Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer
https://www.mdpi.com/2073-4409/8/4/321/pdf
"... 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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