Systematic literature review of clinical trials of endocrine therapies for premenopausal women with metastatic HR+ HER2− breast cancer

Several endocrine‐based therapies have recently been evaluated as treatments for premenopausal women with hormone‐receptor‐positive/human‐epidermal‐growth‐factor‐receptor 2 negative (HR+/HER2−) metastatic breast cancer (mBC). We conducted a systematic review and assessed the feasibility of an indirect treatment comparison (ITC) to characterize the comparative efficacy of endocrine‐based therapies in this setting. A systematic literature review (SLR) of Medline, EMBASE, Cochrane Library and key conferences was performed to identify randomized clinical trials (RCTs) satisfying the following criteria: (a) included pre/perimenopausal women with HR+/HER2− mBC, (b) included endocrine‐based therapies, (c) reported efficacy, safety, or quality of life outcomes, and (d) was published in 2007 or later (when HER2 testing was standardized). The clinical and methodological similarities across trials were assessed to evaluate the feasibility of an ITC. Four RCTs (PALOMA‐3, MONARCH‐2, KCSG BR10‐04 and MONALEESA‐7) and eight regimens (palbociclib + fulvestrant + goserelin, fulvestrant + goserelin, abemaciclib + fulvestrant + gonadotropin‐releasing hormone agonist [GnRHa], fulvestrant + GnRHa, anastrozole + goserelin, goserelin, ribociclib + NSAI/tamoxifen + goserelin and NSAI/tamoxifen + goserelin) were selected. MONALEESA‐7 was the only phase 3 trial investigating endocrine‐based therapies as first‐line in only pre/perimenopausal women with HR+/HER2− mBC; the other three trials focused on the ET‐failure setting and their pre/perimenopausal populations were relatively small. ITCs were methodologically unfeasible due to critical differences in treatment settings and lack of common comparators across trials. Therefore, we were not able to characterize the relative efficacy of the different endocrine‐based therapies available in the premenopausal HR+/HER2− mBC setting. This systematic review provides a comprehensive assessment of the available trial evidence on the efficacy and safety of endocrine‐based therapies for premenopausal women with HR+/HER2− mBC. Only four trials have reported relevant data in this setting, and MONALEESA‐7 is currently the only trial focused on premenopausal HR+ HER2− mBC in the first‐line setting.


| INTRODUC TI ON
Breast cancer (BC) is the most common cancer among women in the United States, with approximately 252 710 new cases and 40 610 deaths in 2017. 1 Hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2−) is the most common BC subtype, accounting for approximately 70% of BC cases. 2 More than 90% of BC cases are detected in early stage (stage I-II), with approximately one-quarter diagnosed in premenopausal women, 3 although the majority of cases progress to advanced or metastatic disease. 4 A recent study reported that about one third of de novo metastatic BC (mBC) cases were diagnosed in premenopausal women. 5 Typically, younger women are diagnosed with BC less often than older women. For instance, 20% of all breast cancers in the USA are diagnosed in women younger than 50 years, 6 although in other regions, such as the Middle East and Latin America, the estimated percentages are almost 50%. 7,8 However, BC in premenopausal women tend to be more often diagnosed in a higher stage compared to BC in postmenopausal women, 9,10 partly due to the lack of routine screening mammography guidelines for younger women. Also, younger women tend to have tumors with a more aggressive phenotype and poor prognostic features; recent studies have reported that women <40 years had worse survival outcomes than women of older age groups. 10,11 Large registrational trials assessing the efficacy of endocrine therapy for mBC have generally excluded premenopausal women.
As a result, clinical data for premenopausal women remains remarkably limited and treatment recommendations for premenopausal patients has been largely based on studies in the postmenopausal population. Consequently, current treatment guidelines for premenopausal patients often recommend chemical or surgical castration, thus converting these patients to postmenopausal from a physiological perspective. Therefore, the task of finding optimal strategies for endocrine-based therapies in premenopausal HR+/ HER2− mBC remains an important challenge.
Among premenopausal women with mBC, the National Comprehensive Cancer Network (NCCN) guidelines recommend tamoxifen or toremifene alone, or ovarian ablation or suppression (eg, goserelin) plus endocrine-based therapy, similar to guidelines for postmenopausal women. 12 The endocrine-based therapy options include endocrine monotherapy (ET) and ET + targeted therapy (TT, eg, palbociclib, ribociclib and abemaciclib) in the first-line setting or after failure with ET. Since BC in premenopausal women tends to be more aggressive, chemotherapy (CT) can also be part of the first-line treatment plan. 13,14 Recent phase 3 trials in this setting include PALOMA-3, 15 MONARCH-2, 16 and MONALEESA-7. 17 PALOMA-3 is a phase 3 randomized controlled trial (RCT) that assessed the efficacy and safety of palbociclib + fulvestrant + goserelin vs placebo + fulvestrant + goserelin in a subgroup of 108 pre/perimenopausal women with HR+/HER2− mBC who had progressed on prior ET. The median progression-free survival (PFS) in the palbociclib and placebo arms were 9.5 and 5.6 months respectively (hazard ratio [HR], 0.50). MONARCH-2 is a phase 3 RCT that compared abemaciclib + fulvestrant + GnRHa (gonadotropin-releasing hormone agonist, eg, goserelin) vs placebo + fulvestrant+GnRHa in a subgroup of 114 pre/perimenopausal women. The median PFS in the abemaciclib arm was not yet reached as of the latest report, and was 10.5 months for the placebo arm (HR = 0.45). Finally, MONALEESA-7 is also a phase 3 RCT that compared ribociclib + NSAI/tamoxifen + goserelin vs placebo + NSAI/tamoxifen + goserelin as the first-line therapy among premenopausal women with HR+/HER2− mBC. The PFS in the ribociclib and placebo arms was 23.8 and 13.0 months respectively (HR = 0.55). This is the first phase 3 trial investigating a CDK4/6 inhibitor in only pre/perimenopausal women with mBC in the first-line setting, and included a large population of 672 patients.
Despite the abundance of evidence in the postmenopausal setting, 18 limited data exist regarding the efficacy of endocrine-based therapies among premenopausal women with HR+/HER2− mBC. With the recent changes in the treatment landscape in this setting, there is a need for patients, clinicians, and payers to assess the relative benefits and risks of the emerging and currently available endocrine-based therapies. Such an evaluation has to comprehensively examine all the available evidence to characterize the comparative efficacy of the treatments. However, given the lack of head-to-head comparison data of endocrine-based therapies for HR+/HER2− mBC, indirect comparison methods (eg, network meta-analysis [NMA]) can be used to synthesize information on multiple treatment alternatives across different RCTs to evaluate the comparative efficacy and safety of all these treatments.
To conduct these indirect treatment comparisons (ITC), a comprehensive literature search is needed to assess the feasibility of such analyses. To our knowledge, no previous study has performed a systematic literature review (SLR) of ETs in premenopausal women with HR+/HER2− mBC, nor examined the comparative efficacy and safety of these treatments via ITC. Therefore, the objectives of this study were to systematically review the literature to summarize the evidence on therapies for premenopausal women with HR+/HER2− mBC. Only four trials have reported relevant data in this setting, and MONALEESA-7 is currently the only trial focused on premenopausal HR+ HER2− mBC in the first-line setting.

K E Y W O R D S
hormone receptor positive/human epidermal growth factor receptor-2 negative (HR+/HER2−), metastatic breast cancer, premenopausal, systematic literature review efficacy and safety of existing endocrine-based therapies for premenopausal HR+/HER2− mBC, and to evaluate the feasibility of an ITC to quantitatively synthesize their efficacy and safety in this setting. To reduce patient heterogeneity, the search was restricted to articles published on or after 2007, the year the American Society of Clinical Oncology/College of American Pathologists developed the guidelines for standardizing HER2 testing. 19 The SLR was designed, performed, and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. 20 Study quality was assessed using the Cochrane Collaboration's tool for assessing risk of bias. 21 The inclusion and exclusion criteria (Table 1) were defined a priori. Based on the inclusion and exclusion criteria listed in Table 1

| Data extraction
Study level information (eg, trial acronym, population), PFS outcomes (eg, HR and standard errors) and the reported baseline characteristics were extracted from selected studies. To ensure accuracy of the study selection and data extraction, literature screening and data extraction were performed by two researchers independently. A third researcher was consulted to reach a consensus if there was a disagreement on inclusion/exclusion decisions or extracted data. For the MONARCH-2 trial, the outcome data were obtained from the more recent reports at ASCO 2018, 16 and for MONALEESA-7, the extracted data were supplemented with information in the Clinical Study Report (CSR).

| Indirect treatment comparison assessment
To evaluate the feasibility of an ITC (eg, network meta-analysis or match-adjusted indirect comparison), included studies were examined to assess their clinical and methodological similarities. The between-trial similarity of the following elements were inspected during this assessment: patient population (eg, disease status, HR, and HER2 status); outcomes reported (eg, availability and defini-

| Study selection
The SLR identified three journal articles and three conference abstracts that met the eligibility criteria ( Figure 1). Two journal articles corresponded to PALOMA 3 trial, 15,22 and one journal article corresponded to the MONARCH-2 trial. 23 The three identified conference abstracts corresponded, respectively, to the PALOMA-3 trial, 24 MONALEESA-7 trial, 17 and KCSG BR 10-04 trial. 25 The baseline characteristics of the selected trials are summarized in Table 2 Key outcomes from all the selected trials are shown in Table 3, although several of these outcomes were not reported for some of the trials. PFS HR for the premenopausal population was re- Although there were differences between the PALOMA-3 and

| Quality assessment
Quality assessment of the identified RCTs were based on the criteria described in Table 4, adapted from the "Systematic reviews: CRD's guidance for undertaking reviews in health care" (University of York Centre for Reviews and Dissemination). 26 The included trials were all well-conducted and the risk of bias was low to moderate, with concealment of allocation (with the exception of KCSG BR10-04).
a Baseline characteristics are for the entire trial population. Trials with * have 100% pre-or peri-menopausal population or report baseline characteristics for the pre-or peri-menopausal population. b Age was reported as number and percentage for the following age groups: ≤40, 40-50, and >50 y old.  PFS results correspond to subgroup analysis that may be underpowered (in the case of MONARCH-2, the subgroup analyses in the premenopausal population was not pre-specified in the study protocol).
One of the limitations of the present study is that, due to the lack of clinical trial data available for the premenopausal HR+/HER2− mBC population, we could not perform an ITC of all the therapies in the studies identified in the literature search. Hence, it was not feasible to assess the relative efficacy of the different treatments available in this setting. Additionally, there were gaps in the reporting of patient characteristics or outcomes for the premenopausal population in some of the identified studies. is currently the only phase 3 trial focused on premenopausal HR+ HER2− mBC in the first-line setting. Efficacy results from the selected trials indicated that combining a CDK4/6 inhibitor with an endocrine monotherapy and a GnRHa led to improvements in PFS and ORR in premenopausal women with HR+/HER2− mBC in the first-line and ET-failure settings.

CO N FLI C T O F I NTE R E S T
OP-L, RA, OL, and ED are employees of Analysis Group Inc, which has received consultancy fees from Novartis. AAD, EP, and DC are employees of Novartis and may own stock/stock options. JAO received consultancy fees from Novartis.