Hormone Receptor-positive Advanced Breast Cancer Research Articles

Abstract P6-03-01: Development of patient-derived xenograft tumor model with organ-specific metastatic potential for evaluation of new therapeutics for hormone receptor-positive advanced breast cancer

Abstract Background: Breast cancer (BC) is a heterogeneous disease with most common metastatic sites of liver, lung, brain, and bone. Endocrine resistance in hormone receptor-positive (HR+) advanced BC (ABC) cancer is a clinical challenge. ESR1 mutations are a key mechanism in acquired resistance, primarily occurs after exposure to endocrine therapy such as aromatase inhibitors but also selective estrogen modulators and degraders (i.e. Tamoxifen and Fulvestrant). Circulating tumor cells (CTCs) enumeration is a prognostic biomarker in ABC but the relation between the onset of ESR1 mutations and CTCs status is still unclear. Aim of this project is to define the clinical behavior of ESR1 mutated ABC in terms of metastasizing potential, through CTC enumeration and pattern; and to establish ESR1 mutated HR+ ABC PDX models able to recapitulate these characteristics. Methods: CTCs and circulating tumor DNA (ctDNA) were characterized in 55 HR+ ABC patients. ESR1 mutations status from 55 patient plasma cell-free DNA were generated using Guardant Next Generation Sequencing. Samples were also examined for numbers of CTCs by CellSearch. Association of ESR1 mutations with sites of distant organ metastasis and with CTC enumeration was analyzed by Chi square test and Kruskal–Wallis test, respectively. In preclinical model development, six samples of pleural effusion-derived tumor cells from Stage IV HR+ ABC patients were collected to establish HR+ ABC with ESR1 mutation PDX tumor model and its derived 3D organoid/spheroid cultures Results: ESR1 mutations were identified in 10 out of 55 patients (4 Y537S variant and 3 D538G variant, 4 other variants, 1 patient with both variants). In 55 patients, 72 visceral vs 27 bone metastatic incidences were observed; the data indicated 9 observed vs 4.5 expected in ESR1 mutated and 16 observed vs 20.5 expected in wild type (WT) (P=0.003) for liver metastasis; 10 observed vs 7.1 expected in ESR1 mutated and 29 observed vs 31.9 expected in WT (P=0.026) for bone metastasis. Further liver metastasis analysis of individual hot spot mutation site indicated 4 observed vs 1.8 expected in Y537S and 21 observed vs 23.2 expected in WT (P=0.037); and 3 observed vs 1.4 expected in D538G and 22 observed vs 23.6 expected in wild type (P=0.088). The analysis of correlation/distribution between CTCs numbers and ESR1 mutated suggested CTCs median of 13 (IQR 7-49) in ESR1 mutated and 0 (IQR 0-4) in WT HR+ patients (P=0.0044). Four ABC PDX tumor models were developed in immunodeficient NSG female mice demonstrated by pathology to have highly heterogeneous characteristics and metastatic features of the origin patient tumor, in particular, breast fat pad xenografted PDX tumor can result in metastasis to liver and lung tissue. In addition, two patient 3D tumor organoid/spheroid cultures were successfully established. Conclusions: ESR1 mutated ABC is associated with more aggressive (Stage IV) clinical behavior demonstrated by association with visceral metastases and CTCs detection. ESR1-mutated PDX models recapitulate aggressive features of the disease and can be used for preclinical testing of novel agents in endocrine resistant disease. Citation Format: Qiang W, Zhong Z, Gerratana L, Zhang Y, Zhang Q, Gursel D, Wei J-J, Bleher R, James C, O'Halloran T, Cristofanilli M. Development of patient-derived xenograft tumor model with organ-specific metastatic potential for evaluation of new therapeutics for hormone receptor-positive advanced 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 P6-03-01.

Abstract P4-13-01: Endocrine treatment for hormone receptor-positive advanced breast cancer patients with endocrine-sensitive or endocrine-resistant disease: A systematic review and network meta-analysis

Abstract Background: For patients with hormone receptor-positive (HR+) advanced breast cancer (ABC), the choice of endocrine treatment should be based on the best available evidence. However, no direct head-to-head comparison of all tested regimens is currently available. This network meta-analysis aims at providing detailed inference-based data to guide decision making on endocrine therapy for HR+ ABC patients in two different clinical scenarios: endocrine-sensitive and endocrine-resistant ABC, as defined by the ABC guidelines criteria. Methods: Phase II/III randomized clinical trials published or presented up to June 15, 2018 and comparing two or more different endocrine treatments (with or without associated targeted therapies) for HR+, HER2-negative ABC patients were included, irrespective of treatment line. Relative treatment effects were pooled as hazard ratios (HRs) and modeled in a network meta-analysis using a Bayesian framework with fixed-effects models in order to infer the best approach. The main outcomes were progression-free survival (PFS) and overall survival (OS). Four separate analyses were carried out: PFS and OS networks in both endocrine-sensitive and endocrine-resistant populations. Results: A total of 26 trials were included in this meta-analysis (N=11330 patients). In the endocrine-sensitive setting, 12 trials were included in the PFS network (N=5200 patients; 10 different regimens) and 3 trials in the OS network (N=1295; 3 regimens). In terms of PFS, the combination of Fulvestrant 500 mg (F500)+CDK4/6 inhibitors (CDKi) had a 80% probability of being the most effective treatment, followed by aromatase inhibitor (AI)+CDKi (17% chance of being the best approach). The HR for the comparison between F500+CDKi vs. AI+CDKi was 0.82 (95% credibility interval [CrI] 0.54-1.25). Regarding OS, the AI+CDKi approach had a 63% chance of being the most effective regimen, followed by F500 (36% likelihood) – the comparison between the two regimens yielded a HR of 0.93 (95% CrI 0.61-1.40). In the endocrine-resistant setting, 18 trials were included in the PFS network (N=6130; 20 regimens) and 7 in the OS network (N=2701; 10 regimens). For PFS, F500+CDKi had a 59% probability of being the most effective treatment, followed by F500+Everolimus (11% likelihood). The HR of the comparison between F500+CDKi vs. F500+Everolimus was 0.84 (95% CrI 0.57-1.25). In terms of OS, F500+FGFR inhibitors had a 29% chance of being the best treatment option, followed by AI+everolimus (24% likelihood) – the HR for the comparison of F500+FGFR inhibitors vs. AI+everolimus was 1.07 (95% CrI 0.36-3.18). Conclusion: This network meta-analysis provides for the first time a comparison of all tested treatment options for HR+ ABC patients in both endocrine-sensitive and endocrine-resistant settings. In terms of PFS, F500+CDKi appears to be the best treatment option for both disease settings. As for OS, AI+CDKi is possibly the best choice for endocrine-sensitive ABC patients. Concerning endocrine-resistant disease, F500+FGFR inhibitors may be an effective regimen which should be further studied, while AI+everolimus remains the best available option in this setting. Citation Format: Brandão M, Maurer C, Ziegelmann P, Pondé N, Ferreira AR, Martel S, Piccart-Gebhart M, Debiasi M, de Azambuja E, Lambertini M. Endocrine treatment for hormone receptor-positive advanced breast cancer patients with endocrine-sensitive or endocrine-resistant disease: A systematic review and network meta-analysis [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 P4-13-01.

Abstract P2-07-05: A clinical calculator to predict disease outcomes in women with hormone receptor-positive advanced stage breast cancer treated with first-line endocrine therapy

Abstract Purpose: Endocrine based therapy is an effective strategy to manage hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). However, nearly all patients exhibit/develop either de novo or acquired resistance. While prognostic biomarkers of endocrine responsiveness are well established for the adjuvant treatment in ER+ breast cancer, less is known regarding prognostic and predictive biomarkers of response in the first line ABC setting. We sought to develop a clinical calculator based on clinical criteria for predicting progression-free survival (PFS) and overall survival (OS) of women with HR+/HER2- ABC who will be receiving endocrine monotherapy as first-line treatment for ABC. Methods: The development of the clinical calculator will be based on data from modern clinical trials in women with HR+/HER2- ABC. The studies to be included in the final analyses are given in Table 1. The control arm data from trials1-6 will form the training dataset (N = 1,223) and be used to construct the clinical prediction models. Variables considered include age, race, ECOG status, disease measurability, body mass index, disease-free interval, number of metastatic sites, locations of metastatic sites, prior endocrine therapy, and prior chemotherapy. Missing values will be imputed using single imputation with all variables included in the imputation model. For continuous variables, restricted cubic splines will be used to determine if non-linear effects may be more appropriate. The Lasso regression will be used as a variable selection technique to reduce the dimensionality of covariates; initially all pairwise interactions will be included in the model. Following Lasso regression, the multivariable Cox proportional hazards models will be constructed for PFS and OS including only variables retained in Lasso. The final model will be internally validated for discrimination and calibration using 10-fold cross-validation. External validation will be performed using control arm data from EGF 30008 (N = 536). Results: To date, control arm data from four trials (trials 1-4) have been received. The preliminary results presented here are based on pooled data from C40503 and LEA, for which data elements have been harmonized. Models for predicting PFS and OS have good calibration and are associated with bias-corrected C-indices of 0.61 and 0.65, respectively. These models will be updated using pooled data from trials 1-6. Conclusions: Our preliminary data demonstrate that clinical calculators based on baseline clinical factors can provide accurate prediction of PFS and OS in patients with HR+/HER2- ABC treated with first-line ET. If validated, these tools may be used for risk stratification in future clinical trials and to identify patients who may require more or less aggressive therapy. Table 1:Studies to be includedTrial NumberTrial NameTrial PISample Size in Control Arm1C40503Maura Dickler152 (letrozole)2LEAMiguel Martin179 (letrozole)3FACTJonas Bergh188 (anastrozole)4FALCONJohn Robertson194 (anastrozole)5S0226Rita Mehta345 (anastrozole)6MONARCH 3Matthew Goetz165 (nonsteroidal AI)7EGF 30008Stephen Johnston536 (letrozole) Citation Format: Polley M-YC, Dickler MN, Johnston S, Goetz MP, de la Haba J, Loibl S, Mehta RS, Bergh J, Roberston J, Barlow W, Liu H, Tenner K, Martin M. A clinical calculator to predict disease outcomes in women with hormone receptor-positive advanced stage breast cancer treated with first-line endocrine therapy [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 P2-07-05.

Abstract P6-18-23: Palbociclib and endocrine therapy in fourth line and beyond for hormone receptor-positive HER2-negative advanced breast cancer: The UK compassionate access program experience

Abstract Background Palbociclib is approved in 1st line for hormone receptor (HR)-positive HER2-negative advanced breast cancer (ABC). A Compassionate Access Program (CAP) previously allowed patients to receive it in 4th line. However, Palbociclib has not been specifically tested in this population. We aimed to determine the safety and efficacy profile of Palbociclib within the CAP across ten institutions in the United Kingdom. Methods We retrospectively identified HR-positive HER2-negative ABC patients on the Palbociclib CAP between December 2015 and September 2017. Demographics, disease characteristics, prior treatments, blood tests, toxicities, treatment delays and responses were recorded. Simple statistics, Fisher's exact test, chi-squared method and Cox regression were used as appropriate. Results 118 patients identified had median age of 59 (32-82). 97 (82.20%) were postmenopausal and 109 (92.37%) had ECOG Performance Status 0-1. 96 (81.36%) had visceral involvement, 19 (16.10%) bony only and 15 (12.71%) visceral only disease. Patients received a median 5 (range 3-11) prior lines of treatment and 3 (range 0-8) prior chemotherapy lines. 105 patients (89.74%) developed neutropenia (grade ≥3 in 59 [56.19%]). 6 experienced febrile neutropenia (5.13%). 57 (48.72%) had a dose reduction, down to 100mg in 48 (41.03%) and 75mg in 9 (7.69%) due to hematologic toxicity in 46 (80.70%). Dose delays were in median 7 days long (range: 0-56). Palbociclib was discontinued due to disease progression in 97 (82.91%) and to toxicity in 5 (4.27%). Grade 3 neutropenia occurred in 45 patients (67.16%) who received ≥3 and in 22 (32.84%) who received <3 prior chemotherapies (p 0.351). Palbociclib produced clinical benefit rate (CBR) of 47.52% and overall response rate of 15.84% in 101 patients assessed. CBR was 45.45% with previous endocrine treatment (ET) progression-free survival (PFS) <6 months versus 49.12% if PFS ≥6 months (p 0.714). Overall, median PFS was 4.5 months (95% CI 3.7-5.9). The PFS seen in different subgroups showed no impact in relation to the number of lines of prior chemotherapy (<3 lines: 5.9 months [95% CI 3.7-11.0]; ≥3 lines: 4.3 months [95% CI 3.3-5.5], p 0.159), but was numerically greater in those who had previous benefit from ET (PFS ≥6 months: 5.9 months [95% CI 4.4-8.0]; <6 months: 3.7 months [95% CI 2.8-4.5], p. 0.055) or in those with bone only disease (bone only: 11.0 months [95% CI 2.3-not reached]; other sites involved: 4.4 months [95% CI 3.6-5.5], p 0.024). Median OS was 15.8 months (95% CI 13.3-18.7) for the whole cohort and it was greater in patients who derived longer PFS from prior ET (≥6 months: 18.1 months [95% CI 13.0-NR]; <6 months: 14.4 months [95% CI 7.7-18.3], p. 0.052). Conclusions To date, this is the most extensive analysis of Palbociclib outcomes in ≥4th-line setting. In this heavily pretreated population clinical benefit was confirmed particularly for endocrine-sensitive disease and predominantly involving the bones and in earlier lines of treatment. Grade ≥3 neutropenia rates were similar to PALOMA trials, but the higher incidence of febrile neutropenia need to be carefully considered. Citation Format: Battisti NML, Kingston B, King J, Denton A, Waters S, Sita-Lumsden A, Rehman F, Stavraka C, Kristeleit H, Sawyer E, Houghton D, Davidson N, Howell S, Choy J, Harper P, Roylance R, Fharat R, Mohammed K, Ring A, Johnston S. Palbociclib and endocrine therapy in fourth line and beyond for hormone receptor-positive HER2-negative advanced breast cancer: The UK compassionate access program experience [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 P6-18-23.

Abstract OT1-12-04: A phase IIIb, open-label, local, multicenter study of the molecular features of postmenopausal women with hormone receptor-positive (HR+) HER2-negative advanced breast cancer on first-line treatment with ribociclib and letrozole (BioItaLEE)

Abstract Background: characterizing the molecular features associated with prolonged benefit from CDK 4/6 inhibitors in HR+ HER2- BC and the acquired genomic alterations following treatment progression remains an unmet need and is crucial for leveraging the efficacy of CDK4/6 inhibitors and for elucidating resistance mechanisms. Identifying pre-treatment or pharmacodynamic predictive markers of treatment benefit, as well as predictive markers of toxicity by correlating pharmacogenomics with adverse events, could help physicians to select patients who may benefit the most from these therapies and improve the clinical management. Trial design: this is an Italian, multicenter, open-label, single-arm trial (NCT03439046) enrolling approximately 350 HR+ HER2- aBC first line patients in 48 sites. Patients are treated with ribociclib and letrozole and eligibility criteria are similar to the MONALEESA-2 trial. Patients will be followed for safety and efficacy outcomes. An extensive prospective collection of biological samples at different time points will be performed as follow: whole blood and plasma at baseline, cycle 1-D15, cycle 2-D1, at first imaging evaluation, at cycle 24-D1, as well as upon progression of disease; newly obtained tissue biopsies at baseline and at progression; a buccal swab for pharmacogenetics at baseline. Efficacy and safety data will be collected for all patients. Aims: the primary objective of this study is to identify circulating tumor DNA (ctDNA) alterations at baseline, to describe their evolution during treatment and to evaluate the association with clinical outcome. An optimized Next Generation Sequencing approach for the detection of low abundance events in ctDNA will be adopted. Single nucleotide variants and copy number alterations in a customized panel of genes relevant for BC will be analyzed. Secondary objectives include the evaluation of: serum thymidine kinase 1 activity over time as blood marker of early response; ctDNA alterations across different patient profiles and clonal evolution of ctDNA alterations under treatment; ctDNA alterations at time of tumor progression; correlation between mutational status detected in ctDNA and matched tissue samples; features of tumor microenvironment before and after treatment; association of pharmacogenomics patterns with adverse events and clinical outcomes. Clinical efficacy and safety of ribociclib + letrozole will be correlated with all biological endpoints. Statistical methods: the study is descriptive in nature and no formal statistical testing is necessary or applicable. Sample size is aligned with other biomarker studies and is based on a feasibility analysis of the trial and relative timelines. Present accrual: The first study patient was screened in Feb 2018, as in June 2018, 126 patients have been screened and 78 patients have been enrolled. Citation Format: De Laurentiis M, Arpino G, Bianchini G, Malorni L, Castelletti D, De Vecchi R, Grasso D. A phase IIIb, open-label, local, multicenter study of the molecular features of postmenopausal women with hormone receptor-positive (HR+) HER2-negative advanced breast cancer on first-line treatment with ribociclib and letrozole (BioItaLEE) [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 OT1-12-04.

ACT-FASTER, a Prospective Cohort Study Exploring Treatment Patterns with Fulvestrant and Exemestane in Postmenopausal Patients with Advanced Hormone Receptor-Positive Breast Cancer under Real-Life Conditions in Germany

Background: Endocrine therapy is recommended for the treatment of postmenopausal women with hormone receptor-positive (HR+) advanced breast cancer (ABC). Methods: ACT-FASTER was a German prospective non-interventional cohort study in postmenopausal women with HR+ ABC receiving fulvestrant 500 mg as first line (1 L), second line (2 L) or third line (3 L), or exemestane (any line) in the real-world palliative setting. Primary study objectives included the effectiveness of fulvestrant according to line of palliative treatment measured by time to progression (TTP), and real-life data on the epidemiology and management of these patients. Results: Of 498 evaluable patients (mean age 67.5 years), 99% were estrogen receptor-positive. On study, 86.7% of patients received fulvestrant 500 mg and 13.3% exemestane. Median TTP was 9.7 months in patients receiving fulvestrant 1 L; 6.8 months for 2 L; and 6.7 months for 3 L. The comparison between fulvestrant 1 L palliative treatment and 2 L or 3 L showed that early initiation of treatment prolonged TTP (hazard ratio 1.26; 95% confidence interval 1.08-1.48). Treatments were well tolerated. Conclusion: Fulvestrant 500 mg was administered successfully to patients under daily practice conditions, and both medications were well tolerated. TTP was longest in patients treated with fulvestrant 500 mg 1 L compared with 2 L and 3 L in the palliative care setting.

Everolimus plus Exemestane for Hormone Receptor-Positive Advanced Breast Cancer: A PAM50 Intrinsic Subtype Analysis of BOLERO-2.

The prognostic and predictive value of the two nonluminal (human epidermal growth factor receptor 2 [HER2]-enriched and basal-like) subtypes within advanced hormone receptor-positive (HR+) breast cancer is currently unknown. This study retrospectively analyzed 261 tumors (80.7% primary; 19.3% metastatic) from the BOLERO-2 study; BOLERO-2 randomized 724 patients with advanced HR+/HER2-negative breast cancer to everolimus plus exemestane or placebo plus exemestane. Tumors were classified using a PAM50 subtype predictor. Multivariable Cox regression analyses tested the independent prognostic significance of PAM50, and associations between PAM50 subtypes and treatment upon progression-free survival (PFS) were evaluated. Subtype distribution was 46.7% luminal A (n = 122), 21.5% HER2-enriched (n = 56), 15.7% luminal B (n = 41), 14.2% normal-like (n = 37), and 1.9% basal-like (n = 5); HER2-enriched subtypes were more common in metastatic versus primary tumors (32.0% vs. 18.7%; p = .038). Median PFS differences between luminal and nonluminal (6.7 vs. 5.2 months; adjusted hazard ratio, 0.66; 95% confidence interval [CI], 0.47-0.94; p = .020) and HER2-enriched and non-HER2-enriched subtypes (5.2 vs. 6.2 months; adjusted hazard ratio, 1.53; 95% CI, 1.07-2.19; p = .019) were significant. Everolimus plus exemestane significantly improved median PFS versus placebo plus exemestane among patients with HER2-enriched tumors (5.8 vs. 4.1 months; adjusted hazard ratio, 0.49; 95% CI, 0.26-0.90; p = .034); however, the association between HER2-enriched tumors and everolimus benefit was nonsignificant (p = .433). The HER2-enriched subtype was identified in a substantial proportion of advanced HR+/HER2-negative breast tumors, and was a consistent biomarker of poor prognosis. Tailored therapies are therefore needed for HER2-enriched tumors in the advanced HR+/HER2-negative breast cancer setting. Using 261 tumor samples from the BOLERO-2 phase III clinical trial, this study shows that a substantial proportion (20%-30%) of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancers do not have a luminal A or B gene expression profile. This group of patients with nonluminal disease has a poor survival outcome regardless of the addition of everolimus to exemestane. This is the second study that confirms the prognostic value of this biomarker. Overall, these findings indicate a necessity to design novel clinical trials targeting nonluminal disease within HR+/HER2-negative breast cancer.

Everolimus Reverses Palbociclib Resistance in ER+ Human Breast Cancer Cells by Inhibiting Phosphatidylinositol 3-Kinase(PI3K)/Akt/Mammalian Target of Rapamycin (mTOR) Pathway

BackgroundPalbociclib, a specific inhibitor of CDK4/6, has been shown to provide a survival benefit in hormone receptor-positive advanced breast cancer; however, its resistance and related mechanisms are unclear.Material/MethodsIn this study, we constructed palbociclib-resistant hormone receptor-positive breast cancer cells (MCF-7-P) via culturing with palbociclib for at least 6 months. Quantitative real-time PCR (qRT-PCR) and western blot were used to detect the expression of stemness markers in MCF-7-P and MCF-7 cells. Additionally, cell spheroid formation, Transwell migration, ALDH1 activity, and flow cytometry assays were performed to detect stemness and migration ability of MCF-7-P cells, and the effects of everolimus on MCF-7-P cells stemness and migration ability. Growth inhibition assay was used to examine the effect of everolimus on the sensitivity of palbociclib in MCF-7-P and MCF-7 cells.ResultsMCF-7-P cells had stronger stemness and higher expression of ABCG2 and MDR1. Moreover, PI3K/Akt/mTOR signaling was hyper-activated in MCF-7-P cells. Additionally, everolimus, which is a mTOR inhibitor, attenuated MCF-7-P cells stemness and re-sensitized MCF-7-P cells to palbociclib. Importantly, everolimus enhanced the antitumor effect of palbociclib in palbociclib-sensitive hormone receptor-positive cells (MCF-7 cells).ConclusionsThese findings provide a rationale for future clinical trials of palbociclib and everolimus combination-based therapy in hormone receptor-positive breast cancer.

CDK4/6 inhibition versus mTOR blockade as second-line strategy in postmenopausal patients with hormone receptor-positive advanced breast cancer: A network meta-analysis.

Background:Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (palbociclib and abemaciclib) and mammalian target of rapamycin (mTOR) inhibitors (everolimus) are effective agents for restoring endocrine sensitivity in patients with advanced breast cancer progression on prior aromatase inhibitors. We conducted a network meta-analysis to compare these treatments in terms of progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR).Methods:The PubMed and Embase databases were searched for relevant publications between January 2000 and June 2018. Treatments were ranked based on a network meta-analysis. Ranking was determined by P-score. A random-effect model was used when heterogeneity was detected; otherwise, a fixed-effect model was used.Results:Six trials comprising 4063 patients formed the comparison network. Compared with everolimus plus exemestane, the combinations of palbociclib or abemaciclib with fulvestrant showed similar efficacies in PFS and no differences in ORR. For the CBR, palbociclib demonstrated improvement, while abemaciclib did not. Incidences of severe adverse events did not significantly differ. A total of 29%, 15.9%, and 4% of patients discontinued everolimus, abemaciclib, and palbociclib, respectively, due to toxicity.Conclusion:These results suggest similar efficacies between CDK4/6 inhibition and mTOR blockade; however, CDK4/6 inhibitors were associated with favorable toxicity profiles.

Palbociclib plus endocrine therapy in HER2 negative, hormonal receptor-positive, advanced breast cancer: A real-world experience.

Data from 423 human epidermal growth factor receptor 2-negative (HER2-), hormone receptor-positive (HR+) advanced breast cancer (aBC) patients treated with palbociclib and endocrine therapy (ET) were provided by 35 Italian cancer centers and analyzed for treatment outcomes. Overall, 158 patients were treated in first line and 265 in second/later lines. We observed 19 complete responses and 112 partial responses. The overall response rate (ORR) was 31% (95% confidence interval [CI], 26.6-35.4) and clinical benefit was 52.7% (95% CI, 48-57.5). ORR was negatively affected by prior exposure to everolimus/exemestane ( p = 0.002) and favorably influenced by early line-treatment ( p < 0.0001). At 6 months, median progression-free survival was 12 months (95% CI, 8-16) and median overall survival was 24 months (95% CI, 17-30). More favorable outcomes were associated with palbociclib in early lines, no visceral metastases and no prior everolimus/exemestane. The main toxicity reported was neutropenia. Our results provide further support to the use of palbociclib with ET in HER2-, HR+ aBC. Differences in outcomes across patients subsets remain largely unexplained.

Correction to: Fulvestrant-Based Combination Therapy for Second-Line Treatment of Hormone Receptor-Positive Advanced Breast Cancer

The article Fulvestrant-Based Combination Therapy for Second-Line Treatment of Hormone Receptor-Positive Advanced Breast Cancer, written by Sarah Sammons, Noah S. Kornblum and Kimberly L. Blackwell, was originally published electronically on the publisher's internet portal (currently SpringerLink).

Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy

CDK4 & 6 inhibitors have enhanced the effectiveness of endocrine therapy (ET) in patients with advanced breast cancer (ABC). This paper presents exploratory analyses examining patient and disease characteristics that may inform in whom and when abemaciclib should be initiated. MONARCH 2 and 3 enrolled women with HR+, HER2- ABC. In MONARCH 2, patients whose disease had progressed while receiving ET were administered fulvestrant+abemaciclib/placebo. In MONARCH 3, patients received a nonsteroidal aromatase inhibitor+abemaciclib/placebo as initial therapy for advanced disease. A combined analysis of the two studies was performed to determine significant prognostic factors. Efficacy results (PFS and ORR in patients with measurable disease) were examined for patient subgroups corresponding to each significant prognostic factor. Analysis of clinical factors confirmed the following to have prognostic value: bone-only disease, liver metastases, tumor grade, progesterone receptor status, performance status, treatment-free interval (TFI) from the end of adjuvant ET, and time from diagnosis to recurrence. Prognosis was poorer in patients with liver metastases, progesterone receptor-negative tumors, high grade tumors, or short TFI (<36 months). Benefit (PFS hazard ratio, ORR increase) from abemaciclib was observed in all patient subgroups. Patients with indicators of poor prognosis had the largest benefit from the addition of abemaciclib. However, in MONARCH 3, for patients with certain good prognostic factors (TFI ≥ 36 months, bone-only disease) ET achieved a median PFS of >20 months. These analyses identified prognostic factors and demonstrated that patients with poor prognostic factors derived the largest benefit from the addition of abemaciclib.

Correction to: Efficacy and safety of fulvestrant in postmenopausal patients with hormone receptor-positive advanced breast cancer: a systematic literature review and meta-analysis.

In the original publication of the article, the authors' affiliation was published incorrectly. The corrected affiliation is given in this correction. The author also found few corrections in the article which are given below.

Selecting the optimal position of CDK4/6 inhibitors in hormone receptor-positive advanced breast cancer \u2013 the SONIA study: study protocol for a randomized controlled trial

BackgroundCombining cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors with endocrine therapy is an effective strategy to improve progression-free survival in hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. There is a lack of comparative data to help clinicians decide if CDK4/6 inhibitors can best be added to first- or second-line endocrine therapy. Improvement in median progression-free survival in first-line studies is larger than in second-line studies, but CDK4/6 inhibitors have not consistently shown to improve overall survival or quality of life. They do come with added toxicity and costs, and many patients have lasting disease remission on endocrine therapy alone. No subgroup has been identified to select patients who are most likely to benefit from the addition of CDK4/6 inhibition in any line of treatment. Altogether, these factors make that the optimal strategy for using CDK4/6 inhibitors in clinical practice is unknown.MethodsThe SONIA study is an investigator-initiated, multicenter, randomized phase III study in patients with HR+/HER2-negative advanced breast cancer. Patients are randomly assigned to receive either strategy A (first-line treatment with a non-steroidal aromatase inhibitor combined with CDK4/6 inhibition, followed on progression by fulvestrant) or strategy B (first-line treatment with a non-steroidal aromatase inhibitor, followed on progression by fulvestrant combined with CDK4/6 inhibition). The primary objective is to test whether strategy A is more effective than strategy B. The primary endpoint is time from randomization to second objective progression (PFS2). Secondary endpoints include overall survival, safety, quality of life, and cost-effectiveness. Five-hundred seventy-four events yield 89% power to show that strategy A has statistically significant, clinically meaningful superior PFS2 (according to ESMO-MCBS) in a log-rank test at the two-sided 95% confidence level. Given an accrual period of 42 months and an additional 18 months follow-up, inclusion of 1050 evaluable patients is required.DiscussionThis study design represents daily clinical practice, and the results will aid clinicians in deciding when adding CDK4/6 inhibitors to endocrine therapy will benefit their patients most. Additional biomarker analyses may help to optimize patient selection.Trial registrationhttp://clinicaltrials.gov: NCT03425838 (8 February 2018). EudraCT-number: 2017–002334-23 (29 September 2017).

A comparison of fulvestrant plus a targeted agent with fulvestrant alone in hormone receptor-positive advanced breast cancer that progressed on prior endocrine therapy: a meta-analysis.

Fulvestrant is recommended for the hormone receptor-positive metastatic breast cancer (MBC) patients progressed during or after prior endocrine therapy. Notably, recent evidence has also demonstrated that adding a targeted agent to fulvestrant conferred a significantly clinical benefit in these patients. Since these results were inconsistent among the studies, this meta-analysis herein was conducted to compare the efficacy and toxicities of the fulvestrant-based combination therapy with fulvestrant monotherapy. Thus, a systemic research was performed in PubMed, Embase, and Cochrane library to identify relevant Phase II or Phase III randomized controlled trials. The progression-free survival (PFS), overall response rate (ORR), and toxicities were evaluated. And HR, risk ratio (RR), and their 95% CIs were employed to complete the pooled analyses. In total, 13 studies with 3,910-hour positive MBC patients progressed on prior endocrine therapy were included in our meta-analysis. Improvements of doublet-agents group were proven in terms of PFS (HR 0.73, 95% CI =0.63–0.86, P=0.000) and ORR (RR 2.07, 95% CI =1.67–2.58, P=0.000). And the further subgroup analysis also demonstrated that fulvestrant in combination with a cyclin-dependent kinase (CDK4/6) inhibitor or a PI3K/mTOR inhibitor was associated with a superior efficacy (RR 2.72, 95% CI =1.93–3.83, P=0.000 and RR 1.60, 95% CI =1.15–2.23, P=0.005, respectively). However, the efficacy was comparable between the other combination strategies and fulvestrant alone. With respect to the adverse effects, adding a targeted agent to fulvestrant also produced more frequent grade 3/4 toxicities (RR 3.86, 95% CI =2.66–5.61, P=0.000). Taken together, combination of fulvestrant with a targeted agent, especially inhibitors targeting CDK4/6 or PI3K/mTOR pathway, may open a new avenue for more effective therapies in relapse or metastatic hormone receptor-positive breast cancer after prior aromatase inhibitors or tamoxifen treatment. In addition, identifying reliable biomarkers to delineate which subgroup of patients will specially benefit from fulvestrant-based combination therapy is warranted.

The impact of mammalian target of rapamycin inhibition on bone health in postmenopausal women with hormone receptor-positive advanced breast cancer receiving everolimus plus exemestane in the phase IIIb 4EVER trial

BackgroundBreast cancer and its treatments are associated with a detrimental effect on bone health. Here we report the results of an exploratory analysis assessing changes in levels of biomarkers of bone metabolism in patients enrolled in the phase IIIb 4EVER study. MethodsThe 4EVER trial investigated everolimus in combination with exemestane in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer. In this prespecified exploratory analysis, changes in biomarkers of bone turnover were assessed in patients from baseline to weeks 4, 12, and 24. The serum bone markers assessed were procollagen type 1 N-terminal propeptide (P1NP), C-terminal cross-linking telopeptide of type 1 collagen (CTX), osteocalcin, parathyroid hormone (PTH), and 25-hydroxyvitamin D (25-OH-vitamin D). On-treatment changes in bone markers over time were described per subgroup of interest and efficacy outcomes. ResultsBone marker data were available for 241 of 299 enrolled patients. At the final assessment, P1NP, osteocalcin, PTH, 25-OH-vitamin D (all P < 0.001), and CTX (P = 0.036) were significantly decreased from baseline values per the Wilcoxon signed-rank test. At the last assessment (24 weeks or earlier), levels of serum CTX and PTH were significantly lower (P = 0.009 and P = 0.034, respectively) among patients with vs. without prior antiresorptive treatment (ART). Serum CTX levels were significantly lower (P < 0.001), and 25-OH-vitamin D concentrations significantly higher (P = 0.029), at the last postbaseline assessment in patients receiving concomitant ART vs. those without ART. Changes from baseline in PTH and 25-OH-vitamin D concentrations to the final assessment were significantly smaller in patients with prior ART. Lower baseline serum concentrations of osteocalcin and PTH were associated with clinical response (partial vs. non-response) at 24 weeks. High serum levels of CTX and P1NP at baseline were risk factors for progression at 12 weeks. ConclusionsThese exploratory analyses support use of everolimus plus exemestane for the treatment of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer, and add to the body of evidence suggesting a potentially favorable impact of everolimus on bone turnover. Trial registrationNCT01626222. Registered 22 June 2012, https://clinicaltrials.gov/ct2/show/NCT01626222.

283O_PR - Phase III trial of chidamide, a subtype-selective histone deacetylase (HDAC) inhibitor, in combination with exemestane in patients with hormone receptor-positive advanced breast cancer

283O_PR - Phase III trial of chidamide, a subtype-selective histone deacetylase (HDAC) inhibitor, in combination with exemestane in patients with hormone receptor-positive advanced breast cancer

344P - First report of real-world patient characteristics and treatment patterns from POLARIS: Palbociclib in hormone receptor-positive (HR+) advanced breast cancer: A prospective, multicenter, noninterventional study

344P - First report of real-world patient characteristics and treatment patterns from POLARIS: Palbociclib in hormone receptor-positive (HR+) advanced breast cancer: A prospective, multicenter, noninterventional study

The efficacy and safety of targeted therapy plus fulvestrant in postmenopausal women with hormone-receptor positive advanced breast cancer: A meta-analysis of randomized-control trials.

ObjectiveTo evaluate the efficacy and safety of targeted therapy plus fulvestrant for postmenopausal patients with hormone receptor-positive advanced breast cancer.MethodsPubmed, Embase and Web of Science databases were systematically searched on February 26, 2018. Eligible studies were screened according to selection criteria, and two reviewers independently extracted outcome data which included progression-free survival, overall survival, objective response rate, clinical benefit rate and toxicities. RevMan 5.3 and STATA 11.0 software were used to conduct meta-analysis.ResultsThirteen articles including twelve randomized-control trials fulfilled selection criteria. There was no evidence regarding the existence of publication bias and high-risk bias of quality in the selected studies. In previously endocrine therapy-treated postmenopausal patients with hormone-receptor positive advanced breast cancer, the PFS (HR = 0.77, 95%CI: 0.66–0.91) and ORR (RR = 1.78, 95%CI: 1.35–2.34) of combination therapy group were significantly higher than that from fulvestrant monotherapy group. Besides, a statistically significant difference in PFS was found across the two arms in postmenopausal women with PIK3CA-mutant ctDNA tumor (HR = 0.52, 95% CI: 0.39–0.69). Moreover, the risk of adverse events (RR = 1.09, 95%CI: 1.05–1.13), CTCAE≥3 (RR = 1.97, 95%CI: 1.49–2.60) and discontinuation due to adverse events (RR = 4.91, 95%CI: 3.37–7.15) were also significantly different between two treatment groups. Sensitivity analysis showed PLOMA-3 trial was an important factor of heterogeneity.DiscussionEven though the combination of targeted therapy plus fulvestrant improved PFS and increased ORR in advanced breast cancer patients, the toxicities of combination therapy were also higher than fulvestrant monotherapy. Further studies related to inhibitors targeting the specific signaling pathway or receptors are urgently needed, and more efforts concerning precision medicine of targeted therapy plus endocrine therapy should be taken to improve the clinical benefits.

Fulvestrant-Based Combination Therapy for Second-Line Treatment of Hormone Receptor-Positive Advanced Breast Cancer.

Fulvestrant is recommended for patients with hormone receptor-positive (HR+) advanced breast cancer (ABC) who progress after aromatase inhibitor therapy. As most patients in this setting have already developed mechanisms of resistance to endocrine therapy, targeting biological pathways associated with endocrine resistance in combination with fulvestrant may improve outcomes. Therefore, evidence supporting a combinatorial treatment approach in the second-line setting was investigated based on a search of PubMed and ClinicalTrials.gov. Twenty-eight studies of targeted therapies plus fulvestrant as second-line treatment for HR+ ABC were identified, including three and six key randomized trials exploring cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors plus fulvestrant respectively. Additional combinations with fulvestrant included inhibitors of epidermal growth factor receptors, androgen receptor, and the bromodomain and extra-terminal family of proteins. Across the studies reviewed with available data, the addition of targeted therapies to fulvestrant resulted in clinically meaningful improvements in progression-free survival compared with fulvestrant alone. While some challenging toxicities were observed, most adverse events could be effectively managed. Selection of second-line targeted therapy for use with fulvestrant should consider prior treatment as well as the mutation status of the tumor. In conclusion, available data indicate that fulvestrant combined with agents targeting mechanisms of endocrine resistance is a promising approach. The ongoing trials identified in this review will help further inform the selection of combination treatments with fulvestrant for HR+ ABC.