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© 2001 American Society for Clinical Oncology
Breast Cancer in South America: Challenges to Improve Early Detection and Medical Management of a Public Health ProblemByFrom the Comprehensive Cancer Center, The Lutheran University of Brazil, and Federal University of Rio Grande do Sul, Porto Alegre, Brazil. Address reprint requests to G. Schwartsmann, MD, PhD, Postgraduate Course in Medicine, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos 2350/3 andar Leste, Porto Alegre, RS, Brazil CP 90035-003; email: fsoad{at}hcpa.ufrgs.br
ABSTRACT: Breast cancer is a public health issue in South America, with about 70,000 cases and 30,000 deaths expected for the year 2001 according to the World Health Organization database. This is especially the case for the so-called temperate region that includes Argentina, Chile, Uruguay, and Southern Brazil. In these areas, the incidence of breast cancer is in the same range as in most countries in Europe. Notably, Argentina has one of the highest incidences of breast cancer in the world, while in Brazil breast cancer is the second most frequent type of cancer (after skin cancer). The potential risk factors for the higher incidence of this disease in temperate South America are, among others, a high-fat diet, more elevated socioeconomic status, and the low average parity of women. In addition, the influence of European immigration on the genetic background of the population should be considered. Late diagnosis is a major factor affecting the mortality rates, as a significant proportion of patients are still diagnosed at clinical stages II and III. In this article, the available data on the incidence and mortality rates of breast cancer in South America, as well as the published literature on risk factors and the limitations of early detection of the disease, are discussed. The overall management of patients diagnosed at clinical stage IIIA is briefly addressed.
BREAST CANCER IS a major problem in public health.1,2 Over one million cases of this disease are projected for the year 2001, with approximately 370,000 breast cancer–related deaths expected for the same period.2 Although there are differences in the incidence rates between developed and developing countries (approximately 580,000 v 470,000 new cases projected for 2001, respectively), mortality rates are proportionally higher in less developed regions of the world.3 The calculated ratios between incidence and mortality rates may express indirectly, among other factors, the influence of early versus late diagnosis of this disease in different parts of the world. More developed countries show a non–age-corrected ratio between incidence and mortality rates of 0.33, whereas the ratio is 0.39 for developing countries (Fig 1).3-6
Although North America and Australia/New Zealand show the highest incidence of breast cancer in the world (86.30 and 71.69 cases per 100,000 women), they also express the lowest incidence/mortality ratios for breast cancer (0.25 and 0.27, respectively), which certainly reflects the impact of early diagnosis. In certain regions, such as most of the African continent and in India, the highest mortality/incidence rates of breast cancer are observed (0.45 and 0.48, respectively), again reflecting their problems in breast cancer awareness and late diagnosis (Fig 2).4,5
BREAST CANCER IN SOUTH AMERICA Breast cancer in less developed countries, such as those in South America, is a major public health issue. It is a leading cause of cancer-related deaths in women in countries such as Argentina, Uruguay, and Brazil. The expected numbers of new cases and deaths due to breast cancer in South America for the year 2001 are approximately 70,000 and 30,000, respectively.1-3,5,6 For the purpose of cancer statistics, South America has to be divided into two geographic regions: tropical South America, which includes Venezuela, Colombia, Peru, Ecuador, Bolivia, Surinam, Guiana, and most regions of Brazil, and temperate South America, which includes Argentina, Chile, Uruguay, and Southern Brazil. Notably, the incidence of breast cancer in temperate South America is almost as high as that in North America, Australia, and New Zealand and slightly higher than that in most regions in Europe. Even for tropical South America, breast cancer is a major public health issue, being comparable to the incidence rate in Eastern Europe (Fig 3). Therefore, the implementation of actions for the prevention, early diagnosis, and management of patients with breast cancer is of great importance for the region.1-3
RISK FACTORS FOR THE DEVELOPMENT OF BREAST CANCER Over the past years, several studies have been performed by various investigators in South America dealing with the evaluation of known risk factors for the development of breast cancer.7-10 Previous observations from researchers in Western countries11 suggesting that the incidence of breast cancer was higher in women coming from a higher socioeconomic background were confirmed in a study performed by investigators in Argentina.12 Previous observations demonstrating that obesity and low parity were also risk factors for the development of breast cancer gained support from studies performed in women in Chile.13 Furthermore, a significant correlation among total meat intake, total and saturated fat intake, and the risk of developing breast cancer was shown for women in Uruguay.9,10 In addition, studies performed in Colombia have implicated organochloride exposure as a potential risk factor for the development of breast cancer in women in certain regions in that country.13,14 In addition, as in previous reports coming from North America, Japanese immigrant women who moved to Sao Paulo, Brazil, after World War II have experienced a progressive increase in their risk of developing breast cancer caused by environmental factors such as high-fat diet.15
CONTRIBUTION OF SOUTH AMERICA TO PATIENT MANAGEMENT The study of new chemotherapeutic agents and/or drug combinations for the palliative management of advanced breast cancer has also been a subject of attention by South American investigators. Vinorelbine, a synthetic vinca alkaloid now in routine use in most parts of the world, was initially developed in both France and Argentina.21 Furthermore, studies of the use of agents to relieve symptoms and improve quality of life in patients with advanced disease, including the use of corticosteroids and megestrol acetate to improve appetite, were performed by researchers in that country.22 Researchers in Brazil performed pioneer studies on the doxorubicin/paclitaxel combination as first-line therapy in women with advanced breast cancer, looking at the potential risk for cardiotoxicity with this regimen,23,24 and on the use of ifosfamide/paclitaxel and gemcitabine/paclitaxel as salvage therapy in patients with refractory disease.25,26
THE PROBLEM OF EARLY DETECTION
The above-mentioned figures do not differ significantly from 5-year survival rates per disease stage reported by other institutions in developed countries.29 However, the percent distribution of patients per stage can be dramatically different when data from more versus less developed countries are compared. The analysis of the distribution of patients with breast cancer according to clinical stage in a series of 1,796 women who attended the Breast Unit of the Academic Hospital at the University of São Paulo, São Paulo, Brazil, between the years 1979 and 1989 showed that 53% of women were diagnosed at stage III (Fig 5) (J.A. Pinotti, personal communication, April 2001). Similarly, the distribution of patients with breast cancer according to clinical stage in a series of 9,005 women admitted to the Instituto de Enfermidades Neoplasicas in Lima, Peru, between 1985 and 1997, revealed that patients with stages II and III disease corresponded to 42% and 33% of the total number of cases, respectively (Fig 6) (C. Vallejos, personal communication, April 2001).
Breast cancer is the second most frequent type of cancer in Brazil, with about 30,000 new cases of this disease per year, according to the Brazilian National Cancer Institute’s projections for the year 2001 (Fig 7). The state of Rio Grande do Sul, whose capital is the city of Porto Alegre, has the highest incidence of breast cancer in the country (Fig 8). More recent data obtained from a hospital-based tumor registry, including 1,783 women with breast cancer at the Academic Hospital of the Federal University of Rio Grande do Sul in Porto Alegre, Brazil, between the years 1975 and 1997, showed that 16% of patients were diagnosed at clinical stage I, while 54% of the cases were in clinical stage II (C.H. Menke, personal communication, April 2001). These data suggest a trend toward earlier diagnosis in geographic areas of Brazil in which higher literacy and socioeconomic levels are encountered.
Several actions are being taken in an attempt to improve the early detection and overall management of patients with breast cancer in South America. Community programs to improve public awareness of breast cancer are being initiated in various countries. In Southern Brazil, this is illustrated by the creation of the Breast Institute of the State of Rio Grande do Sul, a nongovernmental organization that gathers a large group of volunteers from the community to help guide women on how to perform breast self-examination and facilitate their access to mammographic screening and medical care (Fig 9).
THE LATIN AMERICAN GROUP FOR BREAST DISEASES Consensus conferences on the proper diagnostic and therapeutic approach to patients with breast cancer are being held in different countries, and general guidelines are being provided to the medical community in the region.30 In addition, a very interesting project was launched initially in Venezuela, the Latin American Group for the Study of Breast Diseases (GLAMA), which consists of a forum via Internet for the discussion of clinical cases, with the aim of creating a database on breast cancer and promoting education and research on our continent (Fig 10). Presently, a large group of breast specialists, surgeons, medical oncologists, and imaging specialists from various countries in South America are linked via the GLAMA link on the Mastologia Web site (www.mastologia.org; email address: glama@mastologia.org).
THE SOUTH AMERICAN OFFICE FOR ANTICANCER DRUG DEVELOPMENT The South-American Office for Anticancer Drug Development (SOAD) is a not-for-profit organization whose main office is located at the Comprehensive Cancer Center of the Lutheran University in Porto Alegre, Brazil. The mission of SOAD is to promote anticancer drug discovery and development in this part of the world. In addition, SOAD provides the means for the integration of South American scientists interested in anticancer drug development with groups working in other parts of the world.31,32 One of the main emphases of the SOAD drug discovery program is the identification of novel candidate compounds from terrestrial and marine natural sources.32-34 After the initial in vitro testing of semipurified extracts in a panel of human solid tumor cell lines, compounds exhibiting antiproliferative effects are submitted to the United States National Cancer Institute in vitro screening program for confirmatory tests. So far, 12 semipurified plant extracts have confirmed their antiproliferative activity in the National Cancer Institute screen, and some of them are being taken forward into further preclinical evaluation. More recently, a new effort in terms of the collection of marine species, mainly tunicates and spongi, was undertaken in collaboration with researchers at the Institute of Zoobotanics of Rio Grande do Sul, Brazil. Other recent studies performed with marine organisms have shown provocative results, as illustrated by the isolation of the aromatic alkaloids granulatimide and isogranulatimide from the Brazilian tunicate Ascidian didemnum granulatum, which appear to act as G2 checkpoint inhibitors.35 Another important SOAD initiative is to reinforce the implementation of very strict Good Clinical Practice standards in early clinical trials with new anticancer agents in South America. Staff members of the SOAD Clinical Monitoring Unit have received training in all aspects involved in the planning and performance of clinical trials and the necessary requirements to meet Food and Drug Administration standards for drug approval. Guidelines for the organization of ethical committees and institutional review boards have been discussed with researchers from different participating centers. Several courses for the training and education of staff engaged in clinical research have been implemented, including a detailed discussion about the current standards for reporting toxicities and tumor responses. In addition, SOAD offers annual courses for South American institutions interested in participating in our clinical trials network. Table 1 lists SOAD’s current clinical trials programs.
One interesting aspect that deserves a special comment relates to the attitude of cancer patient toward anticancer drug development within the framework of SOAD. In contrast to our initially negative expectations, a review of the applications of written informed consent for SOAD early clinical trials activated between the years 1995 and 2001 demonstrates that the vast majority of patients asked to participate in clinical studies with new anticancer agents and/or drug combinations accepted the procedure and agreed to participate in the studies. Table 2 lists the total number of trials, accrual and refusal numbers, and reasons for patient refusal. Indeed, only seven out of 493 patients refused to give written informed consent and participate in the studies. Therefore, cancer patients in South America are eager to participate in the international effort in drug discovery and development.
THE MANAGEMENT OF PATIENTS WITH STAGE IIIA BREAST CANCER In order to give a clear picture to the readers on how patients with stage IIIA breast cancer are managed in South America, the clinical case presented by the speakers at the 2001 ASCO International Symposium on the Management of Advanced Breast Cancer was discussed with prominent medical oncologists and radiotherapists presently holding senior positions in breast units of major cancer hospitals in Brazil, Argentina, Chile, Peru, Colombia, Venezuela, and Uruguay. The diagnostic approach to the patient included at least a complete medical history and physical examination, routine laboratory work-up, bilateral mammography, chest x-ray, abdominal ultrasound, and a bone scan. Computed tomography and/or nuclear magnetic resonance imaging was considered only in special cases. A core biopsy (preferable) or fine-needle biopsy was recommended for obtaining tumor tissue for pathologic diagnosis. The latter should contain the confirmation of malignancy and histologic subtype, tumor size, grade, and the presence or absence of tumor involvement in the surgical margins. The total number of axillary lymph nodes contained in the surgical specimen, the number of tumor-positive lymph nodes, the hormone receptor status, and, more recently, the Ki-67, erb2, and p53 analyses are also obtained from the pathologic report in most centers. Patients with stage IIIA breast cancer usually receive neoadjuvant chemotherapy, with initial surgery being reserved for special cases in which a complete tumor resection is technically feasible and breast conservation is not a realistic goal. The most commonly used drug regimens include doxorubicin plus cyclophosphamide with or without the addition of fluorouracil (for instance, the AC or FAC regimens). Treatment is administered for three to four cycles (or longer in case of excellent and persistent tumor response) and followed by a modified radical mastectomy or breast-conserving surgery. Immediate reconstruction is being offered in some centers, especially in Brazil. Postoperative chemotherapy is usually given for additional cycles (up to the limit of a safe doxorubicin cumulative dose or guided by its effects on left ventricular ejection fraction). In patients who exhibit a clear tumor response to neoadjuvant chemotherapy, the same drug regimen is applied, while other regimens or agents, such as cyclophosphamide, methotrexate, and fluorouracil or taxanes, can be considered in cases of no or minimal initial tumor response. In most centers, irradiation to the breast region is given afterward. In inoperable cases, irradiation to the breast is given right after the maximum effect of neoadjuvant chemotherapy. Antiestrogen therapy (usually oral tamoxifen 20 mg/d) is offered for 5 years to women with hormone receptor–positive tumors. In conclusion, breast cancer is a public health problem in many countries in South America, especially in the temperate region, where the incidence of this disease is comparable to that in most countries in Europe. Our main challenge is the early detection of the disease, as a large number of patients are diagnosed at clinical stages II and III. Use of breast self-examination and screening mammography is far below the recommended standards. Fortunately, several actions are being taken by governmental and nongovernmental organizations to improve patient awareness of breast cancer and to promote the earlier detection of this disease in the future.
I would like to express my gratitude to physicians working at the Academic Hospital and the Institute of Oncology of Montevideo, Uruguay; University of Buenos Aires and Fleming Institute in Buenos Aires, Argentina; Luiz Rizetti Institute in Caracas, Venezuela; National Cancer Institute in Bogota, Colombia; Institute of Neoplastic Diseases in Lima, Peru; Radiomedicine Institute in Santiago, Chile; and the National Cancer Institute in Rio de Janeiro, Academic Hospital of the University of Sao Paulo, Academic Hospital of the Federal University of Paraná, Erasto Gaertner Hospital in Curitiba, the Breast Institute of Rio Grande do Sul, and the Academic Hospital of the Federal University of Rio Grande do Sul in Porto Alegre, Brazil. They all contributed with their experience to produce the information presented in this article.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
