Clinicopathological factors associated to HER-2 status in a hospital-based sample of breast cancer patients in Puerto Rico.
Breast cancer is the most common female malignancy in Puerto Rico.
Cases with human epidermal growth factor receptor 2 (HER-2) oncoprotein
overamplification are associated with aggressive clinical behavior.
Given the limited availability of information for Puerto Rico, we aimed
to evaluate the prevalence and clinical correlates of HER-2 gene
overexpression among a hospital-based female population of breast cancer
cases. We analyzed data from 1,049 female patients with invasive breast
cancer (diagnosed 2000-2005) at the I. Gonzalez Martinez Oncologic
Hospital and the Auxilio Mutuo Hospital. HER-2 status and other clinical
characteristics were retrieved from the hospitals' cancer
registries, from the Puerto Rico Central Cancer Registry, and from a
review of medical and pathological records. Prevalence odds ratios were
estimated with 95% confidence intervals, using logistic regression
models to quantify the association between HER-2 status and different
clinicophatological factors. The overall prevalence of positive HER-2
expression was 22.5%. In the multivariate logistic regression model,
factors significantly associated with HER-2 positivity included a
diagnosis age of <50 years, having a tumor with negative progesterone
receptor (PR) status, and having regional disease (p < 0.05). No
significant differences in HER-2 positivity were observed by tumor
histology or estrogen receptor (ER) status (p > 0.05). This is the
most comprehensive epidemiological study to date on HER-2 status in
Puerto Rico. The prevalence and correlates of HER-2 overexpression in
this study are comparable to those observed in US populations. Study
results will aid in the development of breast cancer control strategies
in Puerto Rico. [P R Health Sci J 2010;3:265-271]
Key words: Breast cancer, HER-2, Puerto Rico
El cancer de mama es el mas comun entre las mujeres en Puerto Rico. Casos con sobreexpresion de la proteina tumoral conocida como HER-2 (por sus siglas en ingles) se asocian con un comportamiento clinico mas agresivo. Dado que los datos para Puerto Rico son limitados, nuestro objetivo fue evaluar la prevalencia y los factores clinicos asociados a sobreexpresion del gen HER-2 en una poblacion hospitalaria de mujeres pacientes de cancer de mama. Analizamos los datos de mujeres pacientes de cancer invasivo de mama diagnosticadas entre 2000-2005 en el Hospital I. Gonzalez Martinez y el Hospital Auxilio Mutuo (n=1,049). Informacion sobre HER-2 y otras caracteristicas clinicas fue extraida de los registros de cancer hospitalarios, del Registro Central de Cancer de Puerto Rico, y de revision de expedientes medicos y patologicos. La prevalencia de sobreexpresion de HER-2 fue de 22.5%. A base del modelo de regresion logistica multivariado, los factores significativamente asociados a tener un tumor positivo para HER-2 incluyeron edad al diagnostico <50 anos, tener un tumor negativo a receptores de progesterona, y tener enfermedad regional (p<0.05). No se demostraron diferencias significativas por la histologia y los receptores de estrogeno del tumor (p>0.05). La prevalencia y factores asociados a la sobreexpresion de HER-2 en este estudio es comparable a resultados de poblaciones en Estados Unidos de America; estos son de importancia para el desarrollo de estrategias de control de cancer en Puerto Rico.
|Article Type:||Perspectiva general de la enfermedad/trastorno|
Cancer de la mama
Cancer de la mama (Analisis de casos)
Cancer de la mama (Causas)
Genetica (Investigacion cientifica)
Genetica (Analisis de casos)
Ortiz, Ana P.
|Publication:||Name: Puerto Rico Health Sciences Journal Publisher: Universidad de Puerto Rico, Recinto de Ciencias Medicas Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 Universidad de Puerto Rico, Recinto de Ciencias Medicas ISSN: 0738-0658|
|Issue:||Date: Sept, 2010 Source Volume: 29 Source Issue: 3|
|Geographic:||Geographic Name: Puerto Rico|
Breast cancer is the most common cancer diagnosed among females and
represents the most common cause of cancer death among women worldwide
(1). In Puerto Rico, breast cancer accounted for 34.3% of all incident
cases in 2003 and 19.7% of all cancer related deaths in 2004 (2).
Variations in disease occurrence and outcome according to geographic
regions and ethnic background exist (3). In the United States (US), the
rate by which breast cancer incidence is increasing differs among ethnic
populations. For example, the risk of developing breast cancer is
increasing at a faster rate among females residing in Puerto Rico than
among non-Hispanic white (4) females residing in the US. Whereas
although higher incidence rates exist for non-Hispanic white and
Hispanic women in the US as compared to women in Puerto Rico, incidence
rates are increasing for Puerto Ricans, even though they have remained
stable for Hispanic and nonHispanic whites in the US (5).
The c-erbB-2 proto-oncogene encodes for the human epidermal growth factor receptor 2 (HER-2/neu) oncoprotein, a receptor tyrosine kinase protein, and it is associated with certain tumors of the breast. While normal breast cells carry two copies of the c-erbB-2 gene on chromosome 17, certain breast tumors demonstrate amplification of this oncogene, thus exhibiting overexpression of the HER-2 oncoprotein (6). This can lead to excessive growth and invasion of mammary tissue, resulting in the development of malignant tumors. HER-2 overexpression has been inversely correlated with estrogen receptor (ER) and progesterone receptor (PR) status and positively correlated with stage and histological grade (7-8).
Patients with HER-2-positive tumors are subject to target therapies (9-10); thus, the American Society for Clinical Oncology recommends that HER-2 status be determined for each patient with invasive breast cancer (9). In fact, since 1996, the American Society of Clinical Oncology (ASCO) has published clinical practice guidelines that specify that newly diagnosed breast cancers be assayed for HER-2-positive oncogene expression (11). Trastuzumab (Herceptin; Genentech, South San Francisco, CA), a humanized monoclonal antibody against the HER-2 protein, improves response, time-to-progression, and breast cancer survival rates as well as reduces the risk of recurrence and mortality (9, 12). More recently, a dual HER-1/HER-2 tyrosine kinase inhibitor of HER-2 tyrosine kinase activity, lapatinib (Tykerb, GlaxoSmithKline, Philadelphia, PA), has also been shown to improve clinical outcomes in patients with advanced disease (13). Thus, HER-2 is a useful marker for therapeutic decision-making in patients with breast cancer, highlighting the importance of understanding its prevalence and correlates in the population.
Several studies conducted in the late 1980s and early 1990s estimated that the prevalence of HER-2 overexpression in women with invasive breast cancer tumors was approximately 20-34% (7, 14-19), although a recent study suggests that the proportion (but not the incidence) of HER-2-positive tumors may be declining in the population (20). So far, two small-scale studies investigating the prevalence of HER-2 overexpression among females in Puerto Rico have been published (6, 21), the results of which estimate the prevalence of HER-2 overexpression among invasive breast cancer tumors in women living in Puerto Rico to be 20-28%. However, these studies have been limited both in sample size and in their ability to associate HER-2 overexpression with other relevant clinical outcomes. Even though differences in the prevalence of overexpression of HER-2 among ethnic groups have not been consistently found (8, 22-26), a recent study supports the theory that race modifies the association between pathologic prognostic indicators of breast carcinoma, such as stage and grade, and the likelihood of an individual having HER-2-positive carcinoma (8). More specifically, even though significant associations were seen between HER-2 positivity and more advanced stage and grade tumors in Caucasians, these associations were not seen for African Americans (8). In addition, biological factors associated with poor prognosis are found with a significantly higher frequency in breast tumors from Hispanic and black women in the US (25). This is of special relevance, as tumors with a more aggressive biology can lead to a higher stage at diagnosis, resulting in a poorer prognosis for survival (25).
The main obj ective of this study is to estimate the prevalence and clinicopathological correlates of HER-2 overexpression in female patients (from a hospital-based population in Puerto Rico) with invasive breast cancer. Even though the prevalence of HER-2 overexpression in breast cancer tumors has been well documented in the US, information on the prevalence of HER-2 status in Puerto Rican cancer patients and its association with disease outcomes is still limited. Given that breast cancer tumors overexpressing the HER-2 oncoprotein are associated with a more aggressive clinical behavior (27-30), information regarding the prevalence of this protein among females with breast cancer in Puerto Rico may be useful for the development of cancer control strategies in this area, including secondary and tertiary prevention strategies. For example, more precise estimates of HER-2 overexpression and its correlates in this population may help us to better understand the clinical necessities of that population regarding targeted breast cancer treatment, with the aim of increasing survival of and reducing mortality from the disease.
The study consisted of a retrospective review of breast cancer cases diagnosed in two major cancer care hospitals in Puerto Rico. More specifically, our study population consisted of newly diagnosed (2000-2005) cases of invasive breast cancer, categorized according to the International Classification of Disease (ICD-O-3, codes C50.0-C50.9) (31) and diagnosed at the I. Gonzalez Martinez Oncologic Hospital and the Auxilio Mutuo Hospital in Puerto Rico. HER-2 overexpression began to be evaluated as a standard of care in the late 1990s. Thus, evaluation of this parameter after this period is more accurate and complete. This study was approved by the Institutional Review Board (IRB) committees of the Medical Sciences Campus, the I. Gonzalez Martinez Oncologic Hospital, and the Auxilio Mutuo Hospital.
From 2000 to 2005, 2,047 incident cases of breast cancer were identified in the above hospitals. Of those cases, 455 were eliminated because the patients had in situ breast cancer, 6 were eliminated because there was no information on tumor behavior, and 537 were eliminated because there was no information on HER-2 status. The study population consisted of 1,049 invasive breast cancer cases diagnosed from 2000 to 2005 at the I. Gonzalez Martinez Oncologic Hospital (n = 540 cases) and the Auxilio Mutuo Hospital (n = 509 cases); all cases included information on HER-2 status, corroborated by the presence of an immunohistochemistry (IHC) pathology report. Conclusive cases had HER-2 scores of 0, 1+, or 3+. From the inconclusive cases (n=134) (HER-2 score of 2+), 81 were re-evaluated using available flouorescence in situ hybridization (FISH) reports, for a final study population with conclusive HER-2 status of 985 women.
Information from cases was collected from the cancer registries of each of the participating hospitals. In addition, information on relevant covariates not available in the registries was abstracted from pathology reports and medical records. Also, clinical characteristics of study participants were corroborated with information from the Puerto Rico Central Cancer Registry (PRCCR). Information on HER-2 protein expression for all cases was obtained from IHC pathological analyses. According to the staining intensity, the pathologist categorized HER-2 status as positive (IHC score = 3+), negative (IHC score = 0, or equivocal (inconclusive IHC score = 2+). In addition, we collected information on age at diagnosis, on ER and PR receptor status (positive, negative), and on tumor histology (lobular, ductal, other), size (<2cm, [greater than or equal to] 2cm), and grade (I, well-differentiated; II, moderately well-differentiated; III, poorly differentiated; and IV, undifferentiated). Information on stage at diagnosis (localized, regional, distant, unknown) was defined according to Surveillance Epidemiology and End Results Staging (SEER Summary Staging) criteria. For cases diagnosed in the year 2000, the SEER Summary Staging 1977 (SSS1977) codes were used (32), while for cases diagnosed between 2001 and 2005, the SEER Summary Staging 2000 (SSS2000) codes were used (33). The use of both codes to track staging of breast cancer cases is supported by the fact that coding changes in SSS2000 had little effect on the classification of staging (Kappa = 0.84, p < 0.001) of breast cancer cases (34). For example, breast cancer cases with supraclavicular lymph node involvement were distant according to SSS1977 but are considered regional under SSS2000. Lymph node metastasis (yes, no) at time of diagnosis was also assessed. We did not compare statistics regarding race, as there is no clear demarcation of race in Puerto Rico.
Descriptive statistics such as frequency, mean, and standard deviation were used to describe the study population. For bivariate analysis, chi-square distribution was used to assess the comparison of the characteristics associated with HER-2 overexpression status among breast cancer patients. To determine the magnitude of these associations, the prevalence odds ratio (POR) was estimated (with a 95% confidence interval) using a simple logistic regression model. Multivariate logistic regression models were used to adjust the previous associations by potential confounder variables. Interaction terms formed by all pairs of the combinations of the predictor variables within the multivariate model were tested with the likelihood-ratio test (35). The hospital effect was considered as a random component, using a multilevel approach to estimate the parameters of the logistic regression model. Data analysis was done using the statistical software package Stata 10.
Characteristics of the study population
Overall, 21.2% of the cases were HER-2-positive, 72.7% of the cases were HER-2-negative, and 6.1% had inconclusive results (Table 1). When inconclusive cases were eliminated, the prevalence of HER-2-positive tumors was 22.5%, whereas 16.6% had triple-negative status (Table 2). Even though the overall prevalence of HER-2 did not differ between the years studied (p = 0.378), we saw a higher prevalence of HER-2 positivity in the I. Gonzalez Martinez Oncologic Hospital (26.8%) as compared to the Auxilio Mutuo Hospital (18.1%) (p = 0.001) (data not shown).
The clinical and pathological characteristics of the study population with conclusive HER-2 status (n = 985) are summarized in Table 3. The average age at diagnosis was 58.3 [+ or -] 14 years, while 68.6% of the study population was 50 years or older at the time of diagnosis. Most of the cases had invasive ductal carcinoma (75.7%). Regarding hormone receptor status, 72.2% and 58.6% of the study population were ER positive and PR positive, respectively, whereas 55.2% had combined ER/PR positive status. Most patients (63.0%) had tumor grades ranging from well to moderately differentiated, 64.1% had localized disease at the time of diagnosis, 53.3% had a tumor size of [greater than or equal to]2 cm, and 38.5% had positive lymph nodes (Table 3).
Table 3 also shows the association of HER-2 overexpression with common clinicopathological characteristics of the cases at the time of diagnosis. In our study population, HER-2 overexpression was significantly associated with a younger age at diagnosis (<50 years), invasive ductal cancer type, negative PR and ER hormonal receptor status, a larger tumor size ([greater than or equal to] 2 cm), and positive lymph node metastasis (p < 0.05). In addition, the likelihood of HER-2 positivity increased by increasing grade and stage ([p-value.sub.trend] < 0.001). When data were stratified by hospital of diagnosis, similar results were observed regarding clinicopathological factors associated with HER-2 status (data not shown).
Despite their statistical significance in bivariate analysis, the variables tumor size and lymph node metastasis were excluded from the multivariate logistic regression model in order to reduce the potential problems of collinearity, as these are already contemplated in the variable stage at diagnosis. We also excluded tumor grade, given its strong correlation with tumor stage (p = 0.001) (data not shown). Results of the multivariate analysis are shown in Table 4. In the multivariate logistic model, women with an age at diagnosis of <50 years were 55% (95% CI: 1.09 2.21) more likely to be HER-2-positive as compared to those with an age at diagnosis of [greater than or equal to] 50 years, after adjusting for ER status, PR status, tumor histology, tumor staging, and hospital of diagnosis. Regarding hormone receptors, women with PR-negative status were two times more likely to be HER-2-positive compared to those with PR-positive tumors, when adjusting for age at diagnosis, ER status, tumor histology, tumor staging, and hospital of diagnosis. However, no significant differences (p = 0.218) were observed in HER-2 positivity when compared to ER status. Those with invasive ductal tumor histology were 64% more likely to be HER-2-positive compared to those with invasive lobular histology, when adjusting for the same covariates, although this result was marginally significant (p = 0.087). Women with regional disease were significantly more likely to be HER-2-positive compared to those with localized disease (POR 1.71; 95% CI: 1.20-2.43), when adjusting for age at diagnosis, ER and PR status, tumor histology, and hospital of diagnosis. In addition, the likelihood of HER-2 positivity increased when tumor stage increased ([p-value.sub.trend] < 0.001). No significant interaction terms were detected in the model (LR Test: [X.sup.2] = 32.34, p = 0.1822).
This is one of the first epidemiological studies to assess HER-2 expression, an important tumor marker that has proven effective for the clinical management of breast cancer patients, among Puerto Rican females with invasive breast cancer (6, 21). Our estimate of the prevalence of HER-2-positive breast cancer (23%) is closer to estimates by Peredo and colleagues (20%), although lower than those from Colon and colleagues (28%). This difference could be explained by the fact that, similar to our study, Peredo's study was based on newly diagnosed breast cancer cases, while Colon's included both new and recurrent cases. Nonetheless, our and previous estimates for Puerto Rico fall within the range of HER-2 positivity established by studies in the US and other populations (20-34%) (7, 14-19, 36).
Correlates of HER-2 positivity in this hospital-based sample of women in Puerto Rico show that hormone receptors and other important prognostic factors of breast cancer were significantly associated with HER-2 overexpression status. Consistent with previous studies in other populations (37-40), a positive ER or PR status were negatively associated with HER-2 status, although results for ER were not statistically significant in multivariate analysis. When we considered the combination of ER/PR status, women positive for any of the hormone receptors were more likely to be HER-2-positive compared to those with ER-negative/ PR-negative status, although the results was not statistically significant for those with ER-positive/PR-negative status. This is of relevance, as combined ER-positive/PR-positive tumors are associated with improved survival when compared to those with combined ER-negative/PR-negative tumors (41); in addition, such tumors respond to hormone inhibition treatment.
Among other correlates of HER-2 status, our results showed that HER-2 positivity was also strongly associated with a younger age at diagnosis (< 50 years), ductal tumor histology, moderately to poorly differentiated tumor grade, tumor size greater than 2 cm, and advanced stage at diagnosis. The previous study in Puerto Rico by Peredo and colleagues found a significant association only between HER-2 positivity and nodal involvement, while the study by Colon found an association only for PR status. The smaller sample sizes included for analysis in these studies may have limited their statistical power for detecting these associations. Nonetheless, our results are consistent with previous reports that showed that HER-2 overexpression is associated with earlier age at diagnosis, nodal involvement, and a larger tumor size and is positively correlated with stage and histological grade (7-8, 26, 36, 38-40, 42). Results for tumor grade and stage are of particular interest, as recent data suggest that HER-2 positivity is associated with tumors of more advanced stages and grades in Caucasians, but not in African Americans, making disease behaviors in Puerto Rico similar to those of Caucasians, but not to those of African Americans (8). Also, although results were marginally significant, consistent with previous studies (39, 43), our results also support the notion that invasive lobular cancers infrequently overexpress HER-2 oncoprotein. Thus, as expected, the etiology and clinical characteristics of HER-2-positive tumors in Puerto Rico show similar behaviors to those of other populations.
Of interest is the fact that we saw a higher prevalence of HER-2 positivity in the I. Gonzalez Martinez Oncologic Hospital compared to the Auxilio Mutuo Hospital, even after adjusting for clinicopathological characteristics of patients. This difference could be due to methodological differences in the laboratories that performed the analyses or to socioeconomic differences between the populations served at these hospitals (those from the Auxilio Mutuo tend to belong to higher socioeconomic classes). Given that HER-2 positivity is not a germline mutation, but one that is acquired over the course of the bearer's life, differences in environmental risk factors between these groups could account for some of the observed differences in HER-2 positivity between these populations. This theory is supported by a recent study that showed that vegetable consumption has a protective effect against HER-2-positive cancers (much stronger than the affect against HER-2-negative cancers), supporting the theory that this type of diet protects mainly against a specific breast cancer subtype (44). Further research is warranted to elucidate this finding.
In terms of study limitations, our results might be affected by selection bias, as 34% of the eligible individuals were excluded because they were missing information on HER-2 status. Nonetheless, a comparison of study individuals (n = 1,049), with those excluded because they were missing information on HER-2 status (n = 537), showed that except for differences in the proportion of cases with "other" tumor histology (not lobular or ductal), these groups did not differ in any of the clinical characteristics under study, suggesting that selection bias was not an issue in the study. No differences were neither observed in the clinical characteristics of patients with conclusive or inconclusive HER-2 status (data not shown). Given that studies in the US have shown that demographic and clinical variations exist regarding which breast cancer patients received HER-2 testing (45 ), future studies should assess whether similar discrepancies exist in Puerto Rico, particularly as current guidelines call for all tumors to be assessed in order to adequately characterize prognosis and determine eligibility for HER-2-targeted therapy (45). The large amount of missing information on HER-2 status in medical records (34% of women with invasive breast cancer) is of relevance given that official recommendations for routine screening of breast cancer patients to determine their HER-2 status (in order to determine treatment options) preceded the study period (9, 11). Among other study limitations, caution must be used regarding the generalization of our results to the entire populatio n of invasive breast cancer cases in Puerto Rico, as our results are only directly generalizable to the population of patients diagnosed in these local hospitals between 2000 and 2005. In fact, according to data from the PRCCR, our study population (n = 1,049) represents approximately 12% of all invasive breast cancer cases diagnosed in Puerto Rico during the years of2000 to 2005. Finally, even though IHC techniques were used to access HER-2 status, a disadvantage of this method is that laboratories may use different antibodies for their analyses, resulting in differences in HER-2 expression results (21).
Despite the previous limitations, this is the most comprehensive epidemiological study to date on HER-2 expression in Puerto Rico, and our results provided prevalence estimates similar to those in other populations; approximately one-fifth of all invasive breast cancer cases in this population of women in Puerto Rico were positive for HER-2 overexpression. In addition, as in other populations, overexpression of this marker was strongly correlated with unfavorable clinicopathological characteristics of the tumor, such as negative PR status and advanced tumor stage. Our results underscore the relevance of testing all breast cancer cases for HER-2 positivity in Puerto Rico, as these women may benefit from targeted therapies. Future analysis of this data will help us to understand the associations of disease markers with disease relapse and mortality. This and other comparative studies will be of relevance to the enhanced understanding of the differences in breast cancer mortality, survival, prognosis, and clinical characteristics associated with ethnicity/race distinctions between breast cancer patients in Puerto Rico and those in the US. Moreover, given that studies have determined that some breast cancer risk factors, such as parity, menopausal status, alcohol consumption, and diet, differ by HER-2 status (36, 44, 46), future studies in Puerto Rico should further assess the potential associations and interactions between HER-2positive tumors and established or suspected risk factors for breast cancer in order to increase our understanding of the etiology of breast cancer in this population.
We would like to acknowledge the contribution of the following persons in the data collection process: Yari Valle, MPH, Paula Ortiz-Bachier, Joanne Diaz-Rodriguez, Anjanet Perez, Arelis Santana, Adriana Padilla and Daphne Diaz-Vazquez. In addition, we recognize the contributions of Dr. Li Li, from Case Western Reserve University, in the review of this manuscript. This work was supported by an unrestricted grant from Glaxo SmithKline with additional support from the following grants from the National Institute of Health: Training in Computational Genomic Epidemiology of Cancer (National Cancer Institute [NCI] 5R25CA094186-08), the NCI Grant U54CA96297 for the Puerto Rico Cancer Center / The University of Texas M. D. Anderson Cancer Center, Partners for Excellence in Cancer Research, and the RCMI Program Grant G12RR03051 from the University of Puerto Rico. It was also supported by the Ovarian Cancer Research Program of the Department of Defense [DOD] OC073399.
(1.) Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide IARC CancerBase No. 5, version 2.0 IARCPress, Lyon, 2004.
(2.) Puerto Rico Central Cancer Registry: Puerto Rico Cancer Incidence File. Division Of Epidemiology, Puerto Rico Department of Health 2007.
(3.) Vastag B. Breast cancer racial gap examined: no easy answers to explain disparities in survival. JAMA 2003;290:1838-1842.
(4.) Nazario CM, Figueroa-Valles N, Rosario RV. Breast cancer patterns and lifetime risk of developing breast cancer among Puerto Ricans females. PR Health Sciences Journal. 2000;19(1): 7-13.
(5.) Ortiz AP, Soto-Salgado M, Calo WA, et al. Disparities in breast cancer in Puerto Rico and among Hispanics, Non-Hispanic Whites and Non-Hispanic Blacks in the United States. Breast J 2010; in press.
(6.) Colon E, Reyes JS, Gonzalez-Keelan C, Climents-Perris C. Prevalence of steroid receptors and HER-2-POSITIVE/neu in breast cancer biopsies of women living in Puerto Rico. PR Health Sciences Journal 2002;21(4):299-303.
(7.) Selvarajan S, Wong KY, Khoo KS, et al. Over-expression of c-erbB-2 correlates with nuclear morphometry and prognosis in breast carcinoma in Asian women. Pathology 2006;38(6):528-533.
(8.) Stark AT, Claud S, Kapke A, et al. Race modifies the association between breast carcinoma pathologic prognostic indicators and the positive status for HER-2-POSITIVE/neu. Cancer 2005;104(10):2189-96.
(9.) Wolff A, Hammond ME, Schwartz J, Hagerty K et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for Human Epidermal Growth Factor Receptor 2 testing in breast cancer. J Clin Oncol 2007;25(1):1-28.
(10.) Demonty G, Bernard-Marty C, Puglisi F, et al. Progress and new standards of care in the management of HER-2-positive breast cancer. Eur J Cancer 2007;43:497-509.
(11.) Bast RC, Ravdin P, Hayes D, et al. 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: Clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001;19:1865-1878.
(12.) Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783-792.
(13.) Geyer CE, Cameron D, Lindquist D, et al. A phase III randomized, open-label, international study comparing lapatinib and capecitabine vs. capecitabine in women with refractory advanced metastatic breast cancer (EGF100151). Scientific Special Session. Program and abstracts of the 42nd Annual Meeting of the American Society of Clinical Oncology. Atlanta, Georgia June 2-6, 2006.
(14.) Clark GM, McGuire L. Follow-up study of HER-2-POSITIVE/neu amplification in primary breast cancer. Cancer Res 1991;51:944-948.
(15.) Garcia I, Dietrich PY, Aapro M, et al. Genetic alterations of c-myc, cerbB-2, and c-Ha-ras protooncogenes and clinical associations in human breast carcinomas. Cancer Res 1989;49:6675-6679.
(16.) Ro J, El-Naggar A, Ro JY, Blick M, et al. c-erbB-2 amplification in node-negative human breast cancer. Cancer Res 1989;49(24):6941-6944.
(17.) Vijver VM, Van de Bersselarar R, Devilee P, et al. Amplification of the neu (c-erbB-2) oncogene in human mammary tumors is relatively frequent and is often accompanied by amplification of the linked c-erbA oncogene. Mol Cell Biol 1987;7(5):2019-2023.
(18.) Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2-POSITIVE/neu oncogene. Science 1987;235:177-182.
(19.) Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2-positive/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707-712.
(20.) Koninki K, Tanner M, Auvinen A, Isola J. HER-2 positive breast cancer: decreasing proportion but stable incidence in Finnish population from 1982 to 2005. Breast Cancer Research 2009;11(3).
(21.) Peredo R, Sastre G, Serrano J, Hunter Mellado R. Her-2-positive/neu oncogene expression in Puerto Rican females with breast cancer. Cell Mol Biol 2001;7(6):1025-1032.
(22.) Jones BA, Kasl SV, Howe CL, et al. African-American/White differences in breast carcinoma: p53 alterations and other tumor characteristics. Cancer 2004;101(6):1293-1301.
(23.) Ademuyiwa F, Olopade O. Racial differences in genetic factors associated with breast cancer. Cancer Metastasis Rev 2003;22:47-52.
(24.) Wu Y, Khan H, Chillar R, Vadgama JV. Prognostic value of plasma HER2-positive/neu in African American and Hispanic women with breast cancer. Int J Oncol 1999;14(6):1021-1037.
(25.) Elledge RM, Clark GM, Chamness GC, et al. Tumor biologic factors and breast cancer prognosis among white, Hispanic, and black women in the United States. J Natl Cancer Inst 1994;86:705-712.
(26.) Gonzalez-Angulo AM, Litton JK, Broglio KR, et al. High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1cm or smaller. J Clin Oncol 2009;27(34).
(27.) Tovey SM, Brown S, Doughty JC, et al. Poor survival outcomes in Her-2-positive breast cancer patients with low-grade, node-negative tumours. Br J Cancer 2009;100:680-683.
(28.) Carr JA, Havstad S, Zarbo RJ, et al. The association of HER-2-positive/ neu amplification with breast cancer recurrence. Arch Surg 2000;135(12): 469-1474.
(29.) Latta EK, Tjan S, Parkes RK, O'Malley FP. The role of HER2/neu overexpression/amplification in the progression of ductal carcinoma in situ to invasive carcinoma of the breast. Mod Pathol 2002;15(2):1318-1325.
(30.) Konecny G, Pauletti G, Pegram M, Untch M, et al. Quantitative association between HER-2-positive/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst 2003;95(2):142-153.
(31.) Fritz AG. International classification of diseases for oncology: ICD-O. 3rd ed. Geneva: World health Organization; 2000.
(32.) Shambaugh EM, and MA Weiss, eds. Summary Staging Guide (SSS1977). Cancer Surveillance Epidemiology and End Results Reporting, SEER Program, April 1977. (Reprinted September 2001; NIH Publication No. 01-2313).
(33.) Young JL Jr, SD Roffers, LAG Reis, AG Fritz, and AA Hurlbut, eds. SEER Summary Staging Manual - 2000 Codes and Coding Instructions (SSS2000). National Cancer Institute, NIH Pub. No. 01-4969, Bethesda MD, 2001.
(34.) Phillips JL (editor). Summary stage: data effects of the changes in 2000. Springfield (IL): North American Association of Central Cancer Registries, December 2003. Accesible URL: http://www.naaccr.org.
(35.) Hosmer & Lemeshow. Applied Logistic Regression. Second Edition. New York. John Wiley & Sons, Inc. 2000.
(36.) Menard S, Balsari A, Casalini P, et al. HER-2-positive breast carcinomas as a particular subset with peculiar clinical behaviors. Clin Cancer Res 2002;8(2):520-525.
(37.) Rashed MM, Ragab NM, Galal MK. The association of Her-2-positive/ neu overexpression in relation to p53 nuclear accumulation, hormonal receptor status and common clinicopathological prognostic parameters in a series of Egyptian women with inasive ductal carcinoma . Eur J Gen Med 2007;4(2):73-79.
(38.) Huang HJ, Neven P, Drijkoningen M et al. Association between tumour characteristics and HER-2/neu by immunohistochemistry in 1362 women with primary operable breast cancer. J Clin Pathol 2005;58: 611-616.
(39.) Bartlett JM, Ellis IO, Dowsett M, et al. Human epidermal growth factor receptor 2 status correlates with lymph node involvement in patients with estrogen receptor (ER) negative, but with grade in those with ER-positive early-stage breast cancer suitable for cytotoxic chemotherapy. J Clin Oncol 2007;25(28):4423-4430.
(40.) Ahmad A, Bano U, Gondal M, Khan A. Her-2/neu overexpression in breast carcinoma and its association with clinicopathological characteristics of the disease. Journal of the College of Physicians and Surgeons Pakistan 2009;19 (5):297-299.
(41.) Parise C, Bauer K, Brown M, Caggiano V. Breast cancer subtypes as defined by estrogen receptor(ER), progesterone receptor (PR), and the human epidermalgrowth factor receptor 2 (HER2) among women with invasive breast cancer in California. The Breast Journal 2009;15(6):593-602.
(42.) Allred DC, Clark GM, Molina R, et al. Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer. Hum Pathol 1992;23(9): 974-979.
(43.) Kobayashi S, Iwase H, Itoh Y, Fukuoka H, et al. Estrogen receptor, c-erbB-2 and nm23/NDP kinase expression in the intraductal and invasive components of human breast cancers. Jpn J Cancer Res 1992;83(8):859-865.
(44.) Sant M, Allemani C, Sieri S, et al. Salad vegetables dietary pattern protects against HER-2-positive breast cancer: a prospective Italian study. Int J Cancer. 2007 Aug 15;121(4):911-4.
(45.) Pensa M, Swede H, Brockmeyer JA, Gregorio DI. Patterns of HER2 testing in the management of primary breast cancer. Cancer Epidemiol 2009;33(2):113-117.
(46.) Nichols HB, Trentham-Dietz A, Love RR, et al. Differences in breast cancer risk factors by tumor marker subtypes among premenopausal Vietnamese and Chinese women. Cancer Epidemiol Biomarkers Prev 2005;14:41-47.
Ana P. Ortiz, MPH, PhD *([dagger]); Orquidea Frias, MS *; Carmen Gonzalez-Keelan, MD ([double dagger]); Erick Suarez, PhD ([dagger]); David Capo, MD, MPH ([dagger]); Javier Perez, MPH[section]; Fernando Cabanillas, MD [section][paragraph]; Edna Mora, MD ** ([dagger])([dagger])
* Cancer Control and Population Sciences Program, University of Puerto Rico Comprehensive Cancer Center, San Juan, PR; ([dagger]) Department of Biostatistics and Epidemiology, Graduate School of Public Health, Medical Sciences Campus, University of Puerto Rico, San Juan, PR; ^Department of Pathology, School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR; [section] Puerto Rico Central Cancer Registry, University of Puerto Rico Comprehensive Cancer Center, San Juan, PR; [paragraph] Cancer Center, Hospital Auxilio Mutuo, San Juan, PR; ** Department of Surgery, Medical Sciences Campus, University of Puerto Rico, San Juan, PR; ([dagger])([dagger]) University of Puerto Rico Comprehensive Cancer Center, San Juan, PR
Address correspondence to: Ana Patricia Ortiz, MPH, PhD, Department of Biostatistics and Epidemiology, Graduate School of Public Health, Medical Sciences Campus, University of Puerto Rico, PO Box 365067, San Juan, PR, 00936-5067. Tel: (787) 758-2525 x-1471 *** Fax: (787) 764-5831 *** E-mail: firstname.lastname@example.org
Table 1. HER-2 oncoprotein expression of study participants (n=1,049). HER-2/neu expression n % HER2 + 222 21.2 HER2 - 763 72.7 Inconclusive 64 6.1 Table 2. Clinical groupings in the study population according to receptors (n=974). Clinical groupings n % HER2 + 220 22.5 HER2 -/ER-/PR- 162 16.6 HER2 -/ER+ or PR+ 592 60.9 Table 3. Clinicophatological factors associated to HER-2 status in a hospital-based sample of breast cancer patients in Puerto Rico (n=985). Characteristics Total HER2 + n (%) n (%) Age at diagnosis (n=985) <50 309 (31.4) 93 (41.9) [greater than or equal to] 50 676 (68.6) 129 (58.1) ER Status (n=978) Negative 272 (27.8) 85 (38.5) Positive 706 (72.2) 136 (61.5) PR Status (n=976) Negative 404 (41.4) 121 (55.0) Positive 572 (58.6) 99 (45.0) ER/PR Status (n=974) ER- / PR- 239 (24.5) 77 (35.0) ER- / PR+ 33 (3.4) 8 (3.6) ER+ / PR- 164 (16.8) 44 (20.0) ER+ / PR+ 538 (55.2) 91 (41.4) Tumor histology (n=971) Invasive lobular 163 (16.8) 21 (9.7) Invasive ductal 735 (75.7) 183 (84.7) Other 73 (7.5) 12 (5.6) Tumor grade (n=841) Well differentiated 133 (15.8) 7 (3.5) Moderately differentiated 397 (47.2) 93 (47.0) Poorly differentiated 269 (32.0) 82 (41.4) Undifferentiated aggressive 42 (5.0) 16 (8.1) Tumor size (n=835) < 2 cm 390 (46.7) 66 (37.9) [greater than or equal to] 2 cm 45 (53.3) 108 (62.1) Lymph nodes metastasis (n=842) Negative 518 (61.5) 92 (48.4) Positive 324 (38.5) 98 (51.6) Tumor staging (n=867) Localized 555 (64.1) 102 (53.1) Regional 293 (33.8) 83 (43.2) Distant 19 (2.2) 7 (3.6) Characteristics HER2 - POR (95% CI) n (%) ([dagger]) Age at diagnosis (n=985) <50 216 (28.3) 1.87 (1.37-2.56) [greater than or equal to] 50 547 (71.7) 1.00 ER Status (n=978) Negative 187 (24.7) 1.91 (1.39-2.62) Positive 570 (25.3) 1.00 PR Status (n=976) Negative 283 (37.4) 2.04 (1.51-2.77) Positive 473 (62.6) 1.00 ER/PR Status (n=974) ER- / PR- 162 (21.5) 1.00 ER- / PR+ 25 (3.3) 1.80 (1.19-2.72) ER+ / PR- 120 (15.9) 1.57 (0.69-3.60) ER+ / PR+ 447 (59.3) 2.33 (1.64-3.32) Tumor histology (n=971) Invasive lobular 142 (18.8) 1.00 Invasive ductal 552 (73.1) 2.24 (1.38-3.65) Other 61 (8.1) 1.33 (0.62-2.87) Tumor grade (n=841) Well differentiated 126 (19.6) 1.00 * Moderately differentiated 304 (47.3) 5.51 (2.48-12.20) Poorly differentiated 187 (29.1) 7.89 (3.53-17.64) Undifferentiated aggressive 26 (4.0) 11.08 (4.14-29.61) Tumor size (n=835) < 2 cm 324 (49.0) 1.00 [greater than or equal to] 2 cm 337 (51.0) 1.57 (1.12-2.21) Lymph nodes metastasis (n=842) Negative 426 (65.3) 1.00 Positive 226 (34.7) 2.01 (1.45-2.78) Tumor staging (n=867) Localized 453 (67.1) 1.00 * Regional 210 (31.1) 1.76 (1.26-2.45) Distant 12 (1.8) 2.59 (1.00-6.74) ([dagger]) Using a simple logistic regression model; POR= prevalence odds ratio * P-value trend <0.001. Table 4. Magnitude of the association between HER-2-positive status and clinical characteristics of the study population (n=844). Characteristics Adjusted POR ([dagger]) (95% CI) Age at Diagnosis <50 yrs 1.55 (1.09-2.21) [greater than or equal to] 50 yrs 1.00 ER Status ER+ 1.00 ER- 1.32 (0.85-2.05) PR Status PR+ 1.00 PR- 2.01 (1.32-3.06) Tumor histology Invasive lobular 1.00 Invasive ductal 1.64 (0.93-2.88) Other 1.31 (0.56-3.08) Tumor staging Localized 1.00* Regional 1.71 (1.20-2.43) Distant 1.98 (0.64-6.10) ([dagger]) Hospital effect was considered as random effects using a multilevel approach to estimate the parameters of the logistic regression model. * P-value trend <0.001.
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