Dataset Information

Effects of cyclin D1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study.

ABSTRACT:

Introduction

Gene amplification of CCND1 is observed in a subgroup of breast cancers with poor prognosis, whereas overexpression of the protein cyclin D1 has been linked to both worse and better clinical outcome. CCND1 amplification and protein overexpression have also been associated with resistance to treatment with tamoxifen or even to a potentially detrimental effect of tamoxifen.

Methods

To clarify these challenging and partly contrasting treatment predictive and prognostic links for cyclin D1 we analysed a large cohort of postmenopausal breast cancer patients randomised to receive either adjuvant anastrozole or tamoxifen, as part of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. The CCND1 amplification status and protein expression of cyclin D1 were assessed by chromogenic in situ hybridisation and immunohistochemistry, respectively, in 1,155 postmenopausal, oestrogen-receptor-positive breast cancer patients included in the TransATAC substudy.

Results

Amplification of CCND1 was observed in 8.7% of the tumours and was associated with increased risk of disease recurrence (hazard ratio = 1.61; 95% confidence interval, 1.08 to 2.41) after adjustment for other clinicopathological parameters. In contrast, nuclear expression of cyclin D1 protein was associated with decreased recurrence rate (hazard ratio = 0.6; 95% confidence interval, 0.39 to 0.92). The intensity of nuclear or cytoplasmic expression was not of prognostic value. There was no significant interaction between cyclin D1 status and treatment efficacy, ruling out any major detrimental effect of tamoxifen in CCND1-amplified postmenopausal breast cancer.

Conclusions

In summary, CCND1 amplification and low nuclear expression of cyclin D1 predicted poor clinical outcome in postmenopausal breast cancer patients treated with either anastrozole or tamoxifen.

Trial registration

Current Controlled Trials ISRCTN18233230.

SUBMITTER: Lundgren K

PROVIDER: S-EPMC3446392 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Publications

Effects of cyclin D1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study.

Lundgren Katja K Brown Matthew M Pineda Silvia S Cuzick Jack J Salter Janine J Zabaglo Lila L Howell Anthony A Dowsett Mitch M Landberg Göran G

Breast cancer research : BCR 20120404 2

<h4>Introduction</h4>Gene amplification of CCND1 is observed in a subgroup of breast cancers with poor prognosis, whereas overexpression of the protein cyclin D1 has been linked to both worse and better clinical outcome. CCND1 amplification and protein overexpression have also been associated with resistance to treatment with tamoxifen or even to a potentially detrimental effect of tamoxifen.<h4>Methods</h4>To clarify these challenging and partly contrasting treatment predictive and prognostic l ...[more]

PMID: 22475046

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Project description:BackgroundUp 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 methodsPublications 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].ResultsCCND1 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.ConclusionWhile 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 registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42020208179.

Project description:BackgroundAdjuvant tamoxifen therapy substantially decreases the risk of recurrence and mortality in women with hormone (estrogen and/or progesterone) receptor-positive breast cancer. Previous studies have suggested that metabolic conversion of tamoxifen to endoxifen by cytochrome P450 2D6 (CYP2D6) is required for patient benefit from tamoxifen therapy.MethodsTumor specimens from a subset of postmenopausal patients with hormone receptor-positive early-stage (stages I, II, and IIIA) breast cancer, who were enrolled in the randomized double-blind Arimidex, Tamoxifen, Alone or in Combination (ATAC) clinical trial, were genotyped for variants in CYP2D6 (N = 1203 patients: anastrozole [trade name: Arimidex] group, n = 615 patients; tamoxifen group, n = 588 patients) and UDP-glucuronosyltransferase-2B7 (UGT2B7), whose gene product inactivates endoxifen (N = 1209 patients; anastrozole group, n = 606 patients; tamoxifen group, n = 603 patients). Genotyping was performed using polymerase chain reaction-based TaqMan assays. Based on the genotypes for CYP2D6, patients were classified as poor metabolizer (PM), intermediate metabolizer (IM), or extensive metabolizer (EM) phenotypes. We evaluated the association of CYP2D6 and UGT2B7 genotype with distant recurrence (primary endpoint) and any recurrence (secondary endpoint) by estimating the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) using Cox proportional hazards models. All statistical tests were two-sided.ResultsAfter a median follow-up of 10 years, no statistically significant associations were observed between CYP2D6 genotype and recurrence in tamoxifen-treated patients (PM vs EM: HR for distant recurrence = 1.25, 95% CI = 0.55 to 3.15, P = .64; HR for any recurrence = 0.99, 95% CI = 0.48 to 2.08, P = .99). A near-null association was observed between UGT2B7 genotype and recurrence in tamoxifen-treated patients. No associations were observed between CYP2D6 and UGT2B7 genotypes and recurrence in anastrozole-treated patients.ConclusionThe results do not support the hypothesis that CYP2D6 genotype predicts clinical benefit of adjuvant tamoxifen treatment among postmenopausal breast cancer patients.

Dataset Information

Effects of cyclin D1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study.

Introduction

Methods

Results

Conclusions

Trial registration

Publications

Effects of cyclin D1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study.

Similar Datasets

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