Cyclin E1 Expression and Palbociclib Efficacy in Previously Treated Hormone Receptor-Positive Metastatic Breast Cancer.
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Date
2019-02-26ICR Author
Author
Turner, NC
Liu, Y
Zhu, Z
Loi, S
Colleoni, M
Loibl, S
DeMichele, A
Harbeck, N
André, F
Bayar, MA
Michiels, S
Zhang, Z
Giorgetti, C
Arnedos, M
Huang Bartlett, C
Cristofanilli, M
Type
Journal Article
Metadata
Show full item recordAbstract
PURPOSE: A large-panel gene expression analysis was conducted to identify biomarkers associated with the effectiveness of adding palbociclib to fulvestrant. METHODS: The PALOMA-3 ( ClinicalTrials.gov identifier: NCT01942135) trial randomly assigned 521 endocrine-pretreated patients with metastatic breast cancer to receive palbociclib plus fulvestrant or placebo plus fulvestrant. Primary analysis was first conducted on 10 genes on the basis of pathway biology and evidence from previous studies followed by a systematic panel-wide search among 2,534 cancer-related genes. The association of gene expression with the effect of palbociclib on progression-free survival (PFS) was evaluated using Cox proportional hazards regression analysis, with gene expression as a continuous variable or dichotomized by median. An independent breast cancer cohort from the Preoperative Palbociclib (POP) Clinical Trial ( ClinicalTrials.gov identifier: NCT02008734) was used for validation, in 61 patients with primary breast cancer treated with 2 weeks of palbociclib. RESULTS: In the PALOMA-3 trial, 302 patients had tumor tissue analyzed (palbociclib arm, 194 patients; placebo arm, 108 patients). Palbociclib efficacy was lower in patients with high versus low cyclin E1 (CCNE1) mRNA expression (median PFS: palbociclib arm, 7.6 v 14.1 months; placebo arm, 4.0 v 4.8 months, respectively; interaction P unadjusted = .00238; false discovery rate-adjusted P = .0238). CCNE1 mRNA was more predictive in metastatic than in archival primary biopsy tissue samples. No significant interaction was found between treatment and expression levels of CDK4, CDK6, cyclin D1, and RB1. Palbociclib was efficacious in both luminal A and luminal B tumors. High CCNE1 mRNA expression was associated with poor antiproliferative activity of palbociclib in the POP trial (P = .005). CONCLUSION: Addition of palbociclib to fulvestrant demonstrated efficacy in all biomarker groups, although high CCNE1 mRNA expression was associated with relative resistance to palbociclib.
Collections
Subject
Humans
Breast Neoplasms
Neoplasm Metastasis
Piperazines
Pyridines
Cyclin E
Oncogene Proteins
Receptors, Estrogen
Receptors, Progesterone
RNA, Messenger
Antineoplastic Combined Chemotherapy Protocols
Proportional Hazards Models
Gene Expression Profiling
Female
Biomarkers, Tumor
Fulvestrant
Progression-Free Survival
Research team
Molecular Oncology
Language
eng
Date accepted
2019-01-15
License start date
2019-05
Citation
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2019, 37 (14), pp. 1169 - 1178
Publisher
AMER SOC CLINICAL ONCOLOGY