PO.CL01.01 · 临床研究
Characterization of functional estrogen receptor (ER) dependence via comprehensive epigenomic liquid biopsy stratifies endocrine therapy (ET) responders with metastatic breast cancer (MBC)
作者与单位
摘要 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, ).
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AstraZeneca Independent Contractor, ), Travel.
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Gilead Independent Contractor, ), Travel.
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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 ).
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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.