Introduction

Breast cancer is the most common type of cancer among women globally, accounting for approximately 23.8% in this population in 2022 ¹1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May;74(3):229-63.. In Brazil, excluding non-melanoma skin cancer, it is the most common tumor, with a forecast of 74,000 new cases annually by 2025 ²2. Santos M de O, Lima FC da S de, Martins LFL, Oliveira JFP, Almeida LM de, Cancela M de C. Estimativa de Incidência de Câncer no Brasil, 2023-2025. Revista Brasileira de Cancerologia. 2023 Feb 6;69(1) e-213700..

Among breast cancers, triple-negative breast tumors, defined by the absence of hormone receptors and non-amplification of the human epidermal growth factor receptor-2 gene, are distinguished by their aggressiveness and unfavorable prognosis ³3. Curigliano G, Burstein HJ, Winer EP, Gnant M, Dubsky P, Loibl S, et al. De-escalating and escalating treatments for early-stage breast cancer: The St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Annals of Oncology. 2017 Aug 1;28(8):1700-12.. This characterization makes it unsuitable for hormone therapy and targeted treatments, limiting treatment options, mainly to the use of systemic chemotherapy, which is a clinical challenge ⁴4. Sharma P. Biology and Management of Patients With Triple-Negative Breast Cancer. Oncologist. 2016 Sep 1;21(9):1050-62.^,55. Garrido-Castro AC, Lin NU, Polyak K. Insights into molecular classifications of triple-negative breast cancer: Improving patient selection for treatment.. Cancer Discov. .2019. 9(2):176-198.

In the last decade, there has been significant progress in research aimed at developing new treatments for triple-negative breast tumors, with promising results using immunotherapy and targeted therapies ⁶6. Liedtke C, Rody A. New treatment strategies for patients with triple-negative breast cancer. Curr Opin Obstet Gynecol. 2015;27(1):77-84.^,77. Schmid P, Cortes J, Dent R, Pusztai L, McArthur H, Kümmel S, et al. VP7-2021: KEYNOTE-522: Phase III study of neoadjuvant pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvante pembrolizumab vs. placebo for early-stage TNBC. Annals of Oncology. 2021 Sep 1;32(9):1198-200^,88. Guney Eskiler G, Ozturk M. Therapeutic potential of the PI3K inhibitor LY294002 and PARP inhibitor Talazoparib combination in BRCA-deficient triple negative breast cancer cells. Cell Signal. 2022;91:110229.. International guidelines highlight that, in order to achieve better outcomes, it may be necessary to combine innovative therapies with conventional systemic chemotherapy in different phases of initial treatment ⁹9. Loibl S, André F, Bachelot T, et al. Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2024;35(2):159-182..

However, in Brazil, systemic chemotherapy continues to be the main option available for treating this neoplasm in the Brazilian National Health System (Sistema Único de Saúde - SUS) ¹⁰10. Ministério da Saúde (BR). Secretaria de Ciência, Tecnologia e Insumos Estratégicos. Departamento de Gestão e Incorporação de Tecnologias em Saúde. Diretrizes Diagnósticas e Terapêuticas do Carcinoma de Mama. Brasília: Ministério da Saúde; 2019. 49p.^,1111. Ministério da Saúde (BR). Secretaria de Ciência, Tecnologia e Insumos Estratégicos. Departamento de Gestão e Incorporação de Tecnologias em Saúde. Protocolos Clínicos e Diretrizes Terapêuticas: Câncer de Mama - Relatório de Recomendação Preliminar. Brasília: Ministério da Saúde ; 2024. 117p.. Studies indicate that, in addition to the delay in adopting new technologies, restricted access to quality healthcare, late diagnosis and differences in the availability of innovative treatments contribute to variable outcomes between populations. Such disparities are even more evident in low- and middle-income countries, such as Brazil, where socioeconomic barriers worsen the challenges faced by patients ¹²12. Medeiros GC, Bergmann A, de Aguiar SS, Thuler LCS. Análise dos determinantes que influenciam o tempo para o início do tratamento de mulheres com câncer de mama no Brasil. Cad Saude Publica. 2015 Jan 1;31(6):1269-82.^,1313. Cho B, Han Y, Lian M, Colditz GA, Weber JD, Ma C, et al. Evaluation of Racial/Ethnic Differences in Treatment and Mortality among Women with Triple-Negative Breast Cancer. JAMA Oncol. 2021 Jul 1;7(7):1016-23.^,1414. Acevedo F, Walbaum B, Medina L, Merino T, Camus M, Puschel K, et al. Clinical characteristics, risk factors, and outcomes in Chilean triple negative breast cancer patients: a real-world study. Breast Cancer Res Treat. 2023 Jan 1;197(2):449-59..

Due to the heterogeneity of the characteristics of triple-negative breast tumors and the medications currently available on the SUS, establishing a standard treatment regimen is a challenge. Data on the procedures and protocols adopted to treat this neoplasm in Brazil are scarce. Therefore, this study aimed to characterize the profile of medication use in women with triple-negative breast tumors, with initial neoadjuvant and adjuvant intent, in order to understand the treatment standard adopted.

Methods

Design and background

This was a descriptive and retrospective study with patients diagnosed with triple-negative breast tumor, between January 2018 and December 2019, treated with chemotherapy with initial neoadjuvant and adjuvant intent, in a public hospital that is a reference for cancer treatment in Brazil.

Participants, sample and eligibility criteria

The total population in the period consisted of 311 women over 18 years old. Taking a 5% sampling error and a 95% confidence interval (95%CI), a minimum sample of 138 patients in the study was estimated. The following patients were excluded: pregnant and breastfeeding women; those with concomitant or non-primary breast tumors; those who had received previous systemic treatment in another institution; those selected for research protocols; those whose physical medical records were not located; those who used hormone therapy or trastuzumab and those who had hormone receptor positivity or epidermal growth factor receptor-2 positivity at some point during treatment - despite initially being diagnosed with a triple-negative breast tumor.

Data source and variables

The database used to identify the study population was the Hospital Cancer Record Integrator of the institution where the study was carried out. Subsequently, participants were selected based on information from physical and electronic medical records and the hospital administration system.

The variables collected were categorized into three axes: sociodemographic data (age less than 50 years old and age equal to or greater than 50 years old, family history of cancer, race/skin color, level of education and social habits); clinicopathological data (performance scale, histological subtype, histological grade, Ki-67 marker expression, clinical and pathological staging); therapeutic data (surgery, radiotherapy, treatment goal and chemotherapy regimens used - including doses, number of cycles performed and medications, in addition to reasons for changing therapeutic regimens and lines of palliative treatment, when applicable). Malignant tumor classification, known as TNM (tumor, lymph node, metastasis) ¹⁵15. Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging . CA Cancer J Clin. 2017 Mar;67(2):93-9., was used to define clinical and pathological staging. Those with clinicopathological stages 3B, 3C and 4 were considered to be at an advanced stage. In addition, date of death was collected in order to analyze overall survival.

Data organization and analysis

The data were organized and analyzed using Microsoft 365 Excel® software. We calculated the frequency of categorical variables and measures of central tendency and dispersion of continuous variables. We analyzed the distribution of patients across multiple chemotherapy regimens used and reasons for discontinuing drug treatment. Total patient follow-up time was 48 months, based on the date of diagnosis.

The time (in months) for completion of the regimens used as first line was estimated using the initial and

final dates of treatment. Once this parameter was established, the transitions of the treatment lines were analyzed using Python software version 3.12.1, at 30, 60 and 180 days.

When identifying the most used regimen in the first line of initial therapy, we analyzed the average interval between the start and failure of treatment, over 24 months, using the Kaplan-Meier method

¹⁶16. Kaplan, E. L., & Meier, P. Nonparametric Estimation from Incomplete Observations. Journal of the American Statistical Association,1958 Jun 1;53(282),457-481. https://doi.org/10.2307/2281868
https://doi.org/10.2307/2281868... . The following were considered failures: use of the subsequent line with palliative intent, death and exclusive palliative care. Overall survival at 48 months was estimated starting from the date of diagnosis. In cases where loss of follow-up occurred, censoring occurred at the time of the last clinical record held on the institution’s medical records. JAMOVI ® software version 2.3.28 was used for these analyses ¹⁷17. The jamovi project. jamovi: statistical software;. Version 2.4. Sydney: jamovi project; 2024 cited 2024 Oct 8. Available from: Available from: https://www.jamovi.org
https://www.jamovi.org... ^,1818. R Core Team. R: A language and environment for statistical computing;. Vienna: R Foundation for Statistical Computing; 2024;cited 2024 Oct 8;. Available from: Available from: https://www.R-project.org/Simon
https://www.R-project.org/Simon... .

Results

A total of 238 women were recruited, 62 of whom were excluded due to: lack of record of systemic treatment (n=24; 38.7%); showing hormonal positivity and/or using hormone therapy (n=9; 14.5%); history of systemic treatment at another institution (n= 8; 12.9%); history of previous chemotherapy for other tumors and/ or non-primary breast tumor (n=8; 12.9%); showing positivity for human epidermal growth factor 2 and/or use of trastuzumab (n=5; 8.1%); having concomitant tumors (n=4; 6.5%); participation in research protocols (n=3; 4.8%); and physical medical record not being found (n=1; 1.6%).

Of the 176 research participants, 85 (48.3%) were diagnosed in 2018. Median age was 54 (min=24; max=90) years, with 39.0% under the age of 50. Of the total, 77.8% reported being non-White and 50.6% only had elementary education.

The most common tumor subtype was invasive ductal carcinoma (95.5%), and, at the time of diagnosis, the majority had performance status 1 (55.1%), histological grade type II (50.0%), Ki 67 ≥14% (97.0%) and advanced stage (47.7%). Of those who underwent surgery (n=136), 54.4% underwent radical mastectomy. A total of 67.6% underwent adjuvant radiotherapy. Table 1 shows the profile of the patients analyzed.

We identified 12 chemotherapy regimens, with neoadjuvant intent (10.8% of cases) or adjuvant intent (89.2% of cases), for the treatment of triple-negative breast tumors. The combination of doxorubicin, cyclophosphamide and taxane (docetaxel or paclitaxel) was the main treatment regimen used (80.7%). The least frequent regimens were doxorubicin (0.6%), docetaxel (0.6%) and the combination of fluorouracil, methotrexate and cyclophosphamide (0.6%).

In total, 23 patients proceeded to second-line chemotherapy with curative intent, being treated with: carboplatin and paclitaxel (43.0%), paclitaxel (26.0%), capecitabine (9.0%), carboplatin (4.4 %), cyclophosphamide and taxane (4.4%), gemcitabine and cisplatin (4.4%), docetaxel (4.4%) and fluorouracil, methotrexate and cyclophosphamide (4.4%). In the third neoadjuvant line, cisplatin was the drug chosen to treat two patients. The distribution of patients, alongsuccessive lines of chemotherapy, and the reasons for discontinuing treatment are shown in Figure 1 A.

The reasons recorded on the medical records for applying multiple regimens with neoadjuvant or adjuvant intent were: low therapeutic effectiveness; presence of large lesions that made it difficult to perform surgical procedures; clinical condition of the patient; and disease progression.

We found that, after using the first therapeutic regimen with curative intent, 82 (46.6%) participants continued using drug treatment. Of these, 71.9% showed disease progression and started using palliative chemotherapy. The reasons for discontinuation were: therapeutic response - patients were followed up by mastologists, in treatments that did not involve systemic chemotherapy; absence of therapeutic proposal or impeding clinical conditions - for these, it was decided to employ exclusive palliative care or end-of-life care.

Figure 2 shows that, within 30 days after starting treatment, only one patient had switched to a second line of neoadjuvant treatment. We found that, within 60 days, 22 patients started using therapeutic regimens for palliative purposes, and two deaths were recorded. After 180 days, 76.1% of patients continued to undergo the initial treatment.

When analyzing treatment failure within 24 months, two patients were lost to follow-up. Of the remaining 174, 70 (40.2%) presented failures related to the following reasons: 55 (78.6%) used a subsequent therapeutic line for palliative purposes; 11 (15.7%) died; and four (5.7%) were referred to exclusive palliative care. Among the 70 patients, 55 (78.6%) had used the doxorubicin, cyclophosphamide and taxane regimen, with an average time to failure of 7.6 months, over 24 months (Figure 3).

During the systemic treatment period, 56 patients died (31.8%). Additionally, 85 patients (48.3%) progressed to the non-systemic treatment phase. At the end of the follow-up period, we found that: 60 (70.6%) remained under mastology follow-up, without the need to return for additional systemic therapy; 15 (17.6%) died; and five (5.9%) needed to be redirected to systemic therapy. We also found that two (2.3%) participants had disease progression without indication of drug treatment, one (1.2%) was discharged and referred for follow-up at a primary care health service, one (1 .2%) died from COVID-19 and one (1.2%) was admitted to hospital with non-invasive support, with no record after hospitalization.

We found that, after 48 months, all patients who had been referred for end-of-life care, exclusive palliative care, palliative radiotherapy, who chose not to continue with pharmacological treatment, or who for whom there was considered to be no theraputic proposal, died. Figure 4 shows overall survival at 48 months. Median survival of 34 months was found, and only 43.2% of the patients analyzed remained alive at the end of follow-up. Four patients were lost to follow-up at the end of the study, due to lack of clinical records covering a period greater than 24 months.

Discussion

We found that the most used therapeutic regimen in the first line of treatment was the combination of doxorubicin, cyclophosphamide and taxane, and that up to three lines of treatment with curative intent were used. However, a significant proportion of patients required palliative treatment after the first line of curative treatment. Median time to treatment failure with doxorubicin, cyclophosphamide and taxane was 7.6 months, median overall survival was 34 months from diagnosis and, at the end of the follow-up period, less than half of the patients remained alive.

The analysis of the sociodemographic and clinical profile demonstrated similarity to the findings of a retrospective cohort conducted from June 2008 to January 2009, which analyzed women diagnosed in2001 (n=2,198) and 2006 (n=2,714) with different breast cancer subtypes in Brazil ¹⁹19. SD, Bines J, Werutsky G, Nunes JS, Pacheco FC, Segalla JG, et al. Characteristics and prognosis of stage I-III breast cancer subtypes in Brazil: The AMAZONA retrospective cohort study. Breast. 2019 Apr 1;44:113-9.. However, it is worth highlighting the significant prevalence of young women, with low education levels and of non- White race/skin color, in the context in which cancer manifests itself as an issue of wide-reaching relevance, encompassing health, social and economic dimensions ¹1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May;74(3):229-63., since the triple-negative breast tumor is known to affect young women and has a poorer prognosis, compared to other types of breast tumors ²⁰20. Seah DS, Luis IV, Macrae E, et al. Use and duration of chemotherapy in patients with metastatic breast cancer according to tumor subtype and line of therapy. J Natl Compr Canc Netw. 2014;12(1):71-80.^,2121. Shi J, Liu F, Song Y. Progress: Targeted therapy, immunotherapy, and new chemotherapy strategies in advanced triple-negative breast cancer. Cancer Manag Res. 2020;12:9375-87..

Recent studies indicate that poorer prognosis may not only be associated with the biological characteristics of the tumor. Different authors have investigated the influence of social disparities on the clinical outcomes of women with this type of tumor and demonstrated that non-White race/skin color, socioeconomic deprivation and social stress were associated with lack of access to healthcare and worse overall survival ¹²12. Medeiros GC, Bergmann A, de Aguiar SS, Thuler LCS. Análise dos determinantes que influenciam o tempo para o início do tratamento de mulheres com câncer de mama no Brasil. Cad Saude Publica. 2015 Jan 1;31(6):1269-82.^,1313. Cho B, Han Y, Lian M, Colditz GA, Weber JD, Ma C, et al. Evaluation of Racial/Ethnic Differences in Treatment and Mortality among Women with Triple-Negative Breast Cancer. JAMA Oncol. 2021 Jul 1;7(7):1016-23.^,1414. Acevedo F, Walbaum B, Medina L, Merino T, Camus M, Puschel K, et al. Clinical characteristics, risk factors, and outcomes in Chilean triple negative breast cancer patients: a real-world study. Breast Cancer Res Treat. 2023 Jan 1;197(2):449-59.^,2222. Prakash O, Hossain F, Danos D, Lassak A, Scribner R, Miele L. Racial Disparities in Triple Negative Breast Cancer: A Review of the Role of Biologic and Non-biologic Factors. Front Public Health. 2020;8:594256.. This shows that socioeconomic aspects may be related to worse clinical outcomes in patients with triple-negative breast tumors.

The distribution of participants across progressive lines of treatment pointed to rapid progression of the disease after the first line of neoadjuvant and adjuvant treatment, and the need to begin palliative treatment. The data also reveal that, after an unsatisfactory response to the regimen composed of doxorubicin, cyclophosphamide and taxane, the combination of gemcitabine and cisplatin emerged as the most recurrent option, which is a preferred regimen for treatment of metastatic triple-negative breast tumor and is considered safe for patients treated with other lines of chemotherapy, when low doses are administered ²³23. Kim JS, Park IH, Lee KS, Ro J. Outcomes of palliative weekly low-dose gemcitabine-cisplatin chemotherapy in anthracycline- and taxane- pretreated metastatic breast cancer patients. J Breast Cancer. 2014 Dec 1;17(4):339-43.^,2424. Zhang J, Lin Y, Sun XJ, Wang BY, Wang ZH, Luo JF, et al. Biomarker assessment of the CBCSG006 trial: A randomized phase III trial of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine as first- line therapy for patients with metastatic triple-negative Breast cancer. Annals of Oncology. 2018 Aug 1;29(8):1741-7..

Analysis of the failure rate at 24 months for the therapeutic regimen comprised of doxorubicin, cyclophosphamide and taxane revealed considerable ineffectiveness after use of the first line of treatment. It is important to highlight that the therapeutic regimens used to treat the patients in this study were based on internal practices, aligned with the most up-to-date international recommendations for the treatment of triple-negative breast tumors. However, such regimes were dissonant with the diagnostic and therapeutic guidelines in force in 2018 in the Brazilian public health system ¹⁰10. Ministério da Saúde (BR). Secretaria de Ciência, Tecnologia e Insumos Estratégicos. Departamento de Gestão e Incorporação de Tecnologias em Saúde. Diretrizes Diagnósticas e Terapêuticas do Carcinoma de Mama. Brasília: Ministério da Saúde; 2019. 49p., which recommended an even more restrictive therapeutic arsenal for the neoadjuvant or adjuvant treatment of triple-negative breast tumors. In this sense, it is possible to assume that the adoption of outdated therapeutic regimens, provided for in the guidelines, could result in even more unfavorable outcomes in the treatment of these patients.

Analysis of overall survival at 48 months demonstrated that, despite the increase in updates derived from international guidelines - which culminated in the most modern treatment in line with Ministry of Health recommendations -, what was offered to treat these women may not have been enough to obtain better outcomes, given other therapeutic possibilities. Or, furthermore, that treatment may be started by these patients at an inopportune time. Studies demonstrate that access to breast cancer treatment in Brazil’s public health system does not occur as recommended, and that difficulties can be exacerbated when it comes to the younger population ²⁵25. Sousa SMMT, Carvalho M das GF de M, Santos Júnior LA, Mariano SBC. Acesso ao tratamento da mulher com câncer de mama. Saúde em Debate. 2019 Sep;43(122):727-41.^,2626. Mattar A, Yoshimura AA, Fristachi CE, Pessoa EC, Andrade FEM, Tosello G, et al. Clinic, pathologic and molecular landscapes in ultra-young women with breast cancer in the State of São Paulo: a real-world study. Mastology.2021;31:1-8..

A retrospective study that included 8,601 women and evaluated the role of chemotherapy in stage IA triple-negative breast cancer, between 2010 and 2019, demonstrated that use of chemotherapy was associated with improved patient survival. Considering that, in the present study, the majority of patients accessed specialized care with advanced-stage disease, more appropriate management of these patients by the health network, and the consequent early start of treatment, could culminate in more favorable outcomes.

As a suggestion, effective implementation of management strategies in the Brazilian public health system may result in the timely referral of patients to specialized care services, ensuring that the application of technologies already existing in the care network is sufficient to provide more effective treatment. Furthermore, the incorporation of new technologies should be considered, but not at the expense of optimizing referral flows and use of existing resources, in order to ensure that the use of more financially costly medications is done in an optimized and sustainable manner, since paying for them is challenging for health systems ²⁸28. Bermudez, J. A. Z., Oliveira, M. A., & Chaves, G. Novos medicamentos: quem poderá pagar?. Cadernos de Saúde Pública, 2016;32:e00025215..

Regarding the study of medication use, certain limitations must be considered, including the use of data sources such as isolated medical prescriptions or medical records and the collection and consequent standardization of data on medications ⁽²⁹⁾. With the aim of minimizing uncertainties about the data obtained from these data sources, our study compared prescription data and/or physical records with those recorded on the hospital’s computerized systems.

The results showed that the most used therapeutic regimen, in the neoadjuvant and adjuvant setting, was the combination of doxorubicin, cyclophosphamide and taxane, with an average time until treatment failure of 7.6 months, and that more than half of the patients died within 48 months. This information contributes to advances in the treatment of triple-negative breast tumors in Brazil, especially within the scope of the public health system, by highlighting and filling specific knowledge gaps. We also consider that these results may contribute to reflections on the panorama of the treatment of triple-negative breast tumors, as well as to gaining understanding of how the emergence of new technologies can impact the clinical outcomes presented by these patients and how the appropriate management of patients, within the scope of the public health system, can contribute to therapeutic effectiveness and efficiency, especially in contexts where access to innovative technologies is limited.

Acknowledgements

Not applicable

References

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History