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Clinical characteristics and outcomes of older women with breast cancer in Mexico
Journal of Geriatric Oncology 9 (2018) 620–625
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Journal of Geriatric Oncology
Clinical characteristics and outcomes of older women with breast cancer in Mexico Paula Cabrera-Galeana a,1, Enrique Soto-Perez-de-Celis a,b,1, Nancy Reynoso-Noverón a, Cynthia Villarreal-Garza a,c, Claudia Arce-Salinas a, Juan Matus-Santos a, María Teresa Ramírez-Ugalde a, Alberto Alvarado-Miranda a, Abelardo Meneses-García d, Fernando Lara-Medina a, Juan Torres-Dominguez a, Enrique Bargalló-Rocha a, Alejandro Mohar e,⁎ a
Departamento de Tumores Mamarios, Instituto Nacional de Cancerología, Mexico City. Mexico Department of Geriatrics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico c Instituto Tecnológico de Monterrey, Monterrey, Mexico. d Instituto Nacional de Cancerología, Mexico City. Mexico e Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología e Instituto de Biomédicas, Mexico City, Mexico b
a r t i c l e
i n f o
Article history: Received 5 October 2017 Received in revised form 17 February 2018 Accepted 9 April 2018
Keywords: Breast neoplasms Older adults Developing countries Latin America Epidemiology Health services accessibility Mexico Latinas
a b s t r a c t Introduction: Although the epidemiology of breast cancer in older women has been widely described before, little is known about the clinical characteristics and prognosis of older patients living in developing countries. Here, we studied older women with breast cancer treated at a public cancer center in Mexico City, and compared their outcomes with their younger counterparts. Materials and Methods: We retrospectively analyzed a database of 5488 women treated for breast cancer at a single institution. We compared clinical characteristics, treatment and survival between women aged b65 and ≥65 years of age. Survival analyses were performed for each molecular subtype. Results: 851 women (15.5%) were ≥65 years of age, of which 45% presented with Stages III–IV disease. Compared with their younger counterparts, older women had lower grade disease, a larger proportion of hormone receptor positive tumors, and were less likely to receive both chemotherapy and radiotherapy. At 5 years, no differences in both disease free and overall survival were found between younger and older women in a multivariate model including stage, grade, tumor subtype and treatment received. Conclusions: In contrast with reports from high-income countries, older women with breast cancer in developing nations present with more advanced disease requiring more aggressive treatment. Strategies aimed at earlier detection, improved access to care, and downstaging among older adults are greatly needed in Mexico and in the rest of the developing world. © 2018 Elsevier Ltd. All rights reserved.
1. Introduction Breast cancer (BC) is a disease associated with aging, and demographic trends are one of the main drivers of change in global breast cancer incidence and mortality. In 2012, 42.6% of all new BC cases in high-income regions of the world occurred in women aged 65 years and older, compared with only 23.3% of cases in developing regions [1]. However, due to an accelerated aging of the population in the developing world, the absolute number of new BC cases in older women living in developing countries will more than double by the year 2035 [1]. Unfortunately, most of the information regarding the epidemiology, clinical characteristics, and outcomes of breast ⁎ Corresponding author at: Av San Fernando #22, Tlalpan, 14080 Mexico City, Mexico. E-mail address: [email protected] (A. Mohar). 1 Both authors contributed equally to the preparation of this manuscript.
https://doi.org/10.1016/j.jgo.2018.04.003 1879-4068/© 2018 Elsevier Ltd. All rights reserved.
cancer in older adults comes from more developed countries in North America or Western Europe [2], and those data are difficult to extrapolate to countries with different demographic, social, cultural and economic resources. Mexico is an upper-middle income country of 129 million inhabitants, of which 6.8% is 65 years of age and older [3]. Nevertheless, by 2035, this proportion will grow to 12.3%, representing a total of over eighteen million older adults [3]. Breast cancer is the most common malignancy in Mexico since 2006, and women aged 65 and older are among the groups with the highest growth in both incidence and mortality over the last decade [4]. In Mexico, breast cancer screening rates are b20%, and most women with BC are diagnosed at a later stage than in developed countries, with up to 50% presenting with Stage III or IV disease [5]. However, little is known about the clinical characteristics and outcomes of older Mexican women with breast cancer, and that presents a barrier to the creation of programs aimed at preparing for the
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impending increase in the number of new breast cancer cases in this patient population. In 2003, the Mexican Federal Government created Seguro Popular, a public insurance system aimed at providing healthcare coverage to vulnerable people working in the informal sectors of the economy [6]. In 2007, breast cancer was included among the diseases covered by Seguro Popular, providing access to care for about 50% of the country's population who were previously uninsured [6]. Here, we describe the clinical characteristics, prognostic factors, and prognosis of older women with breast cancer treated at the National Cancer Institute of Mexico (INCan) under Seguro Popular coverage, and compare their outcomes with their younger counterparts.
2. Materials and Methods This was a retrospective cohort study that included all patients with breast cancer treated at INCan, a public national cancer center located in Mexico City, between January 2007 and December 2015. All patients were treated under Seguro Popular coverage and had access to the same diagnostic and therapeutic procedures [6]. Ethical approval for this research was obtained from the INCan Ethics Committee and consent was not required due to its minimum risk. Patient characteristics, including stage at diagnosis, demographic and clinical data, histopathological characteristics, immunohistochemistry analysis, treatment, disease free survival (DFS), and overall survival (OS) were recorded in a central database. DFS was analyzed for patients with stage I–III disease and was defined as the time from diagnosis to the first recurrence event (death from any cause, locoregional or distant invasive recurrence, second primary invasive cancer, and ipsilateral/contralateral ductal carcinoma in-situ) [7]. OS was defined as the time from diagnosis to death from any cause. Patients were divided into two groups according to age: b65 years old and ≥65 years old. Clinical stage at diagnosis was determined using clinical and radiologic criteria. Histopathologic assessments were performed by dedicated breast pathologists. Estrogen receptor (ER) and progesterone receptor (PR) were determined by immunohistochemistry (IHC) [8], and their status was assessed using semi quantitative scoring method or “H-score” [9]. An H-score of ≥1 (corresponding to as few as 1–10% positive cells) was used to define ER and PR positivity. Cases with an H-score of b1 were classified as HR negative. For HR positive cases, the “H-score” was used define the intensity of receptor expression. Human epidermal growth factor receptor 2 (HER2) status was determined initially by IHC, followed by fluorescent in situ hybridization (FISH) in cases with 2+ membrane staining. Tumors were considered as HER2 positive in cases reported as 3+ by IHC or with an amplified FISH (ratio of HER2 to CEP17 of N2.2 or average HER2 gene copy number N six signals/nucleus) and negative in cases with 0+, 1+, and 2+ IHC staining with negative FISH amplification [10]. HR-negative, HER2-negative tumors were considered to be triple negative (TN). Data are presented as medians, means or proportions. Descriptive statistics were used to analyze the clinical and demographic characteristics of the population. According to the nature of the variable, the Chi-square test or Student's t-test was used to compare the distribution of baseline characteristics among age groups. Variables which were found to have a statistical significant difference between groups at a p-value b0.05, as well as those variables deemed as clinically relevant by the investigators, were included in multivariate analyses. Cox proportional hazards regression models were used to estimate recurrence and mortality risks between subgroups. Kaplan-Meier analysis was used to calculate DFS and OS outcomes. All statistical analyses were performed using STATA v.12 (StataCorp 2011, Stata Statistical Software: Release 12; StataCorp, College Station, TX). A two-sided p- value b0.05 was considered statistically significant.
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3. Results Between January 2007 and December 2015, 5488 women with a diagnosis of breast cancer were treated at INCan under Seguro Popular coverage. Tumor and treatment characteristics of patients included in this study are shown in Table 1. Median follow up was 40 months. 851 women (15.5%) treated during that period were ≥65 years of age (median age 70.9, range 65–92.6). We found no difference in the distribution of stages at presentation, with 45% of older women presenting with Stage III–IV disease. Tumors in older women were more likely to be low grade (22.4% vs 16.3%, p b 0.001) and HR+ (72.1% vs 58.6%, p b 0.001). Both TN (18% vs 12.7%, p b 0.001) and HER2+ disease (23.4% vs 15.3%, p b 0.001) were more common among younger women. Older women were more likely to have a diagnosis of diabetes (21% vs 9%, p b 0.001) and hypertension (41.1% vs 15.2%, p b 0.001). When treatment strategies between age groups were analyzed, we found significant differences in the use of all treatment modalities with the exception of surgery, with both age groups showing high mastectomy rates (81.1% vs 79.1%, p = 0.18). Older women were less likely to receive chemotherapy (62% vs 83%, p b 0.001) and radiotherapy (53.5% vs 66.5%, p b 0.001), but more likely to receive hormonal therapy (74.6% vs 67.3%, p b 0.001). Among the 748 women aged ≥65 years with Stage I-III disease, 62% (n = 462) received chemotherapy in the adjuvant (n = 195) or neoadjuvant (n = 267) setting. Older women were as likely to be treated with neoadjuvant chemotherapy as those b65 years of age (57.8% vs 60.9%, p = 0.20).
Table 1 Patient, tumor and treatment characteristics by age group. Characteristics
b65 years (n = 4637)
≥65 years (n = 851)
p
N (%)
N (%)
Stage I II III IV Missing data
613 (13.2) 1751 (37.8) 1636 (35.3) 558 (12.0) 79 (1.7)
129 (15.2) 327 (38.4) 280 (32.9) 103 (12.1) 12 (1.4)
0.46
Nuclear grade High Intermediate Low Missing data
2225 (48.0) 1420 (30.6) 712 (15.4) 280 (6.0)
326 (38.3) 285 (33.4) 176 (20.7) 64 (7.6)
b0.01
Subtype HR+,HER2− HR−, HER2− (triple negative) HR−, HER2+ HR+, HER2+ Missing data
2685 (57.9) 822 (17.7) 477 (10.3) 596 (12.9) 57 (1.2)
604 (71.0) 106 (12.4) 56 (6.6) 72 (8.5) 13 (1.5)
b0.01
Received chemotherapy Received surgery Breast conserving surgery Mastectomy Received hormonal therapy Received radiotherapy
3833 (82.7) 4030 (86.9) 844 (20.9) 3186 (79.1) 3119 (67.3) 3079 (66.4)
517 (61) 685 (80.5) 128 (18.7) 557 (81.3) 633 (74.4) 454 (53.3)
b0.01 b0.01 0.18
Comorbidities Diabetes Hypertension No diabetes/hypertension
418 (9.0) 706 (15.2) 3513 (75.8)
179 (21.0) 350 (41.1) 322 (37.9)
b0.01 b0.01 b0.01
Body mass index Low Normal Overweight Obese Missing data
45 (1.0) 1288 (27.8) 1895 (40.8) 1391 (30.0) 18 (0.4)
11 (1.3) 235 (27.6) 352 (41.4) 252 (29.6) 1 (0.1)
0.85
b0.01 b0.01
Abbreviations: HR, Hormone Receptor; HER2, Human Epidermal Growth Factor Receptor 2.
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For patients with Stage I-III disease at diagnosis, we found no difference in DFS between younger and older women (5 years DFS 78.5% vs 75.9%, p = 0.22). We also found no differences in DFS between age groups when each tumor subtype was analyzed independently (Fig. 1, Column A). Multivariate analysis for DFS found that age was not significantly related with a higher probability of recurrence (Table 2). For the entire population, we found no difference in OS at five years between older and younger age groups (83.5% vs. 83.6%, p = 0.25). When each tumor subtype was analyzed independently, we found no difference in OS between younger and older women with TN and HER2+ disease. However, OS was worse for women aged ≥65 years with HR+,HER2− disease when compared with their younger counterparts (5 year OS 85.9% vs 87.4%, p = 0.02) (Fig. 1, Column B). Multivariate analysis for OS found that age was not significantly related with a higher probability of all-cause mortality (Table 3). 4. Discussion This study represents the first description of the characteristics and subtype-specific survival of older women with breast cancer in a Latin American country. In contrast with studies from more developed regions of the world [2], older Mexican women with breast cancer have a higher rate of locally advanced and metastatic disease, and more often require the use of adjuvant or neoadjuvant chemotherapy and mastectomy. However, despite those adverse prognostic factors, age itself was not found to be a predictor of relapse and of all-cause mortality at five years follow-up in a multivariate model correcting for stage, grade, tumor subtype, and treatment received. Understanding the clinical characteristics and outcomes of older women with breast cancer living in developing countries is relevant because most of the world's older adults live in less-developed regions, where healthcare systems are less prepared to treat patients with complex chronic diseases [11]. Our results illustrate the epidemiology of breast cancer among older adults in a country that lacks a comprehensive screening program (only 20% of women potentially eligible for screening can access a mammogram in Mexico), which may explain the low proportion of older adults in our population (15%) [5]. Another possible explanation for the low proportion of older adults could be that many older patients are being treated at smaller centers, or not treated at all, instead of being referred to third-level centers. However, it is important to point out that only about 20% of new breast cancer cases reported by the Epidemiological Surveillance System of the Mexican Ministry of Health occur in women aged 65 years and older, and that the incidence rate of breast cancer among older women in Mexico (45–52 cases per 100,000) is much lower than in more developed countries [4,5]. That being said, it is highly likely that the incidence of breast cancer will continue to rise among Mexican women due to lifestyle changes such as an increase in alcohol consumption; a decrease in fertility rates and breastfeeding; and an increase in sedentary behaviors and obesity [5]. In our series, a large proportion of older women (45%) presented with stage III-IV breast cancer. This high incidence of advanced disease at presentation differs greatly from that reported in series from the United States (US) and Western Europe [2], where the proportion of older women with advanced disease has historically been lower than 15%. Although this observation may be partially related with the limited availability of screening, it could also be explained by the existing barriers in access to care for women with a suspicion of breast cancer, which lead to more advanced disease at presentation [5]. In addition to deficient screening programs, social, cultural and financial barriers like lack of awareness, low health literacy and poverty can also lead to a late diagnosis. A recent publication found that, among Mexican women treated for breast cancer at four major hospitals in Mexico City, the median time between first symptoms and the beginning of treatment was seven months, with the longest interval being that
from first medical consultation to arrival at a cancer center [12]. The median time from symptom identification to first physician visit (patient interval) has been found to be of between ten and 60 days, and N20% of patients wait for more than three months before seeking hep due to a symptomatic breast mass [13,14]. Furthermore, over 65% of patients face diagnostic delays of three months or more after they are first seen by a physician (health system interval) [13]. These delays may be longer in older patients, with another recent survey reporting that among Mexican women aged 65 and older, N40% reported having symptoms for at least twelve months prior to seeking medical attention [15]. A similar study in Colombia showed that the main reason for not seeking medical care was considering that the symptoms were “not important”, and that both increasing age and lower educational levels were strongly associated with longer diagnostic delays [16]. In Mexico, the average schooling of older adults is 5.8 years for those aged 60 to 64, 4.1 years for those aged 65 to 84, and 2.7 years for those aged 85 and older, which means that older Mexican adults also have low schooling levels, which may further contribute to treatment delays [17]. All of these data, combined with the high proportion of patients with advanced stages found in our study, highlight the importance of downstaging of symptomatic disease among older patients with breast cancer in developing countries through improved education and awareness. Treatment patterns in our patient population also differ from those seen in high income nations [2,18], with almost two thirds of older patients receiving chemotherapy in the adjuvant or neoadjuvant setting, and with a large proportion of patients undergoing mastectomy. This is driven both by the late stage at presentation and by the fact that biomarker assays are not available to guide treatment decision-making within the Mexican healthcare system. Our group has previously shown that among women with breast cancer treated at our center, a reduction in chemotherapy use of about 15% can be achieved when biomarker assays are utilized, even in patients with more advanced stages at presentation [19]. Finally, the reported fiveyear OS for the entire patient population was inferior to that found in developed countries, which is most likely also driven by the high proportion of patients for advanced disease stage [2]. However, it is important to highlight that, just as reported in other series, age was not significantly related with five-year mortality when all breast cancer subtypes were analyzed. The fact that a lower five-year OS, but not DFS, was found among older women with HR+, HER2− disease may be related to competing causes of mortality among older women with this subtype. The present study has limitations. Information was collected retrospectively and our follow-up time is relatively short, which may not capture the outcome of women with competing causes of death. Molecular subtypes were categorized using IHC, and previous studies have shown that among older adults, the use of gene expression microarrays may be better at characterizing breast cancer subtypes [18]. Our database has limited information regarding the specific characteristics of treatment (including type of chemotherapy and radiotherapy dosing) as well as adherence to endocrine treatment in those patients who received it. The database also lacks information on the socioeconomic or educational level of the patients, which may potentially impact access to care and stage at presentation. That being said, all of our patients had no private insurance and were not covered by social security. It is also important to mention that our Institution is a national cancer center, and that our results may not be an accurate reflection of the outcomes of patients receiving treatment in smaller cancer centers in other regions of Mexico. Finally, none of the patients in our database had any type of geriatric assessment, and our information on comorbidities and their severity is very minimal, with only hypertension and diabetes recorded within the database. However, we believe that this study will represent a stepping stone towards including the geriatric assessment, as well as more complete datasets, into our everyday clinical practice, as well as documenting geriatric assessment variables in our database.
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Fig. 1. Disease Free Survival (DFS) (Column A) and Overall Survival (OS) (Column B) by age group for the entire patient population and for patients with each breast cancer subtype (HR: Hormone Receptor; HER2: Human epidermal growth factor receptor 2; TN: Triple negative).
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Table 2 Multivariate analysis for recurrence risk (for patients with Stage I–III disease). Characteristic
p
Characteristic
HR (95% CI)
p
1 1.13 (0.93–1.38)
– 0.21
Age group b65 years ≥65 years
1 0.90 (0.7–1.1)
– 0.382
Stage I II III
1 2.31 (1.51–3.53) 6.31 (4.16–9.57)
– b0.01 b0.01
Nuclear grade High Intermediate Low
Stage I II III IV
1 2.70 (1.4–5.3) 11.51 (5.9–22.3) 18.97 (9.6–37.5)
– b0.01 b0.01 b0.01
1 0.86 (0.7–1) 0.98 (0.8–1.2)
– 0.10 0.85
Tumor subtype HR+, HER− Triple negative HR−, HER2+ HR+, HER2+
Nuclear grade High Intermediate Low
1 0.78 (0.6–0.9) 0.65 (0.5–0.8)
– 0.01 b0.01
1 1.57 (1.3–1.9) 0.91 (0.7–1.2) 0.84 (0.7–1.1)
– b0.01 0.45 0.16
Received chemotherapy No Yes
Tumor subtype HR+, HER− Triple negative HR−, HER2+ HR+, HER2+
1 2.26 (1.8–2.8) 1.14 (0.9–1.5) 0.96 (0.7–1.2)
– b0.01 0.36 0.74
1 1.87 (1.33–2.63)
– b0.01
Received surgery No Yes
Received chemotherapy No Yes
1 0.65 (0.5–0.9)
– 0.02
1 0.15 (0.12–0.18)
– b0.01
Received radiotherapy No Yes
Received surgery No Yes
1 0.18 (0.1–0.2)
– b0.01
1 1.13 (0.93–1.36)
– 0.21
Received radiotherapy No Yes
1 0.72 (0.6–0.9)
– b0.01
Body mass index Normal Low Overweight Obese
1 2.21 (0.6–0.9) 0.93 (0.8–1.1) 0.99 (0.8–1.2)
– b0.01 0.47 0.93
Age group b65 years ≥65 years
HR (95% CI)
Table 3 Multivariate analysis for all-cause mortality risk (all patients).
No. Obs = 4429; No. Events = 807; Likelihood ratio ×2 (10) = 733.26; Log Likelihood = −5964.67; prob N ×2 = 0.0000. Diagnosis: Harrell's C = 0.7586; Somers'D = 0.5172. Abbreviations: HR, Hormone Receptor; HER2, Human Epidermal Growth Factor Receptor 2.
In summary, older women with breast cancer living in Mexico present with more advanced disease, require cytotoxic treatment more often and have worse survival than those living in high-income nations. However, when provided with appropriate care and coverage, their prognosis is comparable to their younger counterparts. Better strategies, including improved awareness and access to care, are needed to downstage the disease and to improve the outcomes of older Mexican women with breast cancer.
No. Obs = 4992; No. Events = 604; Likelihood ratio ×2 (15) = 1052.70; Log Likelihood = −4318.48; prob N ×2 = 0.0000. Diagnosis: Harrell's C = 0.8464; Somers'D = 0.6928. Abbreviations: HR, Hormone Receptor; HER2, Human Epidermal Growth Factor Receptor 2.
Soto-Perez-de-Celis, Nancy Reynoso-Noverón, Enrique Bargalló-Rocha, Alejandro Mohar.
Disclosures and Conflict of Interest Statements
References
Cynthia Villarreal-Garza reports consultant or advisory roles from Pfizer and Novartis, research funding from Novartis and speaker fees from Pfizer, Roche and Patia. Enrique Bargalló-Rocha reports speaker fees from Genomic Health. Paula Cabrera-Galeana reports speaker fees from Pfizer. Juan Matus-Santos reports speaker fees from Roche. All the other authors have no financial conflicts of interest to disclose.
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Authorship Contributions Study concepts: Paula Cabrera-Galeana, Enrique Soto-Perez-de-Celis, Nancy Reynoso Noveron, Enrique Bargallo Rocha, Alejandro Mohar. Study design: Paula Cabrera Galeana, Enrique Soto Pérez de Celis, Nancy Reynoso Noveron. Data acquisition: Nancy Reynoso Noveron, Juan Torres-Dominguez, Cynthia Villarreal Garza, Claudia Arce-Salinas, Juan Matus-Santos, Maria Teresa Ramirez-Ugalde, Alberto AlvaradoMiranda. Quality control of data: Nancy Reynoso Noveron, Juan TorresDominguez, Alejandro Mohar. Data analysis and interpretation: Nancy Reynoso Noveron, Juan Torres-Dominguez, Paula Cabrera Galeana, Enrique Soto Pérez de Celis, Enrique Bargallo Rocha. Statistical analysis: Nancy Reynoso Noveron. Manuscript preparation: Enrique Soto Pérez de Celis, Paula Cabrera Galeana. Manuscript editing: All authors. Manuscript review: Paula Cabrera-Galeana, Enrique
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Contents lists available at ScienceDirect
Journal of Geriatric Oncology
Clinical characteristics and outcomes of older women with breast cancer in Mexico Paula Cabrera-Galeana a,1, Enrique Soto-Perez-de-Celis a,b,1, Nancy Reynoso-Noverón a, Cynthia Villarreal-Garza a,c, Claudia Arce-Salinas a, Juan Matus-Santos a, María Teresa Ramírez-Ugalde a, Alberto Alvarado-Miranda a, Abelardo Meneses-García d, Fernando Lara-Medina a, Juan Torres-Dominguez a, Enrique Bargalló-Rocha a, Alejandro Mohar e,⁎ a
Departamento de Tumores Mamarios, Instituto Nacional de Cancerología, Mexico City. Mexico Department of Geriatrics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico c Instituto Tecnológico de Monterrey, Monterrey, Mexico. d Instituto Nacional de Cancerología, Mexico City. Mexico e Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología e Instituto de Biomédicas, Mexico City, Mexico b
a r t i c l e
i n f o
Article history: Received 5 October 2017 Received in revised form 17 February 2018 Accepted 9 April 2018
Keywords: Breast neoplasms Older adults Developing countries Latin America Epidemiology Health services accessibility Mexico Latinas
a b s t r a c t Introduction: Although the epidemiology of breast cancer in older women has been widely described before, little is known about the clinical characteristics and prognosis of older patients living in developing countries. Here, we studied older women with breast cancer treated at a public cancer center in Mexico City, and compared their outcomes with their younger counterparts. Materials and Methods: We retrospectively analyzed a database of 5488 women treated for breast cancer at a single institution. We compared clinical characteristics, treatment and survival between women aged b65 and ≥65 years of age. Survival analyses were performed for each molecular subtype. Results: 851 women (15.5%) were ≥65 years of age, of which 45% presented with Stages III–IV disease. Compared with their younger counterparts, older women had lower grade disease, a larger proportion of hormone receptor positive tumors, and were less likely to receive both chemotherapy and radiotherapy. At 5 years, no differences in both disease free and overall survival were found between younger and older women in a multivariate model including stage, grade, tumor subtype and treatment received. Conclusions: In contrast with reports from high-income countries, older women with breast cancer in developing nations present with more advanced disease requiring more aggressive treatment. Strategies aimed at earlier detection, improved access to care, and downstaging among older adults are greatly needed in Mexico and in the rest of the developing world. © 2018 Elsevier Ltd. All rights reserved.
1. Introduction Breast cancer (BC) is a disease associated with aging, and demographic trends are one of the main drivers of change in global breast cancer incidence and mortality. In 2012, 42.6% of all new BC cases in high-income regions of the world occurred in women aged 65 years and older, compared with only 23.3% of cases in developing regions [1]. However, due to an accelerated aging of the population in the developing world, the absolute number of new BC cases in older women living in developing countries will more than double by the year 2035 [1]. Unfortunately, most of the information regarding the epidemiology, clinical characteristics, and outcomes of breast ⁎ Corresponding author at: Av San Fernando #22, Tlalpan, 14080 Mexico City, Mexico. E-mail address: [email protected] (A. Mohar). 1 Both authors contributed equally to the preparation of this manuscript.
https://doi.org/10.1016/j.jgo.2018.04.003 1879-4068/© 2018 Elsevier Ltd. All rights reserved.
cancer in older adults comes from more developed countries in North America or Western Europe [2], and those data are difficult to extrapolate to countries with different demographic, social, cultural and economic resources. Mexico is an upper-middle income country of 129 million inhabitants, of which 6.8% is 65 years of age and older [3]. Nevertheless, by 2035, this proportion will grow to 12.3%, representing a total of over eighteen million older adults [3]. Breast cancer is the most common malignancy in Mexico since 2006, and women aged 65 and older are among the groups with the highest growth in both incidence and mortality over the last decade [4]. In Mexico, breast cancer screening rates are b20%, and most women with BC are diagnosed at a later stage than in developed countries, with up to 50% presenting with Stage III or IV disease [5]. However, little is known about the clinical characteristics and outcomes of older Mexican women with breast cancer, and that presents a barrier to the creation of programs aimed at preparing for the
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impending increase in the number of new breast cancer cases in this patient population. In 2003, the Mexican Federal Government created Seguro Popular, a public insurance system aimed at providing healthcare coverage to vulnerable people working in the informal sectors of the economy [6]. In 2007, breast cancer was included among the diseases covered by Seguro Popular, providing access to care for about 50% of the country's population who were previously uninsured [6]. Here, we describe the clinical characteristics, prognostic factors, and prognosis of older women with breast cancer treated at the National Cancer Institute of Mexico (INCan) under Seguro Popular coverage, and compare their outcomes with their younger counterparts.
2. Materials and Methods This was a retrospective cohort study that included all patients with breast cancer treated at INCan, a public national cancer center located in Mexico City, between January 2007 and December 2015. All patients were treated under Seguro Popular coverage and had access to the same diagnostic and therapeutic procedures [6]. Ethical approval for this research was obtained from the INCan Ethics Committee and consent was not required due to its minimum risk. Patient characteristics, including stage at diagnosis, demographic and clinical data, histopathological characteristics, immunohistochemistry analysis, treatment, disease free survival (DFS), and overall survival (OS) were recorded in a central database. DFS was analyzed for patients with stage I–III disease and was defined as the time from diagnosis to the first recurrence event (death from any cause, locoregional or distant invasive recurrence, second primary invasive cancer, and ipsilateral/contralateral ductal carcinoma in-situ) [7]. OS was defined as the time from diagnosis to death from any cause. Patients were divided into two groups according to age: b65 years old and ≥65 years old. Clinical stage at diagnosis was determined using clinical and radiologic criteria. Histopathologic assessments were performed by dedicated breast pathologists. Estrogen receptor (ER) and progesterone receptor (PR) were determined by immunohistochemistry (IHC) [8], and their status was assessed using semi quantitative scoring method or “H-score” [9]. An H-score of ≥1 (corresponding to as few as 1–10% positive cells) was used to define ER and PR positivity. Cases with an H-score of b1 were classified as HR negative. For HR positive cases, the “H-score” was used define the intensity of receptor expression. Human epidermal growth factor receptor 2 (HER2) status was determined initially by IHC, followed by fluorescent in situ hybridization (FISH) in cases with 2+ membrane staining. Tumors were considered as HER2 positive in cases reported as 3+ by IHC or with an amplified FISH (ratio of HER2 to CEP17 of N2.2 or average HER2 gene copy number N six signals/nucleus) and negative in cases with 0+, 1+, and 2+ IHC staining with negative FISH amplification [10]. HR-negative, HER2-negative tumors were considered to be triple negative (TN). Data are presented as medians, means or proportions. Descriptive statistics were used to analyze the clinical and demographic characteristics of the population. According to the nature of the variable, the Chi-square test or Student's t-test was used to compare the distribution of baseline characteristics among age groups. Variables which were found to have a statistical significant difference between groups at a p-value b0.05, as well as those variables deemed as clinically relevant by the investigators, were included in multivariate analyses. Cox proportional hazards regression models were used to estimate recurrence and mortality risks between subgroups. Kaplan-Meier analysis was used to calculate DFS and OS outcomes. All statistical analyses were performed using STATA v.12 (StataCorp 2011, Stata Statistical Software: Release 12; StataCorp, College Station, TX). A two-sided p- value b0.05 was considered statistically significant.
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3. Results Between January 2007 and December 2015, 5488 women with a diagnosis of breast cancer were treated at INCan under Seguro Popular coverage. Tumor and treatment characteristics of patients included in this study are shown in Table 1. Median follow up was 40 months. 851 women (15.5%) treated during that period were ≥65 years of age (median age 70.9, range 65–92.6). We found no difference in the distribution of stages at presentation, with 45% of older women presenting with Stage III–IV disease. Tumors in older women were more likely to be low grade (22.4% vs 16.3%, p b 0.001) and HR+ (72.1% vs 58.6%, p b 0.001). Both TN (18% vs 12.7%, p b 0.001) and HER2+ disease (23.4% vs 15.3%, p b 0.001) were more common among younger women. Older women were more likely to have a diagnosis of diabetes (21% vs 9%, p b 0.001) and hypertension (41.1% vs 15.2%, p b 0.001). When treatment strategies between age groups were analyzed, we found significant differences in the use of all treatment modalities with the exception of surgery, with both age groups showing high mastectomy rates (81.1% vs 79.1%, p = 0.18). Older women were less likely to receive chemotherapy (62% vs 83%, p b 0.001) and radiotherapy (53.5% vs 66.5%, p b 0.001), but more likely to receive hormonal therapy (74.6% vs 67.3%, p b 0.001). Among the 748 women aged ≥65 years with Stage I-III disease, 62% (n = 462) received chemotherapy in the adjuvant (n = 195) or neoadjuvant (n = 267) setting. Older women were as likely to be treated with neoadjuvant chemotherapy as those b65 years of age (57.8% vs 60.9%, p = 0.20).
Table 1 Patient, tumor and treatment characteristics by age group. Characteristics
b65 years (n = 4637)
≥65 years (n = 851)
p
N (%)
N (%)
Stage I II III IV Missing data
613 (13.2) 1751 (37.8) 1636 (35.3) 558 (12.0) 79 (1.7)
129 (15.2) 327 (38.4) 280 (32.9) 103 (12.1) 12 (1.4)
0.46
Nuclear grade High Intermediate Low Missing data
2225 (48.0) 1420 (30.6) 712 (15.4) 280 (6.0)
326 (38.3) 285 (33.4) 176 (20.7) 64 (7.6)
b0.01
Subtype HR+,HER2− HR−, HER2− (triple negative) HR−, HER2+ HR+, HER2+ Missing data
2685 (57.9) 822 (17.7) 477 (10.3) 596 (12.9) 57 (1.2)
604 (71.0) 106 (12.4) 56 (6.6) 72 (8.5) 13 (1.5)
b0.01
Received chemotherapy Received surgery Breast conserving surgery Mastectomy Received hormonal therapy Received radiotherapy
3833 (82.7) 4030 (86.9) 844 (20.9) 3186 (79.1) 3119 (67.3) 3079 (66.4)
517 (61) 685 (80.5) 128 (18.7) 557 (81.3) 633 (74.4) 454 (53.3)
b0.01 b0.01 0.18
Comorbidities Diabetes Hypertension No diabetes/hypertension
418 (9.0) 706 (15.2) 3513 (75.8)
179 (21.0) 350 (41.1) 322 (37.9)
b0.01 b0.01 b0.01
Body mass index Low Normal Overweight Obese Missing data
45 (1.0) 1288 (27.8) 1895 (40.8) 1391 (30.0) 18 (0.4)
11 (1.3) 235 (27.6) 352 (41.4) 252 (29.6) 1 (0.1)
0.85
b0.01 b0.01
Abbreviations: HR, Hormone Receptor; HER2, Human Epidermal Growth Factor Receptor 2.
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For patients with Stage I-III disease at diagnosis, we found no difference in DFS between younger and older women (5 years DFS 78.5% vs 75.9%, p = 0.22). We also found no differences in DFS between age groups when each tumor subtype was analyzed independently (Fig. 1, Column A). Multivariate analysis for DFS found that age was not significantly related with a higher probability of recurrence (Table 2). For the entire population, we found no difference in OS at five years between older and younger age groups (83.5% vs. 83.6%, p = 0.25). When each tumor subtype was analyzed independently, we found no difference in OS between younger and older women with TN and HER2+ disease. However, OS was worse for women aged ≥65 years with HR+,HER2− disease when compared with their younger counterparts (5 year OS 85.9% vs 87.4%, p = 0.02) (Fig. 1, Column B). Multivariate analysis for OS found that age was not significantly related with a higher probability of all-cause mortality (Table 3). 4. Discussion This study represents the first description of the characteristics and subtype-specific survival of older women with breast cancer in a Latin American country. In contrast with studies from more developed regions of the world [2], older Mexican women with breast cancer have a higher rate of locally advanced and metastatic disease, and more often require the use of adjuvant or neoadjuvant chemotherapy and mastectomy. However, despite those adverse prognostic factors, age itself was not found to be a predictor of relapse and of all-cause mortality at five years follow-up in a multivariate model correcting for stage, grade, tumor subtype, and treatment received. Understanding the clinical characteristics and outcomes of older women with breast cancer living in developing countries is relevant because most of the world's older adults live in less-developed regions, where healthcare systems are less prepared to treat patients with complex chronic diseases [11]. Our results illustrate the epidemiology of breast cancer among older adults in a country that lacks a comprehensive screening program (only 20% of women potentially eligible for screening can access a mammogram in Mexico), which may explain the low proportion of older adults in our population (15%) [5]. Another possible explanation for the low proportion of older adults could be that many older patients are being treated at smaller centers, or not treated at all, instead of being referred to third-level centers. However, it is important to point out that only about 20% of new breast cancer cases reported by the Epidemiological Surveillance System of the Mexican Ministry of Health occur in women aged 65 years and older, and that the incidence rate of breast cancer among older women in Mexico (45–52 cases per 100,000) is much lower than in more developed countries [4,5]. That being said, it is highly likely that the incidence of breast cancer will continue to rise among Mexican women due to lifestyle changes such as an increase in alcohol consumption; a decrease in fertility rates and breastfeeding; and an increase in sedentary behaviors and obesity [5]. In our series, a large proportion of older women (45%) presented with stage III-IV breast cancer. This high incidence of advanced disease at presentation differs greatly from that reported in series from the United States (US) and Western Europe [2], where the proportion of older women with advanced disease has historically been lower than 15%. Although this observation may be partially related with the limited availability of screening, it could also be explained by the existing barriers in access to care for women with a suspicion of breast cancer, which lead to more advanced disease at presentation [5]. In addition to deficient screening programs, social, cultural and financial barriers like lack of awareness, low health literacy and poverty can also lead to a late diagnosis. A recent publication found that, among Mexican women treated for breast cancer at four major hospitals in Mexico City, the median time between first symptoms and the beginning of treatment was seven months, with the longest interval being that
from first medical consultation to arrival at a cancer center [12]. The median time from symptom identification to first physician visit (patient interval) has been found to be of between ten and 60 days, and N20% of patients wait for more than three months before seeking hep due to a symptomatic breast mass [13,14]. Furthermore, over 65% of patients face diagnostic delays of three months or more after they are first seen by a physician (health system interval) [13]. These delays may be longer in older patients, with another recent survey reporting that among Mexican women aged 65 and older, N40% reported having symptoms for at least twelve months prior to seeking medical attention [15]. A similar study in Colombia showed that the main reason for not seeking medical care was considering that the symptoms were “not important”, and that both increasing age and lower educational levels were strongly associated with longer diagnostic delays [16]. In Mexico, the average schooling of older adults is 5.8 years for those aged 60 to 64, 4.1 years for those aged 65 to 84, and 2.7 years for those aged 85 and older, which means that older Mexican adults also have low schooling levels, which may further contribute to treatment delays [17]. All of these data, combined with the high proportion of patients with advanced stages found in our study, highlight the importance of downstaging of symptomatic disease among older patients with breast cancer in developing countries through improved education and awareness. Treatment patterns in our patient population also differ from those seen in high income nations [2,18], with almost two thirds of older patients receiving chemotherapy in the adjuvant or neoadjuvant setting, and with a large proportion of patients undergoing mastectomy. This is driven both by the late stage at presentation and by the fact that biomarker assays are not available to guide treatment decision-making within the Mexican healthcare system. Our group has previously shown that among women with breast cancer treated at our center, a reduction in chemotherapy use of about 15% can be achieved when biomarker assays are utilized, even in patients with more advanced stages at presentation [19]. Finally, the reported fiveyear OS for the entire patient population was inferior to that found in developed countries, which is most likely also driven by the high proportion of patients for advanced disease stage [2]. However, it is important to highlight that, just as reported in other series, age was not significantly related with five-year mortality when all breast cancer subtypes were analyzed. The fact that a lower five-year OS, but not DFS, was found among older women with HR+, HER2− disease may be related to competing causes of mortality among older women with this subtype. The present study has limitations. Information was collected retrospectively and our follow-up time is relatively short, which may not capture the outcome of women with competing causes of death. Molecular subtypes were categorized using IHC, and previous studies have shown that among older adults, the use of gene expression microarrays may be better at characterizing breast cancer subtypes [18]. Our database has limited information regarding the specific characteristics of treatment (including type of chemotherapy and radiotherapy dosing) as well as adherence to endocrine treatment in those patients who received it. The database also lacks information on the socioeconomic or educational level of the patients, which may potentially impact access to care and stage at presentation. That being said, all of our patients had no private insurance and were not covered by social security. It is also important to mention that our Institution is a national cancer center, and that our results may not be an accurate reflection of the outcomes of patients receiving treatment in smaller cancer centers in other regions of Mexico. Finally, none of the patients in our database had any type of geriatric assessment, and our information on comorbidities and their severity is very minimal, with only hypertension and diabetes recorded within the database. However, we believe that this study will represent a stepping stone towards including the geriatric assessment, as well as more complete datasets, into our everyday clinical practice, as well as documenting geriatric assessment variables in our database.
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Fig. 1. Disease Free Survival (DFS) (Column A) and Overall Survival (OS) (Column B) by age group for the entire patient population and for patients with each breast cancer subtype (HR: Hormone Receptor; HER2: Human epidermal growth factor receptor 2; TN: Triple negative).
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Table 2 Multivariate analysis for recurrence risk (for patients with Stage I–III disease). Characteristic
p
Characteristic
HR (95% CI)
p
1 1.13 (0.93–1.38)
– 0.21
Age group b65 years ≥65 years
1 0.90 (0.7–1.1)
– 0.382
Stage I II III
1 2.31 (1.51–3.53) 6.31 (4.16–9.57)
– b0.01 b0.01
Nuclear grade High Intermediate Low
Stage I II III IV
1 2.70 (1.4–5.3) 11.51 (5.9–22.3) 18.97 (9.6–37.5)
– b0.01 b0.01 b0.01
1 0.86 (0.7–1) 0.98 (0.8–1.2)
– 0.10 0.85
Tumor subtype HR+, HER− Triple negative HR−, HER2+ HR+, HER2+
Nuclear grade High Intermediate Low
1 0.78 (0.6–0.9) 0.65 (0.5–0.8)
– 0.01 b0.01
1 1.57 (1.3–1.9) 0.91 (0.7–1.2) 0.84 (0.7–1.1)
– b0.01 0.45 0.16
Received chemotherapy No Yes
Tumor subtype HR+, HER− Triple negative HR−, HER2+ HR+, HER2+
1 2.26 (1.8–2.8) 1.14 (0.9–1.5) 0.96 (0.7–1.2)
– b0.01 0.36 0.74
1 1.87 (1.33–2.63)
– b0.01
Received surgery No Yes
Received chemotherapy No Yes
1 0.65 (0.5–0.9)
– 0.02
1 0.15 (0.12–0.18)
– b0.01
Received radiotherapy No Yes
Received surgery No Yes
1 0.18 (0.1–0.2)
– b0.01
1 1.13 (0.93–1.36)
– 0.21
Received radiotherapy No Yes
1 0.72 (0.6–0.9)
– b0.01
Body mass index Normal Low Overweight Obese
1 2.21 (0.6–0.9) 0.93 (0.8–1.1) 0.99 (0.8–1.2)
– b0.01 0.47 0.93
Age group b65 years ≥65 years
HR (95% CI)
Table 3 Multivariate analysis for all-cause mortality risk (all patients).
No. Obs = 4429; No. Events = 807; Likelihood ratio ×2 (10) = 733.26; Log Likelihood = −5964.67; prob N ×2 = 0.0000. Diagnosis: Harrell's C = 0.7586; Somers'D = 0.5172. Abbreviations: HR, Hormone Receptor; HER2, Human Epidermal Growth Factor Receptor 2.
In summary, older women with breast cancer living in Mexico present with more advanced disease, require cytotoxic treatment more often and have worse survival than those living in high-income nations. However, when provided with appropriate care and coverage, their prognosis is comparable to their younger counterparts. Better strategies, including improved awareness and access to care, are needed to downstage the disease and to improve the outcomes of older Mexican women with breast cancer.
No. Obs = 4992; No. Events = 604; Likelihood ratio ×2 (15) = 1052.70; Log Likelihood = −4318.48; prob N ×2 = 0.0000. Diagnosis: Harrell's C = 0.8464; Somers'D = 0.6928. Abbreviations: HR, Hormone Receptor; HER2, Human Epidermal Growth Factor Receptor 2.
Soto-Perez-de-Celis, Nancy Reynoso-Noverón, Enrique Bargalló-Rocha, Alejandro Mohar.
Disclosures and Conflict of Interest Statements
References
Cynthia Villarreal-Garza reports consultant or advisory roles from Pfizer and Novartis, research funding from Novartis and speaker fees from Pfizer, Roche and Patia. Enrique Bargalló-Rocha reports speaker fees from Genomic Health. Paula Cabrera-Galeana reports speaker fees from Pfizer. Juan Matus-Santos reports speaker fees from Roche. All the other authors have no financial conflicts of interest to disclose.
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Authorship Contributions Study concepts: Paula Cabrera-Galeana, Enrique Soto-Perez-de-Celis, Nancy Reynoso Noveron, Enrique Bargallo Rocha, Alejandro Mohar. Study design: Paula Cabrera Galeana, Enrique Soto Pérez de Celis, Nancy Reynoso Noveron. Data acquisition: Nancy Reynoso Noveron, Juan Torres-Dominguez, Cynthia Villarreal Garza, Claudia Arce-Salinas, Juan Matus-Santos, Maria Teresa Ramirez-Ugalde, Alberto AlvaradoMiranda. Quality control of data: Nancy Reynoso Noveron, Juan TorresDominguez, Alejandro Mohar. Data analysis and interpretation: Nancy Reynoso Noveron, Juan Torres-Dominguez, Paula Cabrera Galeana, Enrique Soto Pérez de Celis, Enrique Bargallo Rocha. Statistical analysis: Nancy Reynoso Noveron. Manuscript preparation: Enrique Soto Pérez de Celis, Paula Cabrera Galeana. Manuscript editing: All authors. Manuscript review: Paula Cabrera-Galeana, Enrique
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