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Visual Abstract. Addition of everolimus in the first-line treatment of premenopausal women with advanced breast cancer after disease progression while receiving selective estrogen receptor modulators: a randomized phase 2 clinical trial
Addition of everolimus in the first-line treatment of premenopausal women with advanced breast cancer after disease progression while receiving selective estrogen receptor modulators: a randomized phase 2 clinical trial
Figure 1.  CONSORT Diagram
CONSORT Diagram

ET indicates endocrine therapy.

Figure 2.  Kaplan-Meier Summary of Progression-Free Survival (PFS)
Kaplan-Meier Summary of Progression-Free Survival (PFS)

HR indicates hazard ratio.

Table 1.  Demographic and Baseline Disease Characteristics
Demographic and Baseline Disease Characteristics
Table 2.  Summary of Best Overall Responsea
Summary of Best Overall Responsea
1.
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Azim  HA  Jr, Michiels  S, Bedard  PL,  et al.  Elucidating prognosis and biology of breast cancer arising in young women using gene expression profiling.   Clin Cancer Res. 2012;18(5):1341-1351. doi:10.1158/1078-0432.CCR-11-2599 PubMedGoogle ScholarCrossref
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Liao  S, Hartmaier  RJ, McGuire  KP,  et al.  The molecular landscape of premenopausal breast cancer.   Breast Cancer Res. 2015;17:104. doi:10.1186/s13058-015-0618-8 PubMedGoogle ScholarCrossref
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Gabriel  CA, Domchek  SM.  Breast cancer in young women.   Breast Cancer Res. 2010;12(5):212. doi:10.1186/bcr2647 PubMedGoogle ScholarCrossref
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Bachelot  T, Bourgier  C, Cropet  C,  et al.  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. doi:10.1200/JCO.2011.39.0708 PubMedGoogle ScholarCrossref
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US Department of Health and Human Servies. Common terminology criteria for adverse events (CTCAE): version 4.03. Published June 14, 2010. Accessed July 19, 2021. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
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Cardoso  F, Senkus  E, Costa  A,  et al.  4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4).   Ann Oncol. 2018;29(8):1634-1657. doi:10.1093/annonc/mdy192PubMedGoogle ScholarCrossref
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Youlden  DR, Cramb  SM, Yip  CH, Baade  PD.  Incidence and mortality of female breast cancer in the Asia-Pacific region.   Cancer Biol Med. 2014;11(2):101-115. doi:10.7497/j.issn.2095-3941.2014.02.005PubMedGoogle Scholar
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Cardoso  F, Paluch-Shimon  S, Senkus  E,  et al.  5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5).   Ann Oncol. 2020;31(12):1623-1649. doi:10.1016/j.annonc.2020.09.010 PubMedGoogle ScholarCrossref
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Jeong  JH, Kim  JE, Ahn  JH,  et al.  Leuprorelin combined with letrozole with/without everolimus in ovarian-suppressed premenopausal women with hormone receptor–positive, HER2-negative metastatic breast cancer: the LEO study.   Eur J Cancer. 2021;144:341-350. doi:10.1016/j.ejca.2020.11.044 PubMedGoogle ScholarCrossref
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Spring  LM, Wander  SA, Andre  F, Moy  B, Turner  NC, Bardia  A.  Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future.   Lancet. 2020;395(10226):817-827. doi:10.1016/S0140-6736(20)30165-3PubMedGoogle ScholarCrossref
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Tripathy  D, Im  SA, Colleoni  M,  et al.  Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor–positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial.   Lancet Oncol. 2018;19(7):904-915. doi:10.1016/S1470-2045(18)30292-4 PubMedGoogle ScholarCrossref
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Loibl  S, Turner  NC, Ro  J,  et al.  Palbociclib combined with fulvestrant in premenopausal women with advanced breast cancer and prior progression on endocrine therapy: PALOMA-3 results.   Oncologist. 2017;22(9):1028-1038. doi:10.1634/theoncologist.2017-0072 PubMedGoogle ScholarCrossref
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Neven  P, Rugo  HS, Tolaney  SM,  et al. Abemaciclib for pre/perimenopausal women with HR+, HER2- advanced breast cancer.  J Clin Oncol. 2018;36(15_suppl):1002. doi:10.1200/JCO.2018.36.15_suppl.1002
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Lu  YS, Lee  KS, Chao  TY,  et al.  A phase Ib study of alpelisib or buparlisib combined with tamoxifen plus goserelin in premenopausal women with HR-positive HER2-negative advanced breast cancer.   Clin Cancer Res. 2021;27(2):408-417. PubMedGoogle Scholar
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Araki  K, Miyoshi  Y.  Mechanism of resistance to endocrine therapy in breast cancer: the important role of PI3K/Akt/mTOR in estrogen receptor–positive, HER2-negative breast cancer.   Breast Cancer. 2018;25(4):392-401. doi:10.1007/s12282-017-0812-x PubMedGoogle ScholarCrossref
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Boulay  A, Rudloff  J, Ye  J,  et al.  Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer.   Clin Cancer Res. 2005;11(14):5319-5328. doi:10.1158/1078-0432.CCR-04-2402 PubMedGoogle ScholarCrossref
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Yardley  DA, Noguchi  S, Pritchard  KI,  et al.  Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis.   Adv Ther. 2013;30(10):870-884. doi:10.1007/s12325-013-0060-1PubMedGoogle ScholarCrossref
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    Original Investigation
    August 26, 2021

    Effectiveness of Adding Everolimus to the First-line Treatment of Advanced Breast Cancer in Premenopausal Women Who Experienced Disease Progression While Receiving Selective Estrogen Receptor Modulators: A Phase 2 Randomized Clinical Trial

    Author Affiliations
    • 1Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
    • 2Department of Medical Oncology, Liaoning Cancer Hospital & Institute, Shenyang, China
    • 3Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
    • 4Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
    • 5Department of Breast Oncology, Hunan Cancer Hospital, Changsha, China
    • 6Department of Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
    • 7Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
    • 8Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
    • 9Department of Breast Oncology, Zhejiang Cancer Hospital, Hangzhou, China
    • 10Department of Breast Surgery, Peking University People’s Hospital, Beijing, China
    • 11Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
    • 12Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing, China
    • 13Department of Breast Oncology, Ruijin Hospital of Shanghai Jiaotong University, Shanghai, China
    • 14Department of Breast Oncology, The First Hospital of Jilin University, Changchun, China
    JAMA Oncol. 2021;7(10):e213428. doi:10.1001/jamaoncol.2021.3428
    Visual Abstract. Addition of everolimus in the first-line treatment of premenopausal women with advanced breast cancer after disease progression while receiving selective estrogen receptor modulators: a randomized phase 2 clinical trial
    Addition of everolimus in the first-line treatment of premenopausal women with advanced breast cancer after disease progression while receiving selective estrogen receptor modulators: a randomized phase 2 clinical trial
    Key Points

    Question  Is the addition of everolimus to endocrine therapy effective in the first-line treatment of hormone receptor (HR)–positive, ERBB2-negative premenopausal advanced breast cancer after disease progression during selective estrogen receptor modulator (SERM) treatment?

    Findings  In this randomized clinical trial of 199 premenopausal women with SERM-resistant, HR-positive, ERBB2-negative advanced breast cancer, those who received everolimus plus endocrine therapy (letrozole) had longer progression-free survival compared with those who received letrozole alone. The addition of everolimus to the same endocrine agent was effective even after disease progression.

    Meaning  Everolimus plus letrozole is effective in the first-line treatment of premenopausal patients with SERM-resistant, HR-positive, ERBB2-negative advanced breast cancer.

    Abstract

    Importance  The effectiveness of the mammalian target of rapamycin (mTOR) inhibitor everolimus in premenopausal women with hormone receptor (HR)–positive/ERBB2-negative advanced breast cancer who experienced disease progression while receiving selective estrogen receptor modulators (SERMs) is unknown.

    Objective  To compare the effectiveness of everolimus plus letrozole vs letrozole alone in premenopausal women with HR-positive/ERBB2-negative advanced breast cancer who experienced disease progression while receiving SERMs.

    Design, Setting, and Participants  The Everolimus Trial for Advanced Premenopausal Breast Cancer (MIRACLE) was a multicenter, open-label phase 2 randomized clinical trial of everolimus plus letrozole vs letrozole alone as first-line treatment conducted from December 8, 2014, to September 26, 2018. Participants included premenopausal women with HR-positive, ERBB2-negative advanced breast cancer who experienced disease progression while receiving SERMs. Analysis was performed on an intent-to-treat basis from January 5, 2015, to December 30, 2019.

    Exposures  Patients were randomly assigned in a 1:1 ratio to receive everolimus (10 mg orally once daily) plus letrozole (2.5 mg orally once daily) (n = 101) or letrozole alone (2.5 mg orally once daily) (n = 98). Both groups received goserelin, 3.6 mg, subcutaneously on day 1 of each 28-day cycle. Patients in the letrozole group were permitted to cross over to receive everolimus with letrozole if disease progression occurred.

    Main Outcomes and Measures  The primary end point was progression-free survival (PFS), defined as the time from randomization to confirmed disease progression or death due to any cause.

    Results  A total of 199 women (mean [SD] age, 44.3 [6.3] years) were randomized. Patients receiving everolimus plus letrozole achieved a significantly longer median PFS compared with those receiving letrozole alone (19.4 months [95% CI, 16.3-22.0 months] vs 12.9 months [95% CI, 7.6-15.7 months]; hazard ratio, 0.64 [95% CI, 0.46-0.89]; P = .008). A total of 56 of the 98 patients in the letrozole group (57.1%) were crossed over to also receive everolimus. The median PFS after crossover was 5.5 months (95% CI, 3.8-8.2 months).

    Conclusions and Relevance  In this randomized clinical trial, PFS was significantly longer among premenopausal patients with HR-positive/ERBB2-negative advanced breast cancer who received everolimus plus letrozole than among those who received letrozole alone. The results revealed that everolimus was effective even among patients receiving treatment with the same endocrine agent after disease progression.

    Trial Registration  ClinicalTrials.gov Identifier: NCT02313051

    Introduction

    The concept of overcoming endocrine resistance by inhibiting the phosphatidylinositol 3-kinase (PI3K)–protein kinase B (AKT)–mammalian target of rapamycin (mTOR) pathway was confirmed by the Breast Cancer Trials of Oral Everolimus–2 (BOLERO-2),1-3 in which combined treatment with the mTOR inhibitor everolimus plus exemestane resulted in longer progression-free survival (PFS) compared with exemestane treatment alone in postmenopausal women who had experienced disease progression while receiving previous treatment with another aromatase inhibitor (AI). This finding, followed by the success of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors in subsequent trials,4-7 thoroughly changed the treatment strategy in postmenopausal patients with hormone receptor (HR)–positive, ERBB2-negative advanced breast cancer.

    Although younger patients with breast cancer tend to present with a more aggressive form of the disease, premenopausal women are generally treated with endocrine therapy similar to that received by postmenopausal women (except for the addition of ovarian suppression).8 However, evidence suggests that there are important biological differences in breast cancer between premenopausal and postmenopausal women in terms of molecular alterations in genes associated with breast cancer, tumor-suppressor genes, and genes involved in signaling pathways.9-13 Premenopausal patients tend to be underrepresented in breast cancer clinical trials; thus, data for state-of-the-art treatments in this population are often limited. Furthermore, the activation of the PI3K-AKT-mTOR pathway is more likely to be enhanced in patients previously treated with AIs, exacerbating endocrine resistance.14 Given this background, whether mTOR inhibition can also overcome endocrine resistance in premenopausal women who experience disease progression after treatment with selective estrogen receptor modulators (SERMs) is unclear.

    We report the results of the phase 2 Everolimus Trial for Advanced Premenopausal Breast Cancer (MIRACLE), which was designed to investigate the effectiveness of the combination of an mTOR inhibitor and endocrine therapy in premenopausal SERM-resistant patients. Furthermore, we evaluated the effectiveness of the addition of an mTOR inhibitor to endocrine therapy for patients who were treated again with the same endocrine agent after disease progression.

    Methods
    Study Design and Treatments

    The MIRACLE trial (NCT02313051) was a national, multicenter, open-label phase 2 randomized clinical trial conducted from December 8, 2014, to September 26, 2018, that compared everolimus combined with letrozole vs letrozole alone in premenopausal women with HR-positive and ERBB2-negative advanced breast cancer. The trial protocol (Supplement 1) was approved by the ethics committee of the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College. Written informed consent was provided by each patient at screening. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

    Eligibility Criteria

    Competitive enrollment included 19 sites. The trial included adult women (age, >18 years) who were premenopausal at the time of trial entry. Premenopause was defined as age younger than 45 years regardless of ovarian function or from 45 years to younger than 55 years with less than 1 year of amenorrhea, together with positive findings on a premenopausal hormone test (estradiol, >110 pg/mL [to convert to picomoles per liter, multiply by 3.671] or follicle-stimulating hormone, <40 mIU/mL [to convert to units per liter, multiply by 1.0]). Other inclusion criteria were histologically confirmed HR-positive, ERBB2-negative breast cancer; HR positive was defined as a nuclear reaction greater than 1%, and ERBB2 negative was defined as findings on ERBB2 immunohistochemical analysis of 0 or 1 or more, negative fluorescence in situ hybridization results when immunohistochemical analysis findings were 2 or more, and measurable disease according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1)15 or clearly identifiable bone metastases, Eastern Cooperative Oncology Group performance status of 0 to 2, and disease recurrence within 24 months of the end of adjuvant tamoxifen therapy or disease progression while receiving advanced tamoxifen therapy. Patients were required to have received 6 months or more of tamoxifen treatment in the adjuvant setting and were permitted to have received 1 chemotherapy regimen for advanced disease. Eligible patients also had to have adequate organ and hematologic functions. Exclusion criteria included a history of brain metastases and previous treatment with mTOR inhibitors.

    Randomization

    The patients were randomly assigned in a 1:1 ratio to receive everolimus (10 mg orally once daily) plus letrozole (2.5 mg orally once daily) or letrozole alone (2.5 mg orally once daily). Both groups received goserelin, 3.6 mg, subcutaneously on day 1 of each 28-day cycle. Crossover was allowed; patients in the control group could switch to the everolimus group by adding everolimus to letrozole if they experience disease progression at the discretion of physicians (Figure 1 and eFigure 1 in Supplement 2).

    The centralized Interactive Web Response System provided by the Department of Biostatics, School of Public Health, Nanjing Medical University, was used for randomization. Randomization was stratified by the presence or absence of visceral metastases.

    Evaluations

    Patients visited the clinic every 28 days, which constituted 1 cycle. At each visit, a physical examination was conducted and hematologic and laboratory tests were performed. Tumor assessments were performed every 8 weeks by computed tomography or magnetic resonance imaging and bone scans (if indicated) and then every 12 weeks if the disease was stable or in remission after the first year. Tumor response was assessed according to RECIST 1.1.15 Adverse events (AEs) were recorded every cycle and categorized using the Common Terminology Criteria for Adverse Events, version 4.03.16

    End Points and Measurements

    The primary end point was PFS, defined as the time from randomization to confirmed disease progression or death from any cause. Secondary end points included objective response rate, defined as the percentage of patients who achieved a best response of complete response or partial response assessed using RECIST 1.1, and the clinical benefit rate, defined as the percentage of patients who achieved a best response of partial or complete response or stable disease for at least 6 months. Duration of response was defined as the time from the first documented date of objective response to the date of confirmed progression. Treatment response was evaluated by the investigators and radiologists in a nonblinded manner. Because the study allowed inclusion of patients with bone lesions only, response-related end points (partial response, complete response, objective response rate, clinical benefit rate, and duration of response) were calculated only in the subset of patients with measurable disease at baseline according to RECIST 1.1. Overall survival was defined as the time from the date of randomization to death due to any cause.

    Statistical Analysis

    Statistical analysis was conducted from January 5, 2015, to December 30, 2019. Sample size calculation was based on a comparison of the distribution of PFS between the 2 study groups. Assuming a median PFS of 21 months in the everolimus plus letrozole group and 13 months in the letrozole monotherapy group, a hazard ratio of 0.60 was expected for PFS. A total of 122 progression events would provide 80% power at a 2-sided α of .05 to detect this difference in PFS between the everolimus plus letrozole group and the letrozole monotherapy group. Assuming 15 months of accrual and a dropout rate of approximately 10%, a total of 198 patients were required (96 per group).

    Categorical variables were summarized as numbers and percentages and continuous variables were summarized as mean (SD) values. Group comparisons were evaluated using the χ2 test for categorical variables and the t test for continuous variables. Progression-free survival and overall survival were computed using the Kaplan-Meier method and compared using a log-rank test. All statistical analyses were performed using SPSS, version 26.0 (IBM Corp).

    Subgroup analyses were conducted based on endocrine sensitivity (endocrine sensitive vs primary endocrine resistance vs secondary endocrine resistance), receipt of chemotherapy for advanced disease (yes vs no), and presence of visceral metastases (yes vs no). Endocrine sensitivity was assessed based on the ABC4 (Advanced Breast Cancer Consensus version 4) guidelines.17 Endocrine sensitive was defined as a recurrence more than 1 year after completion of adjuvant SERM therapy, primary endocrine resistance was defined as recurrence within 2 years of adjuvant endocrine therapy, and secondary endocrine resistance was defined as relapse during adjuvant SERM therapy after 2 years or more and less than 1 year after completion of therapy with adjuvant SERMs. Because subgroup analyses except for presence of visceral metastasis were not prespecified in the protocol, we performed multiple testing adjustments using the Bonferroni method, which is a strict and commonly used adjustment.

    Results

    A total of 199 women (mean [SD] age, 44.3 [6.3] years) were randomized to receive either everolimus plus letrozole (n = 101) or letrozole alone (n = 98) (Figure 1). Five patients (2.5%) had stage IV disease at diagnosis, 115 patients (57.8%) had visceral disease, 54 patients (27.1%) had bone-only lesions, and 79 patients (39.7%) had cancer at 2 or more sites. Disease-free interval of more than 2 years was reported by 135 patients (67.8%). Only 7 patients (3.5%; 4 in the everolimus plus letrozole group [4.0%] and 3 in the letrozole group [3.1%]) were enrolled in second-line endocrine therapy, and 15 patients (7.5%; 8 in the everolimus plus letrozole group [7.9%] and 7 in the letrozole group [7.1%]) were endocrine sensitive. Furthermore, 33 patients (16.6%; 16 in the everolimus plus letrozole group [15.8%] and 17 in the letrozole group [17.3%]) had previously received toremifene citrate. A total of 97.0% of patients in the everolimus plus letrozole group previously received adjuvant endocrine therapy, with an incidence of resistance of 88.1% (89 of 101). Other characteristics were well balanced between the treatment groups (Table 1).

    Treatment Response

    Treatment response is summarized in Table 2. The objective response rate was 50.0% (33 of 66 patients) in the everolimus plus letrozole group and 39.3% (24 of 61 patients) in the letrozole group (P = .23). The clinical benefit rate was significantly higher in the everolimus plus letrozole group than in the letrozole group (48 of 66 [72.7%] vs 29 of 61 [47.5%]; P = .004). Among patients in the letrozole group who experienced disease progression and crossed over to receive everolimus plus letrozole (n = 56), the clinical benefit rate was 58.5% (31 of 53 patients with measureable disease). The duration of response was 18.7 months (95% CI, 7.6-28.6 months) in the everolimus plus letrozole group and 14.8 months (95% CI, 9.2-20.5 months) in the letrozole group . After crossover, the duration of response was 12.2 months (95% CI, 6.4-21.6 months). After the emergence of tolerance to previous letrozole medication, treatment with the previous endocrine therapy plus everolimus resulted in a median PFS of 5.5 months, and 13.2% of these patients (7 of 53) achieved a partial response.

    Survival

    In the intention-to-treat population, median PFS was 19.4 months (95% CI, 16.3-22.0 months) in the everolimus plus letrozole group and 12.9 months (95% CI, 7.6-15.7 months) in the letrozole group (hazard ratio, 0.64; 95% CI, 0.46-0.89; P = .008). A total of 53 patients in the letrozole group crossed over to receive everolimus plus letrozole after experiencing disease progression and achieved an additional 5.5 months of PFS (95% CI, 3.8-8.2 months) (Figure 2). Overall survival data were immature at the data cutoff, and median overall survival had not been reached. At the data cutoff, there had been 25 deaths in the everolimus plus letrozole group and 27 deaths in the letrozole group (hazard ratio, 0.76 [95% CI, 0.44-1.32]; P = .33).

    Subgroup analyses showed PFS benefits for patients receiving everolimus plus letrozole vs letrozole that were comparable with those observed in the intention-to-treat population among secondary endocrine-resistant patients (19.0 vs 10.9 months; hazard ratio, 0.50 [95% CI, 0.32-0.79]; adjusted P = .02). In primary endocrine-resistant patients, median PFS was 5.2 months (95% CI, 1.8-14.2 months) in the letrozole group and 13.9 months (95% CI, 7.2-19.3 months) in the everolimus plus letrozole group. Furthermore, patients with both visceral and nonvisceral metastases benefited from the addition of everolimus and patients without visceral metastases benefited more from the combination of everolimus and exemestane (median PFS, 19.3 vs 13.8 months; hazard ratio, 0.47; 95% CI, 0.27-0.82; adjusted P = .05) (eFigure 2 in Supplement 2).

    Adverse Events

    The eTable in Supplement 2 summarizes drug-related AEs that occurred in 10% or more of the patients. The AE profiles were comparable with those reported in previous studies. Adverse events more frequently reported in the everolimus plus letrozole group included stomatitis, hypertriglyceridemia, elevated alanine aminotransferase and aspartate aminotransferase, infection, hypercholesterolemia, rash, leukopenia and neutropenia, diarrhea, headache, anemia, pneumonitis, and fatigue. In the everolimus plus letrozole group, AEs leading to dose reduction occurred in 34 patients (33.7%), AEs leading to treatment delays occurred in 54 patients (53.5%), and AEs leading to discontinuation of treatment occurred in 9 patients (8.9%). In the letrozole group, AEs leading to dose reduction occurred in 1 of 92 patients (1.1%), AEs leading to treatment delays occurred in 4 of 92 patients (4.3%), and AEs leading to discontinuation of treatment occurred in no patients. Among 56 patients in the letrozole group who crossed over to receive everolimus after experiencing disease progression, 7 (12.5%) reported dose reductions owing to AEs, 18 (32.1%) reported delayed treatment owing to AEs, and 2 (3.8%) reported dose reductions owing to AEs.

    Discussion

    Breast cancer in young women is usually characterized by an aggressive phenotype and poor prognosis.8 In addition to patient age, menstrual status is also associated with breast cancer prognosis. The incidence of premenopausal breast cancer is higher in Eastern countries, such as China, compared with Western countries.18-20 However, premenopausal patients with breast cancer are generally excluded from large clinical trials. According to the latest guidelines and recommendations of the 5th European School of Oncology and European Society of Medical Oncology International Consensus Guidelines for Advanced Breast Cancer, specialized data are needed to guide the treatment of premenopausal patients.21

    The MIRACLE trial included premenopausal patients with breast cancer receiving first-line treatment. To our knowledge, this trial represents the first evaluation of everolimus added to first-line endocrine treatment of premenopausal women, with the exception of the a trial from Korea22 that was reported at the European Society of Medical Oncology Congress in 2019. In that trial, premenopausal patients with advanced breast cancer previously treated with tamoxifen were randomized to receive letrozole plus leuprorelin with or without everolimus. The patients receiving everolimus achieved 4.3 months longer median PFS compared with those receiving letrozole plus leuprorelin (18.1 vs 13.8 months; hazard ratio, 0.73; 95% CI, 0.48-1.11; P = .14), but the result did not reach statistical significance. In the present study, the addition of everolimus to letrozole resulted in a significantly longer median PFS in the intention-to-treat population (19.4 months vs 12.9 months; hazard ratio, 0.64; 95% CI, 0.46-0.89). Taken together, the findings of both trials indicate a consistent benefit from the addition of everolimus to letrozole and ovarian inhibitors in premenopausal patients with breast cancer who were previously treated with tamoxifen.

    As the first class of targeted drugs to be able to overcome endocrine resistance in patients with HR-positive, ERBB2-negative advanced breast cancer, mTOR inhibitors have been available for approximately 8 years. However, after recent advances, the diagnosis and treatment of breast cancer have changed greatly from the time that the MIRACLE trial was planned. During this period, several studies have found that CDK4/6 inhibitors can improve overall survival among patients with HR-positive, ERBB2-negative breast cancer, and these agents have been established as a standard first-line treatment for postmenopausal patients with breast cancer who experience AI treatment failure.23 However, most of the studies supporting the use of CDK4/6 inhibitors were conducted in postmenopausal patients, and only a small number included premenopausal patients.23 The MONALEESA-7 trial24 was, to our knowledge, the only phase 3 clinical trial to investigate a CDK4/6 inhibitor in premenopausal patients only. This trial evaluated tamoxifen or a nonsteroidal aromatase inhibitor with ribociclib or placebo in the first-line treatment of patients with HR-positive, ERBB2-negative advanced breast cancer. Most patients (70%) were endocrine sensitive, defined as endocrine naive or having experienced progression more than 12 months after adjuvant or neoadjuvant endocrine treatment. The median PFS in the ribociclib plus nonsteroidal aromatase inhibitor group was 27.5 months, which was 13.7 months longer than the median PFS in the control group (hazard ratio, 0.57; 95% CI, 0.44-0.74). In the present study, 97.0% of patients in the everolimus plus letrozole group previously received adjuvant endocrine therapy, with an incidence of resistance of 88.1% (89 of 101), which is in contrast to the patients included in the MONALEESA-7 trial. Other trials investigating CDK4/6 inhibitors that included premenopausal patients were the PALOMA-3 trial and MONARCH-2 trial.25,26 However, both trials enrolled only a limited number of premenopausal patients, most of whom had relatively late-stage disease and were endocrine resistant. In addition, a subgroup analysis of premenopausal women included in the MONARCH-2 trial revealed a negative result.25,26 Owing to differences in patient populations and drug combinations, it is not possible to directly compare the MIRACLE trial with these 3 previous trials of CDK4/6 inhibitors. However, based on the findings of those trials and the present trial, use of everolimus in the first-line treatment of premenopausal patients appears to be reasonable when CDK4/6 inhibitors are not applicable.

    Based on findings of the MONALEESA-7 trial, the CDK4/6 inhibitor ribociclib in combination with an AI and ovarian function suppression is now established as the preferred first-line treatment for premenopausal patients with endocrine sensitivity. For patients with endocrine resistance either after adjuvant endocrine therapy or resistance to first-line endocrine therapy, everolimus combination therapy or CDK4/6 inhibitor therapy combined with fulvestrant represents a good treatment choice. Alpelisib, a PI3K inhibitor that also targets the PI3K-AKT-mTOR pathway, may be an alternative choice.27 The findings of the B-YOND trial initially revealed that in premenopausal patients with or without a PIK3CA mutation, median PFS among patients receiving alpelisib was up to 25.2 months after treatment with a combination of a PI3K inhibitor, tamoxifen, and ovarian function suppression, which also had some value in the premenopausal population.28

    The present trial also supported aspects of the mechanism by which mTOR inhibitors overcome endocrine resistance. One of the reasons for resistance to endocrine therapy is irregular activation of the PI3K-AKT-mTOR signaling pathway.29 Preclinical data suggest that an association between the mTOR pathway and the estrogen receptor signal exists.29 Everolimus has been shown to synergistically inhibit tumor cell proliferation and induce cell apoptosis when combined with an AI.30 The BOLERO-2 study found that everolimus paired with a steroidal AI could also benefit from nonsteroidal aromatase inhibitor resistance, indicating that everolimus could reverse this resistance.2,3 In the present trial, we further proved this concept by demonstrating that after the emergence of tolerance to previous letrozole medication, treatment with the previous endocrine therapy plus everolimus resulted in a median PFS of 5.5 months, and 13.2% of these patients (7 of 53) achieved a partial response. These findings show the role of everolimus in overcoming endocrine resistance.

    In the present trial, everolimus plus letrozole resulted in a relatively high incidence of metabolic disorders, including hypercholesterolemia, hypertriglyceridemia, and hyperglycemia (eTable in Supplement 2). In contrast, the BOLERO-2 study, which included postmenopausal patients, reported a total incidence of hyperlipidemia of less than 10% and an incidence of hyperglycemia of 14%.31 This difference might be a manifestation of the difference between premenopausal and postmenopausal patients. This theory was supported by the trial from Korea that included premenopausal patients,22 in which 53.3% of patients developed hypercholesterolemia. Premenopausal patients developed a menopausal state and a sharp decrease in estrogen level after treatment with ovarian function suppression, which might have a substantial effect on blood lipids. Therefore, changes in blood lipid and glucose levels should be closely monitored and actively managed when everolimus is used in premenopausal patients.

    Limitations

    There are several limitations of this study. First, the study was not placebo-controlled and the primary end point of PFS was investigator assessed with no independent imaging evaluation, which may represent a possible source of bias. Second, assessment of patient quality of life was not included in the study protocol, resulting in a lack of information on the effect of the toxic effects of everolimus on the everyday life of patients. In addition, this was a phase 2 trial, and because CDK4/6 inhibitors are now the standard first-line therapy for patients with HR-positive, ERBB2-negative breast cancer, a large-scale phase 3 study of everolimus in the first-line treatment of premenopausal patients may not be conducted.

    Conclusions

    To our knowledge, this was the first randomized clinical trial to demonstrate a longer PFS with an mTOR inhibitor plus an AI vs AI monotherapy in the first-line treatment of premenopausal patients with advanced HR-positive, ERBB2-negative breast cancer who experienced disease progression while receiving prior SERM therapy. Our results support the use of everolimus plus letrozole in this population in the first-line setting. Furthermore, everolimus was able to overcome endocrine resistance and was effective even for patients treated again with the same endocrine agent after disease progression. Even though the treatment landscape for HR-positive, ERBB2-negative breast cancer has recently expanded to include CDK4/6 inhibitors, our results show that everolimus has therapeutic value and remains an important part of the armamentarium for this disease.

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    Article Information

    Accepted for Publication: May 27, 2021.

    Published Online: August 26, 2021. doi:10.1001/jamaoncol.2021.3428

    Corresponding Author: Binghe Xu, MD, PhD, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China (xubinghe@medmail.com.cn).

    Author Contributions: Dr Xu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Fan, Xu.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Fan, Xu.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Fan, Feng, Song, J. Wang, Ma.

    Administrative, technical, or material support: Fan, Sun, Shao, Q. Zhang, Ouyang, Shusen Wang, Luo, Teng, X. Wang, Shu Wang, Liu, Shen, Li, P. Zhang, Xu.

    Supervision: Liu, Xu.

    Conflict of Interest Disclosures: Dr Xu reported receiving grants from Hengrui Pharmaceutical and receiving personal fees from AstraZeneca, Pfizer, Roche, and Eisai outside the submitted work. No other disclosures were reported.

    Funding/Support: This study was supported by Novartis Oncology China.

    Role of the Funder/Sponsor: Novartis Oncology China had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Meeting Presentation: This study was presented at the virtual San Antonio Breast Cancer Symposium; December 12, 2019.

    Data Sharing Statement: See Supplement 3.

    Additional Contributions: We thank all the patients and their relatives for participating in this trial.

    Additional Information: Novartis Oncology China provided everolimus, one of the drugs used in this study.

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