PO.CL01.22 · 临床研究
循环肿瘤细胞中的有丝分裂与转移性乳腺癌高度侵袭性疾病相关
Mitosis in circulating tumor cells correlates with highly aggressive disease in metastatic breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：循环肿瘤细胞（CTC）是一种众所周知的非侵入性血液生物标志物，可对转移性乳腺癌（mBC）患者进行分层，尤其是那些具有高度侵袭性亚型的患者。最初的初步研究表征了一种正在进行有丝分裂的独特CTC亚型，其存在与比单独CTC更差的生存结局相关。然而，其预后价值及其在不同治疗方案中的影响仍属未知。在一项多机构前瞻性研究中，我们从n=138例mBC患者中分离CTC，对有丝分裂CTC进行分类，评估其与2年内无进展生存期（PFS）和总生存期（OS）的关联，以及其反应率如何影响不同的治疗策略。
方法：从n=138例正在系统治疗中出现进展但尚未开始新的系统治疗的mBC患者采集外周血样本（7.5ml）（即化疗n=48、激素治疗n=17、免疫治疗n=64、靶向治疗n=22）。CellSieve微滤器通过尺寸排阻分离CTC，并对细胞进行CD45、细胞角蛋白和DAPI的荧光染色。使用先前建立的视觉指标，对CTC进行成像、计数，并根据存在≥1个有丝分裂CTC进行亚型分类。通过删失的单因素和多因素分析评估2年内的PFS和OS。通过比较各治疗类别的中位PFS（mPFS）和中位OS（mOS）评估治疗疗效。
结果：CTC类型 治疗 mPFS（月） mOS（月） 无CTC（n=77/138） 全部患者（n=77） 5.0 16.6 化疗（n=23） 4.0 9.2 激素治疗（n=9） >24.0 >24.0 免疫治疗（n=39） 4.3 13.1 靶向治疗（n=11） 13.1 >24.0 非有丝分裂CTC（n=30/138） 全部患者（n=30） 4.0 14.2 化疗（n=9） 3.1 13.0 激素治疗（n=4） 6.7 >24.0 免疫治疗（n=14） 3.3 7.4 靶向治疗（n=5） 14.1 20.0 有丝分裂CTC（n=31/138） 全部患者（n=31） 2.4 4.1 化疗（n=12） 2.4 4.3 激素治疗（n=4） 1.3 7.1 免疫治疗（n=11） 2.0 4.7 靶向治疗（n=6） 3.5 18.6
结论：在本研究中，有CTC的患者结局比无CTC的患者更差，而有有丝分裂CTC的患者结局最差。此外，无CTC或非有丝分裂CTC的患者在某些治疗类型中显示出相似的PFS和OS，而接受激素治疗的无CTC患者PFS更好，接受靶向治疗的有丝分裂CTC患者OS更好。本研究强调需要开展更大规模、更全面的研究以扩展这些预后发现及其与治疗类型的相关性。
查看英文原文 English abstract
Background: Circulating tumor cells (CTCs) are a well-known non-invasive blood biomarker which can stratify metastatic breast cancer (mBC) patients, especially those with highly aggressive subtypes. Initial pilot studies have characterized a distinct subtype of CTCs undergoing mitosis, whose presence correlates with worse survival outcomes than CTCs alone. However, their prognostic value and their influence in different therapeutic regimes remains unknown. In a multi-institutional prospective study, we isolated CTCs from n=138 mBC patients to categorize mitotic CTCs, evaluate their association with progression-free survival (PFS) & overall survival (OS) over 2 years, and how their response rates effect different therapeutic strategies.
Methods: Peripheral blood samples (7.5ml) were collected from n=138 mBC patients progressing on systemic therapies but prior to new systemic therapies (i.e. chemotherapy n=48, hormone therapy n=17, immunotherapy n=64, targeted therapy n=22). CellSieve microfilters isolated CTCs via size exclusion and cells fluorescently stained for CD45, Cytokeratin, and DAPI. CTCs were imaged, enumerated, and subtyped based on the presence of ≥1 mitotic CTC, using previously established visual indicators. PFS and OS were assessed over 2 years by censored univariate and multivariate analyses. Therapy efficacy was assessed by comparing median PFS (mPFS) and median OS (mOS) in the therapy categories.
Results: CTC Type Treatment mPFS (months) mOS (months) No CTCs (n=77/138) All Pts (n=77) 5.0 16.6 Chemotherapy (n=23) 4.0 9.2 Hormone Therapy (n=9) >24.0 >24.0 Immunotherapy (n=39) 4.3 13.1 Targeted Therapy (n=11) 13.1 >24.0 Non-mitotic CTCs (n=30/138) All Pts (n=30) 4.0 14.2 Chemotherapy (n=9) 3.1 13.0 Hormone Therapy (n=4) 6.7 >24.0 Immunotherapy (n=14) 3.3 7.4 Targeted Therapy (n=5) 14.1 20.0 Mitotic CTCs (n=31/138) All Pts (n=31) 2.4 4.1 Chemotherapy (n=12) 2.4 4.3 Hormone Therapy (n=4) 1.3 7.1 Immunotherapy (n=11) 2.0 4.7 Targeted Therapy (n=6) 3.5 18.6
Conclusion: In this study, patients with CTCs had poorer outcomes than patients with no CTCs, while patients with mitotic CTCs had the worst outcomes. Further, patients with no CTCs or non-mitotic CTCs showed similar PFS & OS in some treatment types, while patients with no CTCs treated with hormone therapy had better PFS and patients with mitotic CTCs had better OS if treated with targeted therapy. This study highlights the need for larger more comprehensive studies to expand on these prognostic findings and correlations to therapy types.
利益披露 Disclosure
A. B. Duffy,
Creatv MicroTech, Inc. Employment, Travel.
M. Cristofanilli,
Foundation Medicine Other, Honoraria, Consulting/Advisory Role.
Pfizer Other, Honoraria.
AstraZeneca/Daiichi Sankyo Other, Consulting/Advisory Role.
Ellipses Pharma Other, Consulting/Advisory Role.
Lilly Other, Grant/Contract, Consulting/Advisory Role.
Angle Other, Grant/Contract.
Merck Other, Grant/Contract.
Olaris Other, Consulting/Advisory Role.
Menarini Other, Consulting/Advisory Role.
C. Reduzzi,
Menarini Silicon Biosystems Other, Research Funding.
W. V. Williams,
Briacell Therapeutics Corp. Employment, g., Board of Directors, non-salaried role), Stock, Travel, Patent, Other Intellectual Property.
G. Del Priore,
Briacell Therapeutics Corp. Employment, g., Board of Directors, non-salaried role), Stock, Other Securities, Travel.
S. Chumsri,
AstraZeneca/Daiichi Sankyo Other, Consulting Fees.
Athenex Other, Consulting Fees.
bioTheranostics Other, Consulting Fees.
Eisai Other, Consulting or Advisory Role.
Immunomedics Other, Consulting Fees.
Novartis Other, Consulting or Advisory Role, Research Funding.
Puma Biotechnology Other, Consulting Fees.
Syndax Other, Consulting Fees.
Merck Other, Research Funding.
Pfizer Other, Research Funding.
Salix Pharmaceuticals Other, Research Funding.
Rebiotix Inc. Other, Research Funding.
Athenex Other, Consulting Fees.
Briacell Therapeutics Other, Research Funding.
Seagen Other, Consulting Fees.
Genentech Other, Consulting Fees.
Menarini Stemline Other, Consulting Fees.
Axiom Other, Consulting Fees.
Cardinal Health Other, Consulting Fees.
Cepton Strategies Other, Consulting Fees.
C. Tang,
Creatv MicroTech, Inc. Employment, g., Board of Directors, non-salaried role), Stock, Travel, Patent, Trademark, Copyright.
T. Iwase, None..
N. Ueno, None.
D. L. Adams,
Creatv MicroTech, Inc. Employment, Stock, Travel, Patent.