PO.ET03.06 · 实验与分子治疗
基于拓扑异构酶的治疗药物选择压力下TOP1变异体的演变
Evolution of TOP1 variants under selective pressure from topoisomerase-based therapeutics
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：整合了拓扑异构酶I抑制剂载荷的抗体-药物偶联物(ADC)，包括sacituzumab govitecan(SG)和trastuzumab deruxtecan(T-DXd)，已在多种实体瘤中显示出活性。SG获批用于既往治疗过的三阴性和激素受体阳性乳腺癌，而T-DXd获批用于HER2表达的恶性肿瘤。尽管临床应用广泛，但基于拓扑异构酶的ADC的耐药机制仍未充分明确。近期报道提示，获得性TOP1突变可能促成治疗失败。我们评估了在携带拓扑异构酶载荷的ADC或基于喜树碱的化疗中进展的患者中TOP1改变的频率和特征。
方法：我们回顾了2019年1月至2025年1月期间在德克萨斯大学MD安德森癌症中心通过MDA MAPP平台经肿瘤和/或液体活检二代测序(NGS)进行分析的17,092例实体瘤样本。鉴定出接受基于拓扑异构酶抑制剂的ADC(SG、T-DXd或datopotamab deruxtecan [Dato-DXd])或含伊立替康/拓扑替康化疗的患者(n = 1,807)。其中具有可用配对治疗前和治疗后NGS的患者构成分析队列(n = 343)。我们评估了进展时TOP1变异体的出现、变异等位基因频率(VAF)的变化，并使用ClinVar、InterVar和文献综述对突变进行注释。
结果：在17,092例患者中的160例(0.94%)检测到TOP1突变。其中包括仅液体活检NGS的2,040例患者中的14例(0.68%)、同时具有液体活检和肿瘤NGS的1,324例中的18例(1.35%)、以及仅肿瘤NGS的13,728例中的128例(0.93%)。在进展时出现了9种独特的TOP1变异体：G363S、G365V、G365S、R364C、K333fs、R434Q、R84K、A670G和R364H。新出现的改变发生于3.4%(5/145)接受拓扑异构酶载荷ADC治疗的患者和2.1%(4/193)接受基于伊立替康化疗的患者。G365S和R364H此前已被描述为与喜树碱耐药相关的致病变异，其中R364H也与ADC耐药相关。一例接受SG治疗的乳腺癌患者在进展时同时出现三种改变：G365V(VAF 23%)、G365S(12%)和R364C(8%)。四例接受FOLFIRI联合贝伐珠单抗或帕尼单抗的结直肠癌患者在疾病进展时表现出不同的新出现TOP1突变。
结论：TOP1改变可在暴露于拓扑异构酶载荷ADC或含伊立替康方案后出现，提示在某一亚组患者中存在潜在的耐药机制。这些变异体的功能影响及其与治疗应答的相关性仍未明确，需要进一步的机制和临床研究。
查看英文原文 English 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.
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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.
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E. E. Dumbrava,
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Seagen Stock and Other Ownership Interests.
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S. Williams, None..
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Astellas Pharma, Astellas Pharma, Syros Pharmaceuticals Other, Consulting or Advisory Role.
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Dava Oncology Other, Honoraria.
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