Time interval between diagnosis to treatment of breast cancer and the impact of health insurance coverage: a sub analysis of the AMAZONA III Study (GBECAM 0115).

PURPOSE: Breast cancer (BC) is the most common type of cancer among women in Brazil. Evidence shows that delayed treatment onset is associated with increased mortality. This study aimed to evaluate median days between diagnosis and treatment and factors associated with delayed start of treatment (> 60 days after diagnosis): stage, treatment received, subtype, epidemiological characteristics, and type of healthcare coverage. METHODS: This analysis included 1709 stage I-III BC patients from AMAZONA III, a prospective, observational study, diagnosed from January 2016 to March 2018 in 22 centers in Brazil. RESULTS: The median number of days from diagnosis to beginning of first oncologic treatment was 46 days (IQR 28-75) overall, 43 days (IQR 25-75) for stage I disease, 49 days (IQR 28-81) for stage II, and 44 days (IQR 30-68) for stage III, (p = 0.1180). According to first treatment received, diagnosis-to-treatment interval was 43 days (IQR 29-65) for neoadjuvant chemotherapy and 48 days (IQR 26-81) for surgery. Diagnosis-to-treatment interval was higher in women treated in the public system versus the private system (56 vs. 34 days, p < 0.0001). Patients in the public system had an increased odds of delayed treatment initiation (OR 4.74 95% CI 3.09-7.26, p < .0001). The longer interval from diagnosis to treatment in the public system was independent of clinical stage, type of treatment (systemic vs surgery first), subtype and region of the country. CONCLUSION: By characterizing the delays in care delivery, our study will aid stakeholders to better design interventions and allocate resource to improve timely treatment for breast cancer in Brazil. CLINICALTRIALS: gov Identifier: NCT02663973, registered on January, 26th, 2016.

Open questions and controversies in the systemic treatment of breast cancer.

PURPOSE OF REVIEW: Personalized therapy has revolutionized our approach to breast cancer (BC). Patient selection strategies and new biomarkers are the basis for increasingly complex diagnostic and therapeutic algorithms. In this short review, we discuss recent developments in breast oncology, focusing on controversial topics with relevance for clinical practice. RECENT FINDINGS: The use of gene expression signatures to guide adjuvant therapy in hormone receptor-positive tumors and personalized strategies for systemic treatment of early stage HER2-positive disease represent significant advances. Additionally, the current role of platinum salts, immune checkpoint inhibitors, and CDK4/6 inhibitors in the (neo)adjuvant treatment remains controversial, with several ongoing randomized clinical trials exploring their use. In the metastatic disease setting, we identify important unmet needs such as the development of predictive biomarkers and the definition of the ideal sequencing algorithm with the incorporation of innovative agents in all subtypes of BC. SUMMARY: Advances in understanding the molecular biology and heterogeneity of BC have led to the development of new biomarkers and therapeutic agents that significantly impact current and future clinical practice.

The impact of sociodemographic factors and health insurance coverage in the diagnosis and clinicopathological characteristics of breast cancer in Brazil: AMAZONA III study (GBECAM 0115).

PURPOSE: In Brazil, the available cancer registries are deficient in number and quality and, hence, little information is known regarding sociodemographic, clinicopathological characteristics, treatment patterns, and outcomes of breast cancer (BC) patients. We performed the AMAZONA III/ GBECAM 0115 study and in this analysis, we describe patients' characteristics at diagnosis and their association with health insurance type. METHODS: This is a prospective cohort study developed in 23 sites in Brazil including women with newly diagnosed invasive BC from January 2016 to March 2018. In order to compare healthcare insurance type, we considered patients who were treated under the Brazilian public health system as publicly insured, and women who had private insurance or paid for their treatment as privately insured. RESULTS: A total of 2950 patients were included in the study. Median age at diagnosis was 53.9 years; 63.1% were publicly insured. The majority of patients (68.6%) had stage II-III breast cancer and ductal carcinoma histology (80.9%). The most common breast cancer subtype was luminal A-like (48.0%) followed by luminal B-HER2 positive-like (17.0%) and triple-negative (15.6%). Luminal A was more frequent in private (53.7% vs. 44.2%, p < .0001) than public, whereas Luminal B HER2-positive (19.2% vs. 14.2%, p = 0.0012) and HER2-positive (8.8% vs. 5.1%, p = 0.0009) were more common in patients with public health system coverage. Only 34% of patients were diagnosed by screening exams. Privately insured patients were more frequently diagnosed with stage I disease when compared to publicly insured patients; publicly insured patients had more stage III (33.5% vs. 14.7%; p-value < 0.0001) disease than privately insured ones. Breast cancer was detected by symptoms more frequently in publicly than in privately insured patients (74.2% vs 25.8%, respectively; p-value < 0.0001). CONCLUSIONS: Patients with public health coverage were diagnosed with symptomatic disease, later stages and more aggressive subtypes when compared to privately insured patients.

Implications of tumor-infiltrating lymphocytes in early-stage triple-negative breast cancer: clinical oncologist perspectives.

Breast cancer (BC) is the most common neoplasm in women worldwide and one of the leading causes of female death. The triple-negative subtype, characterized by the absence of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2), tends to occur in younger patients, be more aggressive and less differentiated. Furthermore, this subtype is considered the most immunogenic and associated with higher levels of tumor cell infiltration, mainly lymphocytes. Tumor-infiltrating lymphocytes (TILs) play a crucial role in the interaction of the host's immune system and cancer cells. The microenvironment is critical in tumor development and progression. Assessment of infiltrating lymphocytes can provide valuable information about the immune response and, given the lack of biomarkers to guide treatment decisions and predict outcomes in triple-negative tumors and can be considered as a potential biomarker. Some evidence suggests that higher levels of these lymphocytes are associated with better responses to systemic treatment, longer progression-free survival and overall survival (OS). However, treatment escalation or de-escalation strategies for triple-negative BC (TNBC) currently do not consider the presence or density of TILs for therapeutic decisions. TILs appear to be useful predictive and prognostic indicators. Further clinical studies are needed to confirm these relationships and integrate TILs as a biomarker consistently into clinical practice. This article summarizes key concepts relating to the role of the immune infiltrate in BC, along with the current status and future prospects regarding TILs as a predictive and prognostic biomarker.

The somatic mutation profile of estrogen receptor-positive HER2-negative metastatic breast cancer in Brazilian patients.

Background: Breast cancer is the leading cause of cancer death among women worldwide. Studies about the genomic landscape of metastatic breast cancer (MBC) have predominantly originated from developed nations. There are still limited data on the molecular epidemiology of MBC in low- and middle-income countries. This study aims to evaluate the prevalence of mutations in the PI3K-AKT pathway and other actionable drivers in estrogen receptor (ER)+/HER2- MBC among Brazilian patients treated at a large institution representative of the nation's demographic diversity. Methods: We conducted a retrospective observational study using laboratory data (OC Precision Medicine). Our study included tumor samples from patients with ER+/HER2- MBC who underwent routine tumor testing from 2020 to 2023 and originated from several Brazilian centers within the Oncoclinicas network. Two distinct next-generation sequencing (NGS) assays were used: GS Focus (23 genes, covering PIK3CA, AKT1, ESR1, ERBB2, BRCA1, BRCA2, PALB2, TP53, but not PTEN) or GS 180 (180 genes, including PTEN, tumor mutation burden [TMB] and microsatellite instability [MSI]). Results: Evaluation of tumor samples from 328 patients was undertaken, mostly (75.6%) with GS Focus. Of these, 69% were primary tumors, while 31% were metastatic lesions. The prevalence of mutations in the PI3K-AKT pathway was 39.3% (95% confidence interval, 33% to 43%), distributed as 37.5% in PIK3CA and 1.8% in AKT1. Stratification by age revealed a higher incidence of mutations in this pathway among patients over 50 (44.5% vs 29.1%, p=0.01). Among the PIK3CA mutations, 78% were canonical (included in the alpelisib companion diagnostic non-NGS test), while the remaining 22% were characterized as non-canonical mutations (identifiable only by NGS test). ESR1 mutations were detected in 6.1%, exhibiting a higher frequency in metastatic samples (15.1% vs 1.3%, p=0.003). Additionally, mutations in BRCA1, BRCA2, or PALB2 were identified in 3.9% of cases, while mutations in ERBB2 were found in 2.1%. No PTEN mutations were detected, nor were TMB high or MSI cases. Conclusion: We describe the genomic landscape of Brazilian patients with ER+/HER2- MBC, in which the somatic mutation profile is comparable to what is described in the literature globally. These data are important for developing precision medicine strategies in this scenario, as well as for health systems management and research initiatives.

The impact of a breast cancer diagnosis on marital outcomes and factors associated with divorce and separation.

Objective: To analyze marital outcomes, divorce or separation, and its association with demographic, socioeconomic, and clinicopathological factors among breast cancer (BC) survivors after 2-years of diagnosis. Methods: We performed a retrospective analysis of marital status at baseline and at years 1 and 2 of follow-up of women aged ≥ 18 years diagnosed with invasive BC participating in the AMAZONA III (GBECAM0115) study. The BC diagnosis occurred between January 2016 and March 2018 at 23 institutions in Brazil. Results: Of the 2974 women enrolled in AMAZONA III, 599 were married or living under common law at baseline. Divorce or separation occurred in 35 (5.8%) patients at 2 years of follow-up. In the multivariate analysis, public health insurance coverage was associated with a higher risk of marital status change (8.25% vs. 2.79%, RR 3.09, 95% CI 1.39 - 7.03, p = 0.007). Women who underwent mastectomy, adenomastectomy or skin-sparing mastectomy were associated with a higher risk of divorce or separation (8.1% vs. 4.49%, RR 1.97, 95 CI 1.04 - 3.72, p = 0.0366) than those who underwent breast-conserving surgery. Conclusion: Women covered by the public health system and those who underwent mastectomy, adenomastectomy or skin-sparing mastectomy were associated with a higher risk of divorce or separation. This evidence further supports the idea that long-term marital stability is associated with a complex interplay between socioeconomic conditions and stressors, such as BC diagnosis and treatment. ClinicalTrials Registration: NCT02663973.

Inequalities in Pap smear screening for cervical cancer in Brazil.

OBJECTIVE: To examine the risk factors associated with never being screened for cervical cancer (CC) in Brazil. METHODS: Using the National Household Sample Survey 2008 (PNAD), we analyzed data from 102,108 Brazilian women ages 25-64years. The patients were analyzed as having been or never having been screened with a Pap smear (Yes/No). Age-adjusted prevalence of never-screening was analyzed using a Chi-squared test. Crude and adjusted models using Poisson regression were performed. RESULTS: The prevalence of never-screened women for CC was 12.9%, 11.5% and 22.2% in Brazil in general, urban and rural areas, respectively. The Brazilian region with the highest prevalence of never-screening was the North (17.4%, 14.7% and 27.3% in general, urban and rural areas, respectively). The factors associated with a higher risk for never being screened were the following: poverty, younger age, lower educational level, non-white skin color, a greater number of children, no supplemental health insurance and not having visited a doctor in the past 12months. CONCLUSION: Socioeconomic and demographic conditions lead to inequalities in access to Pap smear screening in Brazil. Public health policy addressing these risk groups is necessary.

Clinical implication of low estrogen receptor (ER-low) expression in breast cancer.

Breast cancer is a heterogeneous disease, and the estrogen receptor (ER) remains the most important biomarker in breast oncology. Most guidelines set a positive expression threshold of 1% staining in immunohistochemistry (IHC) to define ER positivity. However, different expression levels may be associated with diverse degrees of sensitivity to endocrine therapy as ER expression may impact breast cancer molecular biology as a continuous variable. ER-lo tumors, defined as those with 1-10% ER expression, represent a relatively small subgroup of breast cancer patients, with an estimated prevalence of 2-7%. These tumors are similar to ERneg disease in their molecular landscape, clinicopathological characteristics, prognosis, and response to therapy. Nevertheless, a proportion may retain some degree of ER signaling dependency, and the possibility of responding to some degree to endocrine therapy cannot be completely ruled out. This review article discusses the most important considerations regarding the definition of ER positivity, pathology assessment, prognosis, and therapeutic implication of ERlo breast cancer from the medical oncology perspective.

Cost-effectiveness of breast, lung, colon, prostate and cervical cancer outcomes in Brazil: a worldwide comparison.

INTRODUCTION: Cancer is the second leading cause of death in the world, and it is expected to be the main cause by the year 2030. Current trends of higher incidence and the introduction of new treatments lead to the challenge of treating more people with increasing costs per capita. In Brazil, current and future challenges are even more significant because of the limited resources destined for healthcare. METHODS: We propose a methodology to compare cost-effectiveness performance with a regression of cancer lethality against the resources available for different nations, using the gross domestic product and the mortality-to-incidence ratio. Our objective is to evaluate and compare outcomes observed in Brazil. RESULTS: According to our methodology, Brazil is performing well in breast and prostate cancer (observed lethality 9% and 15% lower than expected, respectively). It performs close to expected in colon (0.8% higher) and cervix (2% higher). However, lung cancer had a higher lethality than expected (6.5% higher). We also found that breast, prostate and cervical cancers are the primary sites more related to income. Lung cancer had the weakest relationship with resources. CONCLUSION: Brazil has different cost-effectiveness results in the management of cancer depending on the primary site. Also, national income has a significant and heterogeneous effect on the lethality of different tumour types. This economic analysis is important for low- to middle-income countries seeking to evaluate cancer outcomes in limited-resource settings.

Real-world Data on First-line Systemic Therapy for Hormone Receptor-positive HER2-negative Metastatic Breast Cancer: A Trend Shift in the Era of CDK 4/6 Inhibitors.

Hormone receptor-positive (HR+) human epidermal growth factor receptor-2 negative (HER2-) tumors represent the most common subtype of metastatic breast cancer (MBC). International guidelines clearly state that endocrine therapy (ET) should be considered the preferred first-line therapy for these patients in the absence of very symptomatic visceral disease or evidence of endocrine resistance. Nonetheless compliance with guidelines significantly vary worldwide for many different reasons. Historically, a substantial proportion of patients with HR+ HER2- MBC have been treated with chemotherapy (CT) in first-line setting, jeopardizing patients' quality of life without a significant benefit in outcome. In 17 observational studies, including more than 63,000 patients, ET was most frequently used in first-line treatment of HR+/HER2- MBC (range, 42%-87%), nonetheless a high proportion of patients received CT (13%-66%) as initial therapy. More recently, results of clinical trials with CDK 4/6 inhibitors improved response, progression-free and overall survival in this population and are currently the standard of care. There was a trend toward increased use of ET in recent years. This review article aims to evaluate real-world data on patterns of first-line treatment of HR+ HER2- MBC with a special focus on the use of CT in this setting and the potential implications and perceived preliminary changes after the introduction of CDK 4/6 inhibitors.

Highlights of the 17th St Gallen International Breast Cancer Conference 2021: customising local and systemic therapies.

The 17th edition of the St Gallen International Breast Cancer Conference was held in March 2021 in an entirely virtual mode. More than 3,300 participants took part in this important bi-annual critical review of the 'state of the art' in the multidisciplinary care of early-stage breast cancer (BC). Seventy-four experts from all continents discussed and commented on the previously elaborated consensus questions as well as numerous interrogations on early-BC diagnosis and treatment asked by the audience. The theme of this year's Conference was 'Customising local and systemic therapies'. This paper summarises the results of the 2021 international panel votes as a quick news update. We discuss the most important issues on genetics, pathology, surgery, radiotherapy and systemic therapies presented and debated throughout the conference. We selected the topics based on applicability into the personalised care of BC patients and focused on questions that have a clear impact on our current clinical practice.

Perspectives on the Systemic Staging in Newly Diagnosed Breast Cancer.

Breast cancer is a complex disease, and accurate systemic staging is an essential aspect of the evaluation of a patient with newly diagnosed breast cancer. Considering that the chance of having metastatic disease at breast cancer diagnosis is different in each patient and depends on a variety of anatomic and biologic factors, it is crucial to understand that some populations may benefit from more intensive staging because their pretest probability of metastatic disease is higher than that of the average patient. Identifying these patients with de novo stage IV breast cancer is associated with substantial prognostic and therapeutic implications. Unfortunately, recent advances in understanding breast cancer heterogeneity and molecular biology have not been incorporated in the international guidelines and recommendations about imaging examinations for detecting de novo metastatic breast cancer. This review article discusses important issues regarding the rationale for performing systemic staging, addresses current and innovative imaging methods, and proposes an algorithm for systemic staging in patients with newly diagnosed breast cancer.

Lack of access to CDK4/6 inhibitors for premenopausal patients with metastatic breast cancer in Brazil: estimation of the number of premature deaths.

PURPOSE: A CDK4/6 inhibitor (CDK4/6i) combined with endocrine therapy is the standard of care for patients with hormone receptor-positive (HR+) and HER2-negative (HER2-) metastatic breast cancer (MBC). However, the incorporation of these agents into clinical practice remains challenging. This study aims to estimate the impact of the lack of access to ribociclib on mortality of premenopausal patients with MBC in Brazil. METHODS: Based on published epidemiological studies and national cancer registries, we estimated the number of premenopausal patients with potential indication of ribociclib as first-line treatment for MBC. Efficacy estimates were based on results from the Monaleesa-7 trial. Our analysis is made under the unrealistic assumption that all premenopausal MBC patients would be candidates for the treatment. To estimate the number of yearly premature deaths that could be prevented, we considered the largest absolute effect on mortality when sequentially applying the observed hazard ratio. RESULTS: We estimated an annual incidence of 4,294 premenopausal HR+, HER2- MBC patients in Brazil. Considering these patients, at 12, 24 and 60 months, the number of surviving subjects would be 3,504, 2,859 and 1,553 for endocrine therapy (ET) alone; and 3,717, 3,217 and 2,086 for ET plus ribociclib. The largest difference between both groups was observed at the end of the sixth year when the use of ribociclib would prevent 538 premature deaths (survival of 1,805 versus 1,267 patients by the 72nd month). CONCLUSION: We estimate that lack of access to CDK4/6i for patients with HR+, HER2-, MBC will cause the premature death of a significant number of premenopausal women with MBC. The unavailability of effective therapies has measurable consequences. Progress in this area demands a concerted effort to prevent further loss of lives.

Estimation of the Number of Brazilian Women Living With Metastatic Breast Cancer.

PURPOSE: Breast cancer is the most common cancer and the leading cause of cancer-related death in women worldwide. The number of women living with metastatic breast cancer (MBC) in Brazil is unknown. The objective of this article was to use population-based data to estimate the prevalence of MBC in Brazil. METHODS: Using 4 different sources and cancer registries (DataSUS, Registro Hospitalar de Câncer, the Brazilian National Health Agency, and the National Geography and Statistics Institute) with data from 2008 to 2018, we built a database that represents Brazilian MBC cases. The current number of women in the model living with MBC was considered the prevalence (recurrent or de novo), and new cases in the year 2018 represented the incidence. In each of these outcomes, we were able to separate our population on the basis of cancer subtype, age, and time from diagnosis. RESULTS: We estimate that 44,642 women currently live with MBC in Brazil. This accounts for one in every 2,409 Brazilian women and approximately 41 women per 100,000. A total of 58% have hormone receptor-positive/human epidermal growth factor receptor 2-negative tumors, 25% are human epidermal growth factor receptor 2-positive, and 16% have triple-negative breast cancer. According to our methodology, the estimated median overall survival of Brazilian women after diagnosis of MBC is 26.2 months. CONCLUSION: The significant number of patients living with MBC should inform and raise the interest of the many stakeholders involved. This collaborative effort is a clear requirement to improve the lives of these patients as well as to prepare for future challenges related to the trend of a progressive increase in MBC prevalence.

Access to high-cost drugs for advanced breast cancer in Latin America, particularly trastuzumab.

Provision of high-level healthcare is a challenge for all low- to middle-income countries (LMICs) since healthcare systems are heterogeneous, face many challenges such as inadequate funding, inequitable distribution of resources and services and usually are not adequately equipped to deal with a huge problem such as breast cancer. The development of anti-HER2 therapies can be considered one of the most important examples of the translation of molecular biology knowledge into clinical benefits for cancer patients. While a variety of novel therapeutic strategies are emerging, current treatment regimens remain focussed on targeted therapy with monoclonal antibodies, mainly trastuzumab, the first agent developed in this field. While these results have revolutionised the outcome of HER2+ patients in clinical trials and in high-income countries where they are widely available, results have not impacted the natural history of this aggressive disease in most of the world. Unfortunately, the availability of these drugs is far from universal in many LMICs, and in Latin America, in particular, patients with HER2+ breast cancer are treated exclusively with standard chemotherapy, a more toxic and less efficient therapy. While the complexity of the situation and the multiple factors that have an impact in this scenario are recognised, we need to map the future and develop feasible strategies to address possible solutions to the problem of drug access. A clear and unbiased diagnosis of the situation is a good starting point. Defining healthcare priorities and a clear strategy for the allocation of resources is difficult but mandatory. In this article, we will discuss current and future challenges regarding access (and lack of access) to high-cost cancer drugs in Latin America, with a focus on anti-HER2 therapies.

Association of ESR1 Mutations and Visceral Metastasis in Patients with Estrogen Receptor-Positive Advanced Breast Cancer from Brazil.

Mutations in the ESR1 gene (ESR1m) are important mechanisms of resistance to endocrine therapy in estrogen receptor-positive advanced breast cancer and have been recognized as a prognostic and predictive biomarker as well as a potential therapeutic target. However, the prevalence of ESR1m in real-world patients has not been adequately described. Therefore, we sought to evaluate the prevalence of ESR1m in metastatic samples from Brazilian patients with estrogen receptor-positive (ER+) advanced breast cancer previously treated with endocrine therapy. The presence of ESR1m was evaluated in formalin-fixed paraffin-embedded (FFPE) breast cancer tissue using real-time quantitative polymerase chain reaction (RT-qPCR). Mutations in codons 380, 537, and 538 of the ESR1 gene were analyzed. Out of 77 breast cancer samples, 11 (14.3%) showed mutations in the ESR1 gene. ESR1m were detected in a variety of organs, and the D538G substitution was the most common mutation. In visceral metastasis, ESR1m were detected in 25% (8/32) of the samples, whereas in nonvisceral metastasis, ESR1m were detected in 6.7% (3/45) of the samples. The odds of a sample with visceral metastasis having an ESR1 mutation is 4.66 times the odds of a sample of nonvisceral metastasis having an ESR1 mutation (95% CI: 1.13-19.27; p value = 0.0333). Our study indicates that the prevalence of ESR1m in samples from Brazilian patients with metastatic ER+ breast cancer is similar to that described in patients included in clinical trials. We observed an association of ESR1m with visceral metastasis.

The impact of a breast cancer diagnosis on marital outcomes and factors associated with divorce and separation

Abstract Objective To analyze marital outcomes, divorce or separation, and its association with demographic, socioeconomic, and clinicopathological factors among breast cancer (BC) survivors after 2-years of diagnosis. Methods We performed a retrospective analysis of marital status at baseline and at years 1 and 2 of follow-up of women aged ≥ 18 years diagnosed with invasive BC participating in the AMAZONA III (GBECAM0115) study. The BC diagnosis occurred between January 2016 and March 2018 at 23 institutions in Brazil. Results Of the 2974 women enrolled in AMAZONA III, 599 were married or living under common law at baseline. Divorce or separation occurred in 35 (5.8%) patients at 2 years of follow-up. In the multivariate analysis, public health insurance coverage was associated with a higher risk of marital status change (8.25% vs. 2.79%, RR 3.09, 95% CI 1.39 - 7.03, p = 0.007). Women who underwent mastectomy, adenomastectomy or skin-sparing mastectomy were associated with a higher risk of divorce or separation (8.1% vs. 4.49%, RR 1.97, 95 CI 1.04 - 3.72, p = 0.0366) than those who underwent breast-conserving surgery. Conclusion Women covered by the public health system and those who underwent mastectomy, adenomastectomy or skin-sparing mastectomy were associated with a higher risk of divorce or separation. This evidence further supports the idea that long-term marital stability is associated with a complex interplay between socioeconomic conditions and stressors, such as BC diagnosis and treatment. ClinicalTrials Registration: NCT02663973.

Lung cancer in Brazil.

Lung cancer is one of the most incident types of cancer and a leading cause of cancer mortality in Brazil. We reviewed the current status of lung cancer by searching relevant data on prevention, diagnosis, and treatment in the country. This review highlights several issues that need to be addressed, including smoking control, patient lack of awareness, late diagnosis, and disparities in the access to cancer health care facilities in Brazil. We propose strategies to help overcome these limitations and challenge health care providers, as well as the society and governmental representatives, to work together and to take a step forward in fighting lung cancer.