123P - Pan-cancer homologous recombination deficiency (HRD) evaluation in patients enrolled in a routine molecular screening program

Background

HRD is associated with sensitivity to platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitors. We examined HRD scores distribution and clinical utility across tumor types in patients with advanced solid tumors enrolled in the VHIO's Molecular Prescreening Program (MPP).

Methods

The VHIO300 test is an ISO-accredited custom hybrid capture NGS panel run in tissue in the MPP. The HRD-LOH module of VHIO300 renders an HRD score, that is the sum of large-scale transitions, telomeric allelic imbalance and loss of heterozygosity regions. A cutoff score value of 56 was determined after a cross-validation with Myriad MyChoice CDx to define HRD positive samples. From June 2021 to January 2024, more than 2500 FFPE tumor samples were analyzed. Samples below 40% tumor cellularity were removed. Only tumor types represented by ≥ 15 samples were included in this study. Differences between primary and metastatic specimens within a tumor type required at least 7 samples each. The final cohort comprised 1447 samples in total, representing 24 tumor types.

Results

High-grade serous ovarian, triple negative breast cancer, lung adenocarcinoma and high-grade serous uterine carcinoma had the highest median HRD (mHRD) score values across histologies (mHRD = 57; 51; 39 and 37, respectively). Among sarcomas, osteosarcoma subtype (n = 8) had the highest mHRD score (mHRD = 49). On the other hand, thyroid, kidney and endometroid carcinoma, had the lowest mHRD scores (mHRD = 16.5; 16 and 12, respectively). Highly prevalent tumor types also showed HRD-positive cases: prostate adenocarcinoma (3%) and colorectal carcinoma (CRC) (3%). Metastatic samples showed higher mHRD scores than the primary originated specimens for CRC (p < 0.01), pancreatic adenocarcinoma (p < 0.05), and skin cutaneous melanoma (p < 0.05). Additionally, samples with pathogenic variants and LOH locus in BRCA1 (n=21) and BRCA2 (n=37) showed a significantly higher mHRD score as compared to non-mutated samples (mHRD = 73; 55.5 and 26.0, respectively).

Conclusions

In this pan-cancer cohort of patients, HRD-high scores were present across multiple histologies, supporting its potential clinical use as a tumor-agnostic biomarker and as guidance for treatment options.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Vall d'Herbon Institute of Oncology.

Funding

Has not received any funding.

Disclosure

A. Hernando Calvo: Financial Interests, Personal, Advisory Board: Merus; Financial Interests, Institutional, Research Grant: Gilead; Other, Travel support: Merck Serono, Kyowa Kirin, Bristol Myers Squibb. P.G. Nuciforo: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: MSD Oncology, Bayer; Financial Interests, Personal, Other, Consultant: Targos Molecular Pathology GmbH. E. Garralda: Financial Interests, Personal, Invited Speaker: MSD, Roche, Thermo Fisher, Novartis, Seagen; Financial Interests, Personal, Advisory Board: Roche, Ellipses Pharma, Boehringer Ingelheim, Janssen Global Services, Seattle Genetics, Thermo Fisher, MabDiscovery, Anaveon, Hengrui, F-Star Therapeutics, Sanofi, Incyte, Medscape; Financial Interests, Personal, Full or part-time Employment: NEXT Oncology; Financial Interests, Personal, Stocks/Shares: 1TRIALSP; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho; Financial Interests, Institutional, Research Grant: BeiGene, Janssen. E. Felip: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Regeneron, Sanofi, Takeda, Turning Point, Pfizer, Genmab; Financial Interests, Personal, Invited Speaker: Amgen, Daiichi Sankyo, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, PeerVoice, Pfizer, Sanofi, Takeda, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp & Dohme; Financial Interests, Personal, Member of Board of Directors, Independent member: Grifols; Financial Interests, Institutional, Local PI, Clinical Trial: AstraZeneca AB, AbbVie, Amgen, Bayer Consumer Care AG, BeiGene, Boehringer Ingelheim GmbH, Bristol Myers Squibb International Corporation, Daiichi Sankyo Inc., Exelixis Inc., F. Hoffmann-La Roche Ltd., Genentech Inc., GSK Research and Development Limited, Janssen Cilag International NV, Merck Sharp & Dohme Corp, Merck KGAA, Mirati Therapeutics Inc, Novartis Pharmaceutica SA, Pfizer, Takeda Pharmaceuticals International; Financial Interests, Institutional, Local PI: Nuvalent; Non-Financial Interests, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Member, Member of the Scientiffic Advisory Committee: CAC Hospital Universitari Parc Taulí. C. Saura Manich: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann-La Roche Ltd, Gilead, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, Puma, Roche Farma, Sanofi Aventis, Seagen, Zymeworks, Genentech, Innoup, Millenium, Pharmalex Spain SLU; Financial Interests, Personal, Other, SC: Byondis B.V., GSK, Macrogenics, Menarini, Merus, Synthon Biopharpaceuticals; Financial Interests, Personal, Invited Speaker: Sociedade Portuguesa de Oncología.; Financial Interests, Institutional, Research Grant: AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Cytomx Therapeutics, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La Roche Ltd, Genentech, GSK, Immunomedics, Innoup Farma, Macrogenics, Menarini Ricerche, Merus, Novartis, Pfizer, Puma, Roche, Sanofi Aventis, Seattle Genetics; Financial Interests, Institutional, Coordinating PI: Byondis B.V.; Non-Financial Interests, Member: Spanish Society of Medical Oncology (SEOM), American Society for Clinical Oncology (ASCO), Geicam (Spanish Breast Cancer Research Group), European Society for Medical Oncology (ESMO), Sinology Society of the Official College of Physicians of Barcelona (COMB), The European Association for Cancer Research (EACR.), Advisory Board on Cáncer Infertility and Pregnacy.( ABCIP); Non-Financial Interests, Member, Junta Directiva y Comité Científico: SOLTI group (Academic research group in breast cancer); Other, Member of the Consensus Panellist Group: International multidisciplinary consensus on the integration of radiotherapy with new systemic treatments for breast cancer: European Society for Radiotherapy and Oncology (ESTRO)-endorsed recommendations.: Consensus Panellist Group; Other, Associate Editor and Peer reviewer Breast Care Journal: Karger Publishers; Other, Research funding in the form of third-party medical writing support, furnished by Eleanor Porteous, MSc, of Nucleus Global, an Inizio Company, was provided by F. Hoffmann-La Roche Ltd': F. Hoffmann-La Roche Ltd.. C. Garcia Duran: Financial Interests, Institutional, Invited Speaker: MSD-AstraZeneca, GSK; Financial Interests, Institutional, Other, Educative activity: EISAI; Financial Interests, Personal, Other, Travel expenses: GSK, AstraZeneca. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., Ikena Oncology, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics, Tolremo Therapeutics, CARSgen Therapeutics, hC Bioscience Inc, Takeda Pharmaceuticals International AG, Alentis Therapeutics, Immodulon Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex/HMP; Financial Interests, Personal, Advisory Board: Cardiff Oncology, Aveo Oncology; Financial Interests, Personal, Stocks/Shares: Oniria Therapeuics, 1TRIALSP, Alentis Therapeutics, Pangaea Oncology; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, Merck, Sharp & Dohme de España, SA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc, BeiGene, Boehringer Ingelheim, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Member of Board of Directors, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer - AECC; Non-Financial Interests, Member of Board of Directors, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Leadership Role, External Scientific Committee: Institute for Health Research INCLIVA – Clinical Hospital of Valencia, IdiSNA – Universidad de Navarra; Non-Financial Interests, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer - EORTC; Non-Financial Interests, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutical LP, Boehringer Ingelheim, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Principal Investigator, Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutics LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, Merus NV, Taiho Pharma USA Inc; Non-Financial Interests, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, President: Oncology Master Plan – Catalonia Department of Health; Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System. A. Vivancos: Financial Interests, Personal, Advisory Board: Roche, Bristol Myers Squibb, Guardant Health, Bayer, Incyte; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Bristol Myers Squibb, Roche, Incyte. All other authors have declared no conflicts of interest.