ABSTRACT

Objective:

This study aimed to analyze the prognosis of women with breast cancer by molecular subtypes, sociodemographic variables, and clinical and treatment characteristics.

Methods:

This hospital-based retrospective cohort study analyzed 1,654 women over 18 years of age diagnosed with invasive breast cancer from 2000 to 2018. Data were extracted from Brazil’s Oncocenter Foundation of São Paulo. The variables analyzed were age, histology, molecular subtypes, clinical staging, treatment type, and diagnosis-to-treatment time. Cox regression analysis was applied to estimate death risk.

Results:

Women with HER-2-positive (nonluminal) and triple-negative molecular subtypes were more than twice more likely to be at risk of death, with adjusted hazard ratio — HR_adj=2.30 (95% confidence interval — 95%CI 1.34–3.94) and HR_adj=2.51 (95%CI 1.61–3.92), respectively. A delayed treatment associated with an advanced clinical stage at diagnosis increased fourfold the risk of death (HRadj=4.20 (95%CI 2.36–7.49).

Conclusion:

In summary, besides that interaction between advanced clinical stage and longer time between diagnosis and treatment, HER-2-positive (nonluminal) and triple-negative phenotypes were associated with a worse prognosis. Therefore, actions to reduce barriers in diagnosis and treatment can provide better outcome, even in aggressive phenotypes.

Keywords:
Breast neoplasms; Survival rate; Biomarkers; Social vulnerability

RESUMO

Objetivo:

O objetivo deste estudo foi analisar o prognóstico de mulheres com câncer de mama de acordo com os subtipos moleculares, variáveis sociodemográficas, características clínicas e de tratamento.

Métodos:

Este foi um estudo de coorte retrospectivo de base hospitalar. Foram analisadas 1.654 mulheres maiores de 18 anos diagnosticadas com câncer de mama invasivo entre 2000 a 2018. Os dados foram extraídos da Fundação Oncocentro de São Paulo, Brasil. As variáveis analisadas foram idade, histologia, subtipo moleculares, estadiamento clínico, tipo de tratamento e tempo entre o diagnóstico e tratamento. A análise de regressão de Cox foi aplicada para estimar o risco de morte.

Resultados:

As mulheres que apresentaram os subtipos moleculares HER-2-positivo (não luminal) e triplo negativo tiveram risco de morte quase duas vezes maior respectivamente, com razão de risco ajustada — HR_aj=2,30 (intervalo de confiança de 95% — 95%IC 1,34–3,94) e HR_aj=2,51 (95%IC 1,61–3,92). O atraso no tratamento associado ao avanço do estadiamento clínico ao diagnóstico aumentou em quatro vezes o risco de morte (HR_aj=4,20 (IC95% 2,36–7,49).

Conclusão:

Os fenótipos HER-2-positivo (não luminal) e triplo negativo, além da interação entre estágio clínico avançado e maior tempo entre o diagnóstico e o tratamento, associaram-se a pior prognóstico. Assim, ações para reduzir as barreiras no diagnóstico e tratamento podem proporcionar melhores resultados, mesmo em fenótipos agressivos.

Palavras-chave:
Neoplasias da mama; Taxa de sobrevida; Biomarcadores; Vulnerabilidade social

INTRODUCTION

Breast cancer is the most frequent malignant neoplasm in women worldwide. A total of 2,261,419 million new cases and 684,996 thousand related deaths were estimated in 2020¹1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3): 209-49. https://doi.org/10.3322/caac.21660
https://doi.org/10.3322/caac.21660... . In Brazil, 66,280 new breast cancer cases in women are expected for each year of the 2020–2022 triennium, corresponding to an estimated risk of 6,161 new cases per 100 thousand women. In 2019, 18,068 women died from breast cancer, representing 16.4% of all cancer-related deaths in women²2. Brasil. Ministerio da Saúde. Instituto Nacional de Câncer José Alencar Gomes da Silva. Estimativa 2020: incidência de câncer no Brasil. Rio de Janeiro: INCA; 2019.. According to the CONCORD-3 Study, the highest 5-year relative survival rates among women with breast cancer between 2010 and 2014 were observed in the United States (90.2%) and New Zealand (91.8%). The survival rates in countries such as India and Thailand are lower, approximately 67%, while the relative survival rate is 75.2% in Brazil³3. Allemani C, Matsuda T, Di Carlo V, Harewood R, Matz M, Nikšić M, et al. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet 2018; 391(10125): 1023-75. https://doi.org/10.1016/S0140-6736(17)33326-3
https://doi.org/10.1016/S0140-6736(17)33... .

The main prognostic factors of women’s breast cancer include age at diagnosis, clinical stage, histological classification, treatment options, and molecular subtype⁴4. Prat A, Pineda E, Adamo B, Galván P, Fernández A, Gaba L, et al. Clinical implications of the intrinsic molecular subtypes of breast cancer. Breast 2015; 24 Suppl 2: S26-35. https://doi.org/10.1016/j.breast.2015.07.008
https://doi.org/10.1016/j.breast.2015.07... ,⁵5. Goncalves Jr H, Guerra MR, Duarte Cintra JR, Fayer VA, Brum IV, Bustamante Teixeira MT. Survival study of triple-negative and non-triple-negative breast cancer in a brazilian cohort. Clin Med Insights Oncol 2018; 12: 1179554918790563. https://doi.org/10.1177/1179554918790563
https://doi.org/10.1177/1179554918790563... ,⁶6. Ho-Huynh A, Tran A, Bray G, Abbot S, Elston T, Gunnarsson R, et al. Factors influencing breast cancer outcomes in Australia: a systematic review. Eur J Cancer Care (Engl) 2019; 28(4): e13038. https://doi.org/10.1111/ecc.13038
https://doi.org/10.1111/ecc.13038... ,⁷7. Simon 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; 44: 113-9. https://doi.org/10.1016/j.breast.2019.01.008
https://doi.org/10.1016/j.breast.2019.01... . After the discovery of HER-2, breast cancer was subdivided into the luminal A and B subtypes, the HER-2+ subtype, and the triple-negative subtype, changing the clinical practice. The triple-negative phenotype, which affects 15–20% of women with breast cancer, is associated with the worst prognosis and survival⁷7. Simon 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; 44: 113-9. https://doi.org/10.1016/j.breast.2019.01.008
https://doi.org/10.1016/j.breast.2019.01... ,⁸8. Alvarado-Cabrero I, Alderete-Vázquez G, Quintal-Ramírez M, Patiño M, Ruíz E. Incidence of pathologic complete response in women treated with preoperative chemotherapy for locally advanced breast cancer: correlation of histology, hormone receptor status, Her2/Neu, and gross pathologic findings. Ann Diagn Pathol 2009; 13(3): 151-7. https://doi.org/10.1016/j.anndiagpath.2009.02.003
https://doi.org/10.1016/j.anndiagpath.20... ,⁹9. Sali AP, Sharma N, Verma A, Beke A, Shet T, Patil A, et al. Identification of luminal subtypes of breast carcinoma using surrogate immunohistochemical markers and ascertaining their prognostic relevance. Clin Breast Cancer 2020; 20(5): 382-9. https://doi.org/10.1016/j.clbc.2020.03.012
https://doi.org/10.1016/j.clbc.2020.03.0... ,¹⁰10. Bagaria SP, Ray PS, Sim MS, Ye X, Shamonki JM, Cui X, et al. Personalizing breast cancer staging by the inclusion of ER, PR, and HER2. JAMA Surg 2014; 149(2): 125-9. https://doi.org/10.1001/jamasurg.2013.3181
https://doi.org/10.1001/jamasurg.2013.31... ,¹¹11. Poorolajal J, Nafissi N, Akbari ME, Mahjub H, Esmailnasab N, Babaee E. Breast cancer survival analysis based on immunohistochemistry Subtypes (ER/PR/HER2): a retrospective cohort study. Arch Iran Med 2016; 19(10): 680-6. PMID: 27743431.

Breast cancer has been analyzed within the classic variables tumor, node, metastasis — TNM (AJCC 8th edition), histology, and hormone receptor (HR) status, which classifies high- and low-risk patients for adjuvant treatment. This new approach, observing distinct characteristics of the molecular subtypes concerning age, ethnicity, radiological presentation, response to therapy, and distant metastasis type, has identified patients who are candidates for specific therapies with positive effects on survival rates¹²12. Masood S. Breast cancer subtypes: morphologic and biologic characterization. Womens Health (Lond) 2016; 12(1): 103-19. https://doi.org/10.2217/whe.15.99
https://doi.org/10.2217/whe.15.99... ,¹³13. Han HS, Magliocco AM. Molecular testing and the pathologist’s role in clinical trials of breast cancer. Clin Breast Cancer 2016; 16(3): 166-79. https://doi.org/10.1016/j.clbc.2016.02.016
https://doi.org/10.1016/j.clbc.2016.02.0... ,¹⁴14. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ, et al. Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 2011; 22(8): 1736-47. https://doi.org/10.1093/annonc/mdr304
https://doi.org/10.1093/annonc/mdr304... . Although the molecular analysis of the risk of recurrence in some molecular subtypes is included in the latest American Joint Committee on Cancer (AJCC) guidelines, the molecular subtype still needs to be incorporated into the TNM staging approach¹⁵15. Hortobagyi GN, Connolly Jl, D’Orsi CJ, Edge SB, Mittendorf EA, Rugo HS, etal. Breast. In: American College of Surgeons. AJCC Cancer Staginf Manual. 8th edition. Chicago: American College of Surgeons; 2018. p. 589-636.,¹⁶16. Cserni G, Chmielik E, Cserni B, Tot T. The new TNM-based staging of breast cancer. Virchows Arch 2018; 472(5): 697-703. https://doi.org/10.1007/s00428-018-2301-9
https://doi.org/10.1007/s00428-018-2301-... .

However, limited Brazilian studies have evaluated the link between the molecular subtype’s classification and prognoses in breast cancer patients, due to the higher cost of these tests, mainly for the public health system⁷7. Simon 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; 44: 113-9. https://doi.org/10.1016/j.breast.2019.01.008
https://doi.org/10.1016/j.breast.2019.01... ,¹⁷17. Marques AD, Moura AR, Hora EC, Brito ÉD, Oliviera LS, Feitosa IR, et al. Analysis of breast cancer survival in a northeastern Brazilian state based on prognostic factors: a retrospective cohort study. PLoS One 2022; 17(2): e0263222. https://doi.org/10.1371/journal.pone.0263222
https://doi.org/10.1371/journal.pone.026... . Therefore, this study aimed to analyze prognosis factors in women with invasive breast cancer treated in the public health system in the state of São Paulo, according to sociodemographic, clinical and molecular subtypes.

METHODS

In this retrospective cohort study, we collected data on a hospital-based cancer registry of 1,654 women aged 18 years or above diagnosed with invasive breast cancer in the public health system, from 2000 to 2018. We selected breast cancer using the International Classification of Diseases, Oncology, 3_rd edition (ICD-O-3), topographical codes C50.0 to C50.9, and morphological codes 8050/3, 8211/3, 8480/3, 850_/3, 851_/3, 852_/3, 853_/3, and 854_/3.

The data were obtained from São Paulo’s hospital-based cancer registry (RHC/SP) and the Immunohistochemistry Laboratory database at the Oncocenter Foundation of São Paulo (FOSP). Only patients who had not received prior treatment were eligible. Patients with incomplete or missing data regarding biomarkers estrogen receptor (ER) progesterone receptor (PR), HER-2, Ki-67 and clinical staging (CS) at diagnosis and previous treatment were excluded (Supplementary Figure 1).

Immunohistochemical analysis

Formalin-fixed paraffin-embedded (FFPB) scrolls, with both positive and negative controls, were subjected to automated immunohistochemical examination (Tissue Microarray Assay, TMA), with antigenic recovery PTLink (Dako^®) and incubation, retrieval and counterstaining in AutoStainer Link 48 (Dako^®), using a susceptible polymer with FLEX “ready-to-use” antibodies. Samples with at least 1% estrogen- or progesterone-positive tumor nuclei were considered positive. The colored cell proportion score (PS) applied ranges from 0 to 5, and the coloring intensity (IS) score ranges from 0 to 3. The scoring system used was the Allred Score (AS), calculated by the sum of the PS and IS scores. HER-2 positivity was defined as a score of 3+ (complete and strong staining observed in over 30% of tumor cells). A fluorescence in situ hybridization (FISH) test was performed on tumors with a score of 2+ (moderate staining of the membrane, observed in more than 10% of tumor cells). The tumor was considered positive when the receptor was overexpressed in the amplification analysis¹⁸18. Mohamad IB, Archana B. Hormone receptor (ER, PR, HER2/neu) status and proliferation index marker (Ki-67) in breast cancers: their onco-pathological correlation, shortcomings and future trends. Medical Journal of Dr. D.Y. Patil University 2016; 9(6): 674-9. https://doi.org/10.4103/0975-2870.194180
https://doi.org/10.4103/0975-2870.194180... .

For Ki-67, the samples were subjected to immunohistochemical techniques using the streptavidin-biotin-peroxidase method. Sections of 3 μm thickness were obtained from samples fixed in formalin and embedded in paraffin, which were placed on glass slides labeled with 3-aminopropyltriethoxysilane (Sigma-Aldrich, St. Lois, Missouri, USA). After that, the cuts were deparaffinized and rehydrated, followed by immersion in a 2% H₂O₂/methanol solution to block endogenous peroxidase. Antigenic retrieval was performed in a water bath for 45 minutes with a 0.01 M citrate buffer solution (pH 6.0) at 96°C (Merck, Darmstadt, Hessen, Germany). Samples were incubated with the Ki-67 primary antibody. The LSAB Kit (Dako Corporation, Carpinteira, USA) was used to apply the biotinylated secondary antibody, followed by incubation with the streptavidin-peroxidase complex. Diaminobenzidine chromogen (DAB) (Biocare, Concord, CA, USA) was used to reveal the reaction, and the slides were counterstained with Harris hematoxylin and mounted with Entellan (Merck, Germany). After each step, the slides were washed in phosphate-buffered saline for 5 minutes. Positive controls for all antibodies were included. Negative control was performed by omitting the primary antibody¹⁹19. Hayat MA. Microscopy, immunohistochemistry, and antigen retrieval methods: for light and electron microscopy. New York: Springer Science & Business Media; 2002..

The probabilistic linkage was applied to the data obtained from the immunohistochemistry laboratory’s information systems and the RHC/SP to obtain a single database containing demographic, clinical, and laboratory data, both located at the FOSP, using the Open RecLink III program, version 3.1.615. The technique used was based on research with similar databases that have shown sensitivity (90%) and specificity for breast cancer data (99.0%)²⁰20. Peres SV, Latorre MD, Tanaka LF, Michels FA, Teixeira MP, Coeli CM, et al. Quality and completeness improvement of the population-based cancer registry of São Paulo: linkage technique use. Rev Bras Epidemiol 2016; 19(4): 753-65. https://doi.org/10.1590/1980-5497201600040006
https://doi.org/10.1590/1980-54972016000... . The variables used in the matching process were the patient’s name and date of birth. The Soundex codes of the first name (PBLOCO) and last name (UBLOCO) were used for blocking. Confirmatory variables used to determine a true match were, when available, the mother’s name, home address, public health system (SUS) card number, or another personal identification document. In addition, the first diagnosed tumor was chosen in women with more than one tumor, and the most aggressive histological tumor type was selected in bilateral cases.

Covariates

The database with the following analyzed variables was obtained: age at diagnosis, education level, histology (invasive ductal, invasive lobular, others), tumor size — T1/T2 (≤ 5 centimeters) and T3/T4 (> 5 centimeters) — and lymph nodes — N0, N1/N2 and N3 (TNM 7^th edition), CS at diagnosis, the time between diagnosis and treatment, and treatment types: 1) chemotherapy (CTX); 2) surgery + CTX; surgery + radiotherapy (RXT) + CTX; 3) surgery + RXT + CTX + hormone therapy (HT); and 4) other combinations. The molecular subtypes were classified according to the St. Gallen Consensus¹⁴14. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ, et al. Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 2011; 22(8): 1736-47. https://doi.org/10.1093/annonc/mdr304
https://doi.org/10.1093/annonc/mdr304... : luminal A, luminal B (HER-2 negative), luminal B (HER-2 positive), HER-2 positive (nonluminal), and triple-negative.

The Research Ethics Committee of the Dr. Mário de Moraes Altenfelder Silva Municipal Maternity-School Hospital authorized this study under protocol no. 4.106.934.

Statistical analysis

We performed descriptive data analysis for all patients (n=1,654) through absolute and relative frequencies, central tendency, and dispersion measures. The overall survival (OS) rate was performed over five years on patients diagnosed until December 31, 2013 (n=894). Survival time was determined by the date of diagnosis and the vital status (dead or alive) at the date of the last follow-up. The date of death was confirmed through an active search to determine the vital status of patients using the Registration System for Users of the Unified Health System (CADSUS) platform and passively via linkage with the State Statistical Data Analysis System Foundation (FSEADE), responsible for registering deaths in the state of São Paulo, and updating information through follow-up with the participants’ physicians. The Kaplan-Meier limit product estimator test was applied to calculate the five-year survival probability, and the log-rank test was applied to compare the curves. Cox univariate and multiple regression analyses were used to estimate the hazard ratio (HR) and its respective 95% confidence interval (95%CI).

For multiple modeling, variables with significant statistical values and p<0.20 were selected. A stepwise technique was used, testing the lowest to the highest p-value. The final model was built with the following assumptions:

1. No change in HR >10%;

2. Improved accuracy by 95%CI;

3. Total degrees of freedom allowed for the outcome; and

4. Interaction effect between covariates.

Control for the confounding covariates age, year of diagnosis and treatment were considered adjustments²¹21. Concato J, Feinstein AR, Holford TR. The risk of determining risk with multivariable models. Ann Intern Med 1993; 118(3): 201-10. https://doi.org/10.7326/0003-4819-118-3-199302010-00009
https://doi.org/10.7326/0003-4819-118-3-... .

The Schoenfeld residual scale was applied to test the proportional hazard. The data were analyzed using the STATA software version 14.

RESULTS

Three hundred and seventy-four (22.6%) of the 1,654 women with invasive breast cancer treated by the Brazilian public health system died. The mean age was 56.8 (standard deviation — SD=13.2), with a median of 56, ranging from 22 to 96 years. Of these, 48% completed High School, and 55.7% showed a time between diagnosis and treatment above two months. The histological classification was 71.9% for invasive ductal carcinoma (Table 1). Regarding the biomarkers, 25.9% of the tumors were negative for estrogen receptors, 33.9% were negative for progesterone receptors, 85.5% were negative for HER-2, and 68.3% had a Ki-67 level ≥14%. Regarding the molecular subtypes, the luminal B/HER-2- phenotype was the most frequent (41.2%) (Table 2).

For the 5-year OS, 894 women with invasive breast cancer were analyzed. The median follow-up time was 54.13 months, ranging from 0.3 to 60 months. In general, the 5-year OS was 72.5% (95%CI 69.2–75.5%), with the losses to follow-up at 6.5%. The 5-year OS rate was lower in women >69 years of age, advanced CS at diagnosis, and patients with negative tumors of estrogen and progesterone receptor. In the univariate regression analysis, the risk of death among patients with negative ER and PR was HR=2.45 (95%CI 1.86–3.21) and HR=2.51 (95%CI 1.91–3.28), respectively. For those with HER-2-positive tumors and Ki-67 levels ≥14%, the risk of death was lower [HR=1.65 (95%CI 1.25–2.19)] than that of women with HER-2-negative tumors and Ki-67 levels <14% [HR=2.12 (95%CI 1.55–2.91)]. The worst 5-year OS rates were observed in patients with positive HER-2 (negative) (nonluminal) (55% [HR=3.58; 95%CI 2.21–5.78]) and triple-negative tumors (50% [HR=3.44; 95%CI 2.32–5.10)]. The univariate analysis did not reveal that the time between diagnosis and treatment was a risk factor for death (Supplementary Table 1).

In Table 3, the independent prognostic factors for the risk of death were molecular subtypes, the interaction between CS at diagnosis and time between diagnosis and treatment, adjusted for age at diagnosis, year of diagnosis and treatment. Women with molecular subtypes HER-2-positive tumors (nonluminal) and triple-negative were more than twice at risk of death, HR_adj=2.30 (95%CI 1.34–3.94) and HR_adj=2.51 (95%CI 1.61–3.92), respectively. Likewise, the delayed treatment associated with advancing CS at diagnosis increased three to fourfold the risk of death (p<0.001). Although the Schoenfeld test rejects the hypothesis of proportionality of risk (p=0.022), it is possible to identify the linearity between the categories of molecular subtypes (A) and the interaction between CS at diagnosis and time between diagnosis and treatment (B) during follow-up (Figure 1).

DISCUSSION

In this study, which constitutes the largest Brazilian study in patients treated exclusively by the public health system, molecular subtype was determined to be an independent risk factor, as was the delayed treatment associated with advancing CS at diagnosis to the risk of death in women with breast cancer treated at public health service.

We found that the distribution of the molecular subtypes in this study was similar to that observed nationally and internationally⁵5. Goncalves Jr H, Guerra MR, Duarte Cintra JR, Fayer VA, Brum IV, Bustamante Teixeira MT. Survival study of triple-negative and non-triple-negative breast cancer in a brazilian cohort. Clin Med Insights Oncol 2018; 12: 1179554918790563. https://doi.org/10.1177/1179554918790563
https://doi.org/10.1177/1179554918790563... ,¹⁰10. Bagaria SP, Ray PS, Sim MS, Ye X, Shamonki JM, Cui X, et al. Personalizing breast cancer staging by the inclusion of ER, PR, and HER2. JAMA Surg 2014; 149(2): 125-9. https://doi.org/10.1001/jamasurg.2013.3181
https://doi.org/10.1001/jamasurg.2013.31... ,²²22. Tubtimhin S, Promthet S, Suwanrungruang K, Supaattagorn P. Molecular subtypes and prognostic factors among premenopausal and postmenopausal thai women with invasive breast cancer: 15 years follow-up data. Asian Pac J Cancer Prev 2018; 19(11): 3167-74. https://doi.org/10.31557/APJCP.2018.19.11.3167
https://doi.org/10.31557/APJCP.2018.19.1... ,²³23. Fasching PA, Gass P, Häberle L, Volz B, Hein A, Hack CC, et al. Prognostic effect of Ki-67 in common clinical subgroups of patients with HER2-negative, hormone receptor-positive early breast cancer. Breast Cancer Res Treat 2019; 175(3): 617-25. https://doi.org/10.1007/s10549-019-05198-9
https://doi.org/10.1007/s10549-019-05198... . In Brazil, Carvalho et al.²⁴24. Carvalho FM, Bacchi LM, Pincerato KM, Van de Rijn M, Bacchi CE. Geographic differences in the distribution of molecular subtypes of breast cancer in Brazil. BMC Womens Health 2014; 14: 102. https://doi.org/10.1186/1472-6874-14-102
https://doi.org/10.1186/1472-6874-14-102... . evaluated the molecular subtypes of invasive breast tumors distributed in the country’s five regions and showed a distribution of 27.7% luminal A, 37.1% luminal B, 10.4% luminal B HER-2+, 8.9% HER-2+, and 10.4% triple-negative. In the Southeast region, 28.8% of tumors were luminal A, 39.5% were luminal B, 9.7% were triple-positive, 7.9% were HER-2, and 14.0% were triple-negative. In the AMAZONA study with women with stages I-III tumors exclusively, 49.4% of the tumors were luminal A, 8.7% were luminal B/ negative HER-2, 13.2% were luminal B/ positive HER-2, 7.7% were HER-2+, and 21.0% were triple-negative⁷7. Simon 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; 44: 113-9. https://doi.org/10.1016/j.breast.2019.01.008
https://doi.org/10.1016/j.breast.2019.01... .

The 5-year OS rate in this study was similar to that of the other Brazilian studies and studies of populations in low-income countries (72.5%)¹¹11. Poorolajal J, Nafissi N, Akbari ME, Mahjub H, Esmailnasab N, Babaee E. Breast cancer survival analysis based on immunohistochemistry Subtypes (ER/PR/HER2): a retrospective cohort study. Arch Iran Med 2016; 19(10): 680-6. PMID: 27743431,²²22. Tubtimhin S, Promthet S, Suwanrungruang K, Supaattagorn P. Molecular subtypes and prognostic factors among premenopausal and postmenopausal thai women with invasive breast cancer: 15 years follow-up data. Asian Pac J Cancer Prev 2018; 19(11): 3167-74. https://doi.org/10.31557/APJCP.2018.19.11.3167
https://doi.org/10.31557/APJCP.2018.19.1... , when compared to high-income European countries, the United States, Canada and China³3. Allemani C, Matsuda T, Di Carlo V, Harewood R, Matz M, Nikšić M, et al. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet 2018; 391(10125): 1023-75. https://doi.org/10.1016/S0140-6736(17)33326-3
https://doi.org/10.1016/S0140-6736(17)33... ,²²22. Tubtimhin S, Promthet S, Suwanrungruang K, Supaattagorn P. Molecular subtypes and prognostic factors among premenopausal and postmenopausal thai women with invasive breast cancer: 15 years follow-up data. Asian Pac J Cancer Prev 2018; 19(11): 3167-74. https://doi.org/10.31557/APJCP.2018.19.11.3167
https://doi.org/10.31557/APJCP.2018.19.1... ,²⁵25. Li X, Zhang X, Liu J, Shen Y. Prognostic factors and survival according to tumour subtype in women presenting with breast cancer bone metastases at initial diagnosis: a SEER-based study. BMC Cancer 2020; 20(1): 1102. https://doi.org/10.1186/s12885-020-07593-8
https://doi.org/10.1186/s12885-020-07593... ,²⁶26. Canadian Cancer Society. Survival statistics for breast cancer [Internet]. 2021 [cited on Jul 14, 2021]. Available at: https://www.cancer.ca/en/cancer-information/cancer-type/breast/prognosis-and-survival/survival-statistics/?region=ab
https://www.cancer.ca/en/cancer-informat... . We should highlight that the patients in this study were treated in the public health system, where diagnoses are often delayed and the time between diagnosis and the first treatment is prolonged (approximately 85 days)²⁷27. Governo do Estado de São Paulo. Fundação Oncocentro de São Paulo. Banco de dados do Registro Hospitalar de Câncer [Internet] 2021 [cited on Apr 25, 2023]. Available at: http://www.fosp.saude.sp.gov.br/publicacoes/downloadarquivos.
http://www.fosp.saude.sp.gov.br/publicac... . Our study reported a poor OS rate in patients with more than four months between diagnosis and treatment. An important fact is that 55.7% of the women started treatment after four months, far from the recommended by Brazilian law. Furthermore, the educational level is less than nine years of schooling, low in this population, where 31.3% have High School or Graduate level.

The 5-year OS was superior in those with luminal A and B subtype tumors, 75 to 90%. When stratifying breast cancer patients from the public health system by molecular subtype, the 5-year OS rates were lower in patients with HER-2 positive (nonluminal) and triple-negative tumors independently of clinical stage. However, the lowest 5-year OS were in women with the triple-negative, which agrees with other studies⁵5. Goncalves Jr H, Guerra MR, Duarte Cintra JR, Fayer VA, Brum IV, Bustamante Teixeira MT. Survival study of triple-negative and non-triple-negative breast cancer in a brazilian cohort. Clin Med Insights Oncol 2018; 12: 1179554918790563. https://doi.org/10.1177/1179554918790563
https://doi.org/10.1177/1179554918790563... ,¹⁰10. Bagaria SP, Ray PS, Sim MS, Ye X, Shamonki JM, Cui X, et al. Personalizing breast cancer staging by the inclusion of ER, PR, and HER2. JAMA Surg 2014; 149(2): 125-9. https://doi.org/10.1001/jamasurg.2013.3181
https://doi.org/10.1001/jamasurg.2013.31... ,¹⁷17. Marques AD, Moura AR, Hora EC, Brito ÉD, Oliviera LS, Feitosa IR, et al. Analysis of breast cancer survival in a northeastern Brazilian state based on prognostic factors: a retrospective cohort study. PLoS One 2022; 17(2): e0263222. https://doi.org/10.1371/journal.pone.0263222
https://doi.org/10.1371/journal.pone.026... ,²²22. Tubtimhin S, Promthet S, Suwanrungruang K, Supaattagorn P. Molecular subtypes and prognostic factors among premenopausal and postmenopausal thai women with invasive breast cancer: 15 years follow-up data. Asian Pac J Cancer Prev 2018; 19(11): 3167-74. https://doi.org/10.31557/APJCP.2018.19.11.3167
https://doi.org/10.31557/APJCP.2018.19.1... ,²³23. Fasching PA, Gass P, Häberle L, Volz B, Hein A, Hack CC, et al. Prognostic effect of Ki-67 in common clinical subgroups of patients with HER2-negative, hormone receptor-positive early breast cancer. Breast Cancer Res Treat 2019; 175(3): 617-25. https://doi.org/10.1007/s10549-019-05198-9
https://doi.org/10.1007/s10549-019-05198... . Regarding the women from the public health system in this study, less than 10% of patients were under 40, similar to the other countries⁷7. Simon 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; 44: 113-9. https://doi.org/10.1016/j.breast.2019.01.008
https://doi.org/10.1016/j.breast.2019.01... ,²⁴24. Carvalho FM, Bacchi LM, Pincerato KM, Van de Rijn M, Bacchi CE. Geographic differences in the distribution of molecular subtypes of breast cancer in Brazil. BMC Womens Health 2014; 14: 102. https://doi.org/10.1186/1472-6874-14-102
https://doi.org/10.1186/1472-6874-14-102... ,²⁸28. Chavez-MacGregor M, Mittendorf EA, Clarke CA, Lichtensztajn DY, Hunt KK, Giordano SH. Incorporating tumor characteristics to the american joint committee on cancer breast cancer staging system. Oncologist 2017; 22(11): 1292-300. https://doi.org/10.1634/theoncologist.2017-0116
https://doi.org/10.1634/theoncologist.20... . Several researchers have shown that breast cancer in patients <40 years have a lower OS. This unfavorable prognosis is usually associated with advanced staging, HER-2 overexpression, and nodal metastasis. Concerning tumor differentiation, lymphatic involvement, necrosis, and negative ER were observed²⁹29. Nixon AJ, Neuberg D, Hayes DF, Gelman R, Connolly JL, Schnitt S, et al. Relationship of patient age to pathologic features of the tumor and prognosis for patients with stage I or II breast cancer. J Clin Oncol 1994; 12(5): 888-94. https://doi.org/10.1200/JCO.1994.12.5.888
https://doi.org/10.1200/JCO.1994.12.5.88... .

Most patients were between 50 and 69 years old, reinforcing the importance of screening in this age group²2. Brasil. Ministerio da Saúde. Instituto Nacional de Câncer José Alencar Gomes da Silva. Estimativa 2020: incidência de câncer no Brasil. Rio de Janeiro: INCA; 2019.. The lower 5-year OS rate in women ≥70 years can be explained by low life expectancy and comorbidities³⁰30. Sakhuja S, Deveaux A, Wilson LE, Vin-Raviv N, Zhang D, Braithwaite D, et al. Patterns of de-novo metastasis and breast cancer-specific mortality by race and molecular subtype in the SEER population-based dataset. Breast Cancer Res Treat 2021; 186(2): 509-18. https://doi.org/10.1007/s10549-020-06007-4
https://doi.org/10.1007/s10549-020-06007... . Other studies have shown that worse survival rates are only observed in elderly patients with triple-negative tumors. The relationship between age and the triple-negative subtype is unclear in younger women³¹31. Tzikas AK, Nemes S, Linderholm BK. A comparison between young and old patients with triple-negative breast cancer: biology, survival and metastatic patterns. Breast Cancer Res Treat 2020; 182(3): 643-54. https://doi.org/10.1007/s10549-020-05727-x
https://doi.org/10.1007/s10549-020-05727... ,³²32. Lian J, Li K. A review of breast density implications and breast cancer screening. Clin Breast Cancer 2020; 20(4): 283-90. https://doi.org/10.1016/j.clbc.2020.03.004
https://doi.org/10.1016/j.clbc.2020.03.0... .

In this study, the 5-year OS rate of patients with clinical stage IV of the disease was 28.2%, similar to the study by Marque et al. in the Brazilian Northwest. In Brazil, new targeted therapies became available in SUS in 2013. An increase in the OS rate of patients with clinical stage IV tumors, young patients, and those with different molecular subtypes has been observed³³33. Makdissi FB, Leite FPM, Peres SV, Silva DRM, Oliveira MM, Lopez RVM, et al. Breast cancer survival in a Brazilian Cancer Center: a cohort study of 5,095 patients. Mastology 2019; 29(1): 37-46. https://doi.org/10.29289/2594539420190000437
https://doi.org/10.29289/259453942019000... . Recent studies have revealed that advances in treatment, compared with advances in screening, were associated with more pronounced reductions in overall breast cancer mortality rates and improved survival rates between 2000 and 2012³³33. Makdissi FB, Leite FPM, Peres SV, Silva DRM, Oliveira MM, Lopez RVM, et al. Breast cancer survival in a Brazilian Cancer Center: a cohort study of 5,095 patients. Mastology 2019; 29(1): 37-46. https://doi.org/10.29289/2594539420190000437
https://doi.org/10.29289/259453942019000... ,³⁴34. Torre LA, Islami F, Siegel RL, Ward EM, Jemal A. Global cancer in women: burden and trends. Cancer Epidemiol Biomarkers Prev 2017; 26(4): 444-57. https://doi.org/10.1158/1055-9965.EPI-16-0858
https://doi.org/10.1158/1055-9965.EPI-16... ,³⁵35. Fayer VA, Guerra MR, Cintra JR, Bustamante-Teixeira MT. Ten-year survival and prognostic factors for breast cancer in the southeast region of Brazil. Rev Bras Epidemiol 2016; 19(4): 766-78. https://doi.org/10.1590/1980-5497201600040007
https://doi.org/10.1590/1980-54972016000... ,³⁶36. Goss PE, Lee BL, Badovinac-Crnjevic T, Strasser-Weippl K, Chavarri-Guerra Y, St Louis J, et al. Planning cancer control in Latin America and the Caribbean. Lancet Oncol 2013; 14(5): 391-436. https://doi.org/10.1016/S1470-2045(13)70048-2
https://doi.org/10.1016/S1470-2045(13)70... .

Our results showed that there is a dose-response gradient associated with the molecular subtypes; that is, the greater the tumor’s aggressiveness, the greater the risk of death. Adjusting for clinical stage and proposed treatment revealed that triple-negative breast cancer patients had the worst prognosis over five years of follow-up. In HER-2-positive and triple-negative tumors, the complete pathological response rate can reach 60% or higher, which is related to the longer survival time of these patients, as adjuvant hormonal therapy is indicated mainly for positive hormonal receptor luminal tumors in menopausal women²³23. Fasching PA, Gass P, Häberle L, Volz B, Hein A, Hack CC, et al. Prognostic effect of Ki-67 in common clinical subgroups of patients with HER2-negative, hormone receptor-positive early breast cancer. Breast Cancer Res Treat 2019; 175(3): 617-25. https://doi.org/10.1007/s10549-019-05198-9
https://doi.org/10.1007/s10549-019-05198... ,³⁷37. Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol 2014; 15(10): 1137-46. https://doi.org/10.1016/S1470-2045(14)70320-1
https://doi.org/10.1016/S1470-2045(14)70... . We should highlight that luminal B/positive HER-2 tumors have shown similar survival outcomes to luminal B/negative HER-2 tumors in some studies, which may have been influenced by the development of anti-HER-2 therapy³⁸38. Dai D, Zhong Y, Wang Z, Yousafzai NA, Jin H, Wang X. The prognostic impact of age in different molecular subtypes of breast cancer: a population-based study. PeerJ 2019; 7: e7252. https://doi.org/10.7717/peerj.7252
https://doi.org/10.7717/peerj.7252... ,³⁹39. Cortet M, Bertaut A, Molinié F, Bara S, Beltjens F, Coutant C, et al. Trends in molecular subtypes of breast cancer: description of incidence rates between 2007 and 2012 from three French registries. BMC Cancer 2018; 18(1): 161. https://doi.org/10.1186/s12885-018-4080-8
https://doi.org/10.1186/s12885-018-4080-... . However, not all HER-2-positive patients in this study received anti-HER-2 therapy, as it only became available to patients in the public health system in 2013 and is only administered to those with metastatic disease⁴⁰40. Brasil. Ministério da Saúde. Secretaria de Atenção a Saúde. Portaria no 73, de 30 de janeiro de 2013. Inclui procedimentos na Tabela de Procedimentos, Medicamentos, Órteses/Próteses e Materiais Especiais do SUS e estabelece protocolo de uso do trastuzumabe na quimioterapia do câncer de mama HER-2 positivo inicial e localmente avançado [Internet]. Brasília: Ministério da Saúde; 2013 [cited on Nov 30, 2022]. Available at: https://bvsms.saude.gov.br/bvs/saudelegis/sas/2013/prt0073_30_01_2013.html
https://bvsms.saude.gov.br/bvs/saudelegi... .

This study observed that the longer the time between diagnosis and treatment, regardless of molecular subtype, the worse the OS indices. Even so, this effect is not isolated and is only identified in advanced staging at diagnosis. However, the risk of death can be three to four times higher. According to Brazilian data, the longer the time between diagnosis and treatment, the shorter the patient’s survival. Rapid intervention is essential for treatment effectiveness in the more advanced stages⁴¹41. Medeiros GC, Teodózio CGC, Fabro EAN, Aguiar SS, Lopes AHM, Conte BC, et al. Factors associated with delay between diagnosis and initiation of breast cancer treatment: a cohort study with 204,130 cases in Brazil. Rev Bras Cancerol 2020; 66(3): e-09979. https://doi.org/10.32635/2176-9745.RBC.2020v66n3.979
https://doi.org/10.32635/2176-9745.RBC.2... . Social vulnerability can have a profound impact on a patient’s prognosis. Hence survival factors, such as low education level and lack of immediate access to diagnosis and treatment, must be better evaluated to identify the existent barriers⁴²42. Cabral ALLV, Giatti L, Martínez-Hernáez A, Cherchiglia ML. Inequality in breast cancer care in a Brazilian capital city: a comparative analysis of narratives. Int J Equity Health 2019; 18(1): 88. https://doi.org/10.1186/s12939-019-0989-z
https://doi.org/10.1186/s12939-019-0989-... .

This research has limitations. The analyzed data were extracted from the RHC to describe the sociodemographic and clinical treatment adopted. Nevertheless, with the discovery of biomarkers to guide the treatment, this data has yet to be available in the public database, which precludes more accurate studies. However, this study identified women with a complete set of biomarkers to classify all cases at RHC, analyzing the profile of women with breast cancer in the Brazilian public health system. There is a need to incorporate the new types of therapies available as essential variables. For example, trastuzumab was made available to public health system patients in 2013, and a double blockade was never performed for HER-2 patients. Furthermore, the survival time may be influenced by the type of medication available to public health system patients.

The molecular subtype is an independent risk factor for death among the Brazilian women cohort in the public health system depending on several epidemiological characteristics; those with HER-2-positive (nonluminal) and triple-negative tumors have the worst prognoses. These findings will facilitate the comparison of prognostic factors and epidemiological characteristics between heterogeneous populations, such as Brazilian and Latin American women, with other populations.

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