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INTRODUCTION: Biological monoclonal antibodies play a pivotal role in cancer treatment, with biosimilars significantly enhancing their accessibility. In Brazil's ethnically diverse setting, real-world evidence is crucial for assessing the effectiveness and applicability of these therapies in routine clinical practice. METHODS: We performed a multicentric, observational, prospective real-world study on biosimilar trastuzumab-dkst for adjuvant treatment of early HER2-positive breast cancer in Brazilian patients. Data were collected using a case-report form. RESULTS: Of the 176 recruited, we present data from the first 59 patients (mean age 51.7 ± 12.9 years) who had completed treatment with trastuzumab-dkst. The mean time from diagnosis to the first adjuvant treatment with trastuzumab-dkst was 5.5 ± 2.7 months. Of the patients, 59% of patients achieved at least a 30-month follow-up. The 31.7-month invasive disease-free survival rate (IDFS) was 94.5% (95% CI 83.9-98.2%) and median IDFS was not achieved, since only three patients had invasive disease recurrence. The overall survival rate was 100% until the last assessment. The observed adverse events were similar to those presented by other studies using biosimilar or reference trastuzumab. Four serious adverse events (8.5%) were observed. A reduction in left ventricular ejection fraction of at least 10% was observed in 16.9% of participants. There was no treatment interruption, and three participants (5.1%) had their trastuzumab-dkst dose reduced. CONCLUSION: Our study reinforces the existing pivotal data, underscoring the real-world efficacy and safety of biosimilar trastuzumab-dkst in the adjuvant treatment for early HER2-positive breast cancer. The preliminary long-term effectiveness and safety data we present further validate trastuzumab-dkst's role as a cost-saving alternative in oncological care. These findings have important implications for improving patient access to crucial treatments and for the more efficient use of healthcare resources. GOV REGISTRATION: NCT03892655.

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INTRODUCTION: Neoadjuvant systemic therapy (NAST) is vital in the management of HER2-positive (HER2+) breast cancer. Nevertheless, the indications for NAST in tumors <2 cm remain controversial. METHOD: A total of 7961 patients were screened from the Surveillance, Epidemiology, and End Result database. Independent prognostic factors were identified using multivariate Cox analysis. Subgroup analyses and Kaplan-Meier analyses were used to simulate whether NAST would provide a survival benefit with different high-risk characteristics. Nomograms were constructed, and an internal validation cohort was employed. RESULTS: Of the 7961 included patients, 1137 (14.3%) underwent NAST. In the total population, NAST was associated with poorer overall survival (OS) and breast cancer-specific survival (BCSS) (OS: P = 0.00093; BCSS: P  <  0.0001). Multivariate Cox analysis confirmed that NAST markedly affected the prognosis of enrolled patients. Besides, a direct association between T, N, age, subtype, and prognosis was observed. Subgroup analyses yielded in these three subgroups, T1c, hormone receptor-negative, and 61-69 years of age, NAST and AST had comparable OS, while NAST possessed worse BCSS. Notably, even in the N3, we still did not observe any additional benefit of NAST. The calculated C-index of 0.72 and 0.73 confirmed the predictability of the nomograms. The AUCs exhibit consistency in the training and validation cohorts. CONCLUSION: Our findings suggest that NAST does not provide additional benefit to patients with T1 HER2+ breast cancer, even in the presence of lymph node metastasis, T1c, or hormone receptor negativity. This study facilitates the implementation of individualized management strategies.

Assuntos

Neoplasias da Mama , Terapia Neoadjuvante , Nomogramas , Receptor ErbB-2 , Programa de SEER , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias da Mama/metabolismo , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Idoso , Prognóstico , Adulto , Estimativa de Kaplan-Meier , Taxa de Sobrevida , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Modelos de Riscos Proporcionais , Estadiamento de Neoplasias

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HER2-positive breast cancer is associated with aggressive behavior and reduced survival rates. Calcitriol restores the antiproliferative activity of antiestrogens in estrogen receptor (ER)-negative breast cancer cells by re-expressing ERα. Furthermore, calcitriol and its analog, EB1089, enhance responses to standard anti-cancer drugs. Therefore, we aimed to investigate EB1089 effects when added to the combined treatment of lapatinib and antiestrogens on the proliferation of HER2-positive breast cancer cells. BT-474 (ER-positive/HER2-positive) and SK-BR-3 (ER-negative/HER2-positive) cells were pre-treated with EB1089 to modulate ER expression. Then, cells were treated with EB1089 in the presence of lapatinib with or without the antiestrogens, and proliferation, phosphorylation array assays, and Western blot analysis were performed. The results showed that EB1089 restored the antiproliferative response to antiestrogens in SK-BR-3 cells and improved the inhibitory effects of the combination of lapatinib with antiestrogens in the two cell lines. Moreover, EB1089, alone or combined, modulated ERα protein expression and reduced Akt phosphorylation in HER2-positive cells. EB1089 significantly enhanced the cell growth inhibitory effect of lapatinib combined with antiestrogens in HER2-positive breast cancer cells by modulating ERα expression and Akt phosphorylation suppression. These results highlight the potential of this therapeutic approach as a promising strategy for managing HER2-positive breast cancer.

Assuntos

Neoplasias da Mama , Calcitriol/análogos & derivados , Humanos , Feminino , Lapatinib/farmacologia , Lapatinib/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Calcitriol/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Moduladores de Receptor Estrogênico/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Antagonistas de Estrogênios/uso terapêutico , Linhagem Celular Tumoral

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Breast cancer is the most common cancer in women and the leading cause of death. HER2 overexpression is found in approximately 20% of breast cancers and is associated with a poor prognosis and a shorter overall survival. Tratuzumab, a monoclonal antibody directed against the HER2 receptor, is the standard of care treatment. However, a third of the patients do not respond to therapy. Given the high rate of resistance, other HER2-targeted strategies have been developed, including monoclonal antibodies such as pertuzumab and margetuximab, trastuzumab-based antibody drug conjugates such as trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (T-DXd), and tyrosine kinase inhibitors like lapatinib and tucatinib, among others. Moreover, T-DXd has proven to be of use in the HER2-low subtype, which suggests that other HER2-targeted therapies could be successful in this recently defined new breast cancer subclassification. When patients progress to multiple strategies, there are several HER2-targeted therapies available; however, treatment options are limited, and the potential combination with other drugs, immune checkpoint inhibitors, CAR-T cells, CAR-NK, CAR-M, and vaccines is an interesting and appealing field that is still in development. In this review, we will discuss the highlights and pitfalls of the different HER2-targeted therapies and potential combinations to overcome metastatic disease and resistance to therapy.

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BACKGROUND: Adjuvant chemotherapy with trastuzumab for HER2 positive breast cancers has brought considerable benefits to disease-free survival and overall survival. OBJECTIVE: To conduct a cost-effectiveness analysis of the treatment of patients with early and locally advanced HER2 positive breast cancer, within the scope of the Brazilian public health system, comparing adjuvant chemotherapy with and without trastuzumab, for 1 year of treatment. METHODS: A 4-state Markov model was developed to estimate strategy costs and outcomes. RESULTS: Based on the proposed model, we verified an incremental benefit of trastuzumab therapy compared to treatment without trastuzumab with 0.84 quality-adjusted life years (QALY) and 1.16 life years gained (LYG). The use of adjuvant chemotherapy with trastuzumab has an ICER of US$19,599.26 for each quality-adjusted life year and US$14,180.68 for each life year gained in relation to chemotherapy without trastuzumab. CONCLUSION: In Brazil, adjuvant chemotherapy with trastuzumab may be considered cost-effective only if a cost-effectiveness threshold is stipulated with the value starting at three times the Brazilian GDP per capita for QALY or two times the Brazilian GDP per capita for LYG, from health system perspective.

Assuntos

Antineoplásicos Imunológicos , Neoplasias da Mama , Trastuzumab , Antineoplásicos Imunológicos/economia , Antineoplásicos Imunológicos/uso terapêutico , Brasil , Neoplasias da Mama/tratamento farmacológico , Análise Custo-Benefício , Feminino , Humanos , Trastuzumab/economia , Trastuzumab/uso terapêutico

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Breast cancer is a major cause of death among women worldwide. Resistance to conventional therapies has been observed in HER2-positive breast cancer patients, indicating the need for more effective treatments. Small interfering RNA (siRNA) therapy is an attractive strategy against HER2-positive tumors, but its success depends largely on the efficient delivery of agents to target tissues. In this study, we prepared a magnetic hybrid nanostructure composed of iron oxide nanoparticles coated with caffeic acid and stabilized by layers of calcium phosphate and PEG-polyanion block copolymer for incorporation of siRNA. Transmission electron microscopy images showed monodisperse, neutrally charged compact spheres sized <100 nm. Dynamic light scattering and nanoparticle tracking analysis revealed that the nanostructure had an average hydrodynamic diameter of 130 nm. Nanoparticle suspensions remained stable over 42 days of storage at 4 and 25 °C. Unloaded caffeic acid-magnetic calcium phosphate (Caf-MCaP) nanoparticles were not cytotoxic, and loaded nanoparticles were successfully taken up by the HER2-positive breast cancer cell line HCC1954, even more so under magnetic guidance. Nanoparticles escaped endosomal degradation and delivered siRNA into the cytoplasm, inducing HER2 gene silencing.

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Neoplasias da Mama , Sistemas de Liberação de Medicamentos , Campos Magnéticos , Nanopartículas , RNA Interferente Pequeno , Receptor ErbB-2 , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Células NIH 3T3 , Nanopartículas/química , Nanopartículas/uso terapêutico , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo

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The human epidermal growth factor receptor 2 (HER2) is overexpressed in 20% of breast carcinomas. Prior to the development of targeted therapies, HER2-positive breast cancer was associated with more aggressive disease and poor prognosis. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that results from the combination of trastuzumab and DM1, a derivative of the antimicrotubule agent maytansine. This molecule has the ability to enhance cytotoxic drug delivery to specifically targeted cells that overexpress HER2, therefore, maximizing efficacy while sparing toxicity. In recent years, T-DM1 has shown to improve outcomes in metastatic HER2-positive breast cancer that is resistant to trastuzumab. In addition, T-DM1 is currently being tested in the neoadjuvant and adjuvant settings to identify patients who may benefit from this therapy. This review focuses on the mechanism of action, early and late-phase clinical trials, and ongoing studies of T-DM1 in HER2-positive breast cancer.

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Breast cancer is the most common malignant neoplasm in the world among women. As a result of the dissemination of population screening programmes, about half of non-metastatic breast cancers are now diagnosed at stage I. 10-15% of T1abN0 tumours over-express human epidermal growth factor (HER-2). These tumours have a globally excellent prognosis, however, treatment with chemotherapy and/or targeted therapy may further improve outcomes in selected cases. In this article, we will review studies with information on prognosis and benefit of adjuvant therapy for T1abN0 HER-2+ breast cancer.