Sir Peter MacCallum Department of Oncology - Research Publications

Permanent URI for this collection

http://hdl.handle.net/11343/274

Search Results

Now showing 1 - 10 of 2473

Universal genetic testing for women with newly diagnosed breast cancer in the context of multidisciplinary team care

De Silva, DL ; Stafford, L ; Skandarajah, AR ; Sinclair, M ; Devereux, L ; Hogg, K ; Kentwell, M ; Park, A ; Lal, L ; Zethoven, M ; Jayawardana, MW ; Chan, F ; Butow, PN ; James, PA ; Mann, GB ; Campbell, IG ; Lindeman, GJ (WILEY, 2023-04-02)

OBJECTIVE: To determine the feasibility of universal genetic testing of women with newly diagnosed breast cancer, to estimate the incidence of pathogenic gene variants and their impact on patient management, and to evaluate patient and clinician acceptance of universal testing. DESIGN, SETTING, PARTICIPANTS: Prospective study of women with invasive or high grade in situ breast cancer and unknown germline status discussed at the Parkville Breast Service (Melbourne) multidisciplinary team meeting. Women were recruited to the pilot (12 June 2020 - 22 March 2021) and expansion phases (17 October 2021 - 8 November 2022) of the Mutational Assessment of newly diagnosed breast cancer using Germline and tumour genomICs (MAGIC) study. MAIN OUTCOME MEASURES: Germline testing by DNA sequencing, filtered for nineteen hereditary breast and ovarian cancer genes that could be classified as actionable; only pathogenic variants were reported. Surveys before and after genetic testing assessed pilot phase participants' perceptions of genetic testing, and psychological distress and cancer-specific worry. A separate survey assessed clinicians' views on universal testing. RESULTS: Pathogenic germline variants were identified in 31 of 474 expanded study phase participants (6.5%), including 28 of 429 women with invasive breast cancer (6.5%). Eighteen of the 31 did not meet current genetic testing eligibility guidelines (probability of a germline pathogenic variant ≥ 10%, based on CanRisk, or Manchester score ≥ 15). Clinical management was changed for 24 of 31 women after identification of a pathogenic variant. Including 68 further women who underwent genetic testing outside the study, 44 of 542 women carried pathogenic variants (8.1%). Acceptance of universal testing was high among both patients (90 of 103, 87%) and clinicians; no decision regret or adverse impact on psychological distress or cancer-specific worry were reported. CONCLUSION: Universal genetic testing following the diagnosis of breast cancer detects clinically significant germline pathogenic variants that might otherwise be missed because of testing guidelines. Routine testing and reporting of pathogenic variants is feasible and acceptable for both patients and clinicians.
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.
PRMT5 and CDK4/6 inhibition result in distinctive patterns of alternative splicing in melanoma.

Chan, LH ; Wang, P ; Abuhammad, S ; Lim, LRJ ; Cursons, J ; Sheppard, KE ; Goode, DL ; Palit Deb, S (Public Library of Science (PLoS), 2023)

Drugs targeting cyclin-dependent kinases 4 and 6 (CDK4/6) are promising new treatments for melanoma and other solid malignancies. In studies on CDK4/6 inhibitor resistance, protein arginine methyltransferase 5 (PRMT5) regulation of alternative splicing was shown to be an important downstream component of the CDK4/6 pathway. However, the full effects of inhibition of CDK4/6 on splicing events in melanoma and the extent to which they are dependent on PRMT5 has not been established. We performed full-length mRNA sequencing on CHL1 and A375 melanoma cell lines treated with the CDK4/6 inhibitor palbociclib and the PRMT5 inhibitor GSK3326595 and analysed data for differential gene expression and differential pre-mRNA splicing induced by these agents. Changes in gene expression and RNA splicing were more extensive under PRMT5 inhibition than under CDK4/6 inhibition. Although PRMT5 inhibition and CDK4/6 inhibition induced common RNA splicing events and gene expression profiles, the majority of events induced by CDK4/6 inhibition were distinct. Our findings indicate CDK4/6 has the ability to regulate alternative splicing in a manner that is distinct from PRMT5 inhibition, resulting in divergent changes in gene expression under each therapy.
Long-Term Outcomes of TROG 13.01 SAFRON II Randomized Trial of Single- Versus Multifraction Stereotactic Ablative Body Radiotherapy for Pulmonary Oligometastases

Siva, S ; Sakyanun, P ; Mai, T ; Wong, W ; Lim, A ; Ludbrook, J ; Bettington, C ; Rezo, A ; Pryor, D ; Hardcastle, N ; Kron, T ; Higgs, B ; Le, H ; Skala, M ; Gill, S ; Eade, T ; Awad, R ; Sasso, G ; Vinod, S ; Montgomery, R ; Ball, D ; Bressel, M (LIPPINCOTT WILLIAMS & WILKINS, 2023-07-01)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In a randomized phase II clinical trial, the Trans Tasman Radiation Oncology Group compared single- versus multifraction stereotactic ablative body radiotherapy (SABR) in 90 patients with 133 oligometastases to the lung. The study found no differences in safety, efficacy, systemic immunogenicity, or survival between arms, with single-fraction SABR picked as the winner on the basis of cost-effectiveness. In this article, we report the final updated survival outcome analysis. The protocol mandated no concurrent or post-therapy systemic therapy until progression. Modified disease-free survival (mDFS) was defined as any progression not addressable by local therapy, or death. At a median follow-up of 5.4 years, the 3- and 5-year estimates for overall survival (OS) were 70% (95% CI, 59 to 78) and 51% (95% CI, 39 to 61). There were no significant differences between the multi- and single-fraction arms for OS (hazard ratio [HR], 1.1 [95% CI, 0.6 to 2.0]; P = .81). The 3- and 5-year estimates for disease-free survival were 24% (95% CI, 16 to 33) and 20% (95% CI, 13 to 29), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.6]; P = .92). The 3- and 5-year estimates for mDFS were 39% (95% CI, 29 to 49) and 34% (95% CI, 24 to 44), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.8]; P = .90). In this patient population, where patients receive SABR in lieu of systemic therapy, one-in-three patients are alive without disease in the long term. There were no differences in outcomes by fractionation schedule.
Her6 and Prox1a are novel regulators of photoreceptor regeneration in the zebrafish retina.

Veen, K ; Krylov, A ; Yu, S ; He, J ; Boyd, P ; Hyde, DR ; Mantamadiotis, T ; Cheng, LY ; Jusuf, PR ; Barsh, GS (Public Library of Science (PLoS), 2023-11)

Damage to light-sensing photoreceptors (PRs) occurs in highly prevalent retinal diseases. As humans cannot regenerate new PRs, these diseases often lead to irreversible blindness. Intriguingly, animals, such as the zebrafish, can regenerate PRs efficiently and restore functional vision. Upon injury, mature Müller glia (MG) undergo reprogramming to adopt a stem cell-like state. This process is similar to cellular dedifferentiation, and results in the generation of progenitor cells, which, in turn, proliferate and differentiate to replace lost retinal neurons. In this study, we tested whether factors involved in dedifferentiation of Drosophila CNS are implicated in the regenerative response in the zebrafish retina. We found that hairy-related 6 (her6) negatively regulates of PR production by regulating the rate of cell divisions in the MG-derived progenitors. prospero homeobox 1a (prox1a) is expressed in differentiated PRs and may promote PR differentiation through phase separation. Interestingly, upon Her6 downregulation, Prox1a is precociously upregulated in the PRs, to promote PR differentiation; conversely, loss of Prox1a also induces a downregulation of Her6. Together, we identified two novel candidates of PR regeneration that cross regulate each other; these may be exploited to promote human retinal regeneration and vision recovery.
Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Kast, KM ; John, EL ; Hopper, J ; Andrieu, N ; Nogues, C ; Mouret-Fourme, E ; Lasset, C ; Fricker, J-P ; Berthet, P ; Mari, V ; Salle, LK ; Schmidt, M ; Ausems, MGEM ; Garcia, EBG ; van de Beek, IR ; Wevers, M ; Evans, DG ; Tischkowitz, M ; Lalloo, F ; Cook, J ; Izatt, L ; Tripathi, V ; Snape, K ; Musgrave, H ; Sharif, S ; Murray, JV ; Colonna, SV ; Andrulis, IL ; Daly, MB ; Southey, MC ; de la Hoya, M ; Osorio, A ; Foretova, L ; Berkova, D ; Gerdes, A-M ; Olah, E ; Jakubowska, A ; Singer, CF ; Tan, Y ; Augustinsson, A ; Rantala, J ; Simard, J ; Schmutzler, RK ; Milne, RL ; Phillips, K-A ; Terry, MB ; Goldgar, D ; van Leeuwen, FE ; Mooij, TM ; Antoniou, AC ; Easton, DF ; Rookus, MA ; Engel, C (BMC, 2023-06-20)

INTRODUCTION: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. RESULTS: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively). CONCLUSION: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.
Invasive fungal infections after CLAG-M/CLAG chemotherapy for acute myeloid leukemia and high-grade myeloid neoplasms.

Lindsay, J ; Walti, CS ; Halpern, AB ; Xie, H ; Chung, EL ; Schonhoff, KG ; Huebner, EM ; Cheng, G-S ; Kimball, LE ; Leisenring, WM ; Greenwood, M ; Chen, SC-A ; Kong, DCM ; Slavin, MA ; Boeckh, M ; Fredricks, DN ; Liu, C ; Pergam, SA ; Walter, RB ; Hill, JA (American Society of Hematology, 2023-07-11)
Venetoclax treatment in patients with cancer has limited impact on circulating T and NK cells

Teh, CE ; Peng, H ; Luo, M-X ; Tan, T ; Trussart, M ; Howson, LJ ; Chua, CC ; Muttiah, C ; Brown, F ; Ritchie, ME ; Wei, AH ; Roberts, AW ; Bryant, VL ; Anderson, MA ; Lindeman, GJ ; Huang, DCS ; Thijssen, R ; Gray, DHD (ELSEVIER, 2023-06-27)

Venetoclax is an effective treatment for certain blood cancers, such as chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, most patients relapse while on venetoclax and further treatment options are limited. Combining venetoclax with immunotherapies is an attractive approach; however, a detailed understanding of how venetoclax treatment impacts normal immune cells in patients is lacking. In this study, we performed deep profiling of peripheral blood (PB) cells from patients with CLL and AML before and after short-term treatment with venetoclax using mass cytometry (cytometry by time of flight) and found no impact on the concentrations of key T-cell subsets or their expression of checkpoint molecules. We also analyzed PB from patients with breast cancer receiving venetoclax long-term using a single-cell multiomics approach (cellular indexing of transcriptomes and epitopes by sequencing) and functional assays. We found significant depletion of B-cell populations with low expression of MCL-1 relative to other immune cells, attended by extensive transcriptomic changes. By contrast, there was less impact on circulating T cells and natural killer (NK) cells, with no changes in their subset composition, transcriptome, or function following venetoclax treatment. Our data indicate that venetoclax has minimal impact on circulating T or NK cells, supporting the rationale of combining this BH3 mimetic drug with cancer immunotherapies for more durable antitumor responses.
A cell-based functional assay that accurately links genotype to phenotype in familial HLH

Noori, T ; Rudd-Schmidt, JA ; Kane, A ; Frith, K ; Gray, PE ; Hu, H ; Hsu, D ; Chung, CWT ; Hodel, AW ; Trapani, JA ; Voskoboinik, I (AMER SOC HEMATOLOGY, 2023-05-11)

Familial forms of the severe immunoregulatory disease hemophagocytic lymphohistiocytosis (HLH) arise from biallelic mutations in the PRF1, UNC13D, STXBP2, and STX11 genes. Early and accurate diagnosis of the disease is important to determine the most appropriate treatment option, including potentially curative stem cell transplantation. The diagnosis of familial HLH (FHL) is traditionally based on finding biallelic mutations in patients with HLH symptoms and reduced natural killer (NK)-cell cytotoxicity. However, patients often have a low NK-cell count or receive immunosuppressive therapies that may render the NK-cell cytotoxicity assay unreliable. Furthermore, to fully understand the nature of a disease it is critical to directly assess the effect of mutations on cellular function; this will help to avoid instances in which carriers of innocuous mutations may be recommended for invasive procedures including transplantation. To overcome this diagnostic problem, we have developed a rapid and robust method that takes advantage of the functional equivalence of the human and mouse orthologues of PRF1, UNC13D, STX11, and STXBP2 proteins. By knocking out endogenous mouse genes in CD8+ T cells and simultaneously replacing them with their mutated human orthologues, we can accurately assess the effect of mutations on cell function. The wide dynamic range of this novel system allowed us to understand the basis of, otherwise cryptic, cases of FHL or HLH and, in some instances, to demonstrate that previously reported mutations are unlikely to cause FHL. This novel approach provides valuable new information to enable more accurate diagnosis and treatment of patients with HLH or FHL who inherit mutations of undetermined pathogenicity.
Ethnicity, Immunity, and Outcomes: Biology versus Socioeconomic Status

Bergin, ART ; Salgado, R ; Loi, S (AMER ASSOC CANCER RESEARCH, 2023-06-02)

Substantial advances in our understanding of breast cancer disease biology have led to marked improvements in cancer outcomes over the past two decades. These advances have largely focused on women from developed, high-income countries and as a result, significant disparities exist. In this issue, Bauer and colleagues provide new insight into the breast cancer immune microenvironment from women across geographic regions in sub-Saharan Africa, despite inherent infrastructure limitations. The study amassed data from 1,497 women from sub-Saharan Africa, and 117 women from Germany with breast cancer, suggesting regional variation in immune composition but with no significant prognostic impact. These important findings require validation in large, codesigned prospective studies to fully understand the impact of biology, ethnicity, and socioeconomic status on breast cancer outcomes. See related article by Bauer and colleagues (2) .

Sir Peter MacCallum Department of Oncology - Research Publications

Permanent URI for this collection

Filters

Date

Author

Subject

Type

Settings

Sort By

Results per page

Statistics

Citations

Search Results