PO.TB04.04 · 肿瘤生物学
实体瘤中PDX植入的临床和基因组决定因素
Clinical and genomic determinants of PDX engraftment across solid tumors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：患者来源异种移植（PDX）模型支持对肿瘤生物学和治疗反应的研究，然而成功植入的决定因素以及PDX保留患者肿瘤基因组特征的程度仍未完全明确。本研究评估了与实体瘤中PDX建立相关的临床和可操作基因组特征。
方法：将来自529名患者活检的肿瘤标本（555个肿瘤）植入免疫缺陷小鼠，并根据是否成功植入分类为成功（take）或不成功（no-take）。记录临床诊断和组织学亚型。对匹配的患者肿瘤和PDX进行测序，以评估可操作基因中的突变、扩增、缺失和复合改变事件。
结果：在555个植入的肿瘤中，产生了266个PDX（约47%成功率）。我们从250名患者中产生了PDX，涵盖超过27种肿瘤类型；14名患者贡献了两个模型，一名贡献了三个纵向模型。胰腺和食管肿瘤表现出更高的植入频率，而腹膜和阑尾肿瘤表现出较低的频率。在乳腺癌中，三阴性肿瘤的植入率高于激素受体阳性或HER2阳性亚型（52% TNBC，39% HR+，36% HER2+）。携带TP53改变的肿瘤植入更常见；然而，在多重检验校正后未保持显著性（62.6% vs 50.2%；p=0.007，校正后p=1）。将114个PDX的测序与匹配患者的临床测序进行比较。患者在159个可操作基因中携带改变；其中157个也在PDX中检测到。所有PDX至少携带一个共享的可操作改变，36个PDX保留了其匹配患者肿瘤中存在的所有可操作改变。此外，88个可操作改变在至少一个PDX中检测到但在患者中未检测到，106个PDX携带至少一个此类改变。所有PDX相对于其匹配的患者肿瘤都获得了额外的可操作改变。
结论：从晚期癌症的活检中进行PDX植入是可行的；植入成功率因肿瘤类型而异。测序的PDX广泛保留了患者肿瘤的可操作改变，但也可能获得了额外的事件。
查看英文原文 English abstract
Introduction: Patient-derived xenograft (PDX) models support investigation of tumor biology and treatment response, yet determinants of successful engraftment and the extent to which PDXs retain patient tumor genomic features remain incompletely defined. This study evaluated clinical and actionable genomic characteristics associated with PDX establishment across solid tumors.
Methods: Tumor specimens from biopsies in 529 patients (555 tumors) were implanted into immunodeficient mice and classified as take or no-take based on successful implantation. Clinical diagnoses and histologic subtypes were recorded. Matched patient tumors and PDXs underwent sequencing to assess mutations, amplifications, deletions, and composite alteration events across actionable genes.
Results: Of the 555 implanted tumors, 266 PDXs were generated (~47% take rate). We generated PDXs from 250 patients across more than 27 tumor types; 14 patients contributed two models, and one contributed three longitudinal models. Pancreatic and esophageal tumors demonstrated higher engraftment frequencies, while peritoneal and appendiceal tumors showed lower frequencies. Among breast cancers, engraftment was higher in triple-negative tumors compared with hormone receptor-positive or HER2-positive subtypes (52% TNBC, 39% HR+, 36% HER2+). Engraftment was more common in tumors bearing TP53 alterations; however, significance was not retained after adjustment for multiple testing (62.6% vs 50.2%; p=0.007, adjusted p=1). Sequencing of 114 PDXs were compared to clinical sequencing in matched patients. Patients harbored alterations in 159 actionable genes; 157 were also detected in PDXs. All PDXs harbored at least one shared actionable alteration, and 36 PDXs retained all actionable alterations present in their matched patient tumor. Additionally, 88 actionable alterations were detected in at least one PDX but not in patients, and 106 PDXs harbored at least one such alteration. All PDXs acquired additional actionable alterations relative to their matched patient tumors.
Conclusions: PDX engraftment is feasible from biopsies in advanced cancer; engraftment success varies across tumor types. Sequenced PDXs broadly preserved patient tumor actionable alterations but may also have acquired additional events.
利益披露 Disclosure
L. Gorji, None..
K. W. Evans, None..
X. Zheng, None..
E. Yuca, None..
R. Zhang, None..
H. Le, None..
G. Raso, None..
A. Akcakanat, None..
A. Galan Cobo, None..
T. P. DiPeri, None.
M. Javle,
Abbvie, Array, Astellas, Astrazeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi, GSK, Halozyme, Helsinn, Incyte, Ipsen, Janssen Research, Lilly ), Other, Advisory Board.
Merck Sharp & Dohme, EMD Serono, Novartis, Transthera, Meclun, Eli Lilly, Oncosil, QED, Taiho, Servier, Agios ), Other, Advisory Board.
B. Uzunparmak, None.
F. Meric-Bernstam,
AstraZeneca Pharmaceuticals, Becton Dickinson, Biocartis NV, Calibr a division of Scripps Research Institute, Daiichi Sankyo, Dava Oncology, Debiopharm, eFFECTOR Therapeutics, Elevation Oncology Other, Consulting.
Exelixis, GT Aperion, Incyte, Jazz Pharmaceuticals, LigaChem Biosciences, Lengo Therapeutics, Menarini Group, Molecular Templates, Protai Bio, Ribometrix, SystImmune, Tallac Therapeutics Other, Consulting.
Tempus, Vir Biotechnology, Zymeworks Other, Consulting.
Cybrexa, go Therapeutics, Guardant Health, Harbinger Health, Illumen Therapeutics, Kivu Biosciences, Loxo Oncology, Mersana Therapeutics Other, Advisory Committee.
OnCusp Therapeutics, Sanofi Pharmaceuticals, Seagen, Theratechnologies, Zentalis Pharmaceuticals Other, Advisory Committee.
Aileron Therapeutics, AstraZeneca Pharmaceuticals, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis Inc. ,CytomX Therapeutics, Daiichi Sankyo, Debiopharm ).
eFFECTOR Therapeutics, Genentech, Guardant Health, Jazz Pharmaceuticals, Klus Pharma, Novartis, Puma Biotechnology, Taiho Pharmaceutical, Takeda Pharmaceutical, Zymeworks ).
Dava Oncology Other, Honoraria.
European Society for Medical Oncology (ESMO), European Organisation for Research and Treatment of Cancer (EORTC), Cholangiocarcinoma Foundation, Dava Oncology, Physician Education Resource Travel.