PO.CL01.01 · 临床研究

通过全面的表观基因组液体活检表征功能性雌激素受体（ER）依赖性可对转移性乳腺癌（MBC）内分泌治疗（ET）反应者进行分层

Characterization of functional estrogen receptor (ER) dependence via comprehensive epigenomic liquid biopsy stratifies endocrine therapy (ET) responders with metastatic breast cancer (MBC)

编号 1020 展板 14 时间 4/19 02:00–05:00 区域 Section 40 主讲 Stefania Morganti, MD

分会场 Biomarkers Predictive of Therapeutic Benefit 1

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作者与单位 Authors & Affiliations

Stefania Morganti¹, Jonathan Beagan², Ningxuan (Shirley) Zhou¹, Khoi Nguyen², Kalie Smith¹, Ashka Patel¹, Catherine Stever¹, Katheryn Santos¹, Molly Skeffington¹, Olivia D'Amico¹, Travis Clark², Justin Finkle², Anthony D'Ippolito², Mike Zhong², Jamey Guess², Kristian Cibulskis², Aparna Gorthi², Tyrone Tamakloe², Charlene O'Brien², Baovy Tran², Mary McGillicuddy², Nabihah Tayob¹, Sara M. Tolaney¹, Nancy U. Lin¹, Hillary Heiling¹, Corrie A. Painter², Matthew L. Eaton², J. Carl Barrett², Heather A. Parsons³

¹Dana-Farber Cancer Institute, Boston, MA,²Precede Biosciences, Boston, MA,³Fred Hutch Cancer Center, Seattle, WA

摘要 Abstract

中文摘要

背景：内分泌治疗（ET）是ER+ MBC的标准治疗，但几乎所有患者（pts）在其病程中都会出现ET耐药。缺乏可预测ER依赖性丧失以指导治疗（tx）的生物标志物。方法：我们识别了在达纳法伯癌症研究所EMBRACE研究中入组的122例ER+/HER2- MBC患者，这些患者接受了1-2线（L）ET，并在从1L切换至2L（n=77）或从2L切换至3L（n=53）前后±30天内进行了采血。使用1mL血浆，我们对全基因组增强子、启动子和DNA高甲基化进行谱分析，以推断通路激活和基因表达水平。排除了未达到质量阈值的样本（n=16）或肿瘤分数<0.5%的样本（n=48）。我们应用了Precede ER依赖性指数（PERDI），该指数量化ER驱动的增强子与雌激素饥饿诱导的增强子的相对活性，并使用预定义阈值将样本分类为PERDI高或PERDI低。我们研究了PERDI与下次治疗时间（TTNT）之间的关联。采用条件性地标法，将TTNT定义为从目标治疗（ET或非ET）开始后30天起至下一治疗线开始，仅将因肿瘤进展而进行的治疗切换视为事件。在预先设定的主要分析中，使用时间依赖性ROC曲线研究PERDI与ET早期进展之间的关联。在其他分析中使用了Kaplan-Meier方法和Cox比例风险模型。结果：共纳入71例患者（79份样本）：57例患者在ET前采集样本（40例从1L切换至2L ET，17例从2L切换至3L ET）；22例患者在从2L ET切换至3L非ET时采集样本。最常见的下一线ET方案为SERD（n=17）、SERD+CDK4/6抑制剂（i）（n=14）、芳香化酶抑制剂（AI）+mTORi（n=9）、SERD+其他靶向治疗（n=6）。在57例开始下一线ET的患者中，PERDI与地标TTNT相关（PERDI低者中位TTNT为2.4个月（mo），PERDI高者为4.1 mo，HR 2.65，95%置信区间[CI] 1.24-5.66，p=0.012）。然而，PERDI未能可靠地识别下一线ET的早期进展者（2个月时的时间依赖性AUC c = 0.51）。在22例从ET切换至非ET（主要为化疗）的患者中，PERDI与TTNT无关（HR 0.66，95% CI 0.23-1.85，p=0.426），提示其可能具有专门针对ET的预测作用。在PERDI高但对下一线ET反应不佳的患者中，初步分析识别出6例已知耐药通路（如FGFR1、ERBB2）活性的离群值。结论：我们观察到PERDI与ET获益之间存在显著关联。我们整合ER以外耐药通路的探索性分析进一步识别出PERDI高但ET耐药的患者。经进一步临床验证后，这种基于血液的全面表观基因组检测有望成为指导ER+/HER2- MBC患者治疗的宝贵工具。

查看英文原文 English abstract

Background: Endocrine therapy (ET) is standard of care for ER+ MBC, but virtually all patients (pts) develop ET resistance over their disease course. Biomarkers predictive of loss of ER dependence to guide therapy (tx) are lacking. Methods: We identified 122 pts with ER+/HER2- MBC enrolled in the EMBRACE study at Dana Farber Cancer Institute who received 1-2 lines (L) of ET and had a blood drawn within +/- 30 days of switch from 1L to 2L (n=77) or from 2L to 3L (n=53). Using 1mL plasma, we profiled genome-wide enhancers, promoters and DNA hypermethylation to infer pathway activation and gene expression levels. Samples that did not meet quality thresholds (n=16) or had tumor fraction <0.5% (n=48) were excluded. We applied the Precede ER dependence index (PERDI) that quantifies relative activities of ER-driven vs estrogen-starvation-induced enhancers and classified samples as PERDI-high or -low using a predefined threshold. We investigated the association between PERDI and time-to-next-treatment (TTNT). A conditional landmark approach defined TTNT beginning from 30 days after the start of tx of interest (ET or non-ET) until the start of the next tx line, considering only tx switch for tumor progression as events. Time-dependent ROC curves were used in the prespecified primary analysis investigating the association between PERDI and early progression on ET. Kaplan Meier methods and Cox proportional hazard models were used in additional analyses. Results: A total of 71 pts (79 samples) were included: 57 pts had draws collected before ET (40 switch from 1L to 2L ET, 17 from 2L to 3L ET); 22 pts had samples collected from 2L ET to 3L non-ET. Most common next-line ET regimens were SERD (n=17), SERD + CDK4/6 inhibitors (i) (n=14), aromatase inhibitors (AI) + mTORi (n=9), SERD + other targeted therapy (n=6). Among 57 pts starting next-line ET, PERDI was associated with landmark TTNT (median TTNT 2.4 months (mo) with low vs 4.1 mo with high PERDI, HR 2.65, 95% confidence interval [CI] 1.24-5.66, p=0.012). However, PERDI did not reliably identify early progressors to next-line ET (time-dependent AUC at 2 mo c = 0.51). Among 22 pts who switched from ET to non-ET (primarily chemotherapy), PERDI was not associated with TTNT (HR 0.66, 95% CI 0.23-1.85, p=0.426), suggesting a potential predictive role specifically for ET. Among pts with high PERDI but poor response to next-line ET, preliminary analyses identified 6 outliers for activity of known resistance pathways (e.g. FGFR1 , ERBB2 ). Conclusions: We observed a significant association between PERDI and benefit from ET. Our exploratory analysis integrating resistance pathways beyond ER further identified pts with high PERDI but ET resistance. Upon further clinical validation, this blood based comprehensive epigenomic assay could become a valuable tool to guide tx for pts with ER+/HER2- MBC.

利益披露 Disclosure

S. Morganti, Precede Biosciences ), Other, Dana-Farber Cancer Institute and Dana-Farber Cancer Institute’s Venture Fund, Binney Street Capital, both hold institutional equity in Precede Biosciences. Merck ). Daiichi-Sankyo Independent Contractor. AstraZeneca Other, Expense Reimbursement. J. Beagan, Precede Biosciences Employment, Stock. N. Zhou, None. K. Nguyen, Precede Biosciences Employment, Stock. J&J Stock. Eli Lilly Stock. Merck Stock. Pfizer Stock. Amgen Stock. K. Smith, None.. A. Patel, None.. C. Stever, None.. K. Santos, None.. M. Skeffington, None.. O. D'Amico, None. T. Clark, Precede Biosciences Employment, Stock, Patent. Roche (Foundation Medicine) Patent. J. Finkle, Precede Biosciences Employment, Stock. TensixteenBio Employment. Tempus Stock. A. D'Ippolito, Precede Biosciences Employment, Stock. Syros Pharmaceuticals Employment, Stock. Kymera Therapeutics Employment. M. Zhong, Precede Biosciences Employment, Stock. J. Guess, Precede Biosciences Employment, Stock. K. Cibulskis, Precede Biosciences Employment, Stock. Montage Independent Contractor. Broad Institute Independent Contractor. A. Gorthi, Precede Biosciences Employment, Stock. T. Tamakloe, Precede Biosciences Employment, Stock. C. O'Brien, Precede Biosciences Employment, Stock. C2i Genomics Employment. B. Tran, Precede Biosciences Employment, Stock. M. McGillicuddy, Precede Biosciences Employment, Stock. N. Tayob, None. S. M. Tolaney, Genentech/Roche Independent Contractor, ), Travel. Merck Independent Contractor, ). Exelixis ). Pfizer/SeaGen Independent Contractor, ), Travel. Eli Lilly Independent Contractor, ), Travel. Novartis Independent Contractor, ). Bristol Myers Squibb Independent Contractor, ). AstraZeneca Independent Contractor, ), Travel. NanoString Technologies ). Gilead Independent Contractor, ), Travel. OncoPep ). Daiichi Sankyo Independent Contractor, ). Menarini/Stemline Independent Contractor, ). Jazz Pharmaceuticals Independent Contractor, ), Travel. Arvinas Independent Contractor, Travel. Eisai, Natera, Tango Therapeutics, eFFECTOR, Hengrui USA, Boehringer Ingelheim, Celcuity, Samsung Bioepis Independent Contractor. Systimmune, Cullinan Oncology, Circle Pharma, Avenzo Therapeutics, Atkis Oncology, Olema Pharmaceuticals Independent Contractor. Blueprint Medicines, BioNTech, Launch Therapeutics, Zuellig Pharma, Johnson&Johnson/Ambrx, Bicycle Therapeutics Independent Contractor. Artios Pharma, BeOne Therapeutics, Mersana, Summitt Therapeutics, Tempus, Boundless Bio Independent Contractor. Sumitovant Biopharma, Reveal Genomics, Aadi Bio, Bayer, Denali Therapeutics Independent Contractor. N. U. Lin, Genentech/Roche ). Pfizer/SeaGen Independent Contractor, ). Merck ). Zion Pharmaceuticals ). Olema Pharmaceuticals Independent Contractor, ), Travel. AstraZeneca Independent Contractor, ), Travel. Daichii-Sankyo Independent Contractor, Travel. Stemline/Menarini Independent Contractor. Eisai Independent Contractor. Shorla Oncology Independent Contractor. Denali Therapeutics Independent Contractor. Artera Inc Stock Option. Up to date Other, Royalties. H. Heiling, None. C. A. Painter, Precede Biosciences Employment, Stock. M. L. Eaton, Precede Biosciences Employment, Stock. Syros Pharmaceuticals Employment, Stock. J. Barrett, Precede Biosciences Employment, Stock. AstraZeneca Employment, Stock. Corista Stock. Nexosomes Stock. Akoya Independent Contractor. Leica Independent Contractor. Agilent Independent Contractor. Multiplex Independent Contractor. Bain Capital Independent Contractor. ExAI Independent Contractor. SAGA diagnostics g., Board of Directors, non-salaried role). H. A. Parsons, Foresight Diagnostics Independent Contractor. Gilead Sciences, Inc Independent Contractor. Natera Independent Contractor. Neogenomics Independent Contractor. Pfizer Independent Contractor. SAGA diagnostics Independent Contractor. Sermonix Independent Contractor.

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