AUTHOR=Jeffreys Sarah A. , Becker Therese M. , Khan Sarah , Soon Patsy , Neubauer Hans , de Souza Paul , Powter Branka 

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

JOURNAL=Frontiers in Endocrinology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.895729

DOI=10.3389/fendo.2022.895729

ISSN=1664-2392

ABSTRACT=<sec><title>Background</title><p>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). <italic>CCND1</italic> encodes the protein cyclin D1, responsible for regulation of G1 to S phase transition in the cell cycle. <italic>CCND1</italic> 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 <italic>CCND1</italic> amplification on estrogen receptor positive patients’ disease outcomes, is vital. This review aims to evaluate <italic>CCND1</italic> amplification as a prognostic and predictive biomarker in BCa.</p></sec><sec><title>Materials and Methods</title><p>Publications were retrieved from the databases: PubMed, MEDLINE, Embase and Cochrane library. Exclusion criteria were duplication, publication type, non-English language, <italic>in vitro</italic> and animal studies, not BCa, male BCa, premenopausal BCa, cohort size &lt;35, <italic>CCND1</italic> 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].</p></sec><sec><title>Results</title><p><italic>CCND1</italic> 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). <italic>CCND1</italic> 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, <italic>CCND1</italic> amplification predicted shorter RFS (HR: 2.59, 95% CI: 1.96-3.41, p &lt; 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.</p></sec><sec><title>Conclusion</title><p>While a lack of standardised approach for the detection of <italic>CCND1</italic> amplification is to be considered as a limitation, <italic>CCND1</italic> amplification was found to be prognostic of shorter RFS and OS in BCa. <italic>CCND1</italic> 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 <italic>CCND1</italic> amplification, <italic>CCND1</italic> amplification would have potential as a predictive biomarker in breast cancer patients.</p></sec><sec><title>Systematic Review Registration</title><p><uri xlink:href="https://www.crd.york.ac.uk/prospero/" xmlns:xlink="http://www.w3.org/1999/xlink">https://www.crd.york.ac.uk/prospero/</uri>, identifier CRD42020208179.</p></sec>