This narrative review explores the mechanisms underlying resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor (HR)-positive metastatic breast cancer (MBC), a critical challenge in contemporary oncology. Despite the proven efficacy of CDK4/6i in improving clinical outcomes, both intrinsic and acquired resistance remain substantial challenges. We discuss clinical data that underscore pivotal molecular alterations associated with resistance, including mutations in the Retinoblastoma gene ( RB1 ), germline variants, aberrations in the PIK3CA gene that activate the phosphatidylinositol 3-kinase/protein kinase B (AKT)/mammalian target of rapamycin signaling cascade, and modifications in fibroblast growth factor receptor signaling. Additional resistance mechanisms—such as the loss of the FAT1 tumor suppressor gene and the dysregulation of cell cycle regulators like cyclin E and CDK2 —are also explored. The role of circulating tumor DNA analysis in tracking genomic changes during therapy is also considered. Furthermore, the review assesses emerging therapeutic strategies, particularly combination therapies that target alternative pathways to counteract resistance mechanisms. By synthesizing current evidence and providing actionable insights, this review aims to enhance our understanding of endocrine resistance mechanisms among clinical oncologists and gives them some future perspectives to expand strategies to overcome this challenge.

PURPOSE: A nationwide lockdown was enforced in Brazil starting in March 2020 because of the COVID-19 pandemic when cancer screening activities were reduced. In this study, we evaluated the impact of the COVID-19 pandemic on breast cancer (BC) diagnosis. METHODS: We extracted data from the medical records of patients age older than 18 years who were diagnosed with BC and started treatment or follow-up in private oncology institutions in Brazil between 2018 and 2021. The primary objective was to compare the stage distribution during the COVID-19 pandemic (2020-2021) with a historical prepandemic control cohort (2018-2019). Early BC was defined as stage I-II and advanced disease as stage IV. RESULTS: We collected data for 11,753 patients with an initial diagnosis of BC, with 6,493 patients in the pandemic (2020-2021) and 5,260 patients in the prepandemic period (2018-2019). We observed a lower prevalence of early-stage BC (63.6% v 68.4%) and a higher prevalence of advanced-stage BC (16.9 v 12.7%), after the onset of the pandemic (both P < .01). This pattern was similar for both estrogen receptor–positive/human epidermal growth factor receptor 2–negative and human epidermal growth factor receptor 2–positive tumors: significantly decreased in the early stage from 69% to 67% and 68% to 58%, respectively, and a considerable increase in advanced-stage disease from 13% to 15% and 13% to 20%, respectively. For triple-negative BC, there was a significantly higher percentage of patients with advanced-stage disease during the pandemic (17% v 11%). Overall, age 50 years or older and postmenopausal status were associated with a greater risk of advanced stage at diagnosis during the pandemic period. CONCLUSION: We observed a substantial increase in the number of cases of advanced-stage BC in Brazil during the COVID-19 pandemic.

PURPOSE: Triple-negative breast cancer (TNBC) presents notable treatment difficulties, especially in the public health care systems of low- and middle-income countries where access to advanced therapies is restricted. This study investigates TNBC's clinical, epidemiologic, and economic effects on survival within Brazil's public health care system. METHODS: We conducted a retrospective cohort study of patients with TNBC treated between 2010 and 2019. Overall survival (OS) rates by stage were analyzed across various patient groups, including those receiving neoadjuvant or adjuvant treatment, patients with or without complete pathologic response, Black and non-Black patients, and those treated with or without carboplatin-based therapy. Cox proportional hazards models were applied to estimate hazard ratios (HRs) with 95% CIs, and annual treatment costs were calculated per stage. RESULTS: Among 1,266 patients with TNBC, 710 met eligibility criteria. Kaplan-Meier analysis indicated stage II patients had a 47% lower mortality risk than stage III (HR, 0.53 [95% CI, 0.33 to 0.85]; P = .009). Patients in the adjuvant treatment group had a reduced risk (HR, 0.48 [95% CI, 0.34 to 0.69]) compared with the neoadjuvant group. Achieving complete pathologic response (pCR) greatly improved OS (HR, 0.21 [95% CI, 0.11 to 0.43]; P < .001). Black patients had better survival rates than non-Black (HR, 0.58 [95% CI, 0.40 to 0.86]; P = .006). Carboplatin use did not significantly affect OS (HR, 0.96 [95% CI, 0.65 to 1.43]; P = .857). The average monthly cost for systemic TNBC treatment increased with disease progression, from $101.87 in US dollars (USD) for stage I to $314.77 USD for stage IV second-line therapy. CONCLUSION: This study provides insight into TNBC in Brazil's public health system, showing that OS decreases with disease progression but is higher among Black patients. pCR and adjuvant therapy improve survival, although costs increase significantly at advanced stages, highlighting the economic burden of late-stage TNBC management.

Background: Breast cancer is the most common cancer in women worldwide, with 73,610 new cases expected annually in Brazil between 2023 and 2025. Post-operative radiation therapy (PORT) is a critical component of treatment, and recent advances have allowed for shorter treatment times that can help overcome shortages in low- and middle-income countries. The Brazilian Society of Radiotherapy (SBRT) updated its consensus on hypofractionated whole-breast radiotherapy and included recommendations for partial breast irradiation. Materials and methods: The SBRT convened a national panel of experts to develop updated recommendations. Using a modified Delphi method, the panel reached a consensus through structured rounds of voting. Recommendations were categorized based on the strength of available evidence. Results: The consensus supports hypofractionation, which offers shorter, cost-effective treatment schedules, and partial breast irradiation (PBI), which targets high-risk areas while sparing healthy tissue. Despite high-quality evidence, adopting these techniques has been inconsistent. The panel’s recommendations provide evidence-based guidance to clinicians, tailored to the Brazilian context, emphasizing safety and efficacy. Conclusion: The updated SBRT consensus presents hypofractionation and PBI as practical alternatives to conventional radiation therapy, offering improved access and reduced costs. These recommendations aim to guide clinicians in adopting these approaches and help address barriers to access. Keywords: breast cancer hypofractionation partial breast irradiation post-operative radiation therapy (PORT) radiation oncology low- and middle-income countries consensus guidelines external beam radiation therapy (EBRT)

Purpose: The MammaPrint™ (MP) 70-gene signature, identifies hormone receptor-positive (HR+), HER2-negative breast cancer patients with low genomic risk who are candidates for de-escalation of the systemic therapies employed. Knowing that MP was validated in an exclusively European cohort and understanding the heterogeneity of breast tumors in different populations, we proposed a study to analyze MP performance in the Brazilian population. Methods: Retrospective, prognostic evaluation, real-world cohort study of HR+, HER2- breast cancer patients who underwent MP in Brazil from January 2016 to December 2020 (AGEMA-BRA). Results: Of the 953 patients with high clinical risk, 407 (42.7%) had high genomic risk, and 546 (57.3%) had low genomic risk to MP. In the analysis of epidemiological, clinical, and anato-mopathological data correlating high and low risk to MP, and among the subgroups with low-risk, ultra-low risk, high-risk 1 and high-risk 2, only the histological grade showed statistical significance. Distant metastasis-free survival (DMFS) was 97.8% and overall survival (OS) was 99.8% with a mean follow-up of 40.8 months, with no difference between high and low genomic risk. Conclusions: Applying the MP signature in the AGEMA-BRA cohort enabled greater chemotherapy de-escalation with better DMFS than observed in the MINDACT pivotal study. Equivalent DMFS and OS results between high and low genomic risk carriers demonstrate the appropriate selection of patients by MP to receive or not receive adjuvant chemotherapy. These data make it possible to validate the performance of the signature in the Brazilian population and confirm the importance of testing it in different populations.

In a recent publication, Martin et al. reported the overall survival (OS) results of PEARL, a multicentre phase III study in patients with aromatase inhibitor (AI)-resistant metastatic breast cancer (MBC) that were treated with palbociclib in combination with endocrine therapy (ET) versus capecitabine [ [1] Martín M. Zielinski C. Ruiz-Borrego M. Carrasco E. Ciruelos E.M. Muñoz M. et al. Overall survival with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer in the PEARL study. Eur J Cancer. 2022 Apr; 168 : 12-24 Abstract Full Text Full Text PDF PubMed Google Scholar ]. The trial was negative for both primary survival end-points as negative progression-free survival (PFS) outcomes were previously reported [ [2] Martin M. Zielinski C. Ruiz-Borrego M. Carrasco E. Turner N. Ciruelos E.M. et al. Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL. Ann Oncol Off J Eur Soc Med Oncol. 2021 Apr; 32 : 488-499 Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar ]. Notably, a lower discontinuation rate and toxicity outcomes favoured ET over capecitabine.