1727MO - Can proteomics predict metastatic relapse in leiomyosarcoma (LMS)? Development of an 8 protein signature in a >350 sample study including a validation cohort

Background

Biomarkers to predict metastatic relapse (MR) in LMS are needed to improve risk stratification and could inform adjuvant treatment trials. Recent advances in proteomic technologies may offer novel cancer insights.

Methods

With the primary aim of identifying a prognostic protein signature (PS) of MR, high throughput quantitative (HTQ) proteomic analysis of FFPE samples, using data independent acquisition mass spectrometry, was undertaken in two cohorts: discovery cohort LMS-AUS (n=225), validation cohort LMS-USA (n=127). For the PS, only primary samples of patients with localised disease at diagnosis (LDAD) were included. A novel bioinformatic and machine learning method was developed to identify prognostic proteins and construct a risk score based signature for metastatic free survival (MFS). Bioinformatic methods included feature selection with data partitioning, differential expression analysis, Cox and LASSO regression analysis, and cross validation.

Results

The table summarises the cohorts and results. An 8-PS, developed in LMS-AUS, was highly significant in multivariate analysis (MVA) (MFS HR 5.2, p

Conclusions

HTQ proteomics can define prognostic signatures of MR in LMS that are significant in independent cohorts and MVA. An 8-PS showed good predictive performance when combined with clinical variables, paving the way for development of targeted proteomic panels that may offer enhanced precision and clinical utility.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Chris O’Brien Lifehouse Philanthropy Fund, Children's Medical Research Institute, Australian Cancer Research Foundation, NSW Ministry of Health Cancer Moonshot Proteogenomic Program, Medical Research Future Fund, and the Stafford Fox Medical Research Foundation.

Disclosure

E.A. Connolly: Financial Interests, Institutional, Full or part-time Employment, Employed as research fellow 0.6 FTE, provide ad hoc locum specialist cover.: Chris O Brien Lifehouse; Non-Financial Interests, Project Lead, Project lead of1. translational research (COBLH/ CMRI), collaborating with investigators in Australia and internationally.2. clinical study at COBLH.: Chris O Brien Lifehouse (COBLH )/ Children's Medical research institute (CMRI); Non-Financial Interests, Advisory Board, Honorary appointment as research fellow, conducting PhD with this organisation: Children's Medical Research Institute (CMRI); Non-Financial Interests, Leadership Role, Member of research related working groups: Australia New Zealand Sarcoma Association (ANZSA); Non-Financial Interests, Member, National oncology body representing medical oncologists in Australia.: Medical Oncology Group of Australia (MOGA); Non-Financial Interests, Member, National medical body representing physicians in Australia.: Royal Australasia College of Physicians (RACP); Non-Financial Interests, Leadership Role, Committee member of YOGA, affiliated group of MOGA: Young Oncology Group of Australia (YOGA); Non-Financial Interests, Member: Connective Tissue Oncology Society; Non-Financial Interests, Advisory Board, Affiliate position: clinical senior lecturer: University of Sydney. C.L. Scott: Financial Interests, Personal, Advisory Board, Scientific Advisory Board, member, Sept 2021 - current: OncologyOne; Financial Interests, Institutional, Full or part-time Employment, Laboratory Head and Head Clinical Discovery Translation, WEHI: Walter and Eliza Hall Institute of Medical Research; Financial Interests, Institutional, Full or part-time Employment, Chair, Gynaecological Cancer: University of Melbourne; Financial Interests, Institutional, Full or part-time Employment, Specialist Medical Oncologist: Peter MacCallum Cancer Centre, Melbourne Health; Financial Interests, Institutional, Royalties, Royalties via my institution Walter and Eliza Hall Institution of Medical Research: Venetoclax; Financial Interests, Institutional, Research Grant, Research grant, PI, To my laboratory, including provision of drugs for research: AstraZeneca; Financial Interests, Institutional, Funding, Research grant, PI, To my laboratory, including provision of drug: Eisai, Sierra Oncology; Financial Interests, Institutional, Other, In kind research support including provision of drug, to my laboratory: Clovis Oncology; Financial Interests, Institutional, Other, In kind research support, provision of drug, to my laboratory: Beigene; Financial Interests, Institutional, Coordinating PI, Funding of the SOLACE2 trial, Study Chair and PI, Steering committee, Chair: AstraZeneca; Financial Interests, Institutional, Coordinating PI, Provision of study drug, Eribulin, for the EPOCH trial, Study Chair: Eisai; Financial Interests, Institutional, Coordinating PI, Provision of study drug, Pembrolizumab, for the EPOCH trial, Study Chair: MSD; Financial Interests, Institutional, Steering Committee Member, EMBRACE clinical trial, AZ supplied olaparib, My role, member of the steering committee; performing translation (funds from govt grant): AstraZeneca; Financial Interests, Institutional, Funding, Research grant, To my laboratory, including provision of drug for research: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant, Research grant, PI, to my laboratory, including provision of drug: Ideaya Biosciences; Non-Financial Interests, Advisory Role, Advisory Boards, member: AstraZeneca; Non-Financial Interests, Advisory Role, Advisory Board, Member: Eisai; Non-Financial Interests, Advisory Role, Advisory Board, member: Sierra Oncology, Roche, Takeda, MSD, GSK; Non-Financial Interests, Advisory Role, Advisory Board, Chair: EpsilaBio; Non-Financial Interests, Institutional, Proprietary Information, Research collaboration, provision of drugs and discussion of commercial in confidence information: AstraZeneca, Eisai; Non-Financial Interests, Institutional, Product Samples, Research collaboration, provision of drugs: AstraZeneca, Eisai; Non-Financial Interests, Institutional, Proprietary Information, Research collaboration, provision of drugs: Boerhinger Ingelheim, Ideaya Biosciences; Non-Financial Interests, Other, Board, Chair: International Rare Cancer Initiative; Non-Financial Interests, Leadership Role, GCIG Executive Board of Directors, Member: Gynaecological Cancer InterGroup (GCIG), Director; Other, PI, funded by theAustralian Government as part of the Australian Genomic Cancer Medicine Centre (AGCMC) (OMICO).: Australian Rare Cancer Portal. P.J. Robinson: Non-Financial Interests, Institutional, Leadership Role, co-director: ProCan lab. L.G. Horvath: Financial Interests, Personal, Advisory Board, Honorarium donated back to Chris O'Brien Lifehouse (My hospital): Imagion Biosystems; Financial Interests, Institutional, Invited Speaker: Astellas, Janssen, Amgen; Financial Interests, Institutional, Advisory Board: Astellas, Bayer; Financial Interests, Institutional, Invited Speaker, Bayer paid for travel to Lisbon APEX meeting and accomodation. I gave 3 talks and honorarium paid to be institution: Bayer; Financial Interests, Personal, Member of Board of Directors, No payment: ANZUP (Australia and New Zealand Urogenital and Prostate) Clinical Trials Group; Financial Interests, Personal, Full or part-time Employment, I am a medical oncologist, Director of Research and Chief Clinical Officer of this cancer centre: Chris O'Brien Lifehouse; Financial Interests, Personal, Full or part-time Employment, I am a member of the Garvan Faculty and Laboratory Head: Garvan Institute of Medical Research; Financial Interests, Personal, Stocks/Shares, Stock options: Imagion Biosystems; Financial Interests, Personal, Stocks/Shares: My Emergency Doctor; Financial Interests, Institutional, Other, I am inventor of a patent lead by my institution above: International (PCT) Patent Application No. PCT/AU2023/050849Prognostic Markers (plasma lipid prognostic signature in metastatic prostate cancer).Inventors: Horvath L, Meikle P, Scheinberg S, Lin HM, Sullivan D: Chris O'Brien Lifehouse; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Local PI, MK7684-001MK3475-991: MSD; Financial Interests, Institutional, Local PI, AMG160 Phase IAMG509 Phase IAMG757 Phase I: Amgen; Financial Interests, Institutional, Local PI, 9785-CL-0335 (ARCHES): Astellas; Financial Interests, Institutional, Local PI, SHR3680-002: Jiangsu Hengrui Medicines; Financial Interests, Institutional, Local PI, TALAPRO2, TALAPRO3: Pfizer; Financial Interests, Institutional, Local PI, CYCLONE-2, CYCLONE-3: Eli-Lilly; Financial Interests, Institutional, Steering Committee Member, ENZAMET, ENZARAD, DASL-HiCAP, GUIDE, ANZAdapt: ANZUP; Financial Interests, Institutional, Local PI, GALAHADACISPrevalence: Janssen-Cilag; Financial Interests, Institutional, Local PI, GSK204697: GSK; Financial Interests, Institutional, Local PI, XL184-021: Exelexis; Financial Interests, Institutional, Local PI, BGB-A317BGB-283BGB-A317-290: Beigene; Financial Interests, Institutional, Local PI, FPT155-001: Five Prime; Financial Interests, Institutional, Local PI, AB928CSP0003: ARCUS; Financial Interests, Institutional, Local PI, ATG-017 and ATG-019: Antagene; Financial Interests, Institutional, Local PI, JANUX007: Janux; Financial Interests, Institutional, Local PI, Petranha: AstraZeneca; Financial Interests, Institutional, Local PI, ENZAMET, ENZA-P, Upfront PSMA, ANZAdapt, GUIDE: ANZUP; Financial Interests, Institutional, Local PI, HP-518-CS-001: Hinova; Financial Interests, Institutional, Local PI, JANX007: Janux Therapeutics; Non-Financial Interests, Leadership Role, Professor of Medical Oncology (Genitourinary cancer): University of Sydney; Non-Financial Interests, Leadership Role, Adjunct Professor: University of New South Wales. P. Grimison: Financial Interests, Institutional, Local PI, GS-2475: Gilead; Financial Interests, Institutional, Local PI, INCSHR01210: Tigermed; Financial Interests, Institutional, Local PI: Pfizer, Boston Biomedical, Medimmune, Halozyme, Aslan Pharmaceuticals, Janssen, Prime Therapeutics, Epizyme, Plexxikon, Five Prime Therapeutics, Novartis, QED; Financial Interests, Institutional, Local PI, Pembrolizmab: Merck; Financial Interests, Institutional, Local PI, Local PI on commercial trial: PTC Therapeutics; Non-Financial Interests, Project Lead, P3 accelerated BEP clinical trial: Australian and New Zealand Urogenital and Prostate cancer trials group (ANZUP) - non-commercial academic collaborative group; Non-Financial Interests, Leadership Role, TIGER clinical trial - Australia/New Zealand national lead investigator: Australian and New Zealand Urogenital and Prostate cancer trials group (ANZUP) - non-commercial academic collaborative group; Non-Financial Interests, Project Lead, Study chair for government-funded randomised trial of medicinal cannabis with free drug supply by Tilray: NHMRC Clinical Trials Centre, University of Sydney; Non-Financial Interests, Leadership Role, Member of scientific advisory committee: Australian and New Zealand Sarcoma Association (ANZSA) - non-commercial academic collaborative group; Non-Financial Interests, Member: Medical Oncology Group of Australia (MOGA); Other, Other, Member - role in decisions regarding reimbursement of drugs: Australian Government - Pharmaceutical Benefits Advisory Committee. R. Reddel: Non-Financial Interests, Institutional, Leadership Role, co-director: ProCan laboratory; Non-Financial Interests, Institutional, Leadership Role, director: Children’s Medical Research Institute. All other authors have declared no conflicts of interest.