Cyclin E1 Expression and Palbociclib Efficacy in Previously Treated Hormone Receptor-Positive Metastatic Breast Cancer

Abstract

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.

FIG 1.

CONSORT diagram of breast cancer tissues analyzed for gene expression. ITT, intention to treat.

FIG 2.

Association of cell cycle pathway gene expression and the efficacy of palbociclib (PAL) in combination with fulvestrant (FUL). Expression of cell cycle pathway genes dichotomized by median expression, with hazard ratios (HRs) for progression-free survival of PAL plus FUL versus placebo (PBO) plus FUL. HRs were derived from a Cox proportional hazards regression model. Interaction P value for statistical interaction between gene expression and treatment. CCND1, cyclin D1; CCND3, cyclin D3; CCNE1, cyclin E1; CCNE2, cyclin E2; CDK2, cyclin-dependent kinase 2; CDK4, cyclin-dependent kinase 4; CDK6, cyclin-dependent kinase 6; CDKN2A, cyclin-dependent kinase inhibitor 2A; ESR1, estrogen receptor 1; FDR, false discovery rate; RB1, retinoblastoma 1.

FIG 3.

Association between cyclin E1 (CCNE1) mRNA expression and palbociclib (PAL) efficacy. (A) Progression-free survival (PFS) in tumors with low or high CCNE1 mRNA expression by median. Hazard ratios (HRs) were derived from a Cox proportional hazards regression model. P value from the interaction test between gene expression and treatment. (B) Subpopulation treatment effect pattern plot analysis of CCNE1 mRNA expression as measured by HR (PAL plus fulvestrant [FUL] v placebo [PBO] plus FUL). The x-axis represents the median CCNE1 mRNA expression for patients in each overlapping subpopulation. The dashed lines represent the corresponding 95% pointwise CIs. The solid black line indicates a reference HR of 1, with HR less than 1 favoring the PAL plus FUL combination. (C) Subpopulation treatment effect pattern plot analysis of CCNE1 mRNA expression as measured by 6-month PFS rates. mPFS, median progression-free survival.

FIG 4.

Independent validation of high cyclin E1 (CCNE1) mRNA as a marker of palbociclib resistance in the Modulation of Rb Phosphorylation and Antiproliferative Response to Palbociclib: The Preoperative-Palbociclib (POP) Randomized Clinical Trial. (A) Antiproliferative response by CCNE1 expression tertile. (B) Geometric mean change in protein encoded by the MKI67 gene (Ki-67) expression with palbociclib treatment by CCNE1 expression tertile.

FIG 5.

Intrinsic molecular subtype and efficacy of palbociclib (PAL). (A) Intrinsic subtype distribution of tumors in the PALOMA-3 trial. (B) Progression-free survival (PFS) in luminal A (LumA) and B (LumB) tumors. (C) Cyclin E1 (CCNE1) mRNA expression by intrinsic molecular subtype. BasalL, basal-like; FUL, fulvestrant; HER2E, human epidermal growth factor receptor 2–enriched; HR, hazard ratio; mPFS, median progression-free survival; NormL, normal-like; PBO, placebo.