PO.ET03.06 · 实验与分子治疗
Evolution of TOP1 variants under selective pressure from topoisomerase-based therapeutics
作者与单位
摘要 Abstract
Background: Antibody-drug conjugates (ADCs) that incorporate topoisomerase I inhibitor payloads, including sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd), have demonstrated activity across multiple solid tumors. SG is approved for previously treated triple-negative and hormone receptor-positive breast cancers, while T-DXd is approved for HER2-expressing malignancies. Despite broad clinical use, the mechanisms underlying resistance to topoisomerase-based ADCs remain insufficiently defined. Recent reports indicate that acquired TOP1 mutations may contribute to therapeutic failure. We evaluated the frequency and characteristics of TOP1 alterations in patients who progressed on ADCs carrying topoisomerase payloads or on camptothecin-based chemotherapy.
Methods: We reviewed 17,092 solid tumor samples profiled by tumor and/or liquid biopsy next-generation sequencing (NGS) through the MDA MAPP platform at The University of Texas MD Anderson Cancer Center from January 2019 to January 2025. Patients exposed to topoisomerase inhibitor-based ADCs (SG, T-DXd, or datopotamab deruxtecan [Dato-DXd]) or irinotecan/topotecan-containing chemotherapy were identified (n = 1,807). Those with available paired pre- and post-treatment NGS formed the analytic cohort (n = 343). We assessed the emergence of TOP1 variants at progression, changes in variant allele frequency (VAF), and annotated mutations using ClinVar, InterVar, and literature review.
Results: TOP1 mutations were detected in 160 of 17,092 patients (0.94%). This included 14 of 2,040 patients (0.68%) with liquid-biopsy NGS only, 18 of 1,324 (1.35%) with both liquid biopsy and tumor NGS, and 128 of 13,728 (0.93%) with tumor-only NGS. Nine unique TOP1 variants, G363S , G365V , G365S , R364C , K333fs , R434Q , R84K , A670G , and R364H , arose at progression. Emergent alterations occurred in 3.4% (5/145) of patients treated with topoisomerase-payload ADCs and 2.1% (4/193) of those receiving irinotecan-based chemotherapy. G365S and R364H were previously described as pathogenic variants associated with camptothecin resistance, with R364H also linked to ADC resistance. One SG-treated breast cancer patient developed three concurrent alterations, G365V (VAF 23%), G365S (12%), and R364C (8%), at progression. Four colorectal cancer patients receiving FOLFIRI plus bevacizumab or panitumumab exhibited distinct emergent TOP1 mutations at disease progression.
Conclusions: TOP1 alterations can appear after exposure to topoisomerase-payload ADCs or irinotecan-containing regimens, suggesting a potential resistance mechanism in a subset of patients. The functional impact of these variants and their relevance to therapeutic response remain undefined, warranting further mechanistic and clinical investigation.
利益披露 Disclosure
T. Reddy, None..
L. Kang, None..
H. Le, None.
S. Damodaran,
AstraZeneca; Taiho Oncology Other, Consulting or Advisory Role.
AstraZeneca (Inst); Daiichi Sankyo/Astra Zeneca (Inst); DualityBio (Inst); EMD Serono (Inst); Guardant Health (Inst); MediLink Therapeutics (Inst); Novartis (Inst); Sermonix Pharmaceuticals (Inst) Other, Research Funding.
Taiho Pharmaceutical (Inst) Research Funding.
K. P. Raghav,
AstraZeneca, Bayer, Eisai, Daiichi Sankyo Other, Consulting or Advisory Role.
Bayer Other, Speakers' Bureau.
Daiichi Sankyo/Lilly (Inst), Bayer (Inst), Roche/Genentech (Inst), Guardant Health (Inst) Other, Research Funding.
S. Kopetz,
Frontier Medicines; Lutris; Navire Other, Stock and Other Ownership Interests.
Agenus; Amgen; AmMax Bio; Arcus Biosciences; AstraZeneca; AVEO; Bayer Health; BeiGene; Boehringer Ingelheim; Bridgebio; Bristol-Myers Squibb/Medarex; Carina Biotech; Clasp Therapeutics; Cytovation Other, Consulting or Advisory Role.
Dewpoint Therapeutics; EMD Serono; Flame Biosciences; Frontier Medicines; Genentech; Harbinger Oncology, Inc; Ikena Oncology; Kestrel Therapeutics; Marengo Therapeutics; Merck; Mirati Therapeutics Consulting or Advisory Role.
Pfizer; Replimune; Revolution Medicines; Roche; SageMedic; SERVIER; Sibylla; T-Cypher Bio; Tachyon Therapeutics; XAIRA Therapeutics; Zentalis; Zentalis Consulting or Advisory Role.
Amgen; Boehringer Ingelheim; BridgeBio; Daiichi Sankyo; EMD Serono; Genentech/Roche; Guardant Health; Lilly; Pfizer; Zentalis Other, Research Funding.
J. Rodon Ahnert,
AADi; Amgen; Bridgebio Pharma; Ellipses Pharma; iOnctura; Mekanistic Therapeutics; Merus; Monte Rosa Therapeutics; Sardona Therapeutics Other, Consulting or Advisory Role.
280Bio (Inst); AADi (Inst); Adcentrix (Inst); Alnylam (Inst); Alterome (Inst); Amgen (Inst); AstraZenneca (Inst); BeiGene (Inst); Bicycle Therapeutics (Inst); BioAtla (Inst); BioTheryX (Inst) Other, Research Funding.
Blueprint Medicines (Inst); C4 Therapeutics (Inst); Cancer Core Europe (Inst); Debiopharm Group (Inst); Exelixis (Inst); Fog Pharmaceuticals (Inst); Fore Biotherapeutics (Inst); Other, Research Funding.
Fusion Pharmaceuticals (Inst); GlaxoSmithKline (Inst); Hotspot Pharma (Inst); Hummingbird (Inst); Hutchison MediPharma (Inst); IDEAYA Biosciences (Inst); Immuneering (Inst); Incyte (Inst) Other, Research Funding.
Kelun (Inst); Kinnate Biopharma (Inst); Linnaeus Therapeutics (Inst); Loxo (Inst); MapKure (Inst); Merck Sharp & Dohme (Inst); Merus (Inst); Mirati Therapeutics (Inst); Monte Rosa Therapeutics (Inst) Other, Research Funding.
Novartis (Inst); Nuvectis Pharma (Inst); Pfizer (Inst); Relay Therapeutics (Inst); Roche (Inst); Scorpion Therapeutics (Inst); Storm Therapeutics (Inst); Symphogen (Inst); Taiho Pharmaceutical (Inst) Other, Research Funding.
Tango Therapeutics (Inst); Tyra Biosciences (Inst); Vall d'Hebron Institute of Oncology/Cancer Core Europe (Inst); Vividion Therapeutics (Inst); Yingli Pharma (Inst) Other, Research Funding.
280-Biotech; American Society of Medical Oncology; Dava Oncology; ESMO; Loxo; National Taiwan University Cancer Center; STOP Cancer Travel.
Boxer Capital; Chinese University of Hong Kong; Guidepoint Pharmacy; Sequenom; Tang Advisors; Vall d'Hebron Institute of Oncology/Ministerio De Empleo Y Seguridad Social Other, Other Relationship.
E. E. Dumbrava,
Bolt Biotherapeutics; Fate Therapeutics; Mersana; PMV Pharma; Summit Therapeutics Consulting or Advisory Role.
PMV Pharma Speakers' Bureau.
A2A Pharmaceuticals (Inst); Aileron Therapeutics (Inst); Amgen (Inst); Aprea Therapeutics (Inst); Astex Pharmaceuticals (Inst); AstraZeneca (Inst); Bayer (Inst) Research Funding.
Bellicum Pharmaceuticals (Inst); Boehringer Ingelheim (Inst); Bolt Biotherapeutics (Inst); Compugen (Inst); Dragonfly Therapeutics (Inst); Fate Therapeutics (Inst); Genentech (Inst) Research Funding.
Immunocore (Inst); Immunomedics/Gilead (Inst); Mereo BioPharma 5 (Inst); Mersana (Inst); ModeX Therapeutics (Inst); Pfizer (Inst); PMV Pharma (Inst); Poseida (Inst); Rain Therapeutics (Inst); Sanofi Research Funding.
Sotio (Inst); Triumvira Immunologics, Inc (Inst); Volastra Therapeutics (Inst Other, Research Funding.
Boehringer Ingelheim; Rain Oncology; Triumvira Immunologics, Inc Travel, Research Funding.
T. A. Yap,
Seagen Stock and Other Ownership Interests.
858 Therapeutics; Abbvie; Acrivon Therapeutics; Adagene; Aduro Biotech; Almac Group; Amgen; Amphista Therapeutics; Artios; Astex Pharmaceuticals; AstraZeneca; Athenahealth; Atrin Pharmaceuticals Other, Consulting or Advisory Role.
Avenzo; Avoro Capital Advisors; Axiom Biotechnologies; Baptist Health; Bayer; BeiGene; BioCity Pharma; Bloom Burton; Blueprint Medicines; Boxer; BridGene Biosciences; Bristol-Myers Squibb Other, Consulting or Advisory Role.
C4 Therapeutics; Calithera Biosciences; Cancer Research UK; Carrick Therapeutics; Circle Pharma; Clovis Oncology; Cybrexa Therapeutics; Daiichi Sankyo; Dark Blue Therapeutics; Debiopharm Group Other, Consulting or Advisory Role.
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Thryv Therapeutics; Tolremo; Tome; Trevarx Biomedical; Varian Medical Systems; Veeva; Versant Health; Vibliome Therapeutics; Voronoi Health Analytics; Xinthera; Zai Lab; ZielBio Other, Consulting or Advisory Role.
Acrivon Therapeutics (Inst); Artios (Inst); AstraZeneca (Inst); Bayer (Inst); BeiGene (Inst); BioNTech (Inst); Blueprint Medicines (Inst); BMS (Inst); Boundless Bio; Clovis Oncology (Inst) Other, Research Funding.
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Jounce Therapeutics (Inst); Karyopharm Therapeutics (Inst); KSQ Therapeutics (Inst); Kyowa Hakko Kirin (Inst); Lilly (Inst); Merck (Inst); Mirati Therapeutics (Inst); NIH/NCI; Novartis (Inst); Pfizer Other, Research Funding.
Pliant; Prelude Therapeutics; Regeneron (Inst); Repare Therapeutics (Inst); Ribon Therapeutics (Inst); Roche; Rubius Therapeutics (Inst); Sanofi (Inst); Scholar Rock (Inst); Seagen (Inst) Other, Research Funding.
Synnovation; Tango Therapeutics; Tesaro (Inst); V Foundation; Vivace Therapeutics (Inst); Zenith Epigenetics (Inst); Zentalis Other, Research Funding.
S. Williams, None..
M. J. Routbort, None.
K. P. Patel,
Astellas Pharma, Astellas Pharma, Syros Pharmaceuticals Other, Consulting or Advisory Role.
F. Meric-Bernstam,
Dava Oncology Other, Honoraria.
AstraZeneca; Becton Dickinson; Calibr; Cybrexa Therapeutics; Daiichi Sankyo/Astra Zeneca; DAVA Pharmaceuticals; Debiopharm Group; EcoR1 Capital; eFFECTOR Therapeutics; Elevation Oncology; Exelixis Other, Consulting or Advisory Role.
GT Aperion; Guardant Health; Harbinger Health; Incyte; Jazz Pharmaceuticals; LegoChem Biosciences; Loxo/Lilly; Menarini Group; Mersana; Molecular Templates; OnCusp Therapeutics; Protai; Ribometrix Other, Consulting or Advisory Role.
Seagen; Tempus; Theratechnologies; Zentalis; Zymeworks Other, Consulting or Advisory Role.
Aileron Therapeutics (Inst); AstraZeneca (Inst); Bayer (Inst); Boehringer Ingelheim (Inst); Calithera Biosciences (Inst); Curis (Inst); CytomX Therapeutics (Inst); Daiichi Sankyo (Inst) Other, Research Funding.
Debiopharm Group (Inst); eFFECTOR Therapeutics (Inst); Genentech (Inst); Guardant Health (Inst); Jazz Pharmaceuticals (Inst); Klus Pharma (Inst); Novartis (Inst); Pfizer (Inst); PUMA Biotechnology Other, Research Funding.
Seagen (Inst); Taiho Pharmaceutical (Inst); Takeda (Inst); Zymeworks (Inst) Other, Research Funding.
Cholangiocarcinoma Foundation; Dava Oncology; ESMO; European Organisation for Research and Treatment of Cancer (EORTC) Travel.