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Old 05-13-2019, 10:06 AM   #1
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Join Date: Nov 2005
Posts: 324
Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer


CDK4/6 Inhibitors in HER2-Positive Breast Cancer
Amplification or overexpression of the human epidermal growth factor receptor 2 (HER2/Erbb2)
occurs in approximately 15–20% of human breast cancers [61]. In these HER2-positive cancers, the
constitutive activation of downstream signalling pathways by HER2 promotes tumorigenesis and
metastasis. In recent decades, several HER2-targeted therapies have been approved for the treatment
of HER2-positive breast cancer: the monoclonal antibodies, trastuzumab and pertuzumab, the kinase
inhibitor, lapatinib and neratinib, and the antibody-drug conjugate, trastuzumab emtansine (T-DM1).
While these targeted therapies have improved outcomes, metastatic HER2-positive breast cancer
remains incurable as tumors eventually develop therapy resistance. Therefore, understanding the
mechanisms of resistance and investigating other treatment options for HER2-positive breast cancer
patients remains an important research goal.
While most of the clinical research in the past decade focused on the use of CDK4/6 inhibitors in
ER-positive HER2-negative breast cancer, several earlier studies already suggested CDK4/6 inhibition
as a potential treatment for HER2-positive tumors. In one of the first studies on the activity of the
CDK4/6 inhibitor, palbociclib, Finn and colleagues demonstrated that luminal-type breast cancer cells
expressing estrogen receptor, including luminal-type cells with HER2 amplification, were significantly
more sensitive to palbociclib than basal-type ER-negative cells [41].
Moreover, palbociclib showed enhanced activity in combination with trastuzumab or T-DM1 in
HER2-amplified breast cancer cells in vitro [41,62]. These results were in line with genetic studies in
mice that pointed to an essential function of CDK4/6 in HER2-positive breast cancer. For instance,
mice lacking cyclin D1 or CDK4, as well as mice expressing mutant cyclin D1 (incapable of activating
CDK4/6) were resistant to breast cancer induced by the Erbb2/HER2 oncogene [34,63,64]. Furthermore,
the acute deletion of cyclin D1 or inhibition of CDK4/6 kinase activity using palbociclib blocked the
progression of HER2-driven breast cancer in mice [18]. Similar to palbociclib, abemaciclib was recently
shown to exhibit substantial activity against luminal ER-positive HER2-positive breast cancer cells both
in vitro and in xenografts [65]. Its activity was further enhanced in combination with HER2-targeted
therapy [65].
Although these studies suggested the use of CDK4/6 inhibitors in HER2-positive breast cancer, they
did not investigate mechanisms of resistance to HER2-targeted approaches. In the past, alterations in
several proteins and signalling pathways were shown to mediate resistance to HER2-targeted therapies,
including the PI3K–AKT pathway and the HER2 receptor itself. More recently, the study by Goel and
colleagues investigated mechanisms of resistance using a doxycycline-regulated HER2-overexpressing
mouse model for breast cancer [66]. They discovered that tumors recurring after HER2 withdrawal
or after trastuzumab treatment overexpressed cyclin D1 and the CDK4 protein in the nucleus, most
likely as a result of mutations associated with the hyperactivation of the MAPK pathway. Similar
results were obtained by another group who investigated lapatinib-resistant breast cancer cells [62].
Hence, Goel and colleagues hypothesized that cyclin D1 overexpression may mediate resistance
to HER2-targeted therapies. Indeed, the overexpression of cyclin D1 was capable of reducing the
sensitivity of breast cancer cells to HER2-targeted agents [66]. Of note, tumors resistant to HER2
targeting were dependent on cyclin D1–CDK4 complexes and their growth could be inhibited using
the CDK4/6 inhibitor abemaciclib. Importantly, they also showed that the combined targeting of HER2
and CDK4/6 in lapatinib/trastuzumab-resistant HER2-positive breast cancer cells caused not only the
additive but synergistic inhibition of cell growth and cell viability in vitro. Strikingly, the combined
targeting of CDK4/6 and HER2 using abemaciclib and trastuzumab in patient-derived xenograft (PDX)
models of treatment-refractory HER2-positive breast cancer displayed enhanced anti-tumor activity
in vivo.
While numerous preclinical studies already suggested the cyclin D–CDK4/6 axis as an attractive
target in HER2-positive breast cancer (including cancers resistant to HER2-targeting drugs), clinical
studies have mainly focused on ER-positive, HER2-negative breast cancer. Nevertheless, some of
these studies also included patients with HER2-positive disease. For instance, a phase II study
Cells 2019, 8, 321 14 of 24
using palbociclib in Rb-positive advanced breast cancer included two patients with ER-positive
HER2-positive breast cancer [46]. One of these patients had a partial response (PR), while the other
patient had stable disease (SD) lasting five months. Another study in Japan included one patient
with HER2-positive advanced breast cancer, who showed a PR after treatment with abemaciclib [67].
To date, the largest study evaluating CDK4/6 inhibition as novel targeted therapy for patients with
HER2-positive advanced breast cancer was published three years ago [68]. In that trial, eleven patients
with HER2-positive advanced breast cancer were treated with abemaciclib. Of these, four patients
had a PR and seven patients had SD (lasting at least 24 weeks in two patients). This corresponds to a
response rate of 36% and a clinical benefit rate (CR + PR + SD  24 weeks) of 55%. These patients
also showed a median progression-free survival of 7.2 months. While this study was not suited to
compare the ecacy of CDK4/6 inhibition to HER2-targeted approaches, it indicated a substantial
clinical activity of CDK4/6 inhibitors in this patient subgroup.
Currently, a number of clinical phase II and phase III studies are ongoing to evaluate
the clinical benefit of combining HER2-targeted approaches with CDK4/6 inhibitors for treating
HER2-positive advanced breast cancer. Examples are the PATRICIA study (phase II; palbociclib +
trastuzumab  letrozole; NCT02448420), the PATINA study (phase III; HER2-targeted therapy 
palbociclib; NCT02947685), the monarcHER study (phase II, abemaciclib + trastuzumab  fulvestrant;
NCT02675231) and another phase II study (ribociclib + trastuzumab or T-DM1  fulvestrant; NCT
02657343). The results from these studies are expected between 2019 and 2020.
In addition, CDK4/6 inhibitors are also considered in the early stage setting of HER2-positive
breast cancer. While the PALTAN study (phase II; palbociclib + trastuzumab + letrozole; NCT02907918)
is still ongoing, results from the NA-PHER2 study (NCT02530424) were recently published [69]. In
this phase II study, previously untreated HER2-positive ER-positive breast cancer patients received a
combination of palbociclib, trastuzumab, pertuzumab, and fulvestrant (an ER antagonist). Out of 30
patients that were assessed, 29 patients (97%) achieved a clinical objective response. Moreover, during
the following surgery, a pathological complete response could be confirmed for eight of these patients
(27%) [69]. These results suggest a potential use of CDK4/6 inhibitors and HER2-targeted approaches
also in the neo-adjuvant setting, possibly replacing neo-adjuvant chemotherapy.
While questions regarding ecacy are still awaiting results from ongoing and future randomized
trials, these preclinical and clinical results already demonstrate promise for the use of CDK4/6
inhibitors in this subtype of breast cancer. Future directions may also include defining subsets of
HER2-positive breast cancer patients that are most likely to respond to CDK4/6 inhibition. While the
presence of functional Rb protein is a well-established marker correlating with response to CDK4/6
inhibition [39], one report suggested that an 11-probe gene expression signature may predict sensitivity
to palbociclib [70]. Future studies will be necessary to validate the use of such predictors.
6. CDK4

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