (P = .01), IFN-γ–producing CD4+ T cells (P = .01) for A/H1N1 and IFN-γ–producing MAIT-like cells (P = .003) for A/H3N2. Conclusions Influenza strain–specific cellular responses were detectable following vaccination despite expected B-cell depletion in patients receiving active treatment for HM. Clinical Trials Registration Australian New Zealand Clinical Trials Registry ACTRN12622000454774.

<div>AbstractPurpose:<p>Brain involvement occurs in the majority of patients with metastatic melanoma. The potential of circulating tumor DNA (ctDNA) for surveillance and monitoring systemic therapy response in patients with melanoma brain metastases merits investigation.</p>Experimental Design:<p>This study examined circulating <i>BRAF, NRAS</i>, and <i>c-KIT</i> mutations in patients with melanoma with active brain metastases receiving PD-1 inhibitor–based therapy. Intracranial and extracranial disease volumes were measured using the sum of product of diameters, and response assessment performed using RECIST. Longitudinal plasma samples were analyzed for ctDNA over the first 12 weeks of treatment (threshold 2.5 copies/mL plasma).</p>Results:<p>Of a total of 72 patients, 13 patients had intracranial metastases only and 59 patients had concurrent intracranial and extracranial metastases. ctDNA detectability was 0% and 64%, respectively, and detectability was associated with extracranial disease volume (<i>P</i> < 0.01). Undetectable ctDNA on-therapy was associated with extracranial response (<i>P</i> < 0.01) but not intracranial response. The median overall survival in patients with undetectable (<i>n</i> = 34) versus detectable (<i>n</i> = 38) ctDNA at baseline was 39.2 versus 10.6 months [HR, 0.51; 95% confidence interval (CI), 0.28–0.94; <i>P</i> = 0.03] and on-therapy was 39.2 versus 9.2 months (HR, 0.32; 95% CI, 0.16–0.63; <i>P</i> < 0.01).</p>Conclusions:<p>ctDNA remains a strong prognostic biomarker in patients with melanoma with brain metastases, especially in patients with concurrent extracranial disease. However, ctDNA was not able to detect or monitor intracranial disease activity, and we recommend against using ctDNA as a sole test during surveillance and therapeutic monitoring in patients with melanoma.</p></div>

Abstract Background: Immune checkpoint blockade is now established as standard of care in several malignancies. Trials involving combined cytotoxic T lymphocyte associated protein 4 (CTLA4) and programmed cell death protein 1 (PD1) blockade demonstrate improved tumour responses in melanoma but at the cost of severe grade 3-4 immune related adverse events (irAEs) in 55%, and endocrine irAEs in up to 10% [1]. Immune-mediated damage to endocrine glands can be a diagnostic and management challenge. We aimed to review the incidence, biochemical evolution and imaging findings of endocrine toxicity related to combined anti CTLA-4 and anti-PD-1 therapy. Methods: We undertook a retrospective chart review of patients who received combined ipilimumab and nivolumab for metastatic melanoma at a tertiary referral centre between 2016-2019. We recorded onset and duration of abnormal biochemistry in endocrine irAEs, reviewed all available MRI images for pituitary size (mm) and appearance and 18-F FDG PET images for features of hypophysitis, thyroiditis and pancreatitis. Results: 162 patients received combination therapy. At least one irAE was recorded in 135 patients (83%), 100 (62%) required glucocorticoids, and 84 (52%) had an unplanned hospital presentation due to irAEs. Thyroiditis occurred in 50 (30.9%), with median time to onset of 30.9 days (range 1-234 days). 35 cases were identified with routine biochemistry performed every 4-6 weeks. TSH receptor antibody was measured in 13 patients and all were negative. 29 (58%) developed permanent hypothyroidism. Central cortisol deficiency was documented in 31 (19%) with a median time to diagnosis of 67.5 days (range 5-286). 4 cases were diagnosed on routine biochemistry and 14 presented with symptoms prompting investigation. 13 were diagnosed after routine neuroimaging demonstrated a pituitary abnormality, and a further 27 patients without the clinical syndrome had features of hypophysitis on neuroimaging. New onset diabetes occurred in 3 people, in which pancreatic inflammation on imaging was found in 2. A further 3/5 patients with an asymptomatic elevated lipase were found to have abnormal pancreatic imaging. In one patient with no features of endocrine or exocrine failure, there was a significant increase in FDG uptake and a subsequent loss of pancreatic volume. Conclusion: We report real world incidence of endocrine irAEs with combination immunotherapy. Routine biochemistry leads to the detection of some but not all cases. Early recognition and avoidance of unplanned presentations remains a challenge. Opportunistic assessment of endocrine gland appearance on routine imaging studies may provide useful early diagnostic information. Reference: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. (2015) 1:23-34. 10.1056/NEJMoa1504030

Adding ipatasertib to abiraterone and prednisone/prednisolone significantly improved radiographic progression-free survival for patients with metastatic castration-resistant prostate cancer (mCRPC) with PTEN-loss tumours by immunohistochemistry in the IPATential150 trial (NCT03072238). Here we characterise the safety of these agents in subpopulations and assess manageability of key adverse events (AEs).In this randomised, double-blind, phase 3 trial, patients with previously untreated asymptomatic or mildly symptomatic mCRPC were randomised 1:1 to receive ipatasertib-abiraterone or placebo-abiraterone (all with prednisone/prednisolone). AEs were analysed, focusing on key AEs of diarrhoea, hyperglycaemia, rash and transaminase increased.1097 patients received study medication and were assessed for safety (47% with PTEN-loss tumours by immunohistochemistry and 20% were Asian). Ipatasertib was associated with increased Grade 3/4 AEs and AEs leading to treatment discontinuation vs placebo. The rate of discontinuation of ipatasertib was 18% in patients with PTEN-loss and 21% overall. The frequencies of all-grade, Grade 3/4 and serious AEs were similar between the PTEN-loss and overall populations. Diarrhoea, hyperglycaemia, rash and transaminase elevation were more frequent in ipatasertib-treated patients, appearing rapidly after treatment initiation (median onset: 8-43 days for ipatasertib arm and 56-104 days for placebo). The ipatasertib discontinuation rate was 32% and 18% in Asian and non-Asian patients, respectively, despite similar baseline characteristics and Grade 3/4 AE frequencies between groups.Ipatasertib plus abiraterone had an overall tolerable safety profile consistent with known toxicities. More AEs leading to drug discontinuation were observed with ipatasertib than placebo, but incidence would likely be lessened with prophylactic measures.

Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression.

Castration-resistant prostate cancer (CRPC) remains a lethal disease despite the introduction of second generation androgen receptor (AR) directed therapies. Resistance to AR directed therapies, such as abiraterone and enzalutamide, emerges through diverse alterations in the AR pathway or transition to aggressive AR-null phenotypes. Although bromodomain and extra-terminal (BET) inhibitor therapies are in current clinical trials for CRPC, understanding of the full spectrum of patient responders is limited by a lack of models for preclincial testing. Thus, the goal of this study was to examine the efficacy of BET inhibitors in a panel of patient-derived models of CRPC, including AR-null and neuroendocrine differentiated tumors that are inherently resistant to AR-directed therapy. To rapidly screen the sensitivity of tumors to BET inhibitors, we used ex vivo cultures of patient-derived xenograft tissue from the MURAL (Melbourne Urological Research Alliance) cohort of patient tumors and treated them with JQ1. Changes in proliferation and apoptosis were measured using histology for Ki67 and cleaved caspase 3. Consistent with previous studies, our results showed that all AR-positive tumors were sensitive to JQ1, with decreases in proliferation and increases in apoptosis. Importantly, this includes tumors from patients who failed abiraterone and/or enzalutamide and have diverse alterations of the AR, including mutations, genomic amplifications and expression of truncated AR variants. Surprisingly, 50% of AR null tumors were just as sensitive to BET inhibitors and AR-positive tumors. This includes tumors with large cell and small cell neuroendocrine histopathology, which are inherently resistant to AR-directed therapies. We also assessed intra-patient heterogeneity by examining tumors from different metastases of the same patient. We observed consistent responses in one patient, but divergent responses in another, likely due to differences in AR status. Collectively, our data show that BET inhibitors are promising treatments for tumors with diverse mechanisms of resistance to AR-directed therapies; however, the responses of AR-null tumors are more heterogeneous. Therefore, further studies to identify biomarkers of responsiveness to BET inhibitors in AR-null and neuroendocrine tumors are warranted.

In all international medical student (IMS) programs in China, language barriers between IMSs and Chinese patients greatly reduced the learning in clinical practice and brought great challenges to IMSs in their transition from preclinical to clinical practice. This study aimed to investigate the role of bilingual simulated patients (B-SPs) in IMSs learning of medical history collection in China.48 IMSs of grade 4 between October 2020 to Jan 2021 were enrolled in this study. During the training of medical history collection, students were randomly arranged into two groups trained with either B-SPs (B-SP group) or English-speaking SP (E-SP group). All SPs in Objective Structured Clinical Exam station (OSCE) were trained in the Affiliated Hospital of Wuhan University. Clinical skills in medical history collection were assessed by instructors during pre-clinical, post-clinical OSCE and clinical rotations.The scores of IMSs in each group were analyzed in terms of medical history collection including the ability to effectively consult for information and key communication skills related to patient care. Our results indicated that IMS in B-SP group obtained similar scores in preclinical training for history collection (67.3 ± 8.46 vs 67.69 ± 8.86, P < 0.05) compared to E-SP group, while obtaining significantly higher score improvements between pre- and post-OSCE (17.22 (95% CI 12.74 to 21.70) vs 10.84 (95% CI 3.53 to 18.15), P = 0.0007).B-SPs are more conducive to doctor-patient communication and actually improve IMSs learning in medical history collection in China.