Factor Receptor 2-negative Metastatic Breast Research Articles

Abstract OT2-04-07: Phase II study of nivolumab in combination with abemaciclib plus endocrine therapy in patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer (WJOG11418B, NEWFLAME trial)

Abstract Background: In this year, anti-programmed death-ligand 1 (PD-L1) antibody has been approved for PD-L1-positive metastatic triple-negative breast cancer by the U.S. Food and Drug Administration. The synergistic effect of the combination of anti-PD-L1 antibody, CDK4/6 inhibitor and endocrine therapy (ET) has been anticipated based on various preclinical data. A Phase Ib study (JPCE, NCT02779751) of abemaciclib plus pembrolizumab demonstrated manageable safety and promising anti-tumor activity in patients with HR-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC). Therefore, we initiated this investigator-initiated trial to evaluate the efficacy and safety of the combination of nivolumab, abemaciclib and ET (letrozole [LET] or fulvestrant [FUL]) as a first or second-line treatment in patients with HR+, HER2- MBC. Trial Design: This is a multicenter, multi-cohort, nonrandomized, open-label Phase II study to evaluate the efficacy and safety of nivolumab in combination with abemaciclib and ET (LET or FUL) in patients with HR+, HER2- MBC. Since there is no safety data of the combination of nivolumab, abemaciclib and ET, we evaluate safety and tolerability of the combination therapy in the first 6 patients with predefined dose-limiting toxicities. Patients will receive nivolumab 240 mg/body on day 1, 15, abemaciclib 150mg twice daily, and either LET 2.5mg once daily (LET cohort) or FUL 500mg on day1, day15 (FUL cohort) every 4 weeks until disease progression, unacceptable toxicity, or patient refusal. Pre- or perimenopausal women must receive concomitant treatment with a gonadotropin-releasing hormone agonist. Eligibility Criteria: Key eligibility criteria for the LET cohort are: postmenopausal HR+, HER2- MBC with ECOG PS≤1, measurable disease, no prior systemic therapy. ET in the adjuvant setting is permitted if the patient has a disease-free interval > 12 months from the completion of ET. Key eligibility criteria for the FUL cohort are: HR+, HER2- MBC with ECOG PS≤1, measurable disease, no more than one ET or any prior chemotherapy for MBC. Patients are required to have a disease that progressed while receiving adjuvant ET, ≤ 12 months after adjuvant ET, or while receiving ET for MBC. Specific Aims: The primary endpoint is the objective response rate (ORR) and key secondary endpoints include progression-free survival, overall survival, and the safety of the protocol treatment. Statistical Design: The threshold and expected ORR of LET cohort are 55% and 75%, respectively, and 16 patients are needed to ensure a statistical power of 80% (α=0.20). The threshold and expected ORR of FUL cohort are 45% and 60%, respectively, and 32 patients are needed to ensure a statistical power of 80% (α=0.20). Target Accrual: A total of 53 patients (LET cohort: 18, FUL cohort: 35) will be enrolled and duration of enrollment will be 1 year and 4 months. This trial opened to accrual in June 2019. Clinical trial information: JapicCTI-194782. Contact Information: Jun Masuda, Toranomon Hospital, Tokyo, Japan, masu-j@toranomon.gr.jp Citation Format: Jun Masuda, Junji Tsurutani, Norikazu Masuda, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Masato Takahashi, Hiroji Iwata, Tsutomu Iwasa, Toru Mukohara, Kenichi Yoshimura, Takayuki Ueno, Toshimi Takano. Phase II study of nivolumab in combination with abemaciclib plus endocrine therapy in patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer (WJOG11418B, NEWFLAME trial) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-04-07.

Abstract GS2-07: Results from PEARL study (GEICAM/2013-02_CECOG/BC.1.3.006): A phase 3 trial of Palbociclib (PAL) in combination with endocrine therapy (ET) versus Capecitabine (CAPE) in hormonal receptor (HR)-positive/human epidermal growth factor receptor (HER) 2-negative metastatic breast cancer (MBC) patients (pts) whose disease progressed on aromatase inhibitors (AIs)

Abstract Background: PAL is approved for use in combination with ET in HR-positive, HER2-negative MBC pts in first and later lines. However, the relative value of PAL plus ET versus (vs) chemotherapy (CT) in pretreated pts is not established yet. PEARL is a multinational, open label, controlled, randomized phase 3 trial comparing the efficacy and safety of PAL in combination with ET (exemestane [EXE] or fulvestrant [FUL]) vs CAPE in postmenopausal women with HR-positive/HER2-negative MBC whose disease progressed on AIs. Methods: The study had two successive cohorts. In cohort 1 (C1) patients were randomized 1:1 to EXE+PAL vs CAPE. In 2016, after data showing that ESR1 mutations may induce resistance to AIs but not to FUL, cohort 2 (C2), with FUL+PAL vs CAPE, was added to the trial. Stratification criteria were site of disease (visceral vs non-visceral), prior sensitivity to ET (yes vs no), prior CT for MBC (yes vs no) and country. The study has two co-primary objectives: to demonstrate 1) the superiority of PAL+FUL over CAPE in progression-free survival (PFS) and 2) the superiority of PAL+ET (EXE or FUL) over CAPE in PFS in pts with ESR1 wild type (wt) tumors, measured in ctDNA, at study entry. In order to have an 80% power to detect a difference in median PFS between CAPE (6 months) and either PAL+FUL or PAL+ET ESR1 wt (9 months), for a hazard ratio (HR) of 0.667 and a significance level of 5%, a sample size of 300 pts and 193 events were required for each analysis. An exploratory analysis of intrinsic BC subtypes determined by an algorithm derived from the HTG EdgeSeq Oncology Biomarker Panel was also performed. Results: From March 2014 to July 2018, 601 pts were recruited (296 in C1 and 305 in C2) in 4 countries. Median age was 60 (C1) and 61 (C2) years; 26.4% (C1) and 28.2% (C2) had ESR1 mutations; 66.6% (C1) and 65.2% (C2) had visceral disease; 71.3% (C1) and 79.0% (C2) had prior sensitivity to hormonal treatment; 30.1% (C1) and 26.9% (C2) received one prior chemotherapy for MBC; 19.6% (C1) and 26.6% (C2) had not received any prior line for MBC.C2 results: with a median follow-up of 13.5 m (range 0.0 to 30.7), the median PFS was 7.5 m in PAL+FUL vs 10 m in CAPE (adjusted HR [HRa] [confidence interval (CI) 95%]: 1.09 [0.83, 1.44]; p=0.537). The Objective Response Rate (ORR) was 26.7% for PAL+FUL vs 33.3% for CAPE. The analysis of BC subtypes was performed for 74.4% of pts, 89.1% (PAL+ET) and 91.5% (CAPE) had luminal tumors. For luminal pts median PFS was 7.5 m in PAL+FUL vs 10 m in CAPE (HR [CI 95%]: 1.07 [0.77, 1.50]; p=0.684); for non-luminal pts it was 4.4 m in PAL+FUL vs 14.8 m in CAPE (HR [CI 95%]: 2.39 [0.81, 7.08]; p=0.116).ESR1 wt (C1 + C2) results: with a median follow-up of 19.0 m (range 0.0 to 56.3), the median PFS was 8.0 m in PAL+ET vs 10.6 m in CAPE (HRa [CI 95%]: 1.08 [0.85-1.36]; p=0.526). The ORR was 27.8% for PAL+ET vs 36.9% for CAPE.The analysis of BC subtypes was performed for 79.6% of pts, 89.2% (PAL+ET) and 91.8% (CAPE) had luminal tumors. For luminal pts median PFS was 9.3 m in PAL+ET vs 11.0 m in CAPE (HR [CI 95%]: 1.02 [0.77, 1.34]; p=0.913); for non-luminal pts it was 2.7 m in PAL+ET vs 13.7 m in CAPE (HR [CI 95%]: 3.19 [1.28, 7.95]; p=0.013). Most frequent grade 3-4 toxicities with EXE+PAL, FUL+PAL and CAPE respectively were neutropenia (57.4%, 55.7% and 5.5%) with febrile neutropenia (1.3%, 0.7% and 1.4%), hand/foot syndrome (0%, 0% and 23.5%) and diarrhea (1.3%, 1.3% and 7.6%). Conclusions: The PEARL study did not show a statistically superiority in PFS for PAL+ET vs CAPE in MBC pts progressing to AIs. No superiority of PAL+ET was observed in the luminal subgroup either. Treatment with PAL+ET was generally better tolerated than CAPE. Citation Format: Miguel Martín, Christoph Zielinski, Manuel Ruíz-Borrego, Eva Carrasco, Eva Ciruelos, Montserrat Muñoz, Begoña Bermejo, Mireia Margeli, Nicholas Turner, Maribel Casas, Antonio Antón, Tibor Csöszi, Massimo Corsaro, Laura Murillo, Serafín Morales, Emilio Alba, Cynthia H Bartlett, Maria Koehler, Angel Guerrero, Zsuzsanna Kahan, Miguel Gil-Gil. Results from PEARL study (GEICAM/2013-02_CECOG/BC.1.3.006): A phase 3 trial of Palbociclib (PAL) in combination with endocrine therapy (ET) versus Capecitabine (CAPE) in hormonal receptor (HR)-positive/human epidermal growth factor receptor (HER) 2-negative metastatic breast cancer (MBC) patients (pts) whose disease progressed on aromatase inhibitors (AIs) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS2-07.

Abstract PD10-03: Quality of life in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer treated with palbociclib in real-world practice settings

Abstract Background: Palbociclib in combination with endocrine therapy (ie, an aromatase inhibitor [AI] or fulvestrant) is a current standard of care for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer (ABC/mBC). Findings from the PALOMA clinical trials have shown that patients receiving palbociclib with AI or fulvestrant maintained stable quality of life (QoL). However, no data are currently available from real-world settings regarding patients’ QoL experiences while receiving palbociclib. Methods: This noninterventional, prospective, multicenter study evaluated female and male patients diagnosed with HR+/HER2- ABC/mBC and treated with palbociclib as indicated by the attending physician in the routine course of care. QoL was assessed using the European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30). The EORTC QLQ-C30 was collected at enrollment prior to receiving palbociclib (baseline), monthly for the first 3 months of treatment with palbociclib, and then every 3 months until the end of treatment or patient withdrawal or death. The EORTC QLQ-C30 could be completed using an interactive Web response system or a paper questionnaire. Here we report demographic characteristics and interim analysis of QoL assessments as measured by EORTC QLQ-C30 at baseline and at 3 and 6 months postbaseline. Descriptive analyses are presented for subscales of the EORTC QLQ-C30. Results: 522 patients who completed ≥6 months of palbociclib treatment as of May 20, 2019, were included in this interim analysis; 394 were prescribed palbociclib as first-line treatment. The remaining 128 patients initiated palbociclib in second and later lines. Median age at enrollment was 64 years, 98% of patients were female, and 83% were white. More than half of all patients (n=285) received palbociclib in combination with letrozole or anastrozole; of the remaining patients, 218 received palbociclib plus fulvestrant and 19 received palbociclib plus exemestane. Mean (SD) EORTC QLQ-C30 scores remained similar over the first 6 months of treatment: 66.2 (22.6) at baseline, 68.3 (19.7) at 3 months, and 70.2 (21.3) at 6 months. In addition, the mean scores for each functional scale and symptom scale on the EORTC QLQ-C30 also remained stable over the first 6 months (Table). With the exception of pain scores (which declined by 7 points), the change from baseline at 6 months generally was less than 5 points across the different subscales of EORTC QLQ-C30. Conclusions: The 522 patients examined in this interim analysis experienced stable to modestly improved QoL from baseline to 6 months after starting palbociclib. Changes from baseline in EORTC QLQ-C30 scores generally were below the 10-point threshold regarded as clinically meaningful. These early findings indicate that patients enrolled in the study have maintained their baseline QoL while being treated with palbociclib. Funding: Pfizer (NCT03280303) EORTC QLQ-C30Baseline3 Months6 MonthsGlobal Health/Quality of Life*n (missing)474 (48)292 (230)409 (113)Mean (SD) score66.2 (22.6)68.3 (19.7)70.2 (21.3)Functional scales score, mean (SD)*Physical functioning75.6 (23.3)75.8 (21.9)77.2 (21.4)Role functioning72.5 (31.9)76.7 (26.1)77.1 (26.8)Emotional functioning74.8 (22.8)77.7 (22.3)79.7 (20.5)Cognitive functioning78.8 (24.6)82.7 (20.6)80.1 (22.0)Social functioning76.4 (28.3)79.5 (25.5)81.5 (24.7)Symptom scales score, mean (SD)†Fatigue34.3 (25.7)35.0 (23.6)33.7 (22.2)Nausea and vomiting11.3 (20.2)10.4 (16.4)10.6 (19.3)Pain33.5 (30.0)27.3 (27.2)26.5 (26.9)Dyspnea22.2 (28.3)18.7 (22.5)18.8 (24.1)Insomnia29.3 (30.1)27.5 (31.7)27.4 (27.9)Appetite loss21.1 (27.9)19.4 (26.4)17.9 (26.5)Constipation18.4 (26.6)15.2 (23.8)16.0 (23.8)Diarrhea12.3 (22.1)12.0 (20.8)12.6 (22.0)Financial difficulties25.0 (32.4)23.9 (30.4)22.1 (29.5)*Higher scores indicate a better level of functioning. †Higher scores indicate more severe symptoms. Citation Format: Gabrielle Rocque, Joanne L Blum, Aldemar Montero, Ibrahim Nakhoul, Sobha Kurian, Richard C Frank, Bijoy Telivala, Mayank Ajmera, David Coblentz, Joseph C Cappelleri, Yao Wang, Debu Tripathy. Quality of life in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer treated with palbociclib in real-world practice settings [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD10-03.

Abstract P3-11-25: Real-world treatment patterns and clinical outcomes among women with HR+/HER2- advanced or metastatic breast cancer treated in real-world settings in Italy and Germany

Abstract Background: Palbociclib is a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) that, when combined with an aromatase inhibitor (AI) or fulvestrant, has been shown in clinical trials to prolong progression-free survival (PFS) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer (ABC/MBC). This study sought to describe real-world treatment patterns and clinical outcomes among patients with HR+/HER2- ABC/MBC treated with palbociclib in clinical practice settings in Italy and Germany. Methods: MARIA is an ongoing non-interventional, prospective multi-center study that includes women in Italy and Germany initiating their first or second therapy in the HR+/HER2- ABC/mBC setting. Data from 67 sites were used to assess patient and treatment characteristics and progression-free survival (PFS) among patients receiving palbociclib in combination with AI or fulvestrant. Landmark PFS estimates at 6-, 12-, and 18-months were reported by line of therapy (first- and second-line). Results: Overall, 72 patients formed the interim analytic cohort. Among these, 63 (47%) and 9 (7%) received palbociclib + AI as first- and second-line therapy, respectively. Twenty-six (20%) and 37 (27%) of patients received palbociclib + fulvestrant as first- and second-line therapy, respectively. Approximately 96%, 78%, and 64% of patients receiving palbociclib + AI as first-line therapy were progression free at 6-, 12-, and 18-months, respectively. Among patients receiving palbociclib + fulvestrant as first-line therapy, 6-, 12-, and 18-month PFS was 91%, 64%, and 39%, respectively. For second-line therapy, 6-, 12-, and 18-month PFS was 75%, 38%, 38% among palbociclib + AI users and 71%, 54%, and 45% for palbociclib + fulvestrant. Conclusions: This interim analysis indicates that PFS among women with ABC/mBC HR+/HER2-negative breast cancer in Italy and Germany receiving palbociclib, in combination with letrozole or fulvestrant is comparable to published randomized clinical trial results and other real-world observational studies. Further follow-up is required for longitudinal analysis and to estimate overall survival. Funding: Pfizer Citation Format: Michelino De Laurentiis, Nadia Harbeck, Ernest Law, Mayank Ajmera, Debanjali Mitra, Keith Davis, Sara Brucker, Sabino De Placido. Real-world treatment patterns and clinical outcomes among women with HR+/HER2- advanced or metastatic breast cancer treated in real-world settings in Italy and Germany [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-25.

Abstract B104: Combined inhibition of DDR1 and CDK4/6 induces synergistic effects in ER-positive, HER2-negative breast cancer with PIK3CA/AKT1 mutations

Abstract Molecular alterations in the PI3K/AKT/mTOR pathway occur frequently in estrogen receptor-positive (ER-positive) breast tumors. Patients with ER-positive, human epidermal growth factor receptor 2-negative (HER2-negative) advanced or metastatic breast cancer (MBC) are often treated with palbociclib, an FDA approved CDK4/6 inhibitor, in combination with endocrine therapy. In clinical studies (NCT01942135), the combination of fulvestrant plus palbociclib was associated with improved progression-free survival compared with fulvestrant plus placebo, irrespective of PIK3CA mutational status. The purpose of this study is to identify synthetic lethality partner that can be targeted in combination with palbociclib to improve its therapeutic response. We demonstrate that the in vitro efficacy of CDK4/6 inhibitor is reduced in the presence of PIK3CA/AKT1 mutations using ER-positive isogenic breast cancer cell lines. Utilizing a shRNA library screen targeting cancer related human kinases, we identified that genomic suppression of discoidin domain receptor 1 (DDR1), a tyrosine kinase active in various cancers, is synthetic lethal with palbociclib. Performing sulforhodamine B (SRB) proliferation assay, DDR1 knockdown by shRNA significantly reduced growth of PIK3CA/AKT1 mutant as well as wild type ER-positive cell lines. In addition, DDR1 pharmacological inhibitor, 7rh benzamide, activated the P53/P21 pathway and enhanced the sensitivity of PIK3CA/AKT1 mutant cells to palbociclib. Likewise, we found that combined treatment of palbociclib and 7rh further induced cell cycle arrest through decreasing G2-M phase population and reducing FoxM1 and Rb phosphorylation in mutant cell lines. Our data indicate that DDR1 inhibition can augment cell cycle suppressive effect of palbociclib and could be an effective rational strategy approach for targeted therapy of ER-positive, HER2-negative breast cancer harboring PIK3CA/AKT1 mutations. Citation Format: Maryam Shariati, Christopher A Bristow, Alessandro Carugo, Tim Heffernan, Xiaofeng Zheng, Michael D Peoples, Debu Tripathy, Funda Meric-Bernstam. Combined inhibition of DDR1 and CDK4/6 induces synergistic effects in ER-positive, HER2-negative breast cancer with PIK3CA/AKT1 mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B104. doi:10.1158/1535-7163.TARG-19-B104

Phase II Study of Eribulin Mesylate Administered Biweekly in Patients With Human Epidermal Growth Factor Receptor-2–negative Metastatic Breast Cancer

BackgroundPatients with human epidermal growth factor receptor-2–negative metastatic breast cancer (MBC), whose disease progressed on prior chemotherapy, have a poor prognosis. Eribulin, a microtubule dynamics inhibitor, extends overall survival in previously treated MBC. The most common adverse event associated with eribulin is neutropenia, which may result in dose interruptions or reductions. A modified biweekly dosing schedule of eribulin was assessed for efficacy as well as improvements in hematologic toxicity. Patients and MethodsIn this open-label, single-arm, multicenter, phase II study, previously treated (2-5 chemotherapy regimens for metastatic disease) patients with human epidermal growth factor receptor-2–negative MBC received intravenous eribulin 1.4 mg/m2 over 2 to 5 minutes on days 1 and 15 of each 28-day cycle. The primary study endpoints were objective response rate (ORR; complete response [CR] + partial responses [PR]) and disease control rate (DCR; CR + PR + stable disease [SD]). ResultsAmong 58 treated patients, the ORR was 12% (95% confidence interval [CI], 5%-24%), DCR (CR, n = 1; PR, n = 6; SD, n = 30) was 65%, and the median progression-free survival was 3.6 months (95% CI, 2.9-4.1 months). Grade 3 or 4 neutropenia was 31%; 50% of all patients, and 78% of patients with neutropenia (all grades), received hematopoietic growth-factor support. ConclusionThe efficacy and safety results obtained with a biweekly eribulin schedule in this phase II trial appear similar to those associated with the approved eribulin schedule (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) reported in the EMBRACE study.

Outcomes of Older Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-Negative Metastatic Breast Cancer Treated With a CDK4/6 Inhibitor and an Aromatase Inhibitor: An FDA Pooled Analysis.

Many older women will be treated with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and an aromatase inhibitor (AI), given US Food and Drug Administration approval of three agents in this class. The current pooled analysis examines the efficacy and safety of this combination in older women. We pooled data from three randomized controlled studies (N = 1,827) of different CDK4/6 inhibitors in combination with an AI for initial treatment of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. The effect of age on progression-free survival was evaluated using Kaplan-Meier estimates and a Cox proportional hazards regression model. For patients age 75 years or older (n = 198) who were treated with a CDK4/6 inhibitor and an AI, hazard ratio was 0.49 (95% CI, 0.31 to 0.76) with an estimated median progression-free survival of 31.1 months (95% CI, 20.2 months to not reached) versus 13.7 months (95% CI, 10.9 months to 24.9 months) for those treated with an AI. Incidence of grade 3 to 4 adverse events was 88.8% in patients age 75 years and older and 73.4% in patients younger than age 75 years. Patients age 75 years or older reported a decline in quality-of-life measures using the EQ-5D regardless of treatment with AI alone or with the addition of a CDK4/6 inhibitor. There was similar efficacy with a CDK4/6 inhibitor in combination with an AI compared with AI alone for first-line treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer in older women compared with younger patients. Patients older than age 75 years experienced higher rates of toxicity, dose modifications, and a decrease from baseline in quality-of-life measures.

The PI3K/AKT/mTOR and CDK4/6 Pathways in Endocrine Resistant HR+/HER2- Metastatic Breast Cancer: Biological Mechanisms and New Treatments.

Endocrine-based treatments are the normal standard-of-care in women with hormone receptor-positive/Human Epidermal growth factor Receptor 2-negative metastatic breast cancer. Despite the well-known efficacy of these drugs as first-line therapies, about 50% of women develop endocrine resistance and disease progression. The treatment of these patients has represented one of the most important research fields in the last few years, with several multicenter phase II/III trials published or still ongoing. Novel therapies, such as cyclin-dependent kinase (CDK)4/6 and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors, have significantly changed the prognosis of patients progressing to a previous endocrine treatment, allowing a great benefit in terms of progression-free survival and, in some cases, of overall survival. However, identifying response predictors is essential for the rational use of these drugs to avoid unnecessary toxicity and costs, and to ensure the optimal therapeutic sequence is used. In this review, we analyze the PI3K/AKT/mTOR and CDK4/6 pathways and their roles in endocrine resistant metastatic breast cancer. We then focus on the new treatments developed and the roles of these drugs in overcoming endocrine resistance, describing the latest clinical trials that led to the approval of the drugs in clinical practice.

Patient-reported outcomes in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer receiving olaparib versus chemotherapy in the OlympiAD trial

BackgroundThe phase III OlympiAD study (NCT02000622) showed a statistically significant progression-free survival benefit with olaparib versus chemotherapy treatment of physician's choice (TPC) in patients with a germline BRCA mutation and human epidermal growth factor receptor 2-negative metastatic breast cancer. From this study, we report the effect of olaparib on health-related quality of life (HRQoL). MethodsPatients were randomised 2:1 to olaparib monotherapy (300 mg twice daily) or single-agent TPC. The primary HRQoL end-point was mean change from baseline in the two-item global health status/QoL score determined from patient-completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module (EORTC QLQ-C30) questionnaires and assessed using a mixed model for repeated measures. Symptoms and functioning domains, best overall response and time to deterioration of QoL were also evaluated. ResultsOverall questionnaire compliance rates were 93.2% for olaparib and 76.3% for TPC. Between-treatment global health status/QoL comparison showed a significant improvement in the olaparib arm versus the TPC arm, with mean change of 3.9 (standard deviation 1.2) versus −3.6 (2.2), a difference of 7.5 points (95% confidence interval [CI]: 2.48, 12.44; P = 0.0035). A higher proportion of patients in the olaparib arm showed a best overall response of ‘improvement’ in global health status/QoL (33.7% vs 13.4%). Median time to global health status/QoL deterioration was not reached in olaparib patients and was 15.3 months for TPC patients (hazard ratio: 0.44 [95% CI: 0.25, 0.77]; P = 0.004). For EORTC QLQ-C30 symptoms and functioning subscales, only nausea/vomiting symptom score was worse in the olaparib arm than in the TPC arm (across all visits compared with baseline). ConclusionHRQoL was consistently improved for patients treated with olaparib, compared with chemotherapy TPC.

Next-generation sequencing (NGS) results among hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) patients treated with a CDK4 & 6 inhibitor: A retrospective observational study based on real-world data.

1042 Background: Few real-world studies have characterized the frequency of genomic alterations of MBC tumors. Data characterizing alterations before and after treatment containing a CDK4 & 6 inhibitor (CDK4 & 6i) are similarly limited. We explore the genomic landscape of HR+/HER2- MBC tumors from patients (pts) treated with a CDK4 & 6i in order to characterize potential mechanisms underlying sensitivity and resistance. Methods: NGS results of tumor and liquid biopsies obtained from 130 pts with estrogen receptor (ER+)/progesterone receptor (PR+)/HER2- MBC between Jan 2008 to Sept 2016 were analyzed. All pts received therapy containing a CDK4 & 6i for MBC at a community cancer network and had NGS results available before and/or after exposure to CDK4 & 6i. Samples were classified as sensitive (n = 69; duration of therapy ≥6 mo) or resistant (n = 61; duration of therapy < 6 mo). The frequency of genomic alterations with likely or known significance including short variants, indels, copy number variants, and fusions were characterized. Results: Alterations in 215 unique genes were identified from the NGS results; PIK3CA, TP53, ESR1, CCND1, and FGFR1 were the most frequently altered genes. Select alterations in ESR1 (n = 21 vs 9) and RAD21 (n = 5 vs 0) were more frequent after exposure to CDK4 & 6i. In NGS obtained before exposure to CDK4 & 6i, alterations in select genes including RB1, MDM2, AURKA, and MYC were more frequent in the resistant samples, whereas ARID1A alterations were more frequent in sensitive samples. Of the 6 pts with paired NGS samples pre- and post-CDK4 & 6i treatment, alterations in MYC, CDKN2A, PIK3CA, BRCA1, or RB1 were acquired in 3 pts. Conclusions: Based on real-world data, this study describes the genomic landscape of ER+/PR+/HER2- MBC tumors from pts treated with CDK4 & 6i and identifies potential mechanisms underlying sensitivity and resistance to this new class of drugs. Further evaluation in larger datasets is warranted. Data inclusive of other ER/PR subtypes will be presented.

XENERA-1: A phase II trial of xentuzumab (Xe) in combination with everolimus (Ev) and exemestane (Ex) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) and non-visceral involvement.

TPS1103 Background: The mTOR inhibitor Ev, combined with Ex, is a mainstay in the treatment of post-menopausal women with advanced HR+/HER2- BC. However, the activity of Ev is limited by counter-regulatory feedback mechanisms in cancer cells, involving reactivation of insulin-like growth factor (IGF)/mTOR survival signaling. Combining Ev with the humanized IGF-1 and IGF-2 ligand-blocking antibody Xe abrogates this feedback, thus intensifying inhibition of tumor growth; this leads to a pronounced effect in patients with non-visceral (e.g., bone and lymph node) metastases. The phase II XENERA-1 trial evaluates the combination of Xe with Ev and Ex in post-menopausal women with HR+/HER2- BC. Methods: XENERA-1 (NCT03659136) is a double-blind, placebo-controlled, randomized study to assess the efficacy and safety of Xe in combination with Ev and Ex, in post-menopausal women with HR+/HER2- locally advanced/mBC and non-visceral disease. The population comprises post-menopausal mBC patients who have progressed on ≤1 previous line of a non-steroidal aromatase inhibitor, with or without a CDK 4/6 inhibitor, who may have received fulvestrant. Other inclusion criteria are: an Eastern Cooperative Oncology Group Performance Status of 0 or 1; adequate organ function; and non-visceral disease (absence of brain, liver, lung, peritoneal or pleural metastases). Patients are randomized (1:1) to receive Xe (1000 mg/week, iv) or placebo (weekly, iv), in combination with Ev (10 mg/day) and Ex (25 mg/day). Treatment will continue until disease progression, unacceptable toxicity or other reasons. The primary endpoint is progression-free survival according to RECIST 1.1 criteria, by independent review. Secondary endpoints are: overall survival; disease control; duration of disease control; objective response; and time to progression of pain/intensification of palliation. Safety and pharmacokinetic endpoints, and exploratory biomarkers will also be evaluated. The first patient was enrolled in January 2019; target enrollment is 80 patients in 12 countries. Clinical trial information: NCT03659136.

Abstract OT2-05-01: FAMILY: A randomized, multicenter, open-label, phase III trial of fulvestrant versus capecitabine as maintenance therapy after first-line combination chemotherapy in patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer

Abstract Background: Metastatic breast cancer (MBC) is incurable. Although first-line endocrine therapy is preferred to hormone receptor positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) MBC, combination chemotherapy should be reserved as the initial treatment for patients with rapid clinical progression, life-threatening visceral metastases, and need for rapidly symptom control. Either prolonged chemotherapy or endocrine therapy may be used as maintenance after disease control. However, which maintenance strategy is superior in terms of delaying disease progression as well as maintaining quality of life (QOL) remains uncertain. This phase III trial aims to compare the efficacy and safety of fulvestrant or capecitabine as maintenance therapy after first-line combined chemotherapy in HR+/HER2- MBC. Trial Design: FAMILY is a multicenter, randomized, open-label phase III trial for HR+ and HER2- MBC. Eligible participants are randomized (1:1) to receive capecitabine (2000mg/m2 twice daily x 14 days followed by 7 days off) or fulvestrant (500mg Days 0, 14, 28, then every 28 days) until disease progression, unacceptable toxicity, or patient refusal. Stratification factor for randomization is sensitivity to adjuvant hormonal therapy (disease-free interval ≤24 months vs. >24 months). Eligibility Criteria: Eligible patients must have HR+ (ER and/or PR>1%, by IHC) and HER2- MBC; achieved a complete or partial response or stable disease (investigator assessed) after 4-8 cycles of first-line combination chemotherapy. Patients with central nervous system metastasis and/or prior use of endocrine therapy for advanced breast cancer are excluded. Specific Aims: The primary endpoint is progression free survival (PFS). Secondary endpoints include overall survival, overall response rate, disease control rate, safety and QOL. A prospective translational research is also planned to assess the correlations between biomarkers and response. Statistical Design: The planned sample size of 256 patients provides approximately 80% of power to detect a 6 months difference of PFS using a log-rank test with two-sided alpha of 0.05. Target Accrual: Recruitment is ongoing. Up to 256 evaluable subjects will be enrolled within 24 months. (ChiCTR-IIR-17014036). Citation Format: Yao H, Wu W, Ding L, Yu Y, Wang Y, Zeng Y, Zhao J, Li Q. FAMILY: A randomized, multicenter, open-label, phase III trial of fulvestrant versus capecitabine as maintenance therapy after first-line combination chemotherapy in patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-05-01.

Abstract P5-04-29: Efficacy and safety of low-dose everolimus in Chinese HR-positive, HER2-negative metastatic breast cancer patients

Abstract Background: Everolimus has been testified to be effective among postmenopausal women with hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (MBC). However, everolimus at dose of 10mg was accompanied by a higher incidence of mTOR-inhibitor class-effect adverse events (AEs) which usually leading to dose reduction or interruption. Additionally, some studies suggested that there was no correlation between dose intensity (5 vs. 10 mg labeled dose) and efficacy. Consequently, we conducted the present study aiming to explore the efficacy and safety of everolimus at dose of 5 mg plus endocrine therapy in Chinese population. Methods: 68 HR+/HER2- MBC patients were included in this exploratory study who received everolimus at the dose of 5mg in Zhejiang Cancer Hospital between September 2014 and September 2017. Progression free survival(PFS) and overall survival(OS) were estimated by the Kaplan- Meier method, and the hazard ratios(HRs) and corresponding 95% confidence intervals(CIs) were estimated using the Cox proportional harzard model. Besides, objective response rate(ORR), clinical benefitrate(CBR) and safety profile were also evaluated. Results: After a median follow up of 14 months, PFS was 5.3 months (95%CI 4.2-6.4), and OS was immature. 16(23.5%) were at the first or second-line, 52(76.5%) were at third-line or later. PFS for the first and second-line is significantly longer than that for the third-line or later (12.9 months vs. 4.6 months, P=0.009, HR=0.395, 95% CI=0.192-0.811). 11(16.2%) achieved partial response (PR), 42(61.7%) had stable disease (SD), and 15(22.1%) reported progressive disease (PD). The ORR and CBR were 16.2%, 35.2%, respectively. Most common all grade adverse events were stomatitis(26.5%), fatigue(10.0%), infection(11.8%), thrombocytopenia(5.9%), anemia(4.4%), hyperglycemia(4.4%). The most common ≥3 grade adverse events were stomatitis(4.4 %), infection(2.2%) and thrombocytopenia(1.1%). Conclusions: The combination of low-dose everolimus and endocrine therapy was highly effective especially at the earlier line in Chinese population. And the safety profiles were similar to previous studies but the incidences were greatly lower. The combination of low-dose everolimus and endocrine therapy may become a proper option for HR+/HER2- MBC. Citation Format: Shao X, Wang X, Chen Z, Zheng Y. Efficacy and safety of low-dose everolimus in Chinese HR-positive, HER2-negative metastatic breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-29.

Abstract P2-08-66: Outcomes among metastatic breast cancer patients with characteristics that confer a less favorable prognosis

Abstract Background: Recent advances in the treatment of hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) have contributed to increased overall survival (OS). Despite advances, MBC remains incurable and there is a subset of patients with clinical features that are associated with poorer prognosis. This study described the patient characteristics, treatment patterns, and outcomes of a cohort of US patients with HR+, HER2- MBC as a function of various factors associated with poor prognosis, including presence (vs. absence) of liver metastases (LM). Methods: This retrospective study used US community oncology electronic health record data from the Vector Oncology Data Warehouse. Eligible women who received systemic treatment for MBC, had a diagnosis of MBC in 2008 or later, and had completed at least three Patient Care Monitor (PCM) surveys, (a patient-reported outcomes survey collected as a part of clinical care), were included. OS was measured from the start of the first three regimen-based lines (1L, 2L and 3L) of treatment; patients without evidence of death were censored at the last observed visit. The statistical significance of differences in categorical and continuous variables between LM positive (LM+) and LM negative (LM-) were evaluated with chi-square (X2) tests, and t-tests, respectively. Kaplan-Meier and Cox analyses were applied to evaluate differences in OS by LM status and by line of therapy at the start of MBC treatment (unadjusted for treatment). Results: A total of 378 women, 98.4% residing in the South and 40.5% African-American, were included; 295 (78.0%) were LM- at the time of diagnosis. Following 1L, approximately 82.8% and 60.8% of patients received 2L and 3L, respectively. Patients with a LM+ status had a lower mean age (mean: 57.2, SD: 13.8 vs. 61.2, 13.1; p=0.016) and a higher percentage had a grade 3 tumor (36.1 vs. 24.7%; p=0.039) compared to patients with LM-status. Table 1 shows the OS results for 1L-3L. For all 3 lines, median OS for LM+ was shorter than the LM- median OS. LM+ patients had a poorer prognosis as they were more likely to have an OS event across 1L-3L compared to LM- patients. Conclusions: Among this community oncology cohort, median OS in 1L was 14 months shorter in LM+ patients compared to LM- patients. It is important to note that the sample size and selection criteria may limit generalizability of these results. Despite progress in treating women with MBC, treatment options are lacking for patients with less favorable prognosis, including those with LM. Other potential indicators of poor prognosis, such as high tumor grade, are being explored. Table 1.OS (months) by regimen-based line of therapy Measure Liver Mets (LM+) No Liver Mets (LM-) HR p-value 1L, # of Events/ # of Patients55/83168/295 Median (95% CI)23.9 (15.5-28.6)35.2 (30.1-42.3) <0.0001* Cox Hazard Ratio 1.93<0.0001 2L, # of Events/ # of Patients48/72149/241 Median (95% CI)16.6 (12.0-22.6)24.2 (21.3-29.0) 0.002* Cox Hazard Ratio 1.490.040 3L, # of Events/ # of Patients35/52118/178 Median (95% CI)11.5 (7.0-21.0)17.4 (14.7-20.0) 0.038* Cox Hazard Ratio 1.540.060CI=Confidence Interval; *p-value was derived using log rank test. Citation Format: Saverno K, Cuyun Carter G, Dufour R, Price G, Li L, DeLuca A, Nash Smyth E, Battiato L, Gable J, Walker MS, Huang Y-J, Hannas S, Schwartzberg LS. Outcomes among metastatic breast cancer patients with characteristics that confer a less favorable prognosis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-66.

The prognostic and therapeutic implications of circulating tumor cell phenotype detection based on epithelial\u2013mesenchymal transition markers in the first-line chemotherapy of HER2-negative metastatic breast cancer

BackgroundEpithelial–mesenchymal transition (EMT) is implicated in the metastatic process and presents a challenge to epithelial cell adhesion molecule-based detection of circulating tumor cells (CTCs), which have been demonstrated to be a prognostic indicator in metastatic breast cancer. Although evidence has indicated that heterogeneity of CTCs based on EMT markers is associated with disease progression, no standard recommendations have been established for clinical practice. This study aimed to evaluate the prognostic significance of dynamic CTC detection based on EMT for metastatic breast cancer patients.MethodsWe enrolled 108 human epidermal growth factor receptor 2-negative metastatic breast cancer patients from the prospective phase III CAMELLIA study and applied the CanPatrol CTC enrichment technique to identify CTC phenotypes (including epithelial CTCs, biphenotypic epithelial/mesenchymal CTCs, and mesenchymal CTCs) in peripheral blood samples. Receiver operating characteristic curve analyses of total CTC count and the proportion of mesenchymal CTCs for predicting the 1-year progression-free survival (PFS) rate were conducted to determine the optimal cut-off values, and Kaplan–Meier analysis and Cox proportional hazards regression analysis were performed to investigate the prognostic value of the cut-off values of both total CTC count and the proportion of mesenchymal CTCs in combination.ResultsFor predicting the 1-year PFS rate, the optimal cut-off value of total CTC count was 9.5 (Area under the curve [AUC] = 0.538, 95% confidence interval [CI] = 0.418–0.657), and that of the proportion of mesenchymal CTCs was 10.7% (AUC = 0.581, 95% CI = 0.463–0.699). We used the two cut-off values in combination to forecast PFS in which the total CTC count was equaled to or exceeded 10/5 mL with the proportion of mesenchymal CTCs surpassed 10.7%. Patients who met the combined criteria had significantly shorter median PFS than did those who did not meet the criteria (6.2 vs. 9.9 months, P =0.010). A nomogram was constructed based on the criteria and significant clinicopathological characteristics with a C-index of 0.613 (P = 0.010).ConclusionsThe criteria, which combine the total CTC count and the proportion of mesenchymal CTCs, may be used to monitor therapeutic resistance and predict prognosis in patients with metastatic breast cancer.Trial registrationClinicalTrials.gov. NCT01917279. Registered on 19 July 2013, https://clinicaltrials.gov/ct2/show/NCT01917279?term=NCT01917279&rank=1.

Cyclin-Dependent Kinases 4/6 Inhibitors in Breast Cancer: Current Status, Resistance, and Combination Strategies.

Dysregulated activation of the cyclin-dependent kinases (CDKs) 4/6, leading to uncontrolled cell division, is hallmark of cancers. Further study of the cell cycle will advance the cancer treatment. As powerful and effective drugs, inhibitors of CDK 4/6 have been widely used in clinical practice for several malignancies, particularly against breast cancers driven by the estrogen receptor (ER). Three CDK4/6 inhibitors, including palbociclib (PD0332991), ribociclib (LEE011) and abemaciclib (LY2835219), have been approved by the US Food and Drug Administration (FDA) for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer. However, CDK4/6 inhibitors act downstream of many mitogenic signaling pathways, and this has implications for resistance. It is worth to note that the mechanisms of resistance are not very clear. Up to now, a small number of preclinical and clinical studies have explored potential mechanisms of CDK4/6 inhibitors resistance in breast cancer. On this basis, rational and effective combination therapy is under development. Here we review the current knowledge about the mechanisms and efficacy of CDK4/6 inhibitors, and summarize data on resistance mechanisms to make future combination therapies more accurate and reasonable.

Efficacy and Safety of Palbociclib and Fulvestrant in Japanese Patients With ER+/HER2- Advanced/Metastatic Breast Cancer.

Published data have shown that palbociclib-fulvestrant can significantly improve the progression-free survival (PFS) of estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) metastatic breast cancer patients, but not of Japanese patients. We conducted this retrospective study to verify the efficacy and safety of palbociclib-fulvestrant in Japanese patients. ER+/HER2- metastatic breast cancer patients treated with fulvestrant (n=39) or palbociclib-fulvestrant (n=31) at the Saitama Medical Center from July 2012 to November 2018 were evaluated. Overall response rates (ORRs) were 2.6% (fulvestrant) and 41.9% (palbociclib-fulvestrant) (p<0.001), and clinical benefit rates (CBRs) were 23.1% and 61.3% (p=0.002), respectively. The palbociclib-fulvestrant group had significantly higher CBR and PFS (hazard ratio(HR):0.272, 95% confidence interval(95CI):0.128-0.574 for PFS). Grade 3/4 neutropenia occurred in 80.6% of the palbociclib-fulvestrant group, while febrile neutropenia was not detected. Japanese ER+/HER2- metastatic breast cancer patients tolerated palbociclib-fulvestrant, with significantly improved clinical outcomes.

Palbociclib in combination with fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-3 subgroup analysis of Japanese patients

BackgroundIn the double-blind, phase 3 PALOMA-3 study, palbociclib–fulvestrant significantly prolonged progression-free survival versus placebo–fulvestrant in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC) whose disease had progressed on prior endocrine therapy. The present study evaluated the efficacy, safety, and pharmacokinetics of palbociclib plus fulvestrant in Japanese patients enrolled in PALOMA-3.MethodsPre/peri/postmenopausal women with HR+/HER2– MBC were randomized 2:1 to fulvestrant (500 mg) and either palbociclib (125 mg/day; 3 weeks on/1 week off; n = 347) or placebo (n = 174). Prespecified exploratory analyses compared the efficacy (data cutoff: October 23, 2015), safety, and pharmacokinetics (data cutoff: December 5, 2014) in Japanese women versus the overall population.ResultsA total of 35 Japanese women were randomized to palbociclib–fulvestrant (n = 27) or placebo–fulvestrant (n = 8). Median progression-free survival was 13.6 months (95% CI, 7.5–not estimable) in the Japanese palbociclib–fulvestrant group and 11.2 months (95% CI, 5.6–not estimable) in the placebo–fulvestrant group. The most common adverse event (AE) in Japanese patients was neutropenia (all grades, 93%); no discontinuations were due to an AE. Geometric mean trough concentration values (within-subject mean steady state) for palbociclib were similar for Japanese Asian (excluding Japanese), and non-Asian patients (84.4 ng/mL, 86.3 ng/mL, and 74.8 ng/mL, respectively).Conclusion(s)The results for the overall population and Japanese patients in PALOMA-3 suggest that palbociclib plus fulvestrant was effective and well tolerated in Japanese patients with HR+/HER2‒ MBC whose disease had progressed on prior endocrine therapy (Pfizer; NCT01942135).

Cost-effectiveness analysis of ribociclib versus palbociclib in the first-line treatment of HR+/HER2- advanced or metastatic breast cancer in Spain.

PurposeThe aim of this study was to evaluate the cost-effectiveness of ribociclib compared to palbociclib, both in combination with letrozole, in the first-line treatment of postmenopausal women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer (ABC) from the perspective of the Spanish National Health System (NHS).Patients and methodsDisease progression was simulated with a partitioned survival model developed from the parameterization and extrapolation of survival curves of postmenopausal women with HR+/HER2− ABC from clinical trials with ribociclib or palbociclib, both in combination with letrozole. The model was structured on the basis of three health states (progression-free, progressed disease, and death), with a 1-month cycle length and inclusion of subsequent treatments administered for disease progression, over a time horizon of 15 years. Clinical, economic, and quality of life parameters were drawn from clinical trials and the literature. The use of resources and clinical practice in the Spanish setting was validated by a panel of experts. The Spanish NHS perspective was adopted, taking into account exclusively direct health costs from 2017 expressed in Euros. Drug prices used were the reported ex-factory prices. Uncertainty of the parameters and robustness of the results were evaluated using deterministic and probabilistic sensitivity analyses (2,000 iterations).ResultsThis cost-effectiveness analysis showed a greater benefit (0.437 and 0.285 life-years gained [LYGs] and quality-adjusted life years [QALYs] gained, respectively) and a slightly higher cost (€439.86) for ribociclib+letrozole compared to palbociclib+letrozole. The resulting incremental cost-effectiveness and cost-utility ratios were €1,007.69 per LYG and €1,543.62 per QALY gained, respectively. The results of the multiple sensitivity analyses showed limited dispersion of the outcomes, thus corroborating their robustness.ConclusionFrom the NHS perspective, considering the most commonly established willingness-to-pay thresholds in the Spanish setting, ribociclib+letrozole would represent a cost-effective therapeutic option compared to palbociclib+letrozole in the first-line treatment of HR+/HER2− ABC in postmenopausal women.

Time to treatment failure of palbociclib and letrozole as second-line therapy or beyond in hormone receptor-positive advanced breast cancer.

The management of endocrine therapy resistance is one of the most challenging facets of advanced breast cancer treatment. Palbociclib is an inhibitor of cyclin-dependent kinases 4 and 6 approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer in combination with fulvestrant in postmenopausal women with disease progression following endocrine therapy. However, treatment responsiveness of tumors to palbociclib after multiple lines of endocrine therapy is not clearly established. The purpose of this study was to determine the efficacy of palbociclib and letrozole in patients pretreated with one or more lines of endocrine therapy. This was a single-center, retrospective cohort study of all postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer patients who received palbociclib and letrozole as a second-line endocrine therapy or beyond (and no prior cyclin-dependent kinases 4 and 6 inhibitor therapy) between February 1, 2015, and July 31, 2016. The primary objective was to evaluate time to treatment failure of palbociclib in combination with letrozole as a second-line of therapy or beyond. Fifty-three patients meeting eligibility criteria were included in the analysis. For the primary outcome, the median time to treatment failure of palbociclib and letrozole was 6.3 months (95% CI 3.1-7.4 months). Progression-free survival of palbociclib and letrozole therapy was 6.4 months (95% CI 4.9-8.3 months). Palbociclib and letrozole therapy is a viable, effective treatment option for metastatic breast cancer patients who were not exposed to cyclin-dependent kinases 4 and 6 inhibitors as a first-line endocrine therapy. The benefits of palbociclib and letrozole therapy were seen without excessive toxicity, and although neutropenia was common, it may be managed with dose reduction.