Closing the gap: prognostic and predictive biomarker validation for personalized care in a Latin American hormone-dependent breast cancer cohort.

BACKGROUND: Several guidelines recommend the use of different classifiers to determine the risk of recurrence (ROR) and treatment decisions in patients with HR+HER2- breast cancer. However, data are still lacking for their usefulness in Latin American (LA) patients. Our aim was to evaluate the comparative prognostic and predictive performance of different ROR classifiers in a real-world LA cohort. METHODS: The Molecular Profile of Breast Cancer Study (MPBCS) is an LA case-cohort study with 5-year follow-up. Stages I and II, clinically node-negative HR+HER2- patients (n = 340) who received adjuvant hormone therapy and/or chemotherapy, were analyzed. Time-dependent receiver-operator characteristic-area under the curve, univariate and multivariate Cox proportional hazards regression (CPHR) models were used to compare the prognostic performance of several risk biomarkers. Multivariate CPHR with interaction models tested the predictive ability of selected risk classifiers. RESULTS: Within this cohort, transcriptomic-based classifiers such as the recurrence score (RS), EndoPredict (EP risk and EPClin), and PAM50-risk of recurrence scores (ROR-S and ROR-PC) presented better prognostic performances for node-negative patients (univariate C-index 0.61-0.68, adjusted C-index 0.77-0.80, adjusted hazard ratios [HR] between high and low risk: 4.06-9.97) than the traditional classifiers Ki67 and Nottingham Prognostic Index (univariate C-index 0.53-0.59, adjusted C-index 0.72-0.75, and adjusted HR 1.85-2.54). RS (and to some extent, EndoPredict) also showed predictive capacity for chemotherapy benefit in node-negative patients (interaction P = .0200 and .0510, respectively). CONCLUSION: In summary, we could prove the clinical validity of most transcriptomic-based risk classifiers and their superiority over clinical and immunohistochemical-based methods in the heterogenous, real-world node-negative HR+HER2- MPBCS cohort.

Implementing Standard Diagnosis and Treatment for Locally Advanced Breast Cancer Through Global Research in Latin America: Results From a Multicountry Pragmatic Trial.

PURPOSE: Breast cancer mortality rates in Latin America (LA) are higher than those in the United States, possibly because of advanced disease presentation, health care disparities, or unfavorable molecular subtypes. The Latin American Cancer Research Network was established to address these challenges and to promote collaborative clinical research. The Molecular Profiling of Breast Cancer Study (MPBCS) aimed to evaluate the clinical characteristics and treatment outcomes of LA participants with locally advanced breast cancer (LABC). PATIENTS AND METHODS: The MPBCS enrolled 1,449 participants from Argentina, Brazil, Chile, Mexico, and Uruguay. Through harmonized procedures and quality assurance measures, this study evaluated clinicopathologic characteristics, neoadjuvant chemotherapy response, and survival outcomes according to residual cancer burden (RCB) and the type of surgery. RESULTS: Overall, 711 and 480 participants in the primary surgery and neoadjuvant arms, respectively, completed the 5-year follow-up period. Overall survival was independently associated with RCB (worse survival for RCBIII-adjusted hazard ratio, 8.19, P < .001, and RCBII [adjusted hazard ratio, 3.69, P < .008] compared with RCB0 [pathologic complete response or pCR]) and type of surgery (worse survival in mastectomy than in breast-conserving surgery [BCS], adjusted hazard ratio, 2.97, P = .001). The hormone receptor-negative-human epidermal growth factor receptor 2-positive group had the highest proportion of pCR (48.9%). The analysis of the ASCO Quality Oncology Practice Initiative breast module revealed high compliance with pathologic standards but lower adherence to treatment administration standards. Notably, compliance with trastuzumab administration varied widely among countries (33.3%-88.7%). CONCLUSION: In LABC, we demonstrated the survival benefit of BCS and the prognostic effect of the response to available neoadjuvant treatments despite an important variability in access to key treatments. The MPBCS represents a significant step forward in understanding the real-world implementation of oncologic procedures in LA.

Trastuzumab-induced cardiotoxicity in early breast cancer over a 10-year period in Uruguay.

This srudy aimed to estimate the prevalence of trastuzumab-induced cardiotoxicity in Uruguayan women diagnosed with human epidermal growth factor receptor 2 (HER2)-positive breast cancer over a 10-year period, who were treated under the financial coverage of the National Resources Fund (Fondo Nacional de Recursos). This was an observational, descriptive study based on the analysis of an anonymized database of Uruguayan women diagnosed with HER2-positive breast cancer who received adjuvant trastuzumab treatment from to 2006 to 2016, provided by the Fondo Nacional de Recursos. Statistical analysis was performed using SPSS Statistics version 25, and variables were assessed using measures of central tendency, dispersion, contingency tables, and proportions. The chi-square test was used to analyze the association between the different variables. The study included 1401 patients diagnosed with stage I to III HER2-positive breast cancer. The mean age at diagnosis was 52 years. The prevalence of cardiotoxicity was 20.3%. Most patients who discontinued treatment owing to cardiotoxicity eventually resumed treatment (92.6%). Moreover, the prevalence of cardiotoxicity was similar among patients who received regimens with and without anthracyclines. No association was observed between prior cardiovascular events or trastuzumab administration (concurrent vs sequential) and the development of cardiotoxicity. In the present study, the prevalence of cardiotoxicity was similar to that reported nationally and internationally. Most patients did not develop cardiotoxicity, while the ones who developed it remained asymptomatic and cardiotoxicity was reversible.

Socioeconomic, Clinical, and Molecular Features of Breast Cancer Influence Overall Survival of Latin American Women.

Molecular profile of breast cancer in Latin-American women was studied in five countries: Argentina, Brazil, Chile, Mexico, and Uruguay. Data about socioeconomic characteristics, risk factors, prognostic factors, and molecular subtypes were described, and the 60-month overall cumulative survival probabilities (OS) were estimated. From 2011 to 2013, 1,300 eligible Latin-American women 18 years or older, with a diagnosis of breast cancer in clinical stage II or III, and performance status ≦̸1 were invited to participate in a prospective cohort study. Face-to-face interviews were conducted, and clinical and outcome data, including death, were extracted from medical records. Unadjusted associations were evaluated by Chi-squared and Fisher's exact tests and the OS by Kaplan-Meier method. Log-rank test was used to determine differences between cumulative probability curves. Multivariable adjustment was carried out by entering potential confounders in the Cox regression model. The OS at 60 months was 83.9%. Multivariable-adjusted death hazard differences were found for women living in Argentina (2.27), Chile (1.95), and Uruguay (2.42) compared with Mexican women, for older (≥60 years) (1.84) compared with younger (≤40 years) women, for basal-like subtype (5.8), luminal B (2.43), and HER2-enriched (2.52) compared with luminal A subtype, and for tumor clinical stages IIB (1.91), IIIA (3.54), and IIIB (3.94) compared with stage IIA women. OS was associated with country of residence, PAM50 intrinsic subtype, age, and tumor stage at diagnosis. While the latter is known to be influenced by access to care, including cancer screening, timely diagnosis and treatment, including access to more effective treatment protocols, it may also influence epigenetic changes that, potentially, impact molecular subtypes. Data derived from heretofore understudied populations with unique geographic ancestry and sociocultural experiences are critical to furthering our understanding of this complexity.

The Transcriptomic Portrait of Locally Advanced Breast Cancer and Its Prognostic Value in a Multi-Country Cohort of Latin American Patients.

Purposes: Most molecular-based published studies on breast cancer do not adequately represent the unique and diverse genetic admixture of the Latin American population. Searching for similarities and differences in molecular pathways associated with these tumors and evaluating its impact on prognosis may help to select better therapeutic approaches. Patients and Methods: We collected clinical, pathological, and transcriptomic data of a multi-country Latin American cohort of 1,071 stage II-III breast cancer patients of the Molecular Profile of Breast Cancer Study (MPBCS) cohort. The 5-year prognostic ability of intrinsic (transcriptomic-based) PAM50 and immunohistochemical classifications, both at the cancer-specific (OSC) and disease-free survival (DFS) stages, was compared. Pathway analyses (GSEA, GSVA and MetaCore) were performed to explore differences among intrinsic subtypes. Results: PAM50 classification of the MPBCS cohort defined 42·6% of tumors as LumA, 21·3% as LumB, 13·3% as HER2E and 16·6% as Basal. Both OSC and DFS for LumA tumors were significantly better than for other subtypes, while Basal tumors had the worst prognosis. While the prognostic power of traditional subtypes calculated with hormone receptors (HR), HER2 and Ki67 determinations showed an acceptable performance, PAM50-derived risk of recurrence best discriminated low, intermediate and high-risk groups. Transcriptomic pathway analysis showed high proliferation (i.e. cell cycle control and DNA damage repair) associated with LumB, HER2E and Basal tumors, and a strong dependency on the estrogen pathway for LumA. Terms related to both innate and adaptive immune responses were seen predominantly upregulated in Basal tumors, and, to a lesser extent, in HER2E, with respect to LumA and B tumors. Conclusions: This is the first study that assesses molecular features at the transcriptomic level in a multicountry Latin American breast cancer patient cohort. Hormone-related and proliferation pathways that predominate in PAM50 and other breast cancer molecular classifications are also the main tumor-driving mechanisms in this cohort and have prognostic power. The immune-related features seen in the most aggressive subtypes may pave the way for therapeutic approaches not yet disseminated in Latin America. Clinical Trial Registration: ClinicalTrials.gov (Identifier: NCT02326857).

Population-based screening of Uruguayan Ashkenazi Jews for recurrent BRCA1 and BRCA2 pathogenic sequence variants.

In Ashkenazi Jews (AJ) three recurring pathogenic sequence variants (PSVs) are detected in ~2.5% of the general population in the BRCA1 (c.68_69del = 185delAG, c.5266dup = 5382insC), and BRCA2 (c.5946del = 6174delT). Population-based screening for these PSVs in AJ women is part of the health basket in Israel. To assess the feasibility and outcome of BRCA genotyping in the Jewish population of Uruguay, AJ in the greater Montevideo area were recruited using ethically approved protocol and without pretest counseling were genotyped for the three predominant AJ PSVs in the BRCA genes. Independently confirmed PSV carriers were counseled, and genetic testing was offered to additional family members. Overall, 327 participants were enrolled: 312 (95%) female, 261 (80%) had all four grandparents AJ, and 14 (4%) women were breast cancer survivors with a mean age ± standard deviation (SD) 50 ± 11.5 years. The BRCA1 c.68_69del PSV was detected in three cancer free participants (0.92%, CI 95% 0.31-2.6), all with a suggestive family history. No carriers of the other two recurrent PSVs were detected. Online oncogenetic counseling was provided for all carriers. In conclusion, the rate of the BRCA1 c.68_69del PSV was similar with the rate in other AJ communities. AJ population BRCA genotyping screens in Uruguay seem feasible and should be promoted.

Prevalence of Known Risk Factors in Uruguayan Women Treated for Breast Cancer at a University Hospital.

INTRODUCTION: In Uruguay, breast cancer has the highest incidence and mortality of all cancer in women. Knowledge of the distribution of risk factors related to disease development supports the implementation of prevention strategies in routine clinical practice. This study aimed to determine the epidemiological profile for breast cancer and the frequency of mammographic surveillance in the surveyed population. MATERIALS AND METHODS: A survey was conducted among Uruguayan women diagnosed with breast cancer who were assisted in the mastology unit of the oncology service of the Hospital de Clínicas in Montevideo, Uruguay, from September 1, 2018, to March 1, 2020. RESULTS: This study included 398 respondents, with a median (SD) age at diagnosis of 61 (34-86) years. A total of 310 respondents (78.0%) had 1 or more risk factors. Most women aged over 50 years (264 out of a total of 338 [78.1%]) underwent mammographic surveillance at least biennially. CONCLUSIONS: Consistent with international reports, most respondents had a risk factor. Among the group of respondents aged over 50 years, most underwent mammographic and clinical surveillance at least biennially. Although it is only possible to formulate conclusions about the surveyed women because of the study design, the obtained data further our understanding of the epidemiological profile of the Uruguayan population, which can contribute to prevention practices.

Discovery of novel DNA methylation biomarkers for non-invasive sporadic breast cancer detection in the Latino population.

Human diversity is one of the main pitfalls in the development of robust worldwide biomarkers in oncology. Epigenetic variability across human populations is associated with different genetic backgrounds, as well as variable lifestyles and environmental exposures, each of which should be investigated. To identify potential non-invasive biomarkers of sporadic breast cancer in the Uruguayan population, we studied genome-wide DNA methylation using Illumina methylation arrays in leukocytes of 22 women with sporadic breast cancer and 10 healthy women in a case-control study. We described a panel of 38 differentially methylated CpG positions that was able to cluster breast cancer patients (BCP) and controls, and that also recapitulated methylation differences in 12 primary breast tumors and their matched normal breast tissue. Moving forward, we simplified the detection method to improve its applicability in a clinical setting and used an independent well-characterized cohort of 80 leukocyte DNA samples from BCP and 80 healthy controls to validate methylation results at specific cancer-related genes. Our investigations identified methylation at CYFIP1 as a novel epigenetic biomarker candidate for sporadic breast cancer in the Uruguayan population. These results provide a proof-of-concept for the design of larger studies aimed at validating biomarker panels for the Latin American population.

Evaluación de la eficacia de la consulta telefónica y el nivel de satisfacción de las pacientes asistidas en la Unidad Docente Asistencial de Mastología durante la alerta sanitaria por COVID 19 / Evaluation of the effectiveness of telephone consultations and the level of satisfaction of patients assisted at the Mastology Teacher Assistance Department with this modality during the COVID health emergency / Avaliação da eficácia da consulta telefônica e do nível de satisfação das pacientes atendidas na Unidade de Docência Assistencial de Mastologia durante o alerta de saúde para o COVID 19

Resumen: Introducción: en marzo de 2020 se decretó la emergencia sanitaria por COVID-19, lo que produjo cambios en la organización de los servicios de la salud. Uno de los objetivos de la reorganización fue minimizar las consultas presenciales (CP) y promocionar las telefónicas (CT). Objetivo: evaluar la eficacia de la CT y el nivel de satisfacción de las pacientes asistidas en la Unidad de Mastología con la misma durante la alerta sanitaria por COVID. Material y métodos: se aplicó una encuesta para valorar la eficacia de la CT y el nivel de satisfacción con la misma. Resultados: se encuestaron 42 pacientes, 69% se encontraba recibiendo tratamiento adyuvante y 14,2% paliativo. En cuanto a la eficacia de la CT, 76,1% fueron resueltas en forma telefónica; 78,6% de las pacientes prefirió realizar la consulta en forma telefónica; 97,6% creyó que el tiempo empleado fue suficiente y que el horario en que se la contactó fue adecuado. Las respuestas mostraron un alto grado de satisfacción con la asistencia. La atención médica cumplió con las expectativas de todas las pacientes, 83,3% creyó que una vez recuperada la normalidad, la CT es una opción para su situación. Conclusión: la CT fue valorada con un alto grado de satisfacción y permitió mantener la asistencia durante la emergencia. Si bien es pronto para evaluar el impacto asistencial de la CT y su capacidad resolutiva, resultados preliminares muestran que es una herramienta útil y valiosa en la práctica clínica durante periodos de emergencia sanitaria.

Summary: Introduction: in March 2020, a national health emergency was declared due to the COVID-19, what resulted in changes in the organization of health services. One of the objectives of this restructure was to minimize in person consultations and to promote telephone consultations. that took place was a reduction in face-to-face consultations (FTFC), and the promotion of telephone consultations (TC). Objective: to evaluate the effectiveness of telephone consultations and the level of satisfaction of patients assisted at Mastology Department with this modality during the COVID 19 health emergency. Materials and methods: a survey was used to assess the effectiveness of telephone consultations and the level of satisfaction with this modality. Results: forty-two patients were surveyed, 69% of which were receiving adjuvant treatment and 14.2% of which were receiving palliative treatment. With regard to the effectiveness of telephone consultations, 76.1% of those surveyed had their need solved by telephone; 78.6% of patients preferred to do the consultation by telephone; 97.6% believed that sufficient time was spent and that the timing of the appointment was appropriate. The responses showed a high level of satisfaction with the care received. The medical care met the expectations of all patients, and 83.3% believed that once the situation went back to normal, telephone consultations would be an option for their requirements. Conclusion: the telephone consultation method was evaluated with a high level of satisfaction and it allowed health care services to be maintained during the emergency. Although it is early to assess the healthcare impact of telephone consultations and the modality's capacity to resolve issues, preliminary results show that it is a useful and valuable tool in clinical practice during periods of healthcare emergency.

Resumo: Introdução: em março de 2020, foi decretada a emergência sanitária decorrente do COVID-19, o que produziu mudanças na organização dos serviços de saúde. Um dos objetivos da reorganização era minimizar as consultas presenciais (CP) e promover as consultas telefônicas (CT). Objetivo: avaliar a eficácia da CT e o nível de satisfação das pacientes atendidas na Unidade de Docência Assistencial de Mastologia com a prestada previamente durante o alerta de saúde para o COVID. Material e métodos: foi realizada uma pesquisa telefônica para avaliar a eficácia da TC e o nível de satisfação com a mesma. Resultados: foram entrevistadas 42 pacientes, 69% estavam recebendo tratamento adjuvante e 14,2% paliativo. Em relação à eficácia da CT, 76,1% foram resolvidas por telefone; 78,6% das pacientes preferiram fazer a consulta por telefone; 97,6% consideraram que o tempo despendido foi suficiente e que o momento em que foram contatados foi adequado. As respostas mostraram alto grau de satisfação com o atendimento. O atendimento médico atendeu às expectativas de todos os pacientes, 83,3% acreditam que, uma vez restaurada a normalidade, a CT é uma opção para sua situação. Conclusão: a CT foi avaliada com alto grau de satisfação e permitiu manter o atendimento durante a emergência. Embora seja muito cedo para avaliar o impacto da CT na saúde e sua capacidade de resolução, resultados preliminares mostram que é uma ferramenta útil e valiosa na prática clínica durante períodos de emergência de saúde.

Genomic Diversity in Sporadic Breast Cancer in a Latin American Population.

Among Latin American women, breast cancer incidences vary across populations. Uruguay and Argentina have the highest rates in South America, which are mainly attributed to strong, genetic European contributions. Most genetic variants associated with breast cancer were described in European populations. However, the vast majority of genetic contributors to breast cancer risk remain unknown. Here, we report the results of a candidate gene association study of sporadic breast cancer in 176 cases and 183 controls in the Uruguayan population. We analyzed 141 variants from 98 loci that have been associated with overall breast cancer risk in European populations. We found weak evidence for the association of risk variants rs294174 (ESR1), rs16886165 (MAP3K1), rs2214681 (CNTNAP2), rs4237855 (VDR), rs9594579 (RANKL), rs8183919 (PTGIS), rs2981582 (FGFR2), and rs1799950 (BRCA1) with sporadic breast cancer. These results provide useful insight into the genetic susceptibility to sporadic breast cancer in the Uruguayan population and support the use of genetic risk scores for individualized screening and prevention.