The cyclin D1-mediated molecular pathway depicts significant cross-talk with the ER/PR and HER2 pathways in patients with advanced breast cancer and these correlations may have clinical implications. We sought to determine the level of activation of the critical components of the cyclin D1-mediated pathway and to evaluate their prognostic significance across the different molecular subtypes of advanced breast cancer.
The study population included 219 trastuzumab-treated women with advanced breast cancer who had been found to have HER2-positive disease by local testing. For all tumors, central testing for HER2 was performed and cyclin D1 (CCND1) gene amplification and mRNA and protein expression were assessed by FISH, qRT-PCR and IHC, respectively.
Only 134 of the 219 patients (61.2%) were HER2-positive (HER2 gene amplification and/or 3+ HER2 protein expression). After a median follow-up of 136.0 months, 105 HER2-positive patients (78.4%) and 76 HER2-negative patients (89.4%) had died, while 80.0% of the former and 87.1% of the latter had disease progression. Median PFS was 14.0 months for HER2-positive and 8.9 months for HER2-negative patients, while median survival was 48.1 months and 35.0 months, respectively. Cyclin D1 mRNA expression was higher in patients with positive ER/PgR. Cyclin D1 (as assessed by FISH, qRT-PCR and IHC) did not reach significance in terms of PFS or survival either in the entire study population or in HER2-positive patients. In the HER2-negative subgroup, negative cyclin D1 protein expression was associated with higher risk of progression (HR = 1.66, 95% CI 1.01-2.72, Wald’s p = 0.045), while in de novo metastatic patients, the risk of progression was higher for patients with non-amplified CCND1 tumors (HR = 2.00 95% CI 1.03-3.90, p = 0.041).
Aberrant activation of the cyclin D1-mediated pathway appears to reduce the risk of progression in HER2-negative tumors, but not in HER2-positive ones. If our results are validated by larger prospective trials, further evaluation of the cyclin D1-mediated pathway might identify prognostic and therapeutic implications in patients with advanced breast cancer.
Clinical trial identification
Legal entity responsible for the study
Hellenic Cooperative Oncology Group (HeCOG).
Roche, Hellenic Cooperative Oncoogy Group.
G. Mountzios, C. Christodoulou, P. Papakostas: Honoraria: Roche; Advisory role: Roche. G. Lazaridis: Honoraria: Roche. A. Koutras, G. Fountzilas: Advisory role: Roche. E. Razis: Advisory role, travel, honoraria: Roche; Research funding: Roche/Genentech. All other authors have declared no conflicts of interest.