Combination of molecular‑targeted drugs with endocrine therapy for hormone‑resistant breast cancer
Abstract Overcoming resistance to endocrine therapy is the most intensive research area in estrogen receptor (ER)- positive breast cancer. A strategy to restore endocrine sen- sitivity using molecular-targeted drugs such as mammalian target of rapamycin inhibitor everolimus along with endo- crine therapy has already been used as a treatment option after the progression of previous aromatase inhibitor ther- apy. Phase II/III clinical trials of several signal pathway inhibitors and cyclin-dependent kinase 4/6 inhibitors are underway. In addition, a randomized phase II trial of the histone deacetylase inhibitor entinostat showed interest- ing findings. In this review, we summarize the mechanis- tic principles of combination therapy of molecular-targeted drugs with endocrine therapy by using a hybrid car model.
Keywords ; Estrogen receptor · Molecular-targeted drugs · Breast cancer · Resistant
Introduction
Metastatic breast cancer (MBC), including advanced stage IV cases and recurrence cases, is generally an incurable dis- ease. The aim of its treatment is to prolong the patient’s sur- vival time. To date, many efforts have been made to achieve this aim, and prolong the survival time [1]. Figure 1 shows a schematic presentation of seven types of treatment approach to improve the overall survival (OS) time of MBC patients. The most common challenge is increasing the overall response rate and prolonging progression-free survival (PFS) through
improvement of drugs or drug combinations. Prolongation of post-progression survival (PPS) or survival post-progression (SPP) is a recent topic that was addressed in two clinical trials of eribulin, in which almost identical PFS times were observed both in a standard arm and an eribulin arm. However, longer OS was obtained in the eribulin arm [2–4]. Primary tumor resection in stage IV disease is an old dogma that has been reported in many retrospective studies [5]. JOCG1017 and ECOG2108 studies are currently being conducted as prospec- tive phase III randomized studies. Periodic imaging screening after primary surgery is not a standard follow-up method. The JCOG1204 study is aimed at confirming the superiority of an intensive follow-up to standard follow-up in terms of OS in high-risk breast cancer patients. Introduction of anti-HER2 agents to HER2-positive disease improved survival time after brain metastasis [6]. Symptom and disease management of brain metastasis with good quality of life have become impor- tant issues, especially for HER2-positive and triple-negative breast cancer patients [7]. Overcoming acquired resistance during treatment has recently become the most intensive research area in endocrine therapy. Especially with estro- gen receptor (ER)-positive breast cancer, a strategy to restore endocrine sensitivity using a combination of molecular-tar- geted drugs, such as everolimus along with endocrine therapy has already been implemented as a treatment option after pro- gression of previous endocrine therapy [8].
Hybrid car model and rationale of combination therapy of signal pathway inhibitor with endocrine therapy
We recently published a simple hybrid car model that could be useful for clinical oncologists to understand hormone-depend- ent breast cancer biology and how to best employ newly devel- oped molecular-targeting therapies (Fig. 2a) [9]. In general, a hybrid car has two power sources—a gasoline engine and an electric motor. These power sources are used either simulta- neously or independently, and each power source affects the other. The gasoline engine and the electric motor of hormone- dependent breast cancer are, respectively, ER and growth fac- tor receptors such as the HER family, IGF-1R and FGFR [10]. Signaling pathways such as the PI3 K/AKT/mTOR and Ras/ MEK/MAPK pathways are transmission systems from the electric motor to the drive shaft, or planetary gears from the motor to the engine to assist engine power. Downstream gene expression from the ER is like transmission from a gasoline (estrogen)-powered engine to the drive shaft.
A basic rationale of combinations of molecular-targeted agents with endocrine therapy is used for adapting de-novo resistance and/or acquired resistance to standard endocrine therapy. For instance, in the hybrid car model, endocrine therapy with a non-steroidal aromatase inhibitor (ns-AI) is similar to the car being out of gas (estrogen). In this situa- tion, cancer tries to activate the electric motor transmission system to overcome lack of fuel. Therefore, a combination of motor transmission inhibitor, mammalian target of rapamy- cin (mTOR) inhibitor, and another type of gasoline-depriva- tion drug, a steroidal AI, should be a reasonable approach to overcome acquired resistance to ns-AIs. After the success of the signaling pathway inhibitor, everolimus, combined with exemestane in MBC patients refractory to ns-AIs [8], several types of molecular-targeting drugs were developed as combi- nation partners for endocrine therapy (Fig. 2b).
Combination of cyclin‑dependent kinase (CDK) 4 and 6 inhibitor and histone deacetylase (HDAC) inhibitor with endocrine therapy metastatic breast cancer. It is noteworthy that some of these phase III trials are recruiting both postmenopausal patients and premenopausal patients under the concurrent usage of luteinizing hormone-releasing hormone (LHRH) analog.
Cyclin D1, one of the representative estrogen-dependent downstream genes of the ER, is involved in the progression of hormone-dependent breast cancer. ER blockade there- fore causes genetic alterations of cyclin-related genes that circumvent the requirement for the ER. A commonly dereg- ulated cell cycle checkpoint is the cyclin D/cyclin-depend- ent kinase (CDK)4/CDK6/Rb pathway. Cyclin D1/CDK4 and Cyclin D3/CDK6 complexes phosphorylate Rb protein, and activate E2F transcription factors to induce expres- sion of gene-encoding proteins for cell cycle progression [11]. In the hybrid car model, a tumor with amplifıcation of cyclin D1 (CCND1 gene) and/or loss of p16 (INK4A or CDKN2A genes), which is like a car having super trans- mission in its engine transmission system, should be the best CDK inhibitor target.
The PALOMA-1/TRIO-18 trial is a randomized phase II study evaluating CDK4/6 inhibitor palbociclib in combina- tion with letrozole compared with toletrozole alone as first- line treatment of ER-positive HER2-negative advanced breast cancer [11]. In all randomized patients (n 165), the median PFS was 10.2 months (95 % CI 5.7–12.6) for the letrozole group and 20.2 months (13.8–27.5) for the pal- bociclib plus letrozole group (HR 0.488, 95 % CI 0.319– 0.748; p 0.0004). This trial recruited two cohorts— cohort 1 on the basis of ER-positive and HER2-negative biomarkers alone; and cohort 2, requiring amplification of cyclin D1 and/or loss of p16 in addition to ER/HER sta- tus. In cohort 1 (n 66), the median PFS was 5.7 months (2.6–10.5) for the letrozole group and 26.1 months (11.2- not estimable) for the palbociclib plus letrozole group (HR 0.299, 0.156–0.572; p < 0.0001). In cohort 2 (n 99), the medians were 11.1 months (7.1–16.4) for the letrozole group and 18.1 months (13.1–27.5) for the palbociclib plus letrozole group (HR 0.508, 0.303–0.853; p 0.0046). In contrast to the basic biological rationale, cyclin D1 amplifi- cation did not exactly predict the sensitivity to the CDK4/6 inhibitor in this trial. Since the benefit of this combination is significant in an ER-positive HER2-negative population, phase III trials of this combination in the MBC setting and in the adjuvant setting (PENELOPE-B study) have been ongoing.
HDACs and histone acetyltransferases (HAT) have critical roles in the maintenance and function of chroma- tin by regulating the acetylation of histones [12]. Enti- nostat is a novel oral HDAC inhibitor with high specific- ity to class 1 HDACs. In the preclinical model, entinostat restores hormone sensitivity as a result of the down-reg- ulation of estrogen-independent growth factor signaling pathways, normalization of ER expression and increase of aromatase enzyme expression. Entinostat is thought to re-sensitize tumors to endocrine therapy by re-induction of ER expression. In the hybrid car model, re-activation of the gasoline engine system is the role of the HDAC inhibitor.
ENCORE 301 is a randomized, placebo-controlled, phase II study evaluating entinostat combined with ste- roidal AI exemestane compared to exemestane alone in postmenopausal women with ER-positive advanced breast cancer progressing on ns-AI [13]. In patients (n 130) in intent-to-treat analysis, treatment with entinostat and exemestane improved median PFS to 4.3 months compared to 2.3 months with placebo and entinostat (HR 0.73; 95 % CI, 0.50–1.07; one-sided p 0.055; two-sided p 0.11 [predefined significance level of 0.10, one-sided]). Inter- estingly, the median overall survival was improved to 28.1 months in the entinostat and exemestane group com- pared to 19.8 months in the placebo and entinostat group (HR, 0.59; 0.36–0.97; p 0.036). More pronounced improvement in OS as compared to the moderate ben- efit in PFS raises the possible mechanistic background of HDAC inhibitors as in favorable differentiation of cancer after treatment. In addition, the effect on patient condition through acetylation in peripheral blood mononuclear cells might contribute to this improvement.
Conclusion
Many molecular-targeted drugs in combination with endo- crine therapy for overcoming endocrine resistance are cur- rently in the evaluation process for phase II/III clinical trials. However, the resistance mechanism varies between cells and is time dependent. Such was the case in a recent finding of an ER (ESR1 gene) mutation in a heavily treated patient. Although we do not have any clinically meaning- ful biomarkers for this approach, continuing to explore the real-time monitoring method for choosing the appropriate molecular-targeted drug at the right time is crucial.