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BACKGROUND: The purpose of this study was to review and summarize the association between preoperative magnetic resonance imaging (MRI) and surgical outcomes in women with newly diagnosed invasive breast cancer from published randomized controlled trials (RCT). MATERIALS AND METHODS: Two independent researchers conducted a systematic review through a comprehensive search of electronic databases, including PubMed, Medline, Embase, Ovid, Cochrane Library, and Web of Science. If there was disagreement between the two reviewers, a third reviewer assessed the manuscript to determine whether it should be included for data extraction. The quality of the papers was assessed using the risk of bias tool, and the evidence was analyzed using GRADE. Meta-analyses using a fixed-effects model were used to estimate the pooled risk ratio (RR) and 95% confidence interval (CI). RESULTS: Initially, 21 studies were identified, 15 of which were observational comparative studies. A total of five RCTs were included, and they suggested that preoperative MRI significantly reduced the rate of immediate breast-conserving surgery and increased the risk for mastectomy. CONCLUSIONS: From the RCT perspective, preoperative MRI for newly diagnosed invasive breast cancer did not improve surgical outcomes and may increase the risk of mastectomy.
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Gene expression assays (GEAs) can guide treatment for early-stage breast cancer. Several large prospective randomized clinical trials, and numerous additional studies, now provide new information for selecting an appropriate GEA. This systematic review builds upon prior reviews, with a focus on five widely commercialized GEAs (Breast Cancer Index®, EndoPredict®, MammaPrint®, Oncotype DX®, and Prosigna®). The comprehensive dataset available provides a contemporary opportunity to assess each GEA's utility as a prognosticator and/or predictor of adjuvant therapy benefit.
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Neoplasias da Mama , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Feminino , Quimioterapia Adjuvante , Perfilação da Expressão Gênica , Biomarcadores Tumorais/genética , Estadiamento de Neoplasias , PrognósticoRESUMO
PURPOSE: Neoadjuvant chemotherapy (NAC) can be used as upfront therapy in aggressive breast cancer (BC). human epidermal growth factor receptor 2 (HER2)-low BC, defined as tumors scoring +1 or +2 on immunohistochemistry without HER2 gene amplification by in situ hybridization, lacks information on real-world data (RWD) outcomes, especially in the NAC setting. This subgroup, which does not reach the HER2 positive criteria due to its lower receptor expression, represents a distinct clinical category potentially requiring tailored therapeutic approaches. STUDY OBJECTIVE: The objective of this study is to characterize patients with BC with HER2-low status who received NAC in a Brazilian public reference center for female tumors and key outcomes such as pathological complete response (pCR), overall survival (OS), and metastasis-free survival (MFS). METHODS: A retrospective cohort study based on a large BC database from a reference cancer center in Brazil. Patients with BC that received NAC, diagnosed between 2011 and 2020, were included if they presented HER2-low status (defined as tumors scoring +1 or +2 on immunohistochemistry without HER2 gene amplification by in situ hybridization) and had complete data on outcomes. Clinical and demographic data were collected, such as age, menopausal status, Ki-67, hormone receptor expression and others. Key outcomes from the study comprised pCR (defined as ypT0/TIs/ypN0), overall survival, and metastasis-free survival (MFS). Survival analyses were conducted through the semiparametric Kaplan-Meier method to assess OS and MFS by pCR status, considering BC diagnosis as the index date. RESULTS: Overall, 297 patients were eligible and 141 were included in the study after matching the HER2-low definition. The pCR was seen in 18 out of 141 patients (12.7%). The median overall survival was 8.2 years, and the median MFS was 2.7 years. The OS of pCR was 83.4% and non-pCR was 58.1%; the DFS of pCR was 55.5% and non-pCR 40.6%. CONCLUSION: This study gives updated insights on pCR, OS, and MFS in women with HER2-low BC exposed to NAC.
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PURPOSE: Cyclin inhibitors plus endocrine therapy represent the reference standard for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic breast cancer (ABC). Efficacy results on hard end points such as overall survival come from well-designed randomized clinical trials (RCTs). However, a limitation of RCTs is the low external results validity, and their extrapolation to a broader population may not be appropriate. Real-world studies can overcome these limitations, also increasing the reliability of RCTs. MATERIALS AND METHODS: The BrasiLEEira was an observational, longitudinal, retrospective, multicenter study to evaluate the effectiveness and safety of ribociclib plus nonsteroidal aromatase inhibitors in Brazilian women age 18 years or older with HR+/HER2- ABC. The study was approved by the institutional review boards of all 11 hospitals. Data were collected anonymously from medical records using an electronic case report form designed by an independent academic research organization, which conducted the study considering all recommendations of international guidelines. The primary end point was 1-year progression-free survival (PFS) rate. Secondary end points included mortality, dose reduction, and safety. RESULTS: The mean age of 76 patients was 57 years, and 28.9% were Black/Brown. The most prevalent comorbidity was arterial hypertension (34.7%). About 26.0% had endocrine-resistant disease, and 54.1% had more than three metastatic sites. The PFS rate was 77.6%. Three patients died (3.9%). Dose reductions occurred in 37.7% of patients. The most common adverse event was neutropenia (68.4%). CONCLUSION: The high-quality evidence from the BrasiLEEira study corroborates the RCTs' findings, expanding its validity to a broader spectrum and underrepresented population who may benefit from ribociclib treatment.
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Inibidores da Aromatase , Neoplasias da Mama , Purinas , Feminino , Humanos , Aminopiridinas/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: False-negative sentinel lymph node biopsy (SLNB) rates following neoadjuvant chemotherapy (NACT) in initially node-positive (cN1/2) breast cancer patients are high, but decrease when lymph nodes are clipped, ≥3 sentinel lymph nodes (SLN) are removed or dual-tracer localization (radioisotope and blue dye) is used. Radiotracer, however, is often unavailable and outcomes with blue dye alone are unknown. MATERIALS AND METHODS: Initially cT1-4, cN1/2 patients treated with NACT in 2013-2023 who underwent SLNB using blue dye alone were evaluated regarding SLN identification, axillary recurrence, disease-free and overall survival rates. RESULTS: Of 119 patients included, 19 remained cN1/2 after NACT. SLNB was performed using blue dye alone in 100 ycN0 cases (84%), with an identification rate of 96%. The SLN was negative in 70/119 cases (i.e. 59% avoided axillary dissection). The number of SLN detected was ≥3 in 55/70 cases (78%) (median 3.1; 1-6). Median age was 49 years (25-84). Most were T2 (n = 40, 57.1%), N1 (n = 64, 91.4%). Predominant subtypes were ERBB2 (52.9%) and triple-negative (20%). No axillary recurrence occurred over a median 36-month period. Five-year disease-free and overall survival were, respectively, 85.9% (95%CI: 74-99.8) and 96.3% (95%CI: 89.4-100). The ERBB2 subtype (1.99, 95%CI: 1.02-3.85, p = 0.04) and N1 lymph node status (2.58, 95%CI: 1.54-9.10, p = 0.03) were associated with a greater likelihood of undergoing SLNB alone without axillary dissection. CONCLUSIONS: SLNB with blue dye alone following NACT in initially cN1/2 patients avoided axillary dissection in almost 60% of cases, with no recurrences during the period evaluated. Longer follow-up studies are necessary.
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Neoplasias da Mama , Linfonodo Sentinela , Humanos , Pessoa de Meia-Idade , Feminino , Biópsia de Linfonodo Sentinela , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Neoplasias da Mama/patologia , Terapia Neoadjuvante , Metástase Linfática/patologia , Excisão de Linfonodo , Linfonodos/patologia , Linfonodo Sentinela/patologia , Axila/patologiaRESUMO
PURPOSE: Trastuzumab was introduced into the Brazilian public health care service for early breast cancer (BC) in 2012. This study describes the survival outcomes and prognostic factors related to early HER2+ BC treatment in a Brazilian reference cancer center. PATIENTS AND METHODS: This were a retrospective, single-center, observational study of early HER2+ BC patients treated with trastuzumab in the (neo)adjuvant setting between 2012 and 2018 at Hospital Pérola Byington. Demographic, clinical, disease-free survival (DFS) and overall survival (OS) data were evaluated. Multivariate analysis was performed to assess independent prognostic factors. RESULTS: One hundred seventy-six and 353 patients treated in the neoadjuvant and adjuvant setting were included, respectively. The 3- and 5-year OS rates were 79% and 56% for the neoadjuvant group and 97% and 92% for the adjuvant group, respectively. Node positivity at diagnosis predicted poor OS for both groups. In the neoadjuvant group, stage III disease at diagnosis, delayed surgery, and lack of pathological complete response (pCR) predicted poor prognosis. The 3- and 5-year DFS rates were 67% and 46% in the neoadjuvant group and 91% and 86% in the adjuvant group, respectively. Histological grade 2, stage III disease at diagnosis, and lack of pCR predicted poor DFS for the neoadjuvant group. For the adjuvant group, node positivity at diagnosis predicted poor DFS. CONCLUSION: Our results reveal multiple clinical parameters affecting survival outcomes according to the treatment setting. Patients treated with neoadjuvant therapy have a poor prognosis since they present with more advanced disease, indicating the importance of early diagnosis and optimized treatment.
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Neoplasias da Mama , Humanos , Feminino , Trastuzumab , Neoplasias da Mama/patologia , Prognóstico , Estudos Retrospectivos , Brasil/epidemiologia , Receptor ErbB-2/uso terapêutico , Intervalo Livre de Doença , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia AdjuvanteRESUMO
Pathological complete response (pCR) is an important surrogate outcome to assess the effects of neoadjuvant chemotherapy (NAC). Nomograms to predict pCR have been developed with local data to better select patients who are likely to benefit from NAC; however, they were never critically reviewed regarding their internal and external validity. The purpose of this systematic review was to critically appraise nomograms published in the last 20 years (2010-2022). Articles about nomograms were searched in databases, such as PubMed/MEDLINE, Embase and Cochrane. A total of 1120 hits were found, and seven studies were included for analyses. No meta-analysis could be performed due to heterogeneous reports on outcomes, including the definition of pCR and subtypes. Most nomograms were developed in Asian centers, and nonrandomized retrospective cohorts were the most common sources of data. The most common subtype included in the studies was triple negative (50%). There were articles that included HER2+ (>80%). In one study, scholars performed additional validation of the nomogram using DFS and OS as outcomes; however, there was a lack of clarity on how such endpoints were measured. Nomograms to predict pCR cannot be extrapolated to other settings due to local preferences/availability of NAC. The main gaps identified in this review are also opportunities for future nomogram research and development.
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Neoplasias da Mama , Nomogramas , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Estudos RetrospectivosRESUMO
OBJECTIVES: We aimed to evaluate the pCR rate in patients receiving NAC for the treatment of breast cancer (BC) in a multicenter cohort in Brazil. Additionally, we aimed to use RWD to assess the impact of pCR on OS and DFS. METHODS: This was a retrospective, multicenter cohort study that included female patients over 18 years of age who were diagnosed with nonmetastatic breast cancer and received NAC. OS and DFS at five years were estimated by the KaplanâMeier method. Additionally, we conducted a multivariate analysis to identify factors that were significantly associated with pCR and OS. RESULTS: From 2011 to 2020, 1891 patients were included in the study, and 421 (22,3%) achieved pCR (ypT0 ypN0). Considering the presence of residual DCIS, pCR was achieved in 467 patients (23,5%). The pCR rate varied between the subtypes: HER-2+ (p = 0,016) and clinical stage IIIA and IIIB (p < 0,001). Among HER-2+ patients, those who received trastuzumab had a significantly higher pCR rate than those who did not receive trastuzumab (p < 0.0001). Similarly, patients with TNBC who received treatment with platinum-based regimens also showed higher pCR rates (p < 0.0001). OS was grouped according to pCR status, and the OS rate was 88,3% in the pCR group and 58.1% in the non-pCR group (p < 0.0001). The five-year DFS was 92.2% in the pCR group and 64.3% in the non-pCR group (p < 0.0001). CONCLUSION: The pCR rate and its prognostic value varied across BC subtypes. In our study, pCR could be used as a surrogate of favorable clinical outcome, as it was associated with higher OS and DFS rates.
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Neoplasias da Mama , Humanos , Feminino , Adolescente , Adulto , Neoplasias da Mama/patologia , Brasil , Terapia Neoadjuvante , Estudos Retrospectivos , Estudos de Coortes , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prognóstico , Trastuzumab/uso terapêutico , Intervalo Livre de DoençaRESUMO
Sentinel lymph node biopsy (SLNB) at upfront surgery is the gold-standard surgical method for axillary lymph node staging in early stage breast cancer: the technique provides adequate information regarding axillary status, with similar oncological safety and lower morbidity compared to axillary dissection, despite the false negative rates. Neoadjuvant chemotherapy (NACT), traditionally used for locally advanced breast cancer, plays an important role in the treatment of early stage breast cancer, making downstaging possible in axillary lymph node and breast cancer, thus minimizing the impact of surgery and reducing morbidity, as well as enabling patients with residual disease to be selected for adjuvant treatment. In this respect, the role of SLNB has proved controversial, particularly in view of the lack of data from randomized clinical trials on this subject. Currently, the de-escalation of axillary surgery after NACT is mainly based on retrospectives studies and false negative rates. This paper reviews current evidence on the management of axillary surgery following NACT under different circumstances, with suggested recommendations in each scenario: clinically negative nodes at diagnosis and SLNB after NACT, clinically positive nodes at diagnosis and SLNB after NACT, positive SLNB following NACT and finally the possibility of omitting axillary surgery in good responders.
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Neoplasias da Mama , Biópsia de Linfonodo Sentinela , Humanos , Feminino , Biópsia de Linfonodo Sentinela/métodos , Terapia Neoadjuvante/métodos , Metástase Linfática , Estadiamento de Neoplasias , Excisão de Linfonodo/métodos , Linfonodos/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Neoplasias da Mama/patologiaRESUMO
During the COVID-19 pandemic, several screening exams were postponed, including mammograms. The aim of this study was to evaluate the impact of COVID-19 in mammographic screening in Brazil, considering 2015 to 2021. This was descriptive ecologic study based on the retrospective data of Brazil's mammographic screening program. A Brazilian national screening database (DATASUS - SISCAN (Cancer System Information)) was used as the data source, and the data in this database are publicly available for download and analysis. We report the number of screening rate from January 2015 to December 2021, using 2020 as reference year for COVID-19. From 2015 to 2021, 10,763,894 mammograms were performed and included in the analysis. Reductions of 39.6% and 13.3% were found in 2020 in 2021, respectively. During the pandemic's peak, the reduction was more pronounced, with maximum reductions of 82.4% in May 2020 and 34.8% in April 2021. There was an increase in the number of mammograms performed on high-risk patients from 11.2% in 2020 to 13.9% in 2021. This research demonstrated a decline in the breast cancer screening rate during the two years of the COVID-19 pandemic; this reduction will increase the burden of advanced breast cancer, potentially impacting morbidity and mortality related to this neoplasm.
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Purpose: To assess the impact and optimize the prescription of tissue-equivalent bolus in postmastectomy radiotherapy (PMRT), we compared the use of different bolus regimens tailored by skin involvement status. Methods: Patients with breast cancer who required PMRT were recruited (NCT01925651) and classified into two groups: standard-risk (SR, without skin involvement) and high-risk (HR, with skin involvement). SR was randomized between no bolus or 5 mm-bolus on alternate days and HR between 5 mm-bolus on alternate days or daily. Conventional fractionation (50.4 Gy; 1.8 Gy/daily) was used. Acute skin toxicity was evaluated blindly and the radiodermatitis-specific toxicity index [rads-TI] calculated. Subsequently, patients were followed up to assess oncologic outcomes, focusing on chest wall (CW) local control. Results: Fifty-eight patients were enrolled (34 SR and 24 HR). Baseline characteristics were similar between arms within the same risk group. Overall, maximal radiodermatitis rates were 29.4 % (G2) and 15.7 % (G3). In the SR group, no difference existed in G2 radiodermatitis incidence between the subgroups (p = 0.70) and no G3 events occurred. In the HR group, incidences of G2 (100 % vs 44.5 %, p = 0.01) and G3 radiodermatitis (70 % vs 11.1 %, p = 0.02) were higher with daily bolus. After adjusting for confounders, the daily bolus had a higher incidence of G2 (p = 0.03), G3 radiodermatitis (p = 0.04), and worse rads-TI (p < 0.01). After a median follow-up of 6.2 years, the 5-year local control was 95.8 % (95 %CI: 88.2 %-100 %) in the SR and 91.7 % (95 %CI: 77.3 %-100 %) in the HR groups. Per risk group, there was no difference in local control between the SR (p = 0.90) or the HR bolus regimens (p = 0.70). Conclusion: Daily 5 mm bolus prescription significantly increased the overall toxicity burden. In this preliminary study, within the same risk group, no detriment in CW local control was detected with less intense bolus regimens (SR: no bolus; HR: alternate-days bolus). Additionally, the rads-TI was able to distinguish overall radiodermatitis burden.
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Objective: This study aims to evaluate the impact of the Pink October Campaign on the increase in mammographic screening in Brazil. Study design: Ecological observational study, based on retrospective data. Methods: Brazilian national screening database (DATASUS/SISMAMA/Information System on Breast Cancer) was used as a data source and is publicly available for download and analysis. We report screening numbers and outcome rates from January 2017 to December 2021 comparing statistically (ANOVA test, post-Tukey test), age groups, regions of Brazil, and the four quarters of the year. Results: During the study period, the average number of exams performed monthly over the five years was 137,400.117. An increase in the number of mammograms performed in October was identified, as well as in the two following months, respectively 33%, 39%, and 22%, with statistical significance (p = 0.000) in relation to the three quarters of the year. In addition, in the other months, we found values below the monthly average. Statistical difference was not found in the increase in mammograms considering age groups (p = 0.5) and different regions of the country (p = 0.6). Conclusions: This study showed an increase in mammographic screening in the three months following the Pink October Campaign, so we should intensify similar actions throughout the year and not just in October.
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BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogenous subtype involving different patterns of behavior and clinical course, demanding a complex, individualized sequence of treatment. The knowledge and attitudes of the affiliated members of the Brazilian Society of Mastology regarding TNBC were evaluated and a consensus regarding management and treatment was reached. METHODS: Affiliates completed a survey involving 44 objective questions. In addition, a specialist meeting was held with 27 experts and 3 ad hoc consultants. The panelists completed the survey before and after brainstorming. Answers achieving 70% of agreement were considered consensual. The chi-square test was used to compare answers between panelists and affiliates and the Kappa coefficient to calculate agreement. RESULTS: Consensus among the panelists increased from 26 (59.1%) to 32 questions (72.7%) following brainstorming (p = 0.17), including 7/10 questions on systemic treatment. Among the affiliates, consensus was achieved for 24 questions (54.5%), resulting in moderate agreement (κ = 0.445). Neoadjuvant chemotherapy should be indicated for almost all cases (except cT1a-b N0) and should include platinum agents. When indicated, immunotherapy is part of the standard of care. The panel reaffirmed the concept of no ink on tumor as indicative of adequate margins and the possibility of sentinel lymph node biopsy for cN1 patients who become cN0 following neoadjuvant therapy. Controversies remain on combining immunotherapy with capecitabine/olaparib in pertinent cases. CONCLUSION: Expert consensus was achieved for > 70% of the questions, with moderate agreement between panelists and affiliates. Educational interventions on systemic breast cancer treatment affected decision-making in 60% of the questions.
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Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/terapia , Brasil , Terapia Neoadjuvante , Imunoterapia , CapecitabinaRESUMO
Pregnancy-associated breast cancer is defined as a diagnosis of breast cancer during pregnancy or within 1 year of childbirth. Current evidence shows that Pregnancy-associated breast cancer is associated with poor prognosis; however, no systematic review has summarized and explored how baseline characteristics could impact survival. We aimed to explore the impact of breast cancer characteristics on death and disease relapse. A systematic review with meta-analyses was conducted by searching articles in the main databases (Medline, Embase, and Cochrane) and congress abstracts. Summarized death and disease-free survival hazard ratios were recalculated, and all meta-analyses used a random-effects model. Heterogeneity was reported using the I2 method. A total of 7143 studies were identified and only 30 studies were included. Pregnancy-associated breast cancer is associated with a 96% (HR 1.96; 95%CI 1.582.35) higher risk of death and 82% (HR 1.82; 95%CI 1.452.20) risk of death or disease relapse in comparison to a population of non-pregnancy-associated breast cancer or nulliparous breast cancer. Through sensitivity analyses, we identified that clinical outcomes were impacted, possibly due to Ki-67 levels, poorly differentiated tumors, and triple-negative breast cancer frequency in the study. As relevant sources of inconsistencies, such clinical cancer-related characteristics should be better investigated as potential confounders for upcoming Pregnancy-associated breast cancer therapeutic strategies.
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PURPOSE: We evaluated the impact of 21-gene test results on treatment decisions for patients with early-stage breast cancer treated under the public health care system in Brazil, Sistema Único de Saúde. METHODS: Eligible patients treated at Hospital Pérola Byington and Santa Casa de Misericórdia de São Paulo in Brazil were required to have the following characteristics: postsurgery with hormone receptor-positive, human epidermal growth factor 2-negative, node-negative and node-positive, and T1/T2 breast cancer and patients with these characteristics were candidates for adjuvant systemic therapy. Treatment recommendations, chemotherapy plus hormonal therapy (CT + HT) or HT alone, were captured before and after 21-gene test results. RESULTS: From August 2018 to April 2019, 179 women were enrolled. The mean age was 58 years (29-86 years), 135 (76%) were postmenopausal, and 58 (32%) had node-positive breast cancer. Most patients (61%) had a tumor > 2 cm, including 7% with tumors > 4 cm. Using Recurrence Score (RS) result cut points on the basis of the TAILORx trial, 40 (22%) had RS 0-10, 91 (51%) had RS 11-25, and 48 (27%) had RS 26-100. Before 21-gene testing, 162 of 179 (91%) patients were recommended for CT. After testing, 117 of 179 patients (65%) had changes in CT recommendation: 112 (63%) who were initially recommended CT received HT alone and five (3%) who were initially recommended HT alone received CT + HT. After 21-gene testing, 99% of physicians reported strong confidence in their treatment recommendations. CONCLUSION: The change in clinical practice at these public hospitals was greater than expected: 66% of initial treatment recommendations were changed to omit CT with 21-gene test results. Clinicopathologic features did not correlate well with 21-gene test results and did not adequately identify those most likely to benefit from CT.
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Neoplasias da Mama , Brasil , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Quimioterapia Adjuvante , Feminino , Hospitais Públicos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Receptores de Estrogênio/uso terapêuticoRESUMO
BACKGROUND: A subcutaneous formulation of pertuzumab and trastuzumab with recombinant human hyaluronidase in one ready-to-use, fixed-dose combination vial (pertuzumab, trastuzumab, and hyaluronidase-zzxf) was approved by the US Food and Drug Administration (FDA) on June 29, 2020. We report the primary analysis of the FeDeriCa study, which was designed to assess the pharmacokinetics, efficacy, and safety of the fixed-dose subcutaneous formulation compared to intravenous pertuzumab plus trastuzumab in patients with HER2-positive early breast cancer in the neoadjuvant-adjuvant setting. METHODS: FeDeriCa, a randomised, open-label, international, multicentre, non-inferiority, phase 3 study, was done across 106 sites in 19 countries. Patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1, HER2-positive, operable, locally advanced, or inflammatory stage II-IIIC breast cancer, and a left ventricular ejection fraction of 55% or more were randomly assigned (1:1), using a voice-based or web-based response system, to receive intravenous pertuzumab (840 mg loading dose, followed by 420 mg maintenance doses) plus intravenous trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg maintenance doses) or the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (1200 mg pertuzumab plus 600 mg trastuzumab loading dose in 15 mL, followed by 600 mg pertuzumab plus 600 mg trastuzumab maintenance doses in 10 mL), both administered every 3 weeks with neoadjuvant chemotherapy. Patients were stratified by hormone receptor status, clinical stage, and chemotherapy regimen. The investigator selected one of the two protocol-approved standard chemotherapy regimens before randomisation. Four cycles of HER2-targeted therapy were administered concurrently with the taxane. After surgery, patients continued the HER2-targeted therapy to receive an additional 14 cycles (total of 18). The primary endpoint was non-inferiority of the cycle 7 pertuzumab serum trough concentration (Ctrough; ie, cycle 8 predose pertuzumab concentration) within the fixed-dose combination for subcutaneous injection versus intravenous pertuzumab plus trastuzumab in the per-protocol pharmacokinetic population (all enrolled patients who adhered to prespecified criteria for pharmacokinetic assessment). Non-inferiority was concluded if the lower bound of the 90% CI of the geometric mean ratio was 0·8 or higher. The safety population included all patients who received at least one dose of study medication, including chemotherapy or HER2-targeted therapy. Enrolment, neoadjuvant therapy, and surgery have been completed; adjuvant treatment and follow-up are ongoing. The trial is registered with ClinicalTrials.gov, NCT03493854. FINDINGS: Between June 14, 2018, and Dec 24, 2018, 252 patients were randomly assigned to the intravenous infusion group and 248 to the fixed-dose combination group. The geometric mean ratio of pertuzumab serum Ctrough subcutaneous to serum Ctrough intravenous was 1·22 (90% CI 1·14-1·31). The most common grade 3-4 adverse events occurring during neoadjuvant treatment with HER2-targeted therapy plus chemotherapy in 5% or more of patients were neutropenia (34 [13%] of 252 patients in the intravenous infusion group vs 35 [14%] of 248 patients in the fixed-dose combination group), decreased neutrophil count (31 [12%] vs 27 [11%]), febrile neutropenia (14 [6%] vs 16 [6%]), diarrhoea (12 [5%] vs 17 [7%]), and decreased white blood cell count (18 [7%] vs nine [4%]). At least one treatment-related serious adverse event was reported in 25 (10%) patients in the intravenous infusion group and 26 (10%) patients in the fixed-dose combination group. One patient in each treatment group had an adverse event that led to death (urosepsis in the intravenous infusion group and acute myocardial infarction in the fixed-dose combination group); neither death was related to HER2-targeted therapy. INTERPRETATION: The study met its primary endpoint: the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection provides non-inferior cycle 7 pertuzumab serum Ctrough concentrations to intravenous pertuzumab plus trastuzumab in the neoadjuvant setting with comparable total pathological complete response rates, supporting the FDA approval. Safety was similar between treatment groups, and in line with other pertuzumab, trastuzumab, and chemotherapy trials. Follow-up is ongoing for long-term outcomes, including efficacy and long-term safety. FUNDING: F Hoffmann-La Roche and Genentech.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/análise , Trastuzumab/administração & dosagem , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Feminino , Humanos , Hialuronoglucosaminidase/administração & dosagem , Injeções Subcutâneas , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Fatores de Tempo , Trastuzumab/efeitos adversos , Trastuzumab/farmacocinética , Resultado do TratamentoRESUMO
Introduction: Breast cancer (BC) centers are increasingly attending "ultra-young" women (UYW) patients (≤ 30 years), who usually present aggressive tumors and face specific problems. Objectives: We aimed to examine a multicentric casuistic view, addressing clinicopathological and molecular characteristics of BC, as well as therapeutic measures and oncological outcomes. Methods: A retrospective multicentric observational study of UYW with infiltrating BC was carried out. The patients were treated between the period from January 1991 to December 2019. Clinical, epidemiological, morphological, molecular, therapeutic and outcomes data were collected from the charts. Results: A total of 293 patients were followed for a average period of 34.5 months. Nulliparity was referred by 204 women (75.5%), of whom 81 (37.1%) were overweight or obese. Positive family history in first-degree relatives was verified in 25 patients (10.1%). Only 30 patients underwent genetic tests, which revealed inherited pathogenic mutations in 12 of them (37.5%). Thirty-two (32) cases were classified as T1 at diagnosis (10.9%), while "De novo" stage IV was found in 29 patients (9.8%). Mastectomy was performed in 175 women (70.2%), quadrantectomy in 46 women (18.4%), and mammary adenectomies in 28 women (11.2%), of which 149 cases were reported after neoadjuvant chemotherapy (56.0%). A total of 111 patients had at least one positive lymph node (47.4%). The rate of patients with estrogen receptor-negative was 32.7% and the rate of patients with Human Epidermal Growth Factor Receptor 2-positive (HER2-positive) was 25%. The frequency of Luminal A neoplasias was 16.6%, Luminal B/HER2- was 35.9%, Luminal B/HER2+ was 15.1%, HER2 overexpressed was 9.3%, and Basal was 22.9%. Taking into account the outcomes, 173 patients were alive without disease (65.7%); 23 patients were alive with any form of recurrence (8.7%); and 67 patients (25.4%) evolved to BC deaths. Conclusions: It was concluded that UYW with BC are commonly diagnosed at advanced stages, present adverse morphological and molecular parameters, and have unfavorable prognosis.
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OBJECTIVES:: To compare the efficacy and safety of two filgrastim formulations for controlling chemotherapy-induced neutropenia and to evaluate the non-inferiority of the test drug relative to the originator. METHODS:: This phase III non-inferiority study had a randomized, multicenter, and open-label design. The patients were randomized at a ratio of 1:1 with a follow-up period of 6 weeks for each patient. In both study arms, filgrastim was administered subcutaneously at a daily dose of 5 mg/kg body weight. The primary endpoint was the rate of grade 4 neutropenia in the first treatment cycle. The secondary endpoints were the duration of grade 4 neutropenia, the generation of anti-filgrastim antibodies, and the rates of adverse events, laboratory abnormalities, febrile neutropenia, and neutropenia of any grade. RESULTS:: The primary efficacy analysis demonstrated the non-inferiority of the test drug compared with the originator drug; the upper limit of the 90% confidence interval (CI) for the rate of neutropenia between the two groups (12.61%) was lower than the established margin of non-inferiority. The two treatments were similar with respect to the secondary endpoints and safety. CONCLUSION:: The efficacy and safety profile of the test drug were similar to those of the originator product based on the rate of grade 4 neutropenia in the first treatment cycle. This study supports Anvisa's approval of the first biosimilar drug manufactured by the Brazilian industry (Fiprima¯).