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

IntroductionGene 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.MethodsTo 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.ResultsAmplification 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.ConclusionsIn 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 RegistrationCurrent Controlled Trials ISRCTN18233230.

Amplification of Cycline D1, C-MYC And EGFR Oncogenes in Tumour Samples of Breast Cancer Patients / AMPLIFIKACIJA CIKLIN D1, C-MYC AND EGFR ONKOGENA U TUMORSKIM UZORCIMA PACIJENTKINJA OBOLELIH OD KANCERA DOJKE

“…However, amplification of EGFR gene showed significant association with the expression of HER-2/neu. The largest and the most comprehensive study analyzing EGFR expression in breast cancer patients showed that EGFR expression was positively correlated with HER-2/neu overexpression, which has been associated with bad prognosis (28). Our results confirm this finding since Kaplan-Meier survival analysis showed that patients with HER-2/neu overexpression had worse prognoses and lived significantly shorter.…”

High proliferation is associated with inferior outcome in male breast cancer patients

“…This is in accordance with the reports in female breast cancer showing that overexpression of cyclin D1 does not correlate to the other cyclins and is more often seen in ER positive and well-differentiated tumors. 23 Studies evaluating the prognostic role of cyclin D1 overexpression in female breast cancer are contradictory, with some reporting a better [23][24][25] and others a poorer outcome. 16,26 We could demonstrate that overexpression of cyclin D1 is predictive of better breast cancer survival in male breast cancer, which has been indicated in previous reports in male breast cancer.…”

Multi-gene fluorescence in situ hybridization to detect cell cycle gene copy number aberrations in young breast cancer patients

“…Cyclin D1 (CCND1) is one of the prime regulating proteins of G 1 /Sphase conversion, and CCND1 gene amplification in breast cancer correlates with poor prognosis. 15,16 Here we employed the multi-gene fluorescence in situ hybridization (M-FISH) to analyze the copy number aberrations of these 4 genes, and to correlate the aberrations with prognosis in the young breast cancer patients.…”