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Background: The first-line treatment for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) involves a combination of trastuzumab, pertuzumab, and a taxane (TPH). This study assessed the efficacy of trastuzumab and pertuzumab (PH) in routine practice, following the treatment protocols of Uruguay's National Resources Fund (FNR), akin to clinical trials. Methods: Patients with advanced MBC treated with PH between 2008 and 2022 per FNR protocols were evaluated. The Kaplan-Meyer method and log-rank test were utilized for analyzing overall survival (OS). Demographic and clinical variables, including age, menopausal status, and hormone receptors (HR), were analyzed. Results: The study included 318 PH-treated patients. The median age was 56 years, with 63.2% being postmenopausal and 60.4% HR and HER-2 positive. With a median follow-up of 17.2 months, the median OS was 29 months. OS varied based on HR status and the presence of metastases at different sites, significantly lower in patients with brain, cutaneous/subcutaneous, and pulmonary metastases. Additionally, OS was higher in patients treated at private institutions compared to public ones. Conclusions: This study demonstrates the disparity in oncological treatment efficacy between clinical trials and clinical reality in Uruguay, emphasizing the importance of authentic environment research for more representative and effective medicine in Latin America.
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PURPOSE: This study aimed to investigate the current therapeutic management of patients with early-stage HER2-positive (HER2+) breast cancer in Spain, while also exploring the perceptions surrounding HER2DX in terms of its credibility, clinical relevance, and impact on therapeutic decision-making. Understanding these aspects is crucial for optimizing treatment strategies and enhancing patient outcomes in the context of HER2+ breast cancer. METHODS: An online questionnaire was conducted by an independent third-party between April and May 2022 across 70 medical oncologists highly specialized in breast cancer management in Spain. The survey included 37 questions regarding treatment decision making in HER2+ early breast cancer. RESULTS: The management of patients with HER2+ early breast cancer exhibited a high degree of heterogeneity. Among the interviewed oncologists, 53% would recommend upfront surgery for node negative tumors measuring 1 cm or less. Interestingly, 69% and 56% of interviewers were open to deescalate the duration of adjuvant trastuzumab in pT1a and pT1b N0 tumors, respectively. Certain clinicopathological characteristics, such as high grade, high Ki-67, and young age, influenced the decision to prescribe neoadjuvant treatment for patients with clinical stage 1 disease. In cases where neoadjuvant treatment was prescribed for cT1-2 N0 tumors, there was a wide variation in the choice of chemotherapeutic and anti-HER2 regimens. Regarding the use of adjuvant trastuzumab emtansine (T-DM1) in patients with residual disease after neoadjuvant therapy, there was diversity in practice, and a common concern emerged that T-DM1 might be overtreating some patients. HER2DX, as a diagnostic tool, was deemed trustworthy, and the reported scores were considered clinically useful. However, 86% of interviewees believed that a prospective trial was necessary before fully integrating the test into routine clinical practice. CONCLUSION: In the context of early-stage HER2+ breast cancer in Spain, a notable diversity in therapeutic approaches was observed. The majority of interviewed medical oncologists acknowledged HER2DX as a clinically valuable test for specific patients, in line with the 2022 SEOM-GEICAM-SOLTI clinical guidelines for early-stage breast cancer. To facilitate the full integration of HER2DX into clinical guidelines, conducting prospective studies to further validate its efficacy and utility was recommended.
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Neoplasias da Mama , Receptor ErbB-2 , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Feminino , Espanha , Receptor ErbB-2/metabolismo , Inquéritos e Questionários , Padrões de Prática Médica/estatística & dados numéricos , Trastuzumab/uso terapêutico , Atitude do Pessoal de Saúde , Tomada de Decisão Clínica , Estadiamento de Neoplasias , Pessoa de Meia-Idade , Quimioterapia Adjuvante , Antineoplásicos Imunológicos/uso terapêutico , Ado-Trastuzumab Emtansina/uso terapêutico , AdultoRESUMO
PURPOSE: HER2-targeted therapies have dramatically improved outcomes of patients with HER2-positive breast cancer (BC), as demonstrated in neoadjuvant trials. This study aims to provide real-world evidence on the use and effectiveness of combined pertuzumab, trastuzumab and chemotherapy (CT) in early-stage HER2-positive BC. METHODS: A retrospective, multicentre study was conducted on patients diagnosed with HER2-positive early BC treated with neoadjuvant pertuzumab and trastuzumab plus CT at 13 Spanish sites. The primary endpoint was pathological complete response (pCR). RESULTS: A total of 310 patients were included. Pertuzumab and trastuzumab were combined with anthracyclines and taxanes, carboplatin and docetaxel, and taxane-based CT in 77.1%, 16.5%, and 6.5% of patients, respectively. Overall, the pCR rate was 62.2%. The pCR was higher amongst patients with hormone receptor-negative tumours and with tumours expressing higher levels of Ki-67 (> 20%). After postoperative adjuvant treatment, 13.9% of patients relapsed. Those patients who did not achieve pCR, with tumours at advanced stages (III), and with node-positive disease were more likely to experience distant relapse. Median overall survival (OS) and distant disease-free survival (D-DFS) were not reached at the study end. The estimated mean OS and D-DFS times were 7.5 (95% CI 7.3-7.7) and 7.3 (95% CI 7.1-7.5) years, respectively (both were significantly longer amongst patients who achieved pCR). Grade 3-4 anti-HER2 related toxicities were reported in six (1.9%) patients. CONCLUSION: Neoadjuvant pertuzumab and trastuzumab plus CT achieve high pCR rates in real-life patients with HER2-positive early BC, showing an acceptable safety profile. Innovative adjuvant strategies are essential in patients at high risk of distant disease recurrence.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Terapia Neoadjuvante , Receptor ErbB-2 , Trastuzumab , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Trastuzumab/uso terapêutico , Trastuzumab/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pessoa de Meia-Idade , Estudos Retrospectivos , Receptor ErbB-2/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Adulto , Idoso , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Taxoides/administração & dosagem , Taxoides/uso terapêutico , Docetaxel/administração & dosagem , Docetaxel/uso terapêutico , Estadiamento de NeoplasiasRESUMO
El cáncer de mama (CM) es la primera causa de muerte por cáncer en mujeres tanto a nivel mundial como en Chile. Basados en características clínicas, histológicas y moleculares, múltiples estudios han identificado cuatro subtipos básicos de CM, los cuales están asociados a estrategias de tratamiento específicas y diferenciadas. El CM HER2-positivo representa un 15%-25% de todas las neoplasias mamarias y se caracteriza por su agresividad, recurrencia temprana y mayor tendencia a presentar compromiso del sistema nervioso central. En las últimas décadas, nuevas terapias dirigidas se han posicionado como el estándar de tratamiento y han cambiado la historia natural de esta enfermedad, transformándola en una enfermedad potencialmente curable incluso en etapas avanzadas. Esta revisión busca entregar un resumen de las bases biológicas de esta enfermedad. Por otro lado, dada la aparición de un creciente número de nuevas estrategias de manejo sistémico, nos proponemos revisar sus mecanismos de acción analizando reportes de datos clínicos publicados y la experiencia de nuestro grupo.
Breast cancer (BC) is the leading cause of cancer death for women both worldwide and in Chile. Based on clinical, histological, and molecular features, studies have identified four BC subtypes that correlate with treatment sensitivity. Human Epidermal growth factor Receptor type 2-positive (HER2+) BC represents 15%-25% of newly diagnosed breast neoplasms; HER2+ BC is characterized by its aggressive behavior, early recurrence, and higher risk of brain metastasis. In recent years, HER2-targeted therapies have become the mainstay of treatment and have redefined the natural history of this subtype, reducing relapse rates for early-stage patients and increasing survival in advanced-stage patients. Herein we review novel treatment strategies and their mechanisms of action, along with clinical and real-world data. We also provide a summary of currently available treatments for this subtype and our local experience regarding the management of this disease.
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PURPOSE: Dual HER2 blockade chemotherapy is the standard of care for localized HER2+ breast cancer (BC). However, despite the efficacy of neoadjuvant therapy, relapses occurring in around 10% of patients highlight the need to improve its clinical approach. Therefore, this study aimed to evaluate the effectiveness/safety of neoadjuvant therapy with subcutaneous (SC) trastuzumab- pertuzumab chemotherapy (real world) to extend the evidence, which comes mainly from clinical trials (selected population; intravenous [IV] trastuzumab). MATERIALS AND METHODS: A prospective, longitudinal, observational study in a Cuban hospital. POPULATION: women aged ≥18 years with histologically confirmed HER2+ early-stage BC (2017-2021) eligible for neoadjuvant treatment (IV pertuzumab, SC trastuzumab, taxane-based chemotherapy). The aim was to determine the pathological complete response (pCR) rate to this scheme, its safety, and the impact of patient's characteristics on the outcomes. RESULTS: Eighty-seven women were included: n=29 (DPT [docetaxel-IV pertuzumab- SC trastuzumab 600 mg; 4 cycles]); n=58 (ddAC-DPT [dose-dense anthracycline-based scheme+DPT]; 8 cycles). The median age was 57 years (range 30-83), ECOG 0: 97%. Time from diagnosis to treatment (median) was 28 days. The overall pCR rate was 62.1% (55.2%, DPT; 66.5%, ddAC-DPT; p =0.351); HR+, 47.7% vs. HR-, 76.7% (p=0.006). There were no statistically significant differences based on nodal status, stage, or Ki-67 levels. Overall, 94.2% of patients experienced ≥1 adverse event related to treatment, all of them grade 1-3 and more common with ddAC-DPT. The main cause of treatment delays (n=19; ddAC-DPT, 16; DPT, 3) was treatment-related toxicities. CONCLUSION: Neoadjuvant trastuzumab (SC) and pertuzumab plus chemotherapy for HER2+ early-stage BC showed benefits in a real-life setting, with an acceptable safety profile.
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Neoplasias da Mama , Humanos , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Trastuzumab/efeitos adversos , Neoplasias da Mama/patologia , Terapia Neoadjuvante/efeitos adversos , Cuba , Estudos Prospectivos , Receptor ErbB-2/análise , Recidiva Local de Neoplasia , Docetaxel/uso terapêuticoRESUMO
Abstract Background The many combinations of chemotherapeutic agents and biologicals available in the Brazilian National Health System for the treatment of metastatic breast cancer require analysis that contribute to decision making. Objective The study's primary aim was to evaluate the first-line treatment of HER2- overexpressing metastatic breast cancer from the Brazilian Unified Health System perspective using multicriteria decision analysis (MCDA). Method The treatment options evaluated were (a) pertuzumab combined with trastuzumab and docetaxel, and (b) trastuzumab in combination with docetaxel. Using the hierarchical analytical method, medical oncologists compared the relevance of five predefined criteria: overall survival, response to treatment, adverse events, cost- effectiveness, and budget impact. Results The therapeutic scheme considered more appropriate by the model was pertuzumab combined with trastuzumab and docetaxel. The most sensitive criteria were adverse events, cost-effectiveness, and budget impact. The results suggest that the classification has a close relationship with the perspective of healthcare professionals participating in the questionnaire. Conclusion Defining the treatment of an incurable disease associated with a short survival time and high-cost treatment options necessitates complex decision-making. MCDA allows the weighting of criteria and considering criteria that would be difficult to measure in other methods, such as cost-effectiveness. These aspects differ from economic models and contribute to a broader evaluation of health decision-making.
Resumo Introdução As diversas combinações de agentes quimioterápicos e biológicos disponíveis no Sistema Único de Saúde brasileiro para o tratamento do câncer de mama metastático requerem análises que contribuam para a tomada de decisões. Objetivo O objetivo principal deste estudo foi avaliar o tratamento de primeira linha para câncer de mama metastático HER2 hiperexpresso sob a perspectiva do Sistema Único de Saúde, utilizando a análise de decisão multicritérios (MCDA). Método As opções de tratamento avaliadas foram: (a) pertuzumabe em combinação com trastuzumabe e docetaxel, e (b) trastuzumabe em combinação com docetaxel. Usando o método analítico hierárquico, médicos oncologistas compararam a relevância dos cinco critérios predefinidos: sobrevida global, resposta ao tratamento, eventos adversos, custo-efetividade e impacto orçamentário. Resultados O esquema terapêutico considerado mais apropriado pelo modelo foi pertuzumabe em combinação com trastuzumabe e docetaxel. Os critérios mais sensíveis foram eventos adversos, custo-efetividade e impacto orçamentário. Os resultados sugerem que a classificação está associada à perspectiva do profissional de saúde participante do questionário. Conclusão Definir o tratamento de uma doença incurável associada a um tempo de sobrevida curto e opções de tratamento de alto custo requer uma tomada de decisão complexa. O MCDA permite ponderar e considerar critérios que seriam difíceis de medir em outros modelos de decisão. Esses aspectos contribuem para uma avaliação mais ampla da tomada de decisões em saúde.
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Humanos , Feminino , Neoplasias da Mama , Técnicas de Apoio para a Decisão , Receptor ErbB-2 , Metástase Neoplásica , AntineoplásicosRESUMO
OBJECTIVES: The addition of pertuzumab to the scheme of docetaxel plus trastuzumab (TH) in patients with metastatic breast cancer with overexpression of human epidermal growth factor receptor 2 increases survival. Nevertheless, this addition could represent a high cost for the health system of a middle-income country such as Colombia. Therefore, it is necessary to evaluate the efficiency of the pertuzumab plus TH (PTH) scheme in comparison with TH. METHODS: A partitioned survival model-based cost-utility analysis was performed. Progression-free survival and overall survival curves for each scheme were obtained from the CLEOPATRA study. The time horizon was 30 years with a discount rate of 5% for costs and quality-adjusted life-years. Total direct costs were calculated using national tariffs. Utilities were obtained from external sources. Model uncertainty was evaluated by deterministic and probabilistic sensitivity analysis. A willingness to pay value of 5180 US dollars was used. RESULTS: The discounted total average costs of TH and PTH were $24 109 and $60 846, respectively. These regimens' average life-years were 5.78 and 8.38, and their quality-adjusted life-years were 3.28 and 4.51, respectively. The incremental cost-effectiveness ratio was $29 867. One-way sensitivity analysis showed that the cost of pertuzumab was the variable that explained the uncertainty in the model. The probability that PTH is cost-effective in the probabilistic sensitivity analysis is 0.0724. CONCLUSIONS: The addition of pertuzumab to the TH regimen in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer has a low probability of being cost-effective from the payer's perspective in the Colombian health system.
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Neoplasias da Mama , Humanos , Feminino , Trastuzumab/uso terapêutico , Docetaxel/uso terapêutico , Análise Custo-Benefício , Neoplasias da Mama/tratamento farmacológico , Colômbia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
The human epidermal growth factor receptor 2 (ERBB2, HER2 or HER2/neu) is a transmembrane tyrosine kinase receptor that is overexpressed in approximately 20% of breast cancers. The use of the anti-HER2 monoclonal antibodies Pertuzumab and Trastuzumab in association with chemotherapy has achieved a higher percentage of pathologic complete response (pCR) than conventional chemotherapy. The purpose of our study was to identify factors that could affect the therapeutic response of patients with breast cancer and HER2 overexpression treated with cytotoxic chemotherapy plus double HER2 blockade in neoadjuvant setting at Fundación Arturo López Pérez (FALP). A case-control study was designed to evaluate the effect of clinical and histopathological variables on the response to neoadjuvant therapy. Ninety-four women with non-metastatic breast cancer and HER2 overexpression received neoadjuvant combination chemotherapy with Trastuzumab and Pertuzumab at FALP during the period 2017-2020. Seventy percent of patients achieved pCR, and in the group of hormone receptor negative patients, 89% of patients achieved pCR. Different variables were analysed trying to look for clinicopathological predictors of complete response. This study provides us with real-world data on the efficacy of using this treatment combination in our population of HER2-overexpressing breast cancer patients.
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Several clinical trials have demonstrated the benefit of adding pertuzumab to trastuzumab plus neoadjuvant chemotherapy in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The comparison of outcomes between nonrandomized groups of patients who received similar treatments in routine practice remains difficult. The present study aimed to evaluate the pathological complete response (pCR) rates achieved with pertuzumab among patients in routine clinical care in Peru using real-world data. The definition of pCR used was the absence of residual invasive cancer from the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy. A total of 44 patients with non-metastatic HER2-positive breast cancer (stages II and III) treated with pertuzumab in the neoadjuvant setting and who underwent surgery at three private clinics in Lima (Peru) were retrospectively evaluated. The pCR was the efficacy endpoint and it was determined and compared with the results from other clinical trials. Furthermore, safety data were described. The median age was 44 years (interquartile range, 39.5-50.5 years) and 65.9% of patients were premenopausal. Regarding the clinical stage, 56.8% were IIA/IIB and 36.4% were IIIA/IIIB/IIIC. All treatment schemes included concurrent trastuzumab. The patients' treatment comprised neoadjuvant therapy of docetaxel/trastuzumab/pertuzumab (THP) with a median of 4 cycles in 30 patients (68.2%) or docetaxel/trastuzumab/pertuzumab/carboplatin (THPCarb) with a median of 6 cycles in 14 patients (31.8%). In total, 70.5% of patients experienced pCR; among hormone receptor-negative cases, 75.0% achieved pCR and in tumors expressing hormone receptors, the rate of pCR was 66.7%. Of those patients subjected to neoadjuvant treatment with THP, 66.7% (20/30) achieved pCR, whereas 78.6% (11/14) of patients who received THPCarb had a pCR. The incidence of drug-related adverse events was 59.1% and in none of the patients, administration was discontinued due to toxicity. The present results of Peruvian patients with HER2 breast cancer treated according to clinical routine demonstrated that dual blockade of HER2 with trastuzumab and pertuzumab in the neoadjuvant setting achieved high rates of pCR even in hormone receptor-positive patients. These results are consistent with those of randomized controlled trials, with a good safety profile.
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PURPOSE: Tumor-associated macrophages (TAM) may participate to antitumor activity of anti-HER2-targeted therapies (Pertuzumab, Trastuzumab) in breast cancers harbouring HER-2 overexpression through antibody-dependent phagocytosis. Additive antitumor effect of concurrent cytotoxic chemotherapies, including Paclitaxel, may be counterbalanced by alteration in TAM infiltrate. The aim of this study is to evaluate the role of TAM in tumor response to anti-HER2-targeted therapies and chemotherapy in an experimental model of HER2-amplified breast cancer. METHODS: A xenograft mouse model was built by subcutaneous injection of the SKBR-3 human HER2-amplified breast cancer cell line in Hu-CD34+ mice. Animals were randomized to receive weekly administration of Cremophor (control), Trastuzumab+Pertuzumab (TP), and Paclitaxel+Trastuzumab+Pertuzumab (PTP) with or without macrophage depletion with clodronate (C). At week 4, mice were euthanised and tumors were harvested for immunohistochemical analysis of TAM infiltration (RBP-J CD163 and CD68 for M1, M2, and overall TAM, respectively). RESULTS: Tumor size was significantly lower in mice treated with TP, PTP, and PTP+C as compared to control, while no meaningful difference was observed in the TP+C arm. Analysis of TAM infiltrate showed significantly lower CD68 and CD163 expression in PTP, TP+C, and PTP+C as compared to TP and control arm. RBP-J expression was significantly decreased in mice treated with clodronate depletion. CONCLUSIONS: Activity of TP is modulated by TAM infiltrate, that is inhibited by concurrent administration of Paclitaxel. To enhance the effect of anti-HER2-targeted therapies and minimize chemotherapy-related side effects, modulation of TAM should be considered in novel therapeutic combinations.