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BACKGROUND: Breast cancer is a leading cause of cancer-related deaths in females, and the hormone receptor-positive subtype is the most frequent. Breast cancer is a common source of brain metastases; therefore, we aimed to generate a brain metastases prediction model in females with hormone receptor-positive breast cancer. METHODS: The primary cohort included 3,682 females with hormone receptor-positive breast cancer treated at a single center from May 2009 to May 2020. Patients were randomly divided into a training dataset (n = 2,455) and a validation dataset (n = 1,227). In the training dataset, simple logistic regression analyses were used to measure associations between variables and the diagnosis of brain metastases and to build multivariable models. The model with better calibration and discrimination capacity was tested in the validation dataset to measure its predictive performance. RESULTS: The variables incorporated in the model included age, tumor size, axillary lymph node status, clinical stage at diagnosis, HER2 expression, Ki-67 proliferation index, and the modified Scarff-Bloom-Richardson grade. The area under the curve was 0.81 (95 % CI 0.75-0.86), p < 0.001 in the validation dataset. The study presents a guide for the clinical use of the model. CONCLUSION: A brain metastases prediction model in females with hormone receptor-positive breast cancer helps assess the individual risk of brain metastases.

Asunto(s)

Neoplasias Encefálicas , Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias Encefálicas/secundario , Persona de Mediana Edad , Medición de Riesgo , Anciano , Receptor ErbB-2/metabolismo , Adulto , Receptores de Estrógenos/metabolismo , Receptores de Estrógenos/análisis , Receptores de Progesterona/metabolismo

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Background: The CDK 4/6 inhibitors, including palbociclib and ribociclib, are the standard first-line treatment for hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer. Proton pump inhibitors are one of the most globally prescribed types of medications as part of the treatment for gastroesophageal reflux and heartburn complaints. Medication interactions have been demonstrated, leading to a decrease in the effectiveness of chemotherapy drugs such as capecitabine and pazopanib. However, their role and interaction with targeted therapies such as CDK inhibitors are still poorly understood. Methods: We searched PubMed, Embase and Web of Science databases for studies that investigated the use of PPI with CDK 4/6 inhibitors versus CDK4/6 alone for advanced or metastatic breast cancer. We systematically searched for the currently available CDK inhibitors: palbociclib, ribociclib and abemaciclib. We computed hazard ratios (HRs), with 95% confidence intervals (CIs). We used DerSimonian and Laird random-effect models for all endpoints. Heterogeneity was assessed using I2 statistics. R, version 4.2.3, was used for statistical analyses. Results: A total of 2,737 patients with advanced breast cancer in 9 studies were included, with six studies described the status menopausal as 217 (7.9%) pre-menopause and 1851 (67.6%) post-menopause, for endocrine sensitivity only five studies described1489 (54.4%) patients were endocrine-sensitive and 498 (182%) endocrine-resistent, 910 (33.2%) patients used PPIs. The overall Progression-Free Survival was in favor of the PPI non-users (HR 2.0901; 95% CI 1.410-2.9498; p < 0.001). As well as the subgroup taking palbociclib, revealing statistical relevance for the PPI non-users (HR 2.2539; 95% CI 1.3213-3.8446; p = 0.003) and ribociclib subgroup with a slight decrease in hazard ratio (HR 1.74 95% CI 1.02-2.97; p = 0.04; I2 = 40%). In the multivariate analysis, there was no statistical signifance with ECOG (HR 0.9081; 95% CI 0.4978-16566; p 0.753) and Age (HR 1.2772; 95% CI 0.8790-1.8559; p = 0.199). Either, the univariate analysis did not show statistical significance. Conclusion: Women with HR+ and HER2-advanced metastatic breast undergoing treatment with targeted therapies, specifically CDK 4/6 inhibitors, should be monitored for the use of proton pump inhibitors. Therefore, the use of PPIs should be discussed, weighing the advantages and disadvantages for specific cases. It should be individualized based on the necessity in clinical practice for these cases. Systematic Review Registration: identifier CRD42023484755.

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Breast cancer remains the most frequently diagnosed cancer in women worldwide. Tumors that express hormone receptors account for 75% of all cases. Understanding alternative signaling cascades is important for finding new therapeutic targets for hormone receptor-positive breast cancer patients. JAK-STAT signaling is commonly activated in hormone receptor-positive breast tumors, inducing inflammation, proliferation, migration, and treatment resistance in cancer cells. In hormone receptor-positive breast cancer, the JAK-STAT cascade is stimulated by hormones and cytokines, such as prolactin and IL-6. In normal cells, JAK-STAT is inhibited by the action of the adaptor protein, LNK. However, the role of LNK in breast tumors is not fully understood. This review compiles published reports on the expression and activation of the JAK-STAT pathway by IL-6 and prolactin and potential inhibition of the cascade by LNK in hormone receptor-positive breast cancer. Additionally, it includes analyses of available datasets to determine the level of expression of LNK and various members of the JAK-STAT family for the purpose of establishing associations between expression and clinical outcomes. Together, experimental evidence and in silico studies provide a better understanding of the potential implications of the JAK-STAT-LNK loop in hormone receptor-positive breast cancer progression.

Asunto(s)

Neoplasias de la Mama , Transducción de Señal , Humanos , Femenino , Transducción de Señal/fisiología , Quinasas Janus/metabolismo , Prolactina/metabolismo , Interleucina-6/metabolismo , Factores de Transcripción STAT/metabolismo

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Background: The addition of cyclin-dependent kinases inhibitors (CDKi) to endocrine therapy (ET) as the first- or second line treatment improves progression-free and overall survival (OS) in hormone receptor-positive, HER2 negative (HR+/HER2-) advanced stage breast cancer (ABC). Our study compared survival rates and prognostic factors in Chilean patients that used palbociclib as first or subsequent (≥second) lines of treatment in a real-world setting. Methods: Our retrospective population-cohort study included HR+/HER2- ABC patients. We calculated 5-year OS and performed a multivariate analysis to determine prognostic factors. Results: A total of 106 patients were included. Median age was 49 years (19-86), 28.3% (30) had de novo stage IV disease; 63% received palbociclib with ET as first line, 54% of them with aromatase inhibitor over fulvestrant. Median OS for the entire cohort was 99 months and 5-year OS was 69%. Patients that received first line palbociclib had a 5-year OS of 89% versus 43% for ET monotherapy or ≥second line palbociclib (p = 0.0062). Multivariate analysis showed that the year at diagnosis and CDKi timing (first line versus ≥second line) were significantly associated with OS. Conclusion: Our real-world data show that first-line CDKi + ET provides a statistically significant benefit in OS versus ≥second line in HR+/HER2- ABC patients.

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Background: Oncotype DX (ODX) is a validated assay for the prediction of risk of recurrence and benefit of chemotherapy (CT) in both node negative (N0) and 1-3 positive nodes (N1), hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early breast cancer (eBC). Due to limited access to genomic assays in Brazil, treatment decisions remain largely driven by traditional clinicopathologic risk factors. ODX has been reported to be cost-effective in different health system, but limited data are available considering the reality of middle-income countries such as Brazil. We aim to evaluate the cost-effectiveness of ODX across strata of clinical risk groups using data from a dataset of patients from Brazilian institutions. Methods: Clinicopathologic and ODX information were analyzed for patients with T1-T3, N0-N1, HR+/HER2- eBC who had an ODX performed between 2005 and 2020. Projections of CT indication by clinicopathologic criteria were based on binary clinical risk categorization based on the Adjuvant! Algorithm. The ODX score was correlated with the indication of CT according to TAILORx and RxPONDER data. Two decision-tree models were developed. In the first model, low and high clinical risk patients were included while in the second, only high clinical risk patients were included. The cost for ODX and CT was based on the Brazilian private medicine perspective. Results: In all, 645 patients were analyzed; 411 patients (63.7%) had low clinical risk and 234 patients (36.3%) had high clinical risk disease. The ODX indicated low (<11), intermediate (11-25), and high (>25) risk in 119 (18.4%), 415 (64.3%), and 111 (17.2%) patients, respectively. Among 645 patients analyzed in the first model, ODX was effective (5.6% reduction in CT indication) though with an incremental cost of United States Dollar (US$) 2288.87 per patient. Among 234 patients analyzed in the second model (high clinical risk only), ODX led to a 57.7% reduction in CT indication and reduced costs by US$ 4350.66 per patient. Conclusions: Our study suggests that ODX is cost-saving for patients with high clinical risk HR+/HER2- eBC and cost-attractive for the overall population in the Brazilian private medicine perspective. Its incorporation into routine practice should be strongly considered by healthcare providers.

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Treatment paradigms in advanced hormone receptor (HR)-positive breast cancer were substantially transformed with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) approval. The addition of these drugs to endocrine treatment profoundly improved progression-free and overall survival. Additionally, other important endpoints, such as the response rate, time to chemotherapy, and a delay in quality of life deterioration, were positively impacted by CDK4/6 inhibitors' addition to the treatment of advanced HR-positive breast cancer. This review article will summarize current knowledge on CDK4/6 inhibitors in clinical practice for advanced HR-positive metastatic breast cancer, as well as describe recent efforts to more precisely characterize mechanisms of sensitivity and resistance to these drugs, both on the molecular and clinical characterization level.

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PURPOSE: The COVID-19 pandemic has impacted early breast cancer (EBC) treatment worldwide. This study analyzed how Brazilian breast specialists are managing EBC. METHODS: An electronic survey was conducted with members of the Brazilian Society of Breast Cancer Specialists (SBM) between April 30 and May 11, 2020. Bivariate analysis was used to describe changes in how specialists managed EBC at the beginning and during the pandemic, according to breast cancer subtype and oncoplastic surgery. RESULTS: The response rate was 34.4% (503/1462 specialists). Most of the respondents (324; 64.4%) lived in a state capital city, were board-certified as breast specialists (395; 78.5%) and either worked in an academic institute or one associated with breast cancer treatment (390; 77.5%). The best response rate was from the southeast of the country (240; 47.7%) followed by the northeast (128; 25.4%). At the beginning of the pandemic, 43% changed their management approach. As the outbreak progressed, this proportion increased to 69.8% (p < 0.001). The southeast of the country (p = 0.005) and the state capital cities (p < 0.001) were associated with changes at the beginning of the pandemic, while being female (p = 0.001) was associated with changes during the pandemic. For hormone receptor-positive tumors with the best prognosis (Ki-67 < 20%), 47.9% and 17.7% of specialists would recommend neoadjuvant endocrine therapy for postmenopausal and premenopausal women, respectively. For tumors with poorer prognosis (Ki-67 > 30%), 34% and 10.9% would recommend it for postmenopausal and premenopausal women, respectively. Menopausal status significantly affected whether the specialists changed their approach (p < 0.00001). For tumors ≥ 1.0 cm, 42.9% of respondents would recommend neoadjuvant systemic therapy for triple-negative tumors and 39.6% for HER2 + tumors. Overall, 63.4% would recommend immediate total breast reconstruction, while only 3.4% would recommend autologous reconstruction. In breast-conserving surgery, 75% would recommend partial breast reconstruction; however, 54.1% would contraindicate mammoplasty. Furthermore, 84.9% of respondents would not recommend prophylactic mastectomy in cases of BRCA mutation. CONCLUSIONS: Important changes occurred in EBC treatment, particularly for hormone receptor-positive tumors, as the outbreak progressed in each region. Systematic monitoring could assure appropriate breast cancer treatment, mitigating the impact of the pandemic.

Asunto(s)

Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/terapia , Infecciones por Coronavirus , Mamoplastia , Mastectomía , Terapia Neoadyuvante , Pandemias , Neumonía Viral , Adulto , Betacoronavirus , Brasil , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , COVID-19 , Atención a la Salud , Manejo de la Enfermedad , Femenino , Genes BRCA1 , Genes BRCA2 , Humanos , Masculino , Mastectomía Segmentaria , Persona de Mediana Edad , Selección de Paciente , Posmenopausia , Premenopausia , Mastectomía Profiláctica , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , SARS-CoV-2 , Sociedades Médicas , Encuestas y Cuestionarios , Carga Tumoral

RESUMEN

BACKGROUND: In hormone receptor-positive, HER-2 negative (HR+/HER2-) advanced breast cancer (ABC) endocrine therapy (ET) plus cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in first and second line improved progression-free survival (PFS), overall response rate (ORR) and clinical benefit rate (CB) without deterioration in quality of life compared with ET alone. In addition, recent data showed improvement in overall survival (OS) for premenopausal women in first line setting and for different subgroups of patients in second line. Since 2015, in Argentina, the combination of ET with CDK4/6i is a standard of care in HR+/HER2- ABC. METHODS: We carried out a prospective analysis of real-world use of palbociclib with ET in HR+/HER2- ABC patients who received treatment between October 2015 and August 2019 in two private institutes from Buenos Aires, Argentina. The aims of the study were to determine efficacy and safety of patients treated with ET and palbociclib, describe patient profile and treatment strategy beyond progression. RESULTS: One-hundred and twenty-eight patients were included in the final analysis. Main baseline characteristics include, median age 57 years, 20% were premenopausal women, 44% had visceral metastasis and 26% bone only disease. More than half of patients had two or more metastatic sites, 44.4% had performance status 1, and most of them (59.4%) were treated with palbociclib in first-line setting. Palbociclib was preferentially associated with aromatase inhibitors in 63.9% of patients, and with fulvestrant in the remaining. All premenopausal women received ovarian suppression or ovarian ablation (OS/OA). The median PFS was 36.7 months in first line and 24.2 months in second line. The ORR was 45.3% and 25.0% in first and second line, respectively. The median OS in the entire population was not reached. Half of patients did not require dose interruption and/or delay, dose reduction was required in 15% of patients and almost no patients required drug discontinuation (2.0%). With regard to safety, 55% of patients developed grade 3-4 adverse events, 20% neutropenia grade 3-4, and 7% febrile neutropenia. Infections were presented in one out of three patients, mostly uncomplicated. CONCLUSIONS: This is the first prospective evidence of real-world use of palbociclib in a Latin American population. We found similar outcomes to the PALOMA-2 and PALOMA-3 randomised trials and Real-World Data already published, with lower incidence of side effects and treatment discontinuation, but with higher incidence of febrile neutropenia.

RESUMEN

BACKGROUND: The prognostic and clinical significance of single hormone receptor expression in breast cancer has not been clearly established. The goal of this study was to conduct a meta-analysis to compare the clinical outcomes of patients with ER+PR- tumours and ER-PR+ tumours to those of patients with ER+PR+ tumours. METHODS: A systematic review of the literature was conducted to identify studies that compared the clinical outcome of patients with ER+PR- tumours or ER-PR+ tumours with those of patients with ER+PR+ tumours. A total of 18 studies met the inclusion criteria and included 217,485 women. Standard methods for meta-analysis were used, including fixed-effect models. RESULTS: Patients with ER+PR- tumours or ER-PR+ tumours had significantly worse DFS (HR 1.60, 95% CI 1.44-1.77 and HR 2.27, 95% CI 1.67-3.09), BCSS (HR 1.43, 95% CI 1.33-1.53 and HR 1.82, 95% CI 1.68-1.98) and OS (HR 1.38, 95% CI 1.28-1.47 and HR 1.48, 95% CI 1.17-1.89) than those of patients with ER+PR+ tumours. In subgroup analyses, patients who had ER+PR- tumours experienced a higher risk of recurrence than patients with ER+PR+ tumours in the HER2- (HR 1.57, 95% CI 1.32-1.87), LN - (HR 2.07, 95% CI 1.44-2.86) and endocrine therapy (HR 1.65, 95% CI 1.45-1.89) subgroup. Patients who had HER2- and ER-PR+ tumours had an increased risk of recurrence compared with patients who had HER2- and ER+PR+ tumours (HR 3.10, 95% CI 1.92-5.10). CONCLUSIONS: Among patients with hormone receptor-positive breast cancer, patients with either ER+PR- tumours or ER-PR+ tumours have a higher risk of recurrence and a shorter survival time than those with ER+PR+ tumours. Patients with both types of breast cancer need additional or better treatments.

Asunto(s)

Neoplasias de la Mama/mortalidad , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Neoplasias de la Mama/química , Femenino , Humanos , Recurrencia Local de Neoplasia/etiología , Receptor ErbB-2/análisis

RESUMEN

BACKGROUND: Over the last 20 years, aromatase inhibitors (AI) have been tested in clinical trials as first-line therapy for hormone receptor-positive (HR-positive) advanced breast cancer (ABC), firstly as experimental arms, when they proved to be effective, and recently as control arms. This analysis aims to evaluate trends in progression-free survival (PFS) and time to progression (TTP) over time. PATIENTS AND METHODS: A literature review was conducted using the MEDLINE database to identify randomized controlled phase II or III trials which reported PFS or TTP of at least one arm using first-line AI HR-positive ABC patients. A linear correlation was used to access the association between the year of the first patient enrolled and the observed PFS/TTP. RESULTS: The search retrieved 19 trials, accounting for 4552 postmenopausal patients divided into 21 separate AI treatment arms. The PFS/TTP increased from 6 to 9 months in the earlier trials to 13-16 months in the current era, representing an absolute gain of approximately 7 months, without the addition of any other drug. Our analysis showed a positive correlation between the year of the first patient enrolled in these trials and median PFS/TTP reported (R 2 = 0.34; p < 0.01). No correlation was found between the year of the first patient included in these trials and other potential prognostic factors such as visceral metastasis at baseline (R 2 = 0.26; p = 0.20) or exposure to adjuvant therapy (R 2 = 0.05; p = 0.18). CONCLUSION: Patients treated with first-line AIs in the more recently conducted trials have longer PFS/TTP when compared to their counterparts treated with the same drugs in older studies. These findings have important implications for the estimation of sample size and follow-up periods for the planning of future trials as well as in the translation of the results into clinical practice decisions.

Asunto(s)

Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Supervivencia sin Progresión , Neoplasias de la Mama/patología , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Progresión de la Enfermedad , Femenino , Humanos , Mortalidad/tendencias , Posmenopausia , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Factores de Tiempo

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INTRODUCTION: This study aimed to describe the efficacy of fulvestrant 500 mg in postmenopausal women with estrogen receptor (ER)-positive advanced/metastatic breast cancer who had disease progression after receiving anti-estrogen therapy in clinical practice, getting real-world data. MATERIALS AND METHODS: Multicenter, retrospective, observational study conducted in Spain. Postmenopausal women with locally advanced/metastatic ER-positive breast cancer who received treatment with fulvestrant 500 mg after progression with a previous anti-estrogen therapy were eligible. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), clinical benefit rate (CBR), duration of clinical benefit (DoCB), and safety profile. RESULTS: A total of 263 women were evaluated (median age, 65.8 years). At a median follow-up of 21.5 months, median PFS and OS were 10.6 and 43.2 months, respectively. PFS according to 1st, 2nd, 3rd, and ≥ 4th lines were 11.5, 10.6, 9.9, and 8.5 months, respectively (p = 0.0245). PFS in patients with visceral involvement was 10 months vs 10.6 months in patients without visceral involvement (p = 0.6604), 9.6 months in patients with high Ki67 vs 10 months in patients with low Ki67 (p = 0.7224), and 10.2 months in HER2+ patients vs 10.3 months in HER2- patients (p = 0.6809). The CBR was 56.5% and the DoCB was 18.4 months. The most frequently adverse events were injection site pain (10.3%) and musculoskeletal disorders (7.6%). CONCLUSIONS: Fulvestrant 500 mg administered in clinical practice was shown to be effective (PFS, 10.6 months; CBR, 56.5%) and well tolerated, in accordance with previous trials.

Asunto(s)

Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Lobular/tratamiento farmacológico , Resistencia a Antineoplásicos , Estradiol/análogos & derivados , Posmenopausia , Anciano , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/secundario , Carcinoma Lobular/metabolismo , Carcinoma Lobular/secundario , Estradiol/uso terapéutico , Femenino , Estudios de Seguimiento , Fulvestrant , Humanos , Metástasis Linfática , Persona de Mediana Edad , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos

RESUMEN

We reviewed randomized phase II/III trials comparing first- or second-line endocrine therapy as monotherapy or in combination with targeted therapies for treatment of postmenopausal patients with hormone receptor-positive advanced breast cancer. First-line was defined as treatment for endocrine therapy-naïve advanced breast cancer or advanced disease treated with endocrine therapy in the adjuvant/neoadjuvant setting. Second-line was defined as endocrine therapy for advanced breast cancer following disease progression on endocrine therapy for advanced disease. Publications reporting progression-free survival (PFS)/time to progression (TTP) or overall survival (OS) for FDA-approved agents anastrozole, exemestane, fulvestrant 250 mg, fulvestrant 500 mg, letrozole (0.5 and 2.5 mg), megestrol acetate, and tamoxifen as monotherapy, or in combination with everolimus, palbociclib or ribociclib, were assessed. First-line monotherapy with anastrozole, fulvestrant 500 mg or letrozole 2.5 mg significantly improved PFS/TTP versus comparator endocrine therapy; however, only fulvestrant 500 mg improved OS. For endocrine therapy in combination with targeted therapies, palbociclib plus letrozole 2.5 mg, and ribociclib plus letrozole 2.5 mg significantly improved PFS versus letrozole 2.5 mg alone first-line. For second-line monotherapies, exemestane, fulvestrant 500 mg and letrozole 2.5 mg significantly improved PFS/TTP versus comparator endocrine therapy; only fulvestrant 500 mg and letrozole 2.5 mg improved OS. For second-line combination therapies, everolimus plus exemestane, and palbociclib plus fulvestrant 500 mg, improved PFS versus endocrine therapy alone. In both first- and second-line settings, aromatase inhibitors demonstrated PFS benefits versus comparator endocrine therapy; however, fulvestrant 500 mg was the only endocrine therapy included in our review to show both PFS and OS advantages compared with other endocrine therapies. Targeted agents in combination with endocrine therapy have demonstrated PFS improvements both first- and second-line; OS data are awaited.