Prognostic and Predictive Value of CCND1/Cyclin D1 Amplification in Breast Cancer With a Focus on Postmenopausal Patients: A Systematic Review and Meta-Analysis

Abstract

Background: Up to 80% of breast cancers (BCa) are estrogen receptor positive and current treatments target the estrogen receptor (endocrine therapies) and/or CDK4/6 (CDK4/6 inhibitors). CCND1 encodes the protein cyclin D1, responsible for regulation of G1 to S phase transition in the cell cycle. CCND1 amplification is common in BCa and contributes to increased cyclin D1 expression. As there are signalling interactions between cyclin D1 and the estrogen receptor, understanding the impact of CCND1 amplification on estrogen receptor positive patients' disease outcomes, is vital. This review aims to evaluate CCND1 amplification as a prognostic and predictive biomarker in BCa.

Materials and methods: Publications were retrieved from the databases: PubMed, MEDLINE, Embase and Cochrane library. Exclusion criteria were duplication, publication type, non-English language, in vitro and animal studies, not BCa, male BCa, premenopausal BCa, cohort size <35, CCND1 amplification not reported. Publications with cohort duplication, and inadequate recurrence free survival (RFS) and overall survival (OS) data, were also excluded. Included publications were assessed for Risk of Bias (RoB) using the Quality In Prognosis Studies tool. Statistical analyses (Inverse Variance and Mantel-Haenszel) were performed in Review Manager. The PROSPERO registration number is [CRD42020208179].

Results: CCND1 amplification was significantly associated with positive estrogen receptor status (OR:1.70, 95% CI:1.19-2.43, p = 0.004) and cyclin D1 overexpression (OR: 5.64, 95% CI: 2.32-13.74, p=0.0001). CCND1 amplification was significantly associated with shorter RFS (OR: 1.64, 95% CI: 1.13-2.38, p = 0.009), and OS (OR: 1.51, 95% CI: 1.19-1.92, p = 0.0008) after removal of studies with a high RoB. In endocrine therapy treated patients specifically, CCND1 amplification predicted shorter RFS (HR: 2.59, 95% CI: 1.96-3.41, p < 0.00001) and OS (HR: 1.59, 95% CI: 1.00-2.49, p = 0.05) also after removal of studies with a high RoB.

Conclusion: While a lack of standardised approach for the detection of CCND1 amplification is to be considered as a limitation, CCND1 amplification was found to be prognostic of shorter RFS and OS in BCa. CCND1 amplification is also predictive of reduced RFS and OS in endocrine therapy treated patients specifically. With standardised methods and cut offs for the detection of CCND1 amplification, CCND1 amplification would have potential as a predictive biomarker in breast cancer patients.

Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42020208179.

Keywords: CCND1; amplification; biomarker; breast cancer; cyclin D1; meta-analysis; systematic review.

Figure 1

Cyclin D1 promotes G1/S phase cell cycle progression via interaction with CDK4/6. Transition between phases of the cell cycle is mediated by cyclins A-E, and cyclin dependent kinases (cdk) 1-6. Cyclins C-E are responsible for the transition from G1 to S phase of the cell cycle. The cyclin D and cdk4/6 complex, activated by PI3K/MAPK pathways or the estrogen receptor (ER), is a key mediator of G1-S phase transition, and this occurs through phosphorylation of retinoblastoma protein (Rb). Phosphorylation of Rb, results in its dissociation with E2F1, enabling transcription of G₁/S phase genes. Transcriptional activity of the ER is stimulated by cyclin D1, and the ER may activate the CCND1 promoter. Current breast cancer drugs target estrogen production (aromatase inhibitors); the estrogen receptor [Selective Estrogen Receptor Modulators (SERMs) or Selective Estrogen Receptor Degraders (SERDs)]; or cdk4/6 (cdk4/6 inhibitors).

Figure 2

Study Selection PRISMA Diagram. Flow diagram shows studies retrieved from databases, and the number of studies excluded and the basis on which they were excluded. OS, Overall Survival; RFS, Relapse Free Survival; HR, Hazard Ratio.

Figure 3

Forrest plot of hazard ratios for CCND1 amplification and worse relapse free survival and overall survival of breast cancer patients. (A) CCND1 Amplification and relapse free survival (B) CCND1 Amplification and overall survival. Z values indicate the magnitude of association, with p-values <0.05 indicating statistically significant association. Red squares indicate hazard ratio, with values >1 indicative of association of the outcome measure (RFS and OS) with CCND1 amplification, with strongest association towards the right of the plot. Black lines either side of squares indicate 95% confidence interval (CI). Size of red boxes is relative to specific study weight with greatest weight given to studies with minimal variance (calculated based on inverse of the variance). Large black diamond represents pooled hazard ratio estimate of the above studies. A random effects approach was taken. SE, Standard Error. Plots were generated in Review Manger.

Figure 4

Forrest plot of hazard ratios for CCND1 amplification and worse relapse free survival and overall survival of endocrine therapy breast cancer patients.(A) CCND1 Amplification and relapse free survival (B) CCND1 Amplification and overall survival. Z values indicate the magnitude of association, with p-values <0.05 indicating statistically significant association. Red squares indicate hazard ratio, with values >1 indicative of association of the outcome measure (RFS and OS) with CCND1 amplification, with strongest association towards the right of the plot. Black lines either side of squares indicate 95% confidence interval (CI). Size of red boxes is relative to specific study weight with greatest weight given to studies with minimal variance (calculated based on inverse of the variance). Large black diamond represents pooled hazard ratio estimate of the above studies. A random effects approach was taken. SE, Standard Error. Plots were generated in Review Manger.