Overcoming resistance to endocrine therapy in hormone receptor-positive human epidermal growth factor receptor 2-negative (HR⁺/HER2^--) advanced breast cancer: a meta-analysis and systemic review of randomized clinical trials

Abstract

New targeted therapies have been developed to overcome resistance to endocrine therapy (ET) and improve the outcome of HR⁺/HER2^-- advanced breast cancer (ABC). We conducted a meta-analysis and systemic review on randomized controlled trials evaluating various targeted therapies in combination with ET in HR⁺/HER2^-- ABC. PUBMED and EMBASE databases were searched for eligible trials. Hazard ratios (HRs) for progression-free survival (PFS), odds ratios (ORs) for objective response rate (ORR), clinical benefit rate (CBR), and toxicity were meta-analyzed. Twenty-six studies with data on 10 347 patients were included and pooled. The addition of cyclin-dependent kinase 4/6 inhibitors to ET significantly improved median PFS (pooled HR= 0.547, P<0.001), overall survival (pooled HR= 0.755, P<0.001), and tumor response rates (ORR, pooled OR= 1.478, P<0.001; CBR, pooled OR= 1.201, P<0.001) with manageable toxicities (pooled OR= 3.280, P<0.001). The mammalian targets of rapamycin inhibitors and exemestane were not clinically beneficial for this pooled population including ET-naïve and ET-resistant patients. Moderate improvement in PFS (pooled HR= 0.686, P<0.001) yet pronounced toxicities (pooled OR=2.154, P<0.001) were noted in the combination of phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitors with fulvestrant. Future studies are warranted to optimize the population and the dosing sequence of these available options.

Keywords

endocrine-resistant / HR ⁺/HER2 ⁻ advanced breast cancer / randomized clinical trials / meta-analysis / targeted therapy

Introduction

As the most prevalent cancer and the leading cause of cancer death among women, breast cancer represents a large burden to global health. A total of 2 088 849 breast cancer cases were diagnosed in 2018 [¹]. The hormone receptor-positive human epidermal growth factor receptor 2-negative (HR⁺/HER2⁻) subtype, characterized by the expression of estrogen receptor (ER) and/or progesterone receptor (PR) without HER2 overexpression/amplification, accounts for approximately 70% of breast cancer patients [²]. Nearly 20%−30% of patients with early stage disease become metastatic throughout the disease course [³].

For decades, hormonally directed therapies, including blockade of estrogen signaling, have been the mainstay treatments for local, advanced, or metastatic HR⁺/HER2⁻ breast cancer. However, some treatment-naïve patients display primary resistance to the treatment, and most of them eventually develop acquired resistance to endocrine therapy (ET). Given the limited options after resistance to previous ET, efforts have been made for the development of novel approaches for addressing endocrine resistance.

Previous studies have provided insights into the underlying mechanisms of endocrine resistance. Initial research identified the upregulation of tyrosine kinase signaling as a common mechanism of endocrine resistance [⁴]. Subsequent findings revealed crucial events contributing to resistance to ET, including mutations in the gene encoding ER (ESR1) [⁵,⁶], activation of mammalian target of rapamycin (mTOR) signaling pathway [⁷], dysregulation of cell cycle due to the overactivation of cyclin-dependent kinase 4 and 6 (CDK4/6) [⁸], epigenetic alterations [⁹], and somatic changes in genes, such as PIK3CA, AKT1, HER2, and FGFR1 [¹⁰]. With the advancement in the understanding of the biology of HR⁺/HER2⁻ disease, new therapies targeting these resistance drivers have been developed to improve the efficacy of ET in advanced settings, namely, therapies using inhibitors for CDK4/6, mTOR, and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K); other receptor tyrosine kinase inhibitors (TKI); and histone deacetylase (HDAC) inhibitor. Additionally, other targeted therapies that enhance sensitivity to chemotherapy, including monoclonal antibodies and anti-angiogenesis agents, have been tested. However, the data are controversial. Evidence of the effectiveness of these drugs in treating endocrine-resistant breast cancer are needed for informed clinical decision making. In this study, a meta-analysis was performed to summarize available data from randomized clinical trials evaluating the efficacies of these targeted therapies in combination with ET in HR⁺/HER2⁻ advanced breast cancer. Given the apparent heterogeneity among different therapies, drug-specific analyses were carried out respectively.

Methods

Literature search and study selection

Systematic search for relevant studies published in English from 1966 to July 13, 2019 was conducted in the MEDLINE and EMBASE databases, and different combinations of keywords were used as follows: “breast OR mammary,” “cancer OR carcinoma OR tumor OR neoplasm OR malignancy,” “advanced OR metastatic OR metastasis OR recurrent OR stage IV OR relapse OR progression OR progressive OR resistant OR resistance,” “hormone receptor-positive OR HR-positive OR HR⁺ OR estrogen/progesterone receptor-positive OR ER/PR-positive OR ER/PR⁺,” “human epidermal growth factor receptor 2-negative OR HER2-negative OR HER2⁻,” “endocrine therapy OR tamoxifen OR fulvestrant OR aromatase inhibitor OR letrozole OR anastrozole OR exemestane OR selective estrogen receptor modulator OR AI OR nonsteroidal aromatase inhibitor OR steroidal aromatase inhibitor OR SERM OR antiestrogen OR estrogen antagonist OR estrogen blocker OR ET OR SERD OR selective estrogen receptor degrader,” and “targeted therapy OR CDK4/6 inhibitor OR palbociclib OR abemaciclib OR ribociclib OR cyclin-dependent kinase inhibitor OR PI3K inhibitor OR phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitor OR mammalian target of rapamycin inhibitor OR mTOR inhibitor OR receptor tyrosine kinase inhibitor OR TKI OR histone deacetylase inhibitor OR HDAC OR monoclonal antibody OR anti-angiogenesis OR anti-angiogenetic OR bevacizumab OR avastin OR endostatin OR VEGFR inhibitor.” The titles and abstracts of collected articles were reviewed, and impertinent studies were excluded. In addition, the reference lists of relevant studies were manually examined for the identification of eligible studies. Only the latest versions of duplicate publications were included.

Phase II and III randomized controlled clinical trials (RCTs) were included. The trials included an intervention arm (therapy of interest+ standard ET) and control arm (standard ET+ placebo). ET included selective estrogen receptor modulators (tamoxifen), aromatase inhibitors (anastrozole, letrozole, and exemestane), selective estrogen receptor downregulators (fulvestrant), and ovarian function inhibition (OFI) for premenopausal women. The study treatment was administered until clinical disease progression, unacceptable toxicity, study withdrawal, completion, or termination. The study population included adult women aged≥18 years with advanced or metastatic HR⁺/HER2⁻ breast cancer resistant to previous ET in either adjuvant or advanced setting. Non-English articles, reviews, letters to editors, cohort studies, case series, case reports, and laboratory studies were excluded.

Outcomes

For this meta-analysis, the primary outcome was progression-free survival (PFS) defined as the duration from randomization to the first identified disease progression or death from any cause. In studies about CDK4/6 inhibitors, primary outcomes included overall survival (OS), which was defined as the duration from randomization to the date of death. Secondary outcomes were tumor response rates and toxicity. Tumor response rates included (1) objective response rate (ORR) defined as the ratio of patients achieving a complete or partial response as their best response and (2) clinical benefit rate (CBR) defined as the ratio of patients with a complete or partial response or with a stable disease as their best response during treatment as evaluated by the Response Evaluation Criteria in Solid Tumors version 1.1 [¹¹]. Toxicities were reported and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.

Quality assessment

All included RCTs were systematically assessed using the Cochrane Collaboration Risk of Bias Tool. The major items examined were as follows: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other potential threats to validity.

Data extraction

Two reviewers extracted data from eligible studies independently. In case of disagreement, a third reviewer was consulted to reach consensus. Data were collected with respect to the following aspects: (1) publication information including the last name of first author, year of publication, and registered name of the trial; (2) basic characteristics of studies, such as sample size, category of therapy, study design, and duration of follow-up; (3) study outcomes, including the median PFS of both arms, hazard ratio (HR), its 95% confidence interval (CI), P value, number of cases with objective response, clinical benefit, and≥grade 3 adverse events in each arm. Specifically, for studies about CDK4/6 inhibitors, the median OS (or survival rate at given time point if median OS has not been reached) of both arms, HR, 95% CI, and P value were extracted. If data on HR and 95% CI was not available, the number of progression/death events and the size of each group were collected for the calculation of HR as previously described [¹²].

Statistical analysis

To evaluate the heterogeneity among included studies, Cochran’s Q test and Higgins I-squared statistic were used. In case of substantial heterogeneity detected (P<0.05), a random effect model was adopted to pool the estimated effect size (ES). If between-study heterogeneity was absent (P>0.05), a fixed effect model was then applied to the calculation of the pooled ES. The funnel plot and the Egger’s bias test were used in evaluating publication bias. All P values were two-sided, and P<0.05 was considered statistically significant. All of the analyses were conducted using STATA version 15 (Stata, College Station, TX, USA).

Results

Literature search and study characteristics

The step-wise description of literature screening and study selection is shown in Fig. 1. A total of 26 randomized trials were eligible and included, of which eight trials were about CDK4/6 inhibitors, four were about PI3K inhibitors, three were about mTOR inhibitors, four were about TKIs, and three were about anti-angiogenesis agents. Two studies on monoclonal antibody and two studies on HDAC inhibitors were discussed separately. Data on 10 347 patients with HR⁺/HER2⁻ advanced breast cancer were pooled in the meta-analysis. The characteristics of the studies are summarized in Table 1.

Risk-of-bias assessment

Table S1 shows the assessments of individual studies using the Cochrane Collaboration Risk of Bias Tool. Generally, the risk of bias was low, especially in terms of randomization and blinding. However, the BELLA-3 study did not report the procedures of sequence generation and allocation [¹³], and the study NCT00454805 by Hyams et al. failed to specify its blinding status [¹⁴]. Data on outcomes was incomplete in the studies by Robertson and Ibrahim [¹⁵,¹⁶], and the study by Ibrahim was not blinded.

Outcomes

CDK 4/6 inhibitor

For CDK 4/6 inhibitors, eight trials with 4634 patients were included in the present analysis. Data on outcomes were complete. Three trials were on palbociclib, three on ribociclib, and two on abemaciclib. No between-study heterogeneity was detected. The addition of CDK 4/6 inhibitor to ET was associated with a statistically significant reduction in the risk of progression (pooled HR 0.547, 95% CI 0.502−0.596, P<0.001, I² = 0.0%, Fig. 2A). We pooled the available data on overall survival (OS) from five trials (Table S2, N = 2807) and found treatment with CDK4/6 inhibitor and ET significantly reduced the risk of mortality (pooled HR 0.755, 95% CI 0.671−0.849, P<0.001, I² = 0.0%, Fig. S1). On response rate, a statistically significant improvement in ORR was observed after the addition of CDK 4/6 inhibitor compared with standard ET alone (pooled odds ratio (OR) 1.478, 95% CI 1.347–1.622, P<0.001, I² = 43.9%, Fig. 2B). Moreover, combining ET with CDK 4/6 inhibitor led to moderate improvement in CBR (pooled OR 1.201, 95% CI 1.115−1.294, P<0.001, I² = 69.2%, Fig. 2C). A significant increase in the risk of adverse events (AEs) with grade of≥3 was identified (pooled OR 3.280, 95% CI 2.575−4.180, P<0.001, I² = 85.7%, Fig. 2D).

PI3K inhibitor

Four trials with a population of 2379 patients were pooled. SOLAR-1 study enrolled two cohorts, cohort 1 (N = 341) comprising of patients with PIK3CA mutation while cohort 2 without (N = 230) [¹⁷]. In FERGI study, part I (N = 168) enrolled patients irrespective of their PIK3CA status, whereas part II (N = 61) only enrolled patients with positive PIK3CA mutation [¹⁸]. Given that PIK3CA mutation status might associate with a higher benefit of PI3K inhibitor, subgroup analysis was performed according to PIK3CA mutation status. In the PIK3CA-mutated group, the addition of PI3K inhibitor reduced risk in disease progression comparing to ET alone (pooled HR 0.686, 95% CI 0.586−0.803, P<0.001, I² = 42.6%, Fig. 3A). ORR was significantly improved (pooled OR 1.844, 95% CI 1.285−2.645, P = 0.001, I² = 0.0%, Fig. 3B) but not for CBR (pooled OR 1.066, 95% CI 0.756−1.502, P = 0.715, I² = 70.2%, Fig. 3C). In the group without PIK3CA-mutated cancer, PI3K inhibitor plus ET mildly decreased the risk of disease progression (pooled HR 0.819, 95% CI 0.701−0.956, P = 0.011, I² = 0.0%, Fig. 3D). No benefit in response rate was derived by adding PI3K inhibitors (for ORR, pooled OR 0.942, 95% CI 0.552−1.610, P = 0.828, I² = 46.9%, Fig. 3E, data were lacking for CBR in PIK3CA nonmutant patients in these trials). Furthermore, the addition of PI3K inhibitors to ET was associated with increased risk of toxicity (AE grade≥3, pooled OR 2.154, 95% CI 1.970−2.356, P<0.001, I² = 37.1%, Fig. 3F).

mTOR inhibitor

After screening and literature review, three RCTs were identified (N = 1947), two of which evaluated everolimus and one evaluated temsirolimus. A trend of risk reduction in disease progression was observed after the addition of mTOR inhibitors (pooled HR 0.606, 95% CI 0.365−1.008, P = 0.054, I² = 93.6%, Fig. 4A). However, no benefit was shown in ORR (pooled OR 1.943, 95% CI 0.523−7.224, P = 0.322, I² = 87.9%, Fig. 4B) or CBR (pooled OR 1.389, 95% CI 0.843−2.289, P = 0.197, I² = 93.1%, Fig. 4C). Meanwhile, the risk of treatment-related toxicity was numerically increased after the addition of mTOR inhibitors (AE grade≥3, pooled OR 2.579, 95% CI 0.739−8.999, P = 0.137, I² = 98.0%, Fig. 4D). Notably, great between-study heterogeneity was present throughout all outcome analyses.

TKI

Four studies with 608 patients were identified. Two of them assessed gefitinib, an epidermal growth factor receptor (EGFR) inhibitor [¹⁹,²⁰]. One trial explored the efficacy of dovitinib and fibroblast growth factor receptor (FGFR) inhibitor, in combination with ET [²¹]. Another study involved vandetanib, an inhibitor of VEGF, EGFR, and RET signaling [²²]. The addition of TKI to ET resulted in a statistically significant reduction in the risk of progression (pooled HR 0.787, 95% CI 0.638−0.971, P = 0.026, I² = 0.1%, Fig. S2A). The addition of TKI was not associated with benefit in ORR (pooled OR 0.770, 95% CI 0.243−2.441, P = 0.658, I² = 66.3%, Fig. S2B) or CBR (pooled OR 1.130, 95% CI 0.931−1.371, P = 0.217, I² = 57.7%, Fig. S2C), but was related to the elevated risk of AEs (AE grade≥3, pooled OR 2.225, 95% CI 1.682−2.943, P<0.001, I² = 0.0%, Fig. S2D).

Anti-angiogenesis agents

Three RCTs were included in the analysis (N = 779), two of which were trials (Alliance and LEA study) on bevacizumab [²³,²⁴] and one on cediranib [¹⁴]. A statistically significant decrease in the risk of progression was observed after the addition of anti-angiogenesis agents (pooled HR 0.794, 95% CI 0.672−0.938, P = 0.007, I² = 0.0%, Fig. S3A). A mild improvement in ORR (pooled OR 1.582, 95% CI 1.255−1.993, P<0.001, I² = 0.0%, Fig. S3B) was observed, but not in CBR (pooled OR 1.079, 95% CI 0.965−1.207, P = 0.182, I² = 0.0%, Fig. S3C). The addition of anti-angiogenetic targeted therapy was associated with statistically higher risk of toxicity (AE grade≥3, pooled OR 3.433, 95% CI 2.657−4.435, P<0.001, I² = 40.0%, Fig. S3D).

Other targeted therapies combining with ET

Two RCTs with consistent findings on monoclonal antibodies were reviewed. In a trial of 156 patients with HR⁺/HER⁻ ABC, Robertson et al. evaluated addition of ganitumab, a blocker of insulin-like growth factor-1 receptor (IGF-1R), to ET [¹⁶]. PFS, tumor response rates and incidence of toxicities did not differ significantly between two arms, but overall survival was poor in the ganitumab group. No further development was performed thereafter. Another trial by Ibrahim et al. (N = 110) assessing AS1402 targeting the aberrantly glycosylated antigen MUC1 was terminated in advance due to the trend toward early disease progression in the experimental arm, confirmed later in their final analysis [¹⁵].

Two RCTs on HDAC inhibitors were identified. Yardley et al. (N = 130) demonstrated a trend toward improved PFS (HR 0.73, 95% CI 0.5−1.07, P = 0.11) by adding entinostat to exemestane in ER+ ABC, with moderately higher rates of grade 3/4 toxicities [²⁵]. One phase III trial (N = 365) evaluating tucidinostat plus exemestane in advanced hormone receptor-positive breast cancer was recently published [²⁶]. The addition of tucidinostat improved the median PFS from 3.8 months to 7.4 months (HR 0.75, 95% CI 0.58−0.98, P = 0.033) with increased risk of toxicities (OR 4.562, 95% CI 3.038−6.852).

Discussion

For decades the paradigm in management of HR⁺/HER2⁻ advanced breast cancer has been endocrine therapy with various mechanisms [²⁷]. Inevitably, at some point during the disease course, patients develop endocrine resistance regardless of initial response. Despite the limited efficacy and apparent toxicities of chemotherapy, it remains the only option after the failure of ET regimens. Numerous molecular signaling pathways underpinning endocrine resistance were discovered, and new compounds targeting these pathways have been developed to overcome resistance to ET. In recent years, these targeted therapies have been evaluated in clinical studies, but inconsistent findings have been obtained. In this meta-analysis and systematic review, we collected and pooled data from randomized trials assessing the efficacy of targeted therapies and ET in comparison with therapies using ET alone in HR⁺/HER2⁻ ABC. Analyses were performed based on the separate categories of therapy in order that therapy-specific evidence for clinical practice could be obtained.

CDK 4/6 inhibitor

Cell cycle modulation using CDK 4/6 inhibitors to block the transition from G₁ into S phase are potent in HR⁺/HER2⁻ ABC [²⁸]. Our analysis validated that adding CDK4/6 inhibitors to ET significantly improved survival and tumor response, but this effect was accompanied with moderately elevated risk of toxicities. Given the high quality of trials, data set with a large sample size, and absence of inter-study heterogeneity, the results were considered to be robust, providing further evidence to support clinical application. Based on the notable benefit in PFS [²⁹–³²], CDK 4/6 inhibition has been approved in the first/second line treatment of ER⁺/HER2⁻ ABC in combination with AI or fulvestrant. Despite their efficacy, toxicities, most commonly hematologic toxicity, should be considered (neutropenia 40%−80%, leukopenia 28%−50%) [¹⁹,³²–³⁵]. Abemaciclib displayed a distinct safety profile, and neutropenia, diarrhea, nausea, and fatigue were the most common AEs [³²,³⁶]. The high incidence of neutropenia was not complicated by infections and was manageable generally.

mTOR inhibitor

mTOR signaling is important to the mediation of resistance to endocrine treatment. mTOR inhibitors include rapalogues (everolimus and temsirolimus) and ATP-competitive inhibitors, and the versatility of the former has been demonstrated in phase III clinical trials. However, in our analysis, no significant benefit in PFS and tumor response was observed after the addition of mTOR inhibitors to ET. The results should be interpreted with caution, given the marked heterogeneity among the three trials. The majority of the participants in the HORIZON study [³⁷] were endocrine therapy-naïve (about 60%), whereas GINECO [³⁸] and BOLERO-2 [³⁹] studies enrolled patients who progressed or recurred on previous nonsteroidal aromatase inhibitors (NSAIs). In the GINECO and BOLERO-2 studies, everolimus was administered daily continuously. In the HORIZON study, temsirolimus was dosed intermittently, and this procedure possibly led to the suboptimal inhibition of mTOR signaling. Although everolimus has been approved for patients who are resistant to NSAIs, further research is needed to identify predictive markers for the selection of the right population.

PI3K inhibitor

Preclinical studies have indicated regulatory feedback loops involving PI3K/Akt/mTOR pathway and found that these loops eventually lead to the failure of potent mTOR inhibitors. Approaches targeting mTOR pathway upstream are theoretically attractive. PI3K inhibitors under clinical evaluation include pan-PI3K [⁷,¹³,¹⁸] and isoform-specific [¹⁷] inhibitors. Given that PIK3CA mutation, as shown in SOLAR-1 and BELLE-3 study, can be a strong indicator of sensitivity to PI3K inhibitor [¹⁷], we performed subgroup analysis based on PIK3CA mutation status, which indicated that adding PI3K inhibitors to fulvestrant significantly improves PFS in PIK3CA mutant patients rather than the nonmutant patients. Moderate heterogeneity was present among involved studies. The possible reasons are the differences in efficacy and safety profiles among the classes of PI3K inhibitors. Given the limited benefit and increased toxicity, further research is needed to identify the optimal population and dosing sequence.

TKI and anti-angiogenesis agents and monoclonal antibody

For compounds targeting oncogenic cellular receptors, such as EGFR, FGFR, VEGFR, and IGF-1R, regardless of small-molecule kinase inhibitor or monoclonal antibody, we derived similar results from pooled data. Mild reduction in risk of disease progression and increased risk of AEs were observed with TKI plus ET. Findings were similar to those of anti-angiogenesis agents. Studies on various monoclonal antibodies suggested disappointing results, and little improvement in clinical outcome was observed. Thus, future studies on biomarkers discriminating potential responders are warranted.

HDAC inhibitor

Another promising approach to overcome endocrine resistance in HR⁺/HER⁻ ABC is to re-sensitize cancer cells to estrogen depletion by using HDAC inhibitors. Previous work showed epigenetic modifications, such as histone deacetylation, can induce the loss or suppressed expression of hormone receptors in breast cancer cells [⁴⁰]. In vitro and in vivo, HDAC inhibitors can increase the expression of ER and aromatase restoring the sensitivity of breast cancer cells to hormonal blockade [⁴⁰]. Adding entinostat or tucidinostat to exemestane improved the median PFS, and significant improvements were observed in patients who were resistant to NSAI [²⁵,²⁶]. Increased protein acetylation in peripheral blood mononuclear cells might indicate sensitivity to entinostat [²⁵].

References

[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394–424

[2] Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA, Cronin KA. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst 2014; 106(5): dju055

[3] Shah AN, Cristofanilli M. The growing role of CDK4/6 inhibitors in treating hormone receptor-positive advanced breast cancer. Curr Treat Options Oncol 2017; 18(1): 6

[4] Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, Schiff R. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 2004; 96(12): 926–935

[5] Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ, Cao X, Kalyana-Sundaram S, Wang R, Ning Y, Hodges L, Gursky A, Siddiqui J, Tomlins SA, Roychowdhury S, Pienta KJ, Kim SY, Roberts JS, Rae JM, Van Poznak CH, Hayes DF, Chugh R, Kunju LP, Talpaz M, Schott AF, Chinnaiyan AM. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet 2013; 45(12): 1446–1451

[6] Fribbens C, O’Leary B, Kilburn L, Hrebien S, Garcia-Murillas I, Beaney M, Cristofanilli M, Andre F, Loi S, Loibl S, Jiang J, Bartlett CH, Koehler M, Dowsett M, Bliss JM, Johnston SR, Turner NC. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol 2016; 34(25): 2961–2968

[7] Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012; 366(6): 520–529

[8] Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M, PALOMA3 Study Group. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 2015; 373(3): 209–219

[9] Saxena NK, Sharma D. Epigenetic reactivation of estrogen receptor: promising tools for restoring response to endocrine therapy. Mol Cell Pharmacol 2010; 2(5): 191–202

[10] Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490(7418): 61–70

[11] Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45(2): 228–247

[12] Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998; 17(24): 2815–2834

[13] Di Leo A, Johnston S, Lee KS, Ciruelos E, Lønning PE, Janni W, O’Regan R, Mouret-Reynier MA, Kalev D, Egle D, Csőszi T, Bordonaro R, Decker T, Tjan-Heijnen VCG, Blau S, Schirone A, Weber D, El-Hashimy M, Dharan B, Sellami D, Bachelot T. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2018; 19(1): 87–100

[14] Hyams DM, Chan A, de Oliveira C, Snyder R, Vinholes J, Audeh MW, Alencar VM, Lombard J, Mookerjee B, Xu J, Brown K, Klein P. Cediranib in combination with fulvestrant in hormone-sensitive metastatic breast cancer: a randomized Phase II study. Invest New Drugs 2013; 31(5): 1345–1354

[15] Ibrahim NK, Yariz KO, Bondarenko I, Manikhas A, Semiglazov V, Alyasova A, Komisarenko V, Shparyk Y, Murray JL, Jones D, Senderovich S, Chau A, Erlandsson F, Acton G, Pegram M. Randomized phase II trial of letrozole plus anti-MUC1 antibody AS1402 in hormone receptor-positive locally advanced or metastatic breast cancer. Clin Cancer Res 2011; 17(21): 6822–6830

[16] Robertson JF, Ferrero JM, Bourgeois H, Kennecke H, de Boer RH, Jacot W, McGreivy J, Suzuki S, Zhu M, McCaffery I, Loh E, Gansert JL, Kaufman PA. Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial. Lancet Oncol 2013; 14(3): 228–235

[17] André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B, Yamashita T, Lu YS, Inoue K, Takahashi M, Pápai Z, Longin AS, Mills D, Wilke C, Hirawat S, Juric D,   SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med 2019; 380(20): 1929–1940

[18] Krop IE, Mayer IA, Ganju V, Dickler M, Johnston S, Morales S, Yardley DA, Melichar B, Forero-Torres A, Lee SC, de Boer R, Petrakova K, Vallentin S, Perez EA, Piccart M, Ellis M, Winer E, Gendreau S, Derynck M, Lackner M, Levy G, Qiu J, He J, Schmid P. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2016; 17(6): 811–821

[19] Cristofanilli M, Valero V, Mangalik A, Royce M, Rabinowitz I, Arena FP, Kroener JF, Curcio E, Watkins C, Bacus S, Cora EM, Anderson E, Magill PJ. Phase II, randomized trial to compare anastrozole combined with gefitinib or placebo in postmenopausal women with hormone receptor-positive metastatic breast cancer. Clin Cancer Res 2010; 16(6): 1904–1914

[20] Osborne CK, Neven P, Dirix LY, Mackey JR, Robert J, Underhill C, Schiff R, Gutierrez C, Migliaccio I, Anagnostou VK, Rimm DL, Magill P, Sellers M. Gefitinib or placebo in combination with tamoxifen in patients with hormone receptor-positive metastatic breast cancer: a randomized phase II study. Clin Cancer Res 2011; 17(5): 1147–1159

[21] Musolino A, Campone M, Neven P, Denduluri N, Barrios CH, Cortes J, Blackwell K, Soliman H, Kahan Z, Bonnefoi H, Squires M, Zhang Y, Deudon S, Shi MM, André F. Phase II, randomized, placebo-controlled study of dovitinib in combination with fulvestrant in postmenopausal patients with HR⁺, HER2⁻ breast cancer that had progressed during or after prior endocrine therapy. Breast Cancer Res 2017; 19(1): 18

[22] Clemons MJ, Cochrane B, Pond GR, Califaretti N, Chia SK, Dent RA, Song X, Robidoux A, Parpia S, Warr D, Rayson D, Pritchard KI, Levine MN. Randomised, phase II, placebo-controlled, trial of fulvestrant plus vandetanib in postmenopausal women with bone only or bone predominant, hormone-receptor-positive metastatic breast cancer (MBC): the OCOG ZAMBONEY study. Breast Cancer Res Treat 2014; 146(1): 153–162

[23] Dickler MN, Barry WT, Cirrincione CT, Ellis MJ, Moynahan ME, Innocenti F, Hurria A, Rugo HS, Lake DE, Hahn O, Schneider BP, Tripathy D, Carey LA, Winer EP, Hudis CA. Phase III trial evaluating letrozole as first-line endocrine therapy with or without bevacizumab for the treatment of postmenopausal women with hormone receptor-positive advanced-stage breast cancer: CALGB 40503 (Alliance). J Clin Oncol 2016; 34(22): 2602–2609

[24] Martín M, Loibl S, von Minckwitz G, Morales S, Martinez N, Guerrero A, Anton A, Aktas B, Schoenegg W, Muñoz M, Garcia-Saenz JÁ, Gil M, Ramos M, Margeli M, Carrasco E, Liedtke C, Wachsmann G, Mehta K, De la Haba-Rodriguez JR. Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: the letrozole/fulvestrant and avastin (LEA) study. J Clin Oncol 2015; 33(9): 1045–1052

[25] Yardley DA, Ismail-Khan RR, Melichar B, Lichinitser M, Munster PN, Klein PM, Cruickshank S, Miller KD, Lee MJ, Trepel JB. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J Clin Oncol 2013; 31(17): 2128–2135

[26] Jiang Z, Li W, Hu X, Zhang Q, Sun T, Cui S, Wang S, Ouyang Q, Yin Y, Geng C, Tong Z, Cheng Y, Pan Y, Sun Y, Wang H, Ouyang T, Gu K, Feng J, Wang X, Wang S, Liu T, Gao J, Cristofanilli M, Ning Z, Lu X. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019; 20(6): 806–815

[27] Başaran GA, Twelves C, Diéras V, Cortés J, Awada A. Ongoing unmet needs in treating estrogen receptor-positive/HER2-negative metastatic breast cancer. Cancer Treat Rev 2018; 63: 144–155

[28] Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G, Slamon DJ. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 2009; 11(5): R77

[29] Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2015; 16(1): 25–35

[30] Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Blackwell KL, André F, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Petrakova K, Hart LL, Villanueva C, Chan A, Jakobsen E, Nusch A, Burdaeva O, Grischke EM, Alba E, Wist E, Marschner N, Favret AM, Yardley D, Bachelot T, Tseng LM, Blau S, Xuan F, Souami F, Miller M, Germa C, Hirawat S, O’Shaughnessy J. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 2016; 375(18): 1738–1748

[31] Dickler MN, Tolaney SM, Rugo HS, Cortés J, Diéras V, Patt D, Wildiers H, Hudis CA, O’Shaughnessy J, Zamora E, Yardley DA, Frenzel M, Koustenis A, Baselga J. MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR⁺/HER2⁻ metastatic breast cancer. Clin Cancer Res 2017; 23(17): 5218–5224

[32] Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke EM, Frenzel M, Lin Y, Barriga S, Smith IC, Bourayou N, Llombart-Cussac A. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR⁺/HER2⁻ advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 2017; 35(25): 2875–2884

[33] Sobhani N, D’Angelo A, Pittacolo M, Roviello G, Miccoli A, Corona SP, Bernocchi O, Generali D, Otto T. Updates on the CDK4/6 inhibitory strategy and combinations in breast cancer. Cells 2019; 8(4): 321

[34] Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martín M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Vidam G, Wang Y, Rodriguez Lorenc K, Miller M, Taran T, Jerusalem G. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol 2018; 36(24): 2465–2472

[35] Sonke GS, Hart LL, Campone M, Erdkamp F, Janni W, Verma S, Villanueva C, Jakobsen E, Alba E, Wist E, Favret AM, Bachelot T, Hegg R, Wheatley-Price P, Souami F, Sutradhar S, Miller M, Germa C, Burris HA. Ribociclib with letrozole vs letrozole alone in elderly patients with hormone receptor-positive, HER2-negative breast cancer in the randomized MONALEESA-2 trial. Breast Cancer Res Treat 2018; 167(3): 659–669

[36] Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Trédan O, Chen SC, Manso L, Freedman OC, Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol 2017; 35(32): 3638–3646

[37] Wolff AC, Lazar AA, Bondarenko I, Garin AM, Brincat S, Chow L, Sun Y, Neskovic-Konstantinovic Z, Guimaraes RC, Fumoleau P, Chan A, Hachemi S, Strahs A, Cincotta M, Berkenblit A, Krygowski M, Kang LL, Moore L, Hayes DF. Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol 2013; 31(2): 195–202

[38] Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaëth D, Legouffe E, Allouache D, El Kouri C, Pujade-Lauraine E. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 2012; 30(22): 2718–2724

[39] Pritchard KI, Burris HA 3rd, Ito Y, Rugo HS, Dakhil S, Hortobagyi GN, Campone M, Csöszi T, Baselga J, Puttawibul P, Piccart M, Heng D, Noguchi S, Srimuninnimit V, Bourgeois H, Gonzalez Martin A, Osborne K, Panneerselvam A, Taran T, Sahmoud T, Gnant M. Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly patients with HER2-negative, hormone receptor-positive breast cancer in BOLERO-2. Clin Breast Cancer 2013; 13(6): 421–432.e8

[40] Sabnis GJ, Goloubeva O, Chumsri S, Nguyen N, Sukumar S, Brodie AM. Functional activation of the estrogen receptor-a and aromatase by the HDAC inhibitor entinostat sensitizes ER-negative tumors to letrozole. Cancer Res 2011; 71(5): 1893–1903

RIGHTS & PERMISSIONS

Higher Education Press