Background: Breast cancer (BC) is the most frequent cancer in women in Brazil, with more than 60,000 cases estimated annually. Forty percent of patients present with stages III and IV and neoadjuvant chemotherapy (NACT) remains the mainstay of treatment for locally advanced breast cancer (LABC). Taxanes usually follow anthracyclines in breast cancer neo/adjuvant treatment, likely because of their later introduction into clinical practice. However, the potential impact of alternative sequencing remains to be studied. A single-center phase II randomized clinical trial conducted in the Brazilian National Cancer Institute showed an improvement in overall survival with taxane-first compared with anthracycline-first sequencing in HER2-negative LABC (Bines J et al, The Oncologist 2020). As a taxane-before-anthracycline sequence carries neither an incremental cost nor increased toxicity, the optimal sequencing of these agents could have significant implications for clinical practice. To confirm this finding, we are currently conducting a multicenter randomized phase III trial comparing a taxane followed by an anthracycline-based regimen with the reverse sequence in the neoadjuvant setting. Trial Design: This randomized, open-label, phase III trial will be conducted in 15 research centers in Brazil. It was approved by the local ethics committee in 2020 and is registered in Clinicatrials.gov with the identifier NCT04540692. Women with HER2-negative LABC are randomized in a 1:1 ratio to anthracycline-before-taxane (AC-T arm) or taxane-before-anthracycline (T-AC arm), stratified by hormone receptor status (positive vs. negative) and axillary lymph node status (N0 vs. N+). The anthracycline-based therapy recommended in this trial is AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) every three weeks for four cycles, whilst the taxane-based therapy is either weekly paclitaxel 80 mg/m2 weekly for 12 weeks, paclitaxel 175 mg/m2 every three weeks, or docetaxel 75-100 mg/m2 every three weeks. The use of carboplatin concomitantly with taxane for triple-negative tumors and dose-dense regimens is allowed following institutional guidelines. Further therapies (surgery, radiotherapy, and endocrine therapy) are performed according to the physicians’ discretion. Tumor samples are collected and stored for translational studies. Eligibility: Inclusion criteria: women ≥18 years of age; histologically confirmed HER2-negative breast cancer (by ASCO/CAP guidelines); stage ≥ IIB (if TNBC) or ≥ III (if HR-positive); PS ECOG 0-2 and adequate organ function. Exclusion criteria: previous use of anti-cancer therapies; bilateral BC and pregnancy. Specific Aims: The primary objective is invasive disease-free survival (iDFS). Secondary objectives include pathological complete response (pCR) rates, overall survival (OS) and safety. Statistical Methods: Considering an unicaudal type I error of 0.05, a type II error of 0.2, and an estimated iDFS of 50% in 5 years in the control arm, a total of 227 evaluable patients should be included per arm to demonstrate a HR of 0.7 favoring the taxane-first arm. Estimating a dropout rate of 10%, 494 patients will need to be included in the study. Present Accrual and Target Accrual: A total of 9 sites of 15 planned are activated. The first patient was enrolled on January 12, 2021, and as of June 24, 2022, a total of 113 patients have been accrued. The target goal of 494 patients is expected to be achieved by 2025 and initial study results will be reported by 2026. Funding: Brazilian Health MInistry, Programa Nacional de Apoio à Atenção Oncológica (PRONON), NUP 25000.183207/2019-50. Acknowledgements: CURA Project, SAS. Citation Format: Tomás Reinert, Cristiano P. Souza, Pedro Liedke, Gustavo Werutsky, Laura Testa, Vivian Antunes, Carlos Barrios, Vivian Vasconcelos, Heloísa Resende, Geraldo Silva Queiroz, Gisah Guilgen, Yeni Nerón, Lilian Arruda Bastos, Sabina Aleixo, Daniel Cubero, Maria Cristina F. Magalhães, Ana Coradazzi, Daniela Galvão B. de Oliveira, João S. Nunes, Rafaela G. Jesus, Gustavo Gössling, José Bines. Sequencing of anthracyclines and taxanes during neoadjuvant therapy of locally advanced HER2-negative breast cancer (NEOSAMBA Study/LACOG 0419) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-22-02.

Background: It is estimated that 50 thousand patients live with metastatic breast cancer (MBC) in Brazil. A recent Brazilian registry (LACOG 0312) on MBC demonstrated a median overall survival (OS) by breast subtype of 15 months for triple negative, 23 months for HER2 positive, and 42 months for Luminal tumors, which are very similar to developed countries except the HER2 positive group which have limited access to targeted agents in the public health system. Recently, CDK 4/6 inhibitors were approved for the treatment of HR+ HER2-negative MBC with an improvement in progression-free survival (PFS) and ribociclib and abemaciclib demonstrating benefit in OS over endocrine therapy alone, establishing the standard of care in first-line setting for this BC subtype. In Brazil, disparities exist in the incorporation of novel anticancer agents between public and private health systems limiting treatment options for patients with HR+ HER2- negative MBC in the public system, which covers most of the population. The BRAVE study aims to describe the patient journey and current patterns of care for HR+ HER2-negative MBC to identify possible gaps and how health insurance type influences treatment patterns in Brazil. Trial Design: This is an observational, retrospective cohort study. All patients diagnosed with mBC (either de novo or recurrent) in the period of January 2018 to December 2020 at participating centers will be included. Data will be collected from medical records. No interventions are proposed. Enrollment of a total of 300 patients (150 patients from public health care system and 150 patients from private health care system) is planned. ClinicalTrials.gov identifier: NCT05034393. Eligibility: Inclusion criteria: women ≥18 years old; histologically confirmed HR-positive HER2-negative invasive breast cancer; HR-positive, defined as 1% to 100% of tumor nuclei positive for ER and/or PgR as per ASCO/CAP Guideline 2020 or Allred score of ≥3; HER2-negative, defined as IHC result is 0/1+ or 2+ with ISH negative as per ASCO/CAP Guideline 2018; diagnosed with de novo or recurrent metastatic breast cancer between January 2018 and December 2020. Exclusion criteria: male BC; first-line treatment for mBC received through clinical trial. Specific Aims: Primary objective is to describe the first-line (1L) treatment of HR-positive, HER2-negative mBC in Brazil. Secondary objectives are to describe progression-free survival (PFS) in the 1L setting until month 24; describe and compare the 1L treatment of HR-positive, HER2-negative mBC and PFS until month 24 according to the health care coverage (public vs. private); describe timelines from symptoms, histopathological diagnosis, molecular test, and treatment; describe the mBC pathological characterization; describe frequency of diagnostic tests to define breast cancer molecular subtypes; describe the subsequent line of treatment and corresponding PFS; describe overall survival (OS); evaluate PFS and OS according to visceral vs. non-visceral metastatic disease, primary endocrine resistance vs. acquired endocrine resistance, de novo versus recurrent disease, public vs. private health system and pre vs postmenopausal status. Statistical Methods: No a priori sample size calculation was performed. The expected sample size of 150 patients in each group allows description of the proportion of patients using CDK 4/6 inhibitors with two-sided 90% confidence interval ranging from 53.4% to 66.6% when the expected proportion is 60% in the private health system. Present Accrual and Target Accrual: A total of 12 sites of 14 planned were activated. The first patient was enrolled on February 8, 2022. As of June 24, 2022, a total of 122 patients were enrolled, 86 from public and 36 from private health system. The target accrual of 300 patients is expected to be completed by November 2022. Results are expected to be presented by April 2023. Funding: Novartis. Acknowledgements: SAS. Citation Format: Gustavo Werutsky, Tomás Reinert, Daniela D. Rosa, Romualdo Barroso-Sousa, Heloísa Resende, Poliana A. Signorini, Juliana G. Martins Fagundes, Jose Marcio B. Figueiredo, Eduardo Cronemberger, Aline C. Vieira, Jorge Henrique Santos Leal, Luiza Nardin Weis, Ludmila Thommen, Rafaela G. Jesus, Gustavo Gössling, José Bines. Real-World Data on First-line Treatment of HR-positive, HER2-negative, Metastatic Breast Cancer in Brazil (BRAVE Study/LACOG 0221) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-07-01.

Background Neoadjuvant chemotherapy (NACT) is the mainstay of treatment of stages II and III triple-negative breast cancer (TNBC). There is interest in the addition of carboplatin to NACT, especially in TNBC patients with germline BRCA mutations or other genomic alterations associated with DNA repair deficiency. This study aims to evaluate if the addition of carboplatin to NACT is associated with an increase in the pathological complete response (pCR) rates in TNBC. Methods We conducted an open-label phase II randomized clinical trial in a single center in Brazil. Patients with stage II and III TNBC were randomized in a 1:1 ratio to receive standard NACT with or without carboplatin. All the patients received doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) both intravenously (i.v.) q21 days for four cycles. Patients were then randomized for additional treatment with weekly (wk) paclitaxel (80 mg/m2 i.v., for 12 cycles) plus wk carboplatin AUC 1.5 (experimental arm) or without wk carboplatin (control arm). Randomization was stratified according to gBRCA status (deleterious mutation vs. no deleterious mutations), age (< 50 vs.≥ 50 years), or AJCC 8th edition clinical stage (II vs. III). The primary endpoint was the pathologic complete response (pCR) rate. Secondary endpoints included recurrence-free survival, overall survival, and toxicity. Results Between 2017 and 2021, 146 patients were randomized; 73 on each arm. The median age was 45 years, and 69.8% were < 50 years. Most patients (66.4%) had locally advanced stage III disease, 67.1% had T3/T4 tumors, and 56.2% had clinically positive axillary lymph nodes. Germline BRCA status was available for all patients, and 19.9% had pathogenic BRCA1/2 variants. The pCR rate (ypT0ypN0) was numerically increased by 13.7%, being 43.8% (31 of 73 patients) in the experimental and 30.1% (22 of 73 patients) in the control arm, not meeting the prespecified goal of increasing the pCR in 15% (p value = 0.08). Survival outcomes are immature. The toxicity profile was consistent with routine clinical practice. There were more dose interruptions and hematological toxicity in the carboplatin arm. However, the incidence of serious adverse effects was low, and there was no difference in treatment discontinuation between the two arms. Conclusion The addition of carboplatin to standard NACT in stages II and III TNBC was associated with a non-statistically significant numerical increase in the pCR rate of 13.7%, consistent with other similar clinical trials. Follow-up for survival outcomes and translational research initiatives are ongoing.

Background Neoadjuvant chemotherapy (NACT) is the mainstay of treatment of stages II and III triple-negative breast cancer (TNBC). This study aims to evaluate if the addition of carboplatin to NACT is associated with an increase in the pathological complete response (pCR) rates in TNBC. Methods We conducted an open-label phase II randomized clinical trial in a single center in Brazil. Patients with stage II and III TNBC were randomized to receive standard NACT with or without carboplatin. All the patients received doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) both intravenously (i.v.) q21 days for four cycles. Patients were then randomized for additional treatment with weekly (wk) paclitaxel (80 mg/m2 i.v., for 12 cycles) plus wk carboplatin AUC 1.5 (experimental arm) or without wk carboplatin (control arm). Randomization was stratified according to gBRCA status, age, and AJCC 8th edition clinical stage (II vs. III). The primary endpoint was the pathologic complete response (pCR) rate. Secondary endpoints included recurrence-free survival and overall survival. Results Between 2017 and 2021, 146 patients were randomized, 73 on each arm. The median age was 45 years. Most patients (66.4%) had locally advanced stage III disease, 67.1% had T3/T4 tumors, and 56.2% had clinically positive axillary lymph nodes. Germline BRCA status was available for all patients, and 19.9% had pathogenic BRCA1/2 variants. The pCR rate (ypT0ypN0) was numerically increased by 13.7%, being 43.8% (31 of 73 patients) in the experimental and 30.1% (22 of 73 patients) in the control arm, not meeting the prespecified goal of increasing the pCR in 15% (p-value = 0.08). Survival outcomes are immature. Conclusion The addition of carboplatin to standard NACT in stages II and III TNBC was associated with a non-statistically significant numerical increase in the pCR rate. Follow-up for survival outcomes and translational research initiatives are ongoing.