The world is facing a cri cal health care problem: in the

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1 BREAST CANCER IN LATIN AMERICA Breast Cancer in La n America: A Map of the Disease in the Region Eduardo Cazap, MD, PhD, FASCO OVERVIEW In the next few decades, breast cancer will become a leading global public health problem as it increases dispropor onately in low- and middle-income countries. Dispari es are clear when comparisons are made with rates in Europe and the United States, but they also exist between the countries of the region or even within the same country in La n America. Large ci es or urban areas have be er access and resource availability than small towns or remote zones. This ar cle presents the status of the disease across 12 years with data obtained through three studies performed in 2006, 2010, and 2013 and based on surveys, reviews of literature, pa ent organiza ons, and public databases. The first study provided a general picture of breast cancer control in the region (La n America); the second compared expert percep ons with medical care standards; and the third was a review of literature and public databases together with surveys of breast cancer experts and pa ent organiza ons. We conclude that breast cancer is the most frequent cancer and kills more women than any other cancer; we also suggest that aging is the principal risk factor, which will drive the incidence to epidemic levels as a result of demographic transi on in La n America. The economic burden also is large and can be clearly observed: in countries that today allocate insufficient resources, women go undiagnosed or uncared for or receive treatment with subop mal therapies, all of which results in high morbidity and the associated societal costs. The vast inequi es in access to health care in countries translates into unequal results in outcomes. Na onal cancer control plans are the fundamental building block to an organized governance, financing, and delivery of health care for breast cancer. The world is facing a cri cal health care problem: in the next few decades, cancer will become a leading global public health threat, with rates increasing dispropor onately in low- and middle-income countries. Breast cancer is a high priority element of this global cancer threat. 1 In the United States, 60% of breast cancer occurrences are diagnosed in the earliest stages; conversely, in Brazil and Mexico, only 20% and 10%, respec vely, are diagnosed at an early stage. The all-cancer mortality-to-incidence ra o for La n America is 0.59, compared with 0.43 for the European Union and 0.35 for the United States. Prac cally, the risk of dying as a result of breast cancer is double in La n America than in the United States. 2 A study done by our group in 2006, Breast cancer in La n America: results of the La n American and Caribbean Society of Medical Oncology/Breast Cancer Research Founda on expert survey 3 obtained, through a 65-ques on telephone interview to 100 breast cancer experts from 12 La n American countries, preliminary informa on about the state of breast cancer care at that me. The methodology was used to obtain fast qualita ve informa on about breast cancer in the region because of the lack of hard data at that moment. With respect to epidemiologic characteristics, the incidence of breast cancer in Latin American countries was lower than that in more developed countries, whereas the mortality rate was higher. These differences probably are related to differences in screening strategies and access to treatment. The authors agreed that popula onbased data were urgently needed to make informed decisions. It was also reported that greater than 90% of countries had, at that me, no na onal laws or guidelines for mammography screening and that the access rate to mammography was approximately 50%. However, diagnostic testing for hormone receptors and biomarkers were available at most centers (> 80%), and, overall, nearly 80% of patients started treatment within 3 months of diagnosis. In most Latin American health systems, doctors work both at academic institutions and public hospitals, so the subjective interpretation of these data may be inaccurate. Alternative data collection strategies that offer a better understanding of the state of breast cancer care in developing countries could help identify areas for improvement. 3 Some of the relevant conclusions of the study are listed in the Sidebar. From the La n American and Caribbean Society of Medical Oncology, Buenos Aires, Argen na. Disclosures of poten al conflicts of interest provided by the author are available with the online ar cle at asco.org/edbook. Corresponding author: Eduardo Cazap, MD, PhD, FASCO, La n American and Caribbean Society of Medical Oncology, Avda Cordoba 2415, Piso 5, 1120, Buenos Aires, Argen na; ecazap@slacom.org American Society of Clinical Oncology asco.org/edbook 2018 ASCO EDUCATIONAL BOOK 451

2 EDUARDO CAZAP TABLE 1. Rela on Between Breast Cancer Incidence and Some Reproduc ve, Socioeconomic, and Lifestyle Factors From the 2013 Study Country ASR Incidence Rate (%) Births in Women Age < 30 Years (%) Mean Childbearing Age (Years) Fer lity Rate (%)15 Overweight and Obesity Rate (%) * Alcohol Consump on (Liters) ** Women's Life Expectancy (Years) Per Capita GDP in 2008 ($) Uruguay , Argen na , Costa Rica , Venezuela , Brazil , Chile , Peru , Colombia , Ecuador ,745 Panama , Mexico , Correla on Coefficient p *Es mated overweight and obesity (BMI 25 kg/m 2 ) prevalence in women age 30 or older in **Per capita consump on of pure alcohol by women age 15 and older; drinkers only. Combined gross enrollment ra o in educa on in Abbrevia ons: ASR, age-standardized rate; BMI, body mass index; GDP, gross domes c product. Female Educa on Rate (%) A subsequent study published in 2010, en tled Breast cancer in La n America: experts percep ons compared with medical care standards, 4 compared expert perceptions with medical care standards through a systema c review of the norms recommenda ons and guidelines considered PRACTICAL APPLICATIONS Breast cancer is the most common cancer in women in La n America, and, for most cases it is diagnosed at a late stage. Educa on, awareness, preven on, and early diagnosis are priori es to be considered for all ac ons performed as part of the breast cancer control con nuum. Because of the demographic transi on, breast cancer rates will approach epidemic propor ons with great economic impact. Health systems and physicians must be prepared to face this cri cal situa on. Lack of data about the disease is common. It is important to promote be er informa on from reliable data that originates from La n American countries. Access and affordability to proper diagnosis and care are important limi ng factors. Na onal general or specific breast cancer plans are fundamental for an organized governance, financing, and health care delivery. Evidence-based treatment guidelines are published in most countries by governmental authori es, cancer ins tutes, or scien fic associa ons. The challenge is the implementa on of policies and mechanisms to ensure a consistent compliance with these guidelines across the whole popula on to be medical care standards (MCS) for breast cancer in 12 La n American countries. Informa on related to MCS was requested from government health authori es, cancer ins tutes, and na onal scien fic and professional socie es. The documents received were reviewed by breast cancer experts from each country. In addition, three key survey ques ons from the 2006 study about early detec on and diagnosis were reprocessed to provide informa on related to the implementa on prac ce of exis ng MCS. We concluded that all countries included in the study had MCS, whether published by government authori es, na onal professional or scientific associations, or cancer institutes, or through the adop on of interna onal MCS. The results were reported at the center level (mainly private institutions) or at the country level (public hospitals). Overall, 85% of the experts reported that less than 50% of the women with no symptoms undergo a mammography at the country level compared with 43% at the center level. For diagnos c suspicion of breast cancer, 80% of diagnos c suspicion originated with the pa ent at a country level compared with 50% screening or medical care at a center. Approximately 30% of pa ents waited more than 3 months for a diagnosis at the country level compared with 7% at the center level. All of the countries in the study reported the use of similar MCS for breast cancer care. The reported difference between care prac ced at a country level versus at a center level suggests that the challenge is not in genera ng new MCS but in implemen ng policies and control mechanisms for compliance with exis ng MCS, which would guarantee their applicability and access to all popula ons ASCO EDUCATIONAL BOOK asco.org/edbook

3 BREAST CANCER IN LATIN AMERICA Our study published in 2013, A review of breast cancer care and outcomes in La n America, performed by the Karolinska Ins tutet, the Stockholm School of Economics, the Pan American Health Organiza on, the American Cancer Society, and the La n-american and Caribbean Society of Medical Oncology, analyzed in more detail the picture of the disease according several aspects. 5 Here, we summarize some conclusions about different aspects of breast cancer control determined in this study, which was the last published and most comprehensive one produced by our group. The study was based on a review of literature and public databases as well as on a survey of clinical experts and pa ent organiza ons. The literature review, which focused specifically on treatment pa erns and costs of breast cancer in each study country, was conducted in MEDLINE, LILACS, and SciELO but included also gray literature that targeted data and informa on about the epidemiology of the disease and its outcomes in the region as well as treatment guidelines, cancer control plans, and documenta on about the cost of breast cancer. The study faced a number of limita ons, mostly because of the lack of data. Perhaps the most important limita on to bear in mind during interpreta on of the results is publica on bias. Many factors influence the research and intellectual produc on in the countries that par cipated in the study, which resulted in diverse volumes of evidence. Although rich materials and data were iden fied for some countries, only a few and sca ered ar cles were found for others. Nevertheless, this study is one of the few bodies of comprehensive data available today about breast cancer in La n America. EPIDEMIOLOGIC BURDEN Breast cancer is the most common type of cancer in women in La n America. Each year, approximately 115,000 women are diagnosed and 37,000 die as a result of breast cancer. Incidence and mortality are increasing: Unlike in Europe or the United States, both incidence and mortality rates are on the rise, and mortality is expected to double in fewer than 20 years. Aging is recognized as the main risk factor for breast cancer; increasing age will cause steep increases in breast cancer occurrences. Popula ons in La n American countries today have relatively low mean ages, but this is bound to change. The demographic profile of Argen na and Uruguay may offer a look into the future of the region: the mean ages there are 5 to 10 years older than the current average, and crude mortality rates as a result of breast cancer are five to six times higher than the current Latin American average. In some countries, including Brazil, breast cancer occurrences are expected to increase quickly and reach epidemic proportions. According to the available (although limited) comparable data and gathered or constructed series of variables, the only correla ons with increased breast cancer risk in La n American countries are wealth and educa on (Table 1). CLINICAL BURDEN Survival rate in La n America is considerably lower than the E.U. benchmark, which achieved 5-year survival rates greater than 80%. Enhanced treatments and earlier diagnoses explain progresses made during past years. The available data show a 5-year survival rate in La n America that fluctuates around 70%, and this difference in survival is caused mainly by the late stage at diagnosis, which is an important predictor for overall survival. Benchmark for detec on of early breast cancer in the European Union is 90%, whereas the La n American average is between 60% and 70%. In countries like Peru, Colombia, or Mexico, approximately 50% of detected breast cancer occurrences are in advanced stages. Late stage at diagnosis nega vely affects survival rate and notably increases per-case health expenditures. SOCIAL AND ECONOMIC BURDEN The costs of breast cancer are directly related to stage of diagnosis, and annual health care costs for a pa ent with stage IV breast cancer in La n America is three to four mes the cost of treatment for a pa ents with stage I disease. 6 The increased morbidity and mortality of pa ents with metastases greatly increase overall expenses throughout the health care system (e.g., by increasing use of primary care facili es or emergency care while depriving society of produc ve years). The ample majority of women are diagnosed when they are s ll at working ages, so produc vity losses as a result of younger age at death are exacerbated by the increased morbidity that results from younger age at diagnosis. Because of insufficient funding, some pa ents are undiagnosed, una ended, untreated, and uncared for and others receive subop mal treatment. General health care expenditure in La n America is far below European and U.S. standards, not only in absolute but also in rela ve terms. Annual expenditures per breast cancer occurrence in Europe are approximately $40,000; conversely, in La n American countries, such as in Brazil for example, values can vary depending on insurance type, from $4,800 in the Sistema Único de Saúde (Brazil's publicly funded health system) to 16,400 in a private facility. 7 ACCESS TO TREATMENT AND FRAMEWORK OF CARE Health care coverage is expanding, although not across all dimensions. Health access in La n American countries has improved con nuously over the years, driven by reforms toward more universal health access and a growing par- cipa on of the private sector. Of the three dimensions to universal health access, expansion has been made mainly in terms of the popula on that is covered. To prevent financial hardship, impoverishment, and social inequity, expansion of the depth of services and propor on of costs covered are cri cal for catastrophic condi ons, such as breast cancer. Nevertheless, there are vast differences in access to breast cancer care across La n America that result mainly from insurance type and geographic loca on. Even within asco.org/edbook 2018 ASCO EDUCATIONAL BOOK 453

4 EDUARDO CAZAP a par cular insurance type or country, great differences in access can exist depending on the wealth of the region (i.e., state or province, municipality) and the willingness to invest in breast cancer care. As an example, Brazil endows different levels of resources to breast cancer care according to the type of insurance. Inequali es exist on the basis of insurance type. In Argen na, the Compulsory Medical Plan guarantees 100% public coverage for oncology drugs. However, the type and quality of provided treatments vary in different provinces or districts, which causes geographic inequali es. Conversely, in Peru, 64% of the popula on depends on the public health insurance, which covers breast cancer diagnosis but not treatments. Not surprisingly, health outcomes in Peru are far lower than average and are among the lowest in the region. It is important to men on that this situa on has improved in recent years. Absence of na onal cancer control programs (NCCPs) contributes to dispari es. NCCPs are recommended by the World Health Organiza on, because they are the blueprint of a holis c cancer control strategy and play a vital role in op mizing health systems and reducing the burden of cancer. The func on of an NCCP is to define cri cal processes in cancer control, such as overall na onal strategy, priori es, governance, financing, service delivery, monitoring, and con nuous improvement. Several La n American countries do not have formal NCCPs in place, and basic elements of a NCCP, such as popula on-based cancer registries, are missing or implemented only with a limited scope. Treatment guidelines exist; the challenge is implementa- on. Evidence-based treatment guidelines are published in most countries by government authori es, cancer ins tutes, or scien fic associa ons. The challenge is the implementa- on of policies and mechanisms to ensure a consistent compliance with these guidelines across the whole popula on. DIAGNOSIS AND TREATMENT Generally speaking, there is low commitment to mammography screening. In La n American countries, most breast cancer occurrences are detected when women seek care a er they no ce a breast lump. Early detec on is an opportunity for improvement in the region, and there is no consistent strategy for breast cancer preven on or detec on that could be recognized. Ac ons are being taken in countries like Mexico, Costa Rica, Argen na, Uruguay, or Brazil, where popula on-based programs have been or are being implemented. Hormone receptor and biomarker determina on are common prac ce. Contrary to the low commitment to mammographic screening, post-diagnos c screening with hormone receptor and biologic marker determina on seems widespread in the La n American region. Some ques ons exist in terms of the differences found in HER2 overexpression, which leads us to conclude (1) that criteria for immunohistochemistry assay interpreta on must be standardized and (2) that it is unclear whether HER2 overexpression has been tested consistently. SIDEBAR. Conclusions From the 2008 Study on Breast Cancer in La n America Lack of epidemiologic data Lack of poli cal commitment Low rate of mammographic screening Hormone receptor and molecular markers not available for all pa ents High percentage of mastectomy Surgery done by gynecologist or general surgeon in an important number of cases Clinical epidemiologic and basic research were insufficient Short interval between diagnosis and treatment in some countries Adequate pallia ve care for pa ents (chemo therapy, hormonotherapy, morphine) Good level of educa on in specialists trea ng breast cancer With regard to medical therapy, all systemic treatments are licensed, but budget considera ons limit the use of some effec ve treatments. Adjuvant chemotherapy reduces the rela ve risk of death each year by almost 40% for women younger than age 50 years and by 20% for women age 50 to 69. Endocrine therapy with tamoxifen in women with estrogen receptor posi ve disease results in a more than 30% rela ve risk reduc on of mortality. One year of adjuvant therapy with trastuzumab in women with HER2-posi ve breast cancer leads to a 50% reduced risk of recurrence. Use of modern drugs greatly differs from country to country and by insurance type. Chemotherapy treatments with anthracyclines are widely accepted, as is tamoxifen, for pa ents with estrogen receptor posi ve tumors. However, new-genera on hormonal treatments like aromatase inhibitors and the biologic therapy trastuzumab are not accessible to all women. In metasta c breast cancer, medical treatment is the most important considera on. Access to modern drugs is cri cal but is not a reality. Targeted therapies, such as trastuzumab, bevacizumab, or lapa nib, are important treatment op ons for pa ents with advanced breast cancer. Access to these drugs follows restric ons similar to those men oned for early breast cancer, which leaves pa ents with few therapeu c alterna ves, uncontrolled disease progression, and consequently poor outcomes. PALLIATIVE CARE Quality of life during the end of life is poor in La n American pa ents with cancer, and symptoms such as pain, fa gue, nausea, physical impairment, and sleeplessness have been persistent problems. Studies show that care is fragmented; suffering, uncontrolled; and communica on among professionals, pa ents, and families, poor. Also a great burden is placed on pa ents, families, and caregivers. The main barriers ASCO EDUCATIONAL BOOK asco.org/edbook

5 BREAST CANCER IN LATIN AMERICA to op mal pain control are inadequate staff knowledge of pain management (70%), inability to pay for services or analgesics (57%), inadequate pain assessment (52%), and excessive regula ons of prescribing opioids (44%) BREAST CANCER IN YOUNG WOMEN IN LATIN AMERICA Breast cancer among La n American women is a growing burden throughout the region. The increased propor on of breast cancer occurrences in young women is important, because their diagnoses and tumor behaviors are usually more aggressive than those in their older counterparts. The findings of a recent study reveal that there is scarce informa on about this ma er in La n American countries, especially about the par cular effects and complica ons that this group of women faces during and a er treatment. Also, there are no specific clinical or educa onal programs that focus on this popula on. A call to ac on from health policy planners, medical providers, researchers, pa ents with breast cancer, families, and the community in general is deserved for be er care of this emergent challenge. 8 CONCLUSION Breast cancer is the most common cancer, and it kills more women than any other cancer in La n America. Despite the scarcity of na onal registries, we corroborated reports of increasing incidence and mortality in most countries. The number of deaths as a result of breast cancer is expected to double by 2030 to 74,000 every year. Aging is the principal risk factor for breast cancer development. Because of the demographic transi on in La n America, breast cancer rates will approach epidemic propor ons. Breast cancer burden has different shapes. In Peru, Mexico, Colombia, and Brazil, younger age at diagnosis and at death deprives socie es of numerous produc ve years, as does the high occurrence of the disease in Argen na and Uruguay. The economic burden is also great, and it is clearly observed that countries today allocate insufficient resources to tackle the disease. Women remain undiagnosed, uncared for, or treated with subop mal therapies, all of which result in high morbidity and the associated societal costs. Universal health care coverage is s ll not the rule in La n American countries; even in those countries where the en tlement to breast cancer health services are guaranteed by law, it is not accompanied by the necessary resources. Vast inequi es in access to breast cancer health in La n American countries, and even among different regions of countries, exist, which translate to unequal results in breast cancer outcomes. Data about survival are scarce and fragmented; what is available shows a wide dispersion across and also within countries. Yet, the evidence signals that only a few countries have 5-year survival outcomes that surpass 70%. Breast cancer outcomes have improved during the past decade, as evidenced by comparison of the mortality-to-incidence ra os between 2002 and Costa Rica is the country where most progress is seen, whereas Brazil, Mexico, and Panama have not been able to greatly improve their mortality-to-incidence ra os during the past years. The reduced survival in La n American countries results in part from diagnosis of approximately 30% to 40% of pa ents when the disease is already in metasta c phases III and IV; conversely, in Europe, late diagnosis occurs in only 10% of the all diagnoses. Currently in La n American countries, the majority of breast cancer occurrences are detected when women seek care a er onset of symptoms. Ini a ves to increase the awareness of breast cancer are important so that women are a en ve and do not postpone seeking care un l the symptoms have reached a cri cal stage. No one-approach-suits-all preven on strategy is feasible given the outstanding epidemiologic contrasts in terms of disease occurrence, risks, and available resources both across and within countries. Popula on-based mammography has been shown to improve outcomes, because it leads to a larger share of breast cancers diagnosed at an early stage; however, in some La n American countries with limited resources and low incidences, the best screening strategies differ. In countries such as Argen na and Uruguay, versus countries such as Ecuador, Peru, or Mexico, higher frequency, lower star ng age, and shorter intervals for screening are jus fied. Because affordability remains a liming factor in the La n American region, recommenda ons from the Breast Health Global Ini a ve and World Health Organiza on highlight the role of preven on but contemplate several addi onal measures, such as health educa on and behavior modifica on, breast self-awareness, and clinical breast examina on. Most La n American countries have medical care standards; the challenge in this region is to implement policies and control mechanisms to ensure their compliance and applicability to the whole popula on. NCCPs are the fundamental building blocks to an organized governance, financing, and health care delivery for cancer. There is a marked absence of NCCPs in La n American countries, which deviates from 2005 World Health Assembly resolu ons. La n American pa ent groups fulfill an important task when health care systems cannot or do not sufficiently assist pa ents with breast cancer. Faulty pa ent informa on services and lack of government inclusion of these services in policy decision-making should be improved. ACKNOWLEDGMENT This work was developed by experts from the La n-american and Caribbean Society of Medical Oncology (SLACOM), Buenos Aires, Argen na, and supported by a grant from the Breast Cancer Research Founda on (BCRF), New York, NY. asco.org/edbook 2018 ASCO EDUCATIONAL BOOK 455

6 EDUARDO CAZAP References 1. Cazap E, Distelhorst SR, Anderson BO. Implementa on science and breast cancer control: a Breast Health Global Ini a ve (BHGI) perspec ve from the 2010 Global Summit. Breast. 2011;20:S1-S2. 2. Goss PE, Lee BL, Badovinac-Crnjevic T, et al. Planning cancer control in La n America and the Caribbean. Lancet Oncol. 2013;14: Cazap E, Buzaid AC, Garbino C, et al; La n American and Caribbean Society of Medical Oncology. Breast cancer in La n America: results of the La n American and Caribbean Society of Medical Oncology/Breast Cancer Research Founda on expert survey. Cancer. 2008; 113: Cazap E, Buzaid A, Garbino C, et al. Breast cancer in La n America: experts percep ons compared with medical care standards. Breast. 2010;19: Justo N, Wilking N, Jönsson B, et al. A review of breast cancer care and outcomes in La n America. Oncologist. 2013;18: Teich N, Pepe C, Viera FM, et al. Retrospec ve cost analysis of breast cancer pa ents treated in a Brazilian outpa ent cancer center. J Clin Oncol. 2010;28 (suppl; abstr e11026). 7. Knaul FM, Arreola-Ornelas H, Velázquez E, et al. The health care costs of breast cancer: the case of the Mexican Social Security Ins tute. Salud Publica Mex. 2009;51:s286-s Villarreal-Garza C, Aguila C, Magallanes-Hoyos MC, et al. Breast Cancer in young women in La n America: an unmet, growing burden. Oncologist. 2013;18: ASCO EDUCATIONAL BOOK asco.org/edbook