Cyclin-dependent kinases (CDK) 4 and 6 are viable therapeutic target in HER2-positive breast cancer models that functions downstream of HER2. Tissue based markers are available to direct rational utilisation of selective CDK4/6 inhibitor palbociclib (PD-0332991), according to the study performed in a combination of cell culture, mouse models, and human primary tumour explants. The results were presented by Dr Erik Knudsen of the Pathology Department, University of Texas Southwestern, Dallas, USA in Best abstracts session at the IMPAKT 2014 Breast Cancer Conference (8-10 May 2014, Brussels, Belgium).
CDK4/6 inhibitior shows activity against HER2-positive models and cooperates with HER2 targeted agents
Predicting response of tumours to CDK4/6 inhibition ex vivo. © Erik Knudsen
In spite of the efficacy of HER2 targeted therapies, recurrence and progression remain a challenge for treatment of advanced HER2-positive breast cancer. Mechanisms of bypass of HER2 targeted agents are complex and include aberrant cellular proliferation in the presence of agents; common deregulated signalling feeds into CDK4/6.
CDK4/6 controls a key pathway downstream of HER2. Inhibition of these kinases represents a therapeutic approach to augment the effectiveness of standard therapies, wrote the investigators in background information.
The researchers used a combination of cell culture, mouse models, and human primary tumour explants to evaluate the therapeutic effect of the CDK4/6 inhibitor palbociclib as a single agent and to define markers of response. Parallel studies evaluated the mechanisms of action in combination with the HER2-targeted agents lapatinib and T-DM1.
CDK4/6 inhibition resulted in profound cytostatic arrest, induction of senescence, and inhibition of invasive properties in HER2-positive cell culture models. These data were recapitulated with significant suppression of Ki67 in the mouse model (p < 0.05) and HER2-positive xenografts (p < 0.01).
Furthermore, in a series of more than 20 primary breast tumour explants, treatment with palbociclib resulted in a greater than 5-fold suppression of the Ki67 (p < 0.01). These effects of palbociclib were dependent on an intact RB-pathway. Loss of RB and high-levels of p16 were associated with resistance to CDK4/6 inhibition.
CDK4/6 inhibition can augment T-DM1 activity. © Erik Knudsen
In models of acquired resistance to HER2-targeted therapies Cyclin D1 was inappropriately activated, and palbociclib treatment was effective at blocking proliferation by targeting this common pathway driving resistance.
Combination studies carried out in cell lines and primary tumour explants illustrated that palbociclib provides a complementary mechanism of action to T-DM1, and efficiently suppresses the proliferation of residual HER2-positive tumour cell populations that survive T-DM1.
The authors concluded that CDK4/6 inhibition has activity against HER2-positive cell culture models, xenografts, and tumour explants. Markers of resistance (p16 and RB) can be identified in clinical specimens. CDK4/6 inhibitor cooperates with multiple small molecules in HER2-positive models. It cooperates with T-DM1 to prevent growth of residual clones.
Moving to the clinical testing
Clinical studies of CDK4/6 inhibition in combination with HER2 targeted therapies have already commenced.
Dr Nicholas Turner, who discussed the study results, said that in a phase II trial of first-line treatment for oestrogen receptor-positive, HER2-negative advanced breast cancer, presented recently at AACR Annual Meeting 2014, a combination of palbociclib and letrozole demonstrated a statistically significant improvement in progression-free survival. This phase II study proved the testing hypothesis that a combination of palbociclib and letrozole is better than letrozole alone in this patient subgroup.
A phase III study of palbociclib in combination with letrozole in same population of metastatic breast cancer is ongoing (PALOMA-2 study). A phase III study of palbociclib’s combination with fulvestrant (PALOMA-3 trial) for metastatic breast cancers is also ongoing, as well as a combination with standard endocrine therapy (PENELOPE-B study) for certain early-stage breast cancers.
Reference
Abstract 59O: E. Knudsen, D. Cox, J. Franco, et al. Targeting CDK4/6 in Her2 positive breast cancer: Therapeutic effect, markers, and combination strategies. Annals of Oncology (2014) 25 (suppl_1): i21-i22. 10.1093/annonc/mdu069.
Dr Knudsen reported that serves as an advisory board member and receives sponsored research funding from Pfizer. All other authors have declared no conflicts of interest.
IMPAKT is an annual conference that was launched in 2009 by the Breast International Group (BIG) and the European Society for Medical Oncology (ESMO), in collaboration with a multidisciplinary alliance of European breast cancer organisations and patient groups - referred to as partners. Partners include the Foundation St. Gallen Oncology Conferences and the EBC Council. It is designed for breast cancer researchers and clinicians who have a specific interest in translational research, new agents, molecular and functional diagnostics, biomarkers and cutting-edge research applications in the clinical setting. The theme of IMPAKT 2014 was 'Anticipating the future of personalised medicine in breast cancer'.