Triple-negative breast cancer in Hispanic patients

Triple-Negative Breast Cancer in HispanicPatientsHigh Prevalence, Poor Prognosis, and Association With Menopausal Status, Body Mass Index,and Parity

Fernando Lara-Medina, MD1,2; Vıctor Perez-Sanchez, MD3; David Saavedra-Perez, MD4; Monika Blake-Cerda, MD5;

Claudia Arce, MD1,2; Daniel Motola-Kuba, MD2; Cynthia Villarreal-Garza, MD1,2; Ana Maria Gonzalez-Angulo, MD6;

Enrique Bargallo, MD1; Jose Luis Aguilar, MD2; Alejandro Mohar, MD, DSc7,8; and Oscar Arrieta, MD2,4,7

BACKGROUND: Triple-negative breast cancer (TNBC) is defined as breast cancer that is negative for estrogen recep-

tor, progesterone receptor, and human epidermal growth factor receptor 2. TNBC represents 15% of all invasive breast

cancers, but some studies have suggested that its prevalence differs between races. To the authors’ knowledge, no

previous studies have determined the prevalence of TNBC and its risk factors among Hispanic women. METHODS:

The authors identified 2074 Hispanic women with breast cancer who attended the National Cancer Institute in Mexico

City from 1998 to 2008. All histopathologic and immunohistochemical diagnoses were rereviewed by a breast cancer

pathologist. The prevalence of TNBC, its association with clinicopathologic characteristics, and its prognostic impact

were determined. RESULTS: The median patient age at diagnosis (�standard deviation) was 50� 12 years. The overall

prevalence of TNBC was 23.1%. Younger age (P<.001), premenopausal status (P¼.002), increased parity (P¼.029),

hormonal contraceptive use (P ¼ .04) high histologic grade (P<.001), and advanced disease (P<.001) were associ-

ated independently with TNBC. Postmenopausal patients who had a body mass index (BMI) <25 kg/m2 (P¼.027) or

<30 kg/m2 (P<.001) were more likely to have TNBC. In multivariate analysis, patients with TNBC had a higher risk of

locoregional recurrence (LRR), lower disease-free survival (DFS) (hazard ratio, 1.62; 95% confidence interval, 1.13-2.32;

P¼.009), and a lower cancer-specific survival (CSS) rate (hazard ratio, 1.66; 95% confidence interval, 1.20-2.30;

P¼.002) than patients with non-TNBC. CONCLUSIONS: The median age at diagnosis of Hispanic women with breast

cancer was 11 years younger than the average age reported in the United States. The prevalence of TNBC in this

study population was higher than that reported in white women with breast cancer. TNBC was associated with a

higher risk of LRR and with lower DFS and CSS than those in patients with non-TNBC. Cancer 2011;117:3658–69.

VC 2011 American Cancer Society.

KEYWORDS: triple-negative breast cancer, Hispanic, overweight, obesity, menopausal status.

Breast cancer is the leading cause of cancer deaths among women in the United States and Mexico.1 Several clinicaland histopathologic prognostic factors for breast cancer have been studied; however, among the most important are theexpression of 3 biomarkers: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor re-ceptor 2 (HER2).2-6 Negative staining for these 3 markers defines the triple-negative (TN) breast cancer (TNBC) pheno-type,7 which represents approximately 15% of all invasive breast cancers.8 TNBCs are characterized by a frequent ductalhistology, high grade, and high proliferation and mitotic rates.9 Women with TNBC have high recurrence rates and poorcancer-specific survival (CSS).10 This subtype is associated with high mortality and few therapeutic options, and conven-tional chemotherapy is the only effective treatment.11

The molecular biology and pathophysiology of TNBC are not completely understood. Nevertheless, TN tumorshave a molecular profile associated with biologic aggressiveness, absence of BCL-2 expression, high p53 content, and

DOI: 10.1002/cncr.25961, Received: June 22, 2010; Revised: December 1, 2010; Accepted: January 3, 2011, Published online March 8, 2011 in Wiley Online

Library (wileyonlinelibrary.com)

Corresponding author: Oscar Arrieta, MD, Department of Medical Oncology, Instituto Nacional de Cancerologıa, San Fernando No. 22, Col. Seccion XVI, 14080

Mexico, D.F., Mexico; Fax: (011) 52-55-555485-6270; [email protected]

1Breast Cancer Clinic, National Cancer Institute (INCan), Mexico City, Mexico; 2Department of Medical Oncology, INCan, Mexico City, Mexico; 3Department of

Pathology, INCan, Mexico City, Mexico; 4Laboratory of Experimental Oncology, INCan, Mexico City, Mexico; 5Department of Radiotherapy, INCan, Mexico City,

Mexico; 6Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; 7Medical School, National Autonomous University of

Mexico, Mexico City, Mexico; 8Unit of Biomedical Research in Cancer, INCan, Mexico City, Mexico

3658 Cancer August 15, 2011

Original Article

breast cancer 1 gene (BRCA1) mutation.12,13 TNBC oftenis categorized as a basal-like tumor: a distinct biologic sub-type that is identified by gene expression profiling.14 Fur-thermore, patients with TNBC have a response tochemotherapy and a recurrence pattern that differ fromthose for patients with other breast cancers.15-17

Breast cancer is a genetic, heterogeneous disease andhas important variability according to ethnicity and racewith respect to incidence, clinical characteristics, andprognosis. Breast cancer in African-American women hasunfavorable characteristics, such as absence of ER expres-sion; in addition, TNBC is more prevalent in African-American women with breast cancer, contributing toincreased mortality.18

Hypertension, diabetes, overweight, and obesity alsohave been associated with increased risk of breast cancerand with decreased survival and poor prognosis in pre-menopausal and postmenopausal women with breast can-cer.19,20 Some studies have associated overweight andobesity with the presence of the TN phenotype.21

To our knowledge, the prevalence and prognosis forHispanic women with TNBC have not been studied pre-viously. Notably, Mexico has a very high prevalence ofoverweight and obesity.22,23 In the current study, wesought to evaluate and compare the demographic, clinical,and pathologic characteristics of breast cancer patientswith and without TNBC who were seen at the NationalCancer Institute (INCan), which is a national referral cen-ter for patients with cancer in Mexico City.

MATERIALS AND METHODS

Study Population and Data Collection

We retrospectively reviewed the clinical records frompatients with breast cancer who were seen at the INCanbetween January 1998 and December 2008. Included inour analysis were all Hispanic women who were diagnosedwith invasive breast cancer for which ER, PR, and HER2status was available. For eligible patients, we obtained thefollowing clinical and general demographic data from thepatient records: age at diagnosis; diagnosis of arterialhypertension and/or diabetes mellitus; body mass index(BMI) at diagnosis; number of pregnancies; use of hor-mone contraceptives; clinical stage at diagnosis (accordingto American Joint Committee on Cancer staging crite-ria)24; histologic type; Scarff-Bloom-Richardson (SBR)grade; lymphovascular invasion; and ER, PR, and HER2status. Subsequently, disease progression, recurrence, andvital status also were obtained. The review and analyses of

the clinical records were approved by the INCan InternalReview Board.

Morphology and Immunohistochemistry

We obtained specimens from the slide archive at theINCan. Tumor samples were examined and classified by adedicated breast cancer pathologist who used the breastcancer classification proposed by the World Health Orga-nization and the SBR grade.25 Regarding pathologic mar-gins, considerable controversy exists about the definitionof a negative pathologic margin. Traditionally, margins<1 mm are considered inadequate, and margins>10 mmare widely accepted as negative. In our department,adequate margins are defined as>3 mm. Surgical marginswere assessed by an expert breast cancer pathologist.

We obtained hormone receptor status by immuno-histochemical analyses of formalin-fixed, paraffin-embed-ded tissue sections from incisional biopsies that were usedfor diagnosis. We determined ER and PR expression levelsby using immunoperoxidase staining (Dako, Glostrup,Denmark) and quantified them with image analysis (Bio-genex, San Ramon, Calif); values <5% were categorizedas negative. HER2 expression was determined by immu-nohistochemistry (Dako). To be characterized as HER2-positive for this study, tumors (primary or metastatic)were required to have either v-erb-b2 erythroblastic leuke-mia viral oncogene homolog 2 (ErbB2) gene amplifica-tion, as measured by fluorescence in situ hybridization(Vysis, Des Plaines, Ill), or ErbB2 protein overexpression,as measured by immunohistochemistry (3þ) (HercepT-est; Dako). One breast cancer pathologist re-evaluated allimmunohistochemical results in each sample.

Statistical Analysis

For descriptive purposes, continuous variables were sum-marized as arithmetic means with standard deviations(SDs) and medians with ranges, and categorical variableswere summarized as relative frequencies, proportions, and95% confidence intervals (CIs). Inferential comparisonswere performed with the Student t test or the Mann-WhitneyU test according to distribution (normal or non-normal) determined by the Kolmogorov-Smirnov test.Pearson chi-square tests and odds ratios (ORs) were usedto compare the clinical and pathologic variables ofTNBC. For multivariate analysis, the variables includedwere those that had clinical significance and those thathad significance or near statistical significance (P< .1) inunivariate analysis.

Hispanic Patients With TNBC/Lara-Medina et al

Cancer August 15, 2011 3659

Locoregional recurrence-free survival (LRFS) anddisease-free survival (DFS) durations were measured fromthe date of breast surgery to the date of locoregional recur-rence (LRR) and the date of locoregional or systemic re-currence, respectively, for patients with stage I, II, and IIITNBC. CSS duration was defined as the period from thedate of diagnosis to the date of death or last follow-up.LRFS, DFS, and CSS were analyzed with the Kaplan-Meier method, and comparisons among subgroups wereperformed with the log-rank test or the Breslow test.

All variables were dichotomized for survival analysis.When the median was not reached, we expressed survivalas 3-year and 5-year rates and 95% CIs. Adjustment ofpotential confounders was carried out with Cox propor-tional hazards regression analysis. All tests were 2-sided,and significance was set at P< .05. SPSS software (version17.0; SPSS, Chicago, Ill) was used for data analysis.

RESULTS

Patients and Samples

In total, 2074 Hispanic patients with breast cancer wereincluded in this analysis. The median age (�SD) at diag-nosis was 50� 12 years (range, 19-96 years). A family his-tory of breast cancer was present in 20.4% of patients.Information regarding the number of births and the his-tory of contraceptive use was obtained in 1647 and 1664of 2074 patients, respectively. The mean number of birthswas 3.1 (range, 0-15 births), and 24.4% of patients hadhistory of hormone contraceptive use. Ductal carcinomawas the most common histology (82.7%). Clinical stagewas distributed as follows: 9.7% of patients had stage Idisease, 34.6% of patients had stage II disease, 44% ofpatients had stage III disease, and 11.7% of patients hadstage IV disease. The SBR grades low, intermediate, andhigh accounted for 12.4%, 36.9%, and 50.8% of patients,respectively. None of the patients who were included inthis study had received previous hormone-replacementtherapy.

Among the patients with stage I, II and III breastcancer who underwent breast-conserving surgery or mas-tectomy, positive/close margins (<3 mm) were obtainedin 55 patients (0.3%). All patients underwent re-excisionto achieve a confirmed negative pathologic margin. Senti-nel lymph node mapping and resection were done for97.5% of patients with clinically lymph node-negative(N0) breast cancer for surgical staging of the axilla. Thepatients who had axillary lymph node involvement identi-fied on sentinel lymph node biopsy underwent complete

axillary lymph node dissection. Sixty-three percent ofpatients received adjuvant radiotherapy according toestablished criteria: Patients who had T4 disease, a pri-mary tumor >4 cm, >3 lymph nodes that were positivefor metastasis, or 1 to 3 positive lymph nodes in the pres-ence of additional risk factors (aged <35 years, lympho-vascular invasion, and a low number of axillary lymphnodes examined). Of the 243 patients who had stage IVdisease at diagnosis, 5.3% (13 patients) underwent sur-gery for local control.

The treatment of patients was determined by clinicalstage. Patients with clinical stage IIB and stage III diseasereceived neoadjuvant chemotherapy with anthracyclinesand taxanes. After neoadjuvant chemotherapy, if therewas significant residual disease (tumor �5 cm in greatestdimension, skin edema, ulceration, or skin involvement),then patients received preoperative radiotherapy. A patho-logic complete response was achieved by 32.8% of allpatients (41% of patients with HER2-positive disease,29% of patients with TNBC, and 9% of patients with ERand/or PR [hormone receptor]-positive disease). Of thepatients with hormone receptor-positive disease, 92.3%received adjuvant hormone treatment.

Patients with hormone-receptor-positive, HER2-positive, and TN tumors made up 56.5%, 20.4%, and23.1% of patients, respectively. The initial estimatedprevalence of TNBC was 28.3% according to the originalassessment of breast cancer samples. After the re-evalua-tion of all immunohistochemical results by our dedicatedbreast cancer pathologist for the purposes of the currentstudy, the prevalence of TNBC was 23.1%. For patientswho were rediagnosed with hormone receptor-positiveand/or HER2-positive breast cancer, a note was added tothe patients’ medical records to let the attending physicianknow the change in the tumor status for guidance of fur-ther treatment.

In univariate analysis, TNBC was associated withyounger age (49.2 years vs 52.2 years; P< .001), pre-menopausal status (OR, 0.72; 95% CI, 0.58-0.88;P¼ .002), increased parity (OR, 1.32; 95% CI, 1.03-1.69; P¼ .029), hormone contraceptive use (OR, 1.20;95% CI, 1.003-1.54; P¼ .04), high SBR grade (OR,4.20; 95% CI, 2.50-7.01; P< .001), and advanced dis-ease stage (stages III and IV vs stages I and II: OR, 1.60;95% CI, 1.33-2.04; P< .001) (Table 1). In multivariateanalysis, only premenopausal status (P¼ .01), the numberof births (P¼ .014), SBR grade (P< .001), and stage(P¼ .002) were associated significantly with TNBC diag-nosis. The frequency of TNBC according to clinical stage

Original Article


I, II, III, and IV at diagnosis was 9.2%, 20.6%, 27.3%,and 23.6%, respectively. TNBC prevalence was not asso-ciated significantly with overweight (BMI �25 kg/m2;P¼ .423) or obesity (BMI�30 kg/m2; P¼ .103). Never-theless, in postmenopausal patients versus premenopausalpatients, a BMI <25 kg/m2 (43.4% vs 35%; OR, 0.70;95% CI, 0.51-0.96; P¼ .027) and a BMI <30 kg/m2

(78.8% vs 68.8%; OR, 0.54; 95% CI, 0.37-0.78;P< .001) were strongly associated with TNBC (Table 2).A family history of breast cancer was identified in 21% ofpatients with non-TNBC, which was not different fromthe 19.5% rate among patients with TNBC (P¼ .46).

Outcomes

The median follow-up was 17 months (range, 3-120months). Of the 2074 patients who were included in this

study, only 75 patients (3.6%) had a median follow-up<3 months. There were 122 LRRs (7.4%). The mediantime to local recurrence was 118.7 months (95% CI, 107-129 months). The 3-year LRFS rate was 92.2% (95% CI,90.5%-93.9%). In multivariate analysis, variables thathad a significant independent association with low LRFSwere the presence of the TN phenotype (hazard ratio[HR], 2.4; 95% CI, 1.6-3.8; P< .001 (Fig. 1A-C), lym-phovascular invasion (HR, 2.7; 95% CI, 1.5-4.9;P< .001), and advanced stage (stages III and IV vs stages Iand II; HR, 1.95; 95%CI, 1.30-2.90; P< .001).

There were 235 (14.6%) systemic recurrences. Thefrequency of TNBC among patients who had systemicrecurrences was 34.4%, and the median DFS was 82months (95% CI, 71.8-92.2 months). In multivariateanalysis, factors that had a significant independent

Table 1. Clinical and Pathologic Characteristics of Patients With Nontriple-Negative and Triple-Negative Breast Cancer

Characteristic Percentage of Patients Univariate Analysis Multivariate LogisticRegression Analysis: P

Nontriple-Negative,n51596

Triple-Negative,n5 469

OR (95% CI) P

Age: Median � SD, y 52.2 � 12.3 49.2 � 12.2 <.001

Menopausal statusPremenopausal 49.1 57.4 0.72 (0.58-0.88) .002 .01

Postmenopausal 50.9 42.6

Births<2 73.7 68 1.32 (1.03-1.69) .029 .014

‡2 26.3 32

Use of contraceptivesNo 77.6 72.4 1.2 (1.003-1.54) .04 .079

Yes 19.6 27.6

MulticentricityNo 91.9 94.4 0.76 (0.68-1.04) .07

Yes 8.1 5.6

HistologyDuctal 81.8 85.3

Lobular 10.3 7.2 0.94 (0.64-1.40) .12

Other 7.8 7.5

Scarff-Bloom-Richardson gradeLow 14.9 4.1

Intermediate 42.8 17.5 4.20 (2.50-7.01) <.001 <.001

High 44.3 78.5

StageI 11.3 3.7

II 35.6 31.4

III 41.3 52.7 1.60 (1.33-2.04) <.001 .002

IV 11.6 12.2

Lymphovascular invasionYes 33.4 36.1 0.88 (0.71-1.10) .282

No 66.6 63.9

OR indicates odds ratio; CI, confidence interval; SD, standard deviation.



association with short DFS were the presence of the TNphenotype (HR, 1.62; 95% CI, 1.13-2.32; P¼ .009)(Fig. 1B), HER2-positive status (HR, 1.40; 95% CI,1.04-1.93; P¼ .025), and advanced stage (stage III vsstages I and II; HR, 2.23; 95%CI, 1.69-2.95; P< .001).

There were 209 (10.2%) deaths. The 3-year survivalrate was 84.70% (95% CI, 82.35%-7.05%), and the 5-year survival rate was 76.40% (95% CI, 72.48%-

80.32%). In multivariate analysis, factors that were associ-ated with CSS duration were presence of the TN pheno-type (HR, 1.66; 95% CI, 1.20-2.30; P¼ .002) (Fig. 1C),HER2-positive status (HR, 1.30; 95% CI, 1.02-1.80;P¼ .031), and advanced stage (stage III vs stages I and II;HR, 2.1; 95% CI, 1.7-2.5; P< .001) (Table 3). SBRgrade had a trend toward significance (HR, 1.3; 95% CI,0.98-1.77; P¼ .062). Particularly in patients with

Table 2. Diagnosis of Arterial Hypertension, Diabetes Mellitus, Body Mass Index, Overweight, andObesity According To Triple-Negative Status

Patient Subset Nontriple-Negative, % Triple-Negative, % Univariate P

All patientsa n5 1595 n5 479Arterial hypertension

No 81.7 86.5 .015

Yes 18.3 13.5

Diabetes mellitus

No 87.7 90.3 .312

Yes 11.3 9.7

BMI: Mean 6 SD, kg/m2 27.7 � 5.1 27.5 � 4.7 .289

BMI, kg/m2

<25 38.2 40.3 .423

‡25 61.8 59.7

BMI, kg/m2

<30 70.9 74.8 .103

‡30 29.1 25.2

Premenopausal patientsa n¼ 778 n¼ 267

Arterial hypertension

No 92.7 94.4 .337

Yes 7.3 5.6

Diabetes mellitus

No 95.2 95.1 .944

Yes 4.8 4.9

BMI: Mean 6 SD, kg/m2 27.3 � 4.6 27.8 � 4.9 .280

BMI, kg/m2

<25 41.6 38 .249

‡25 58.4 62

BMI, kg/m2

<30 75.1 71.8 .295

‡30 24.9 28.2

Postmenopausal patientsa n¼ 800 n¼ 199

Arterial hypertension

No 71 75.9 .167

Yes 29 24.1

Diabetes mellitus

No 82.4 83.9 .606

Yes 17.6 16.1

BMI: Mean 6 SD, kg/m2 28.2 � 5.5 27.1 � 4.8 .008

BMI, kg/m2

<25 35 43.4 .027

‡25 65. 56.6

BMI, kg/m2

<30 68.8 78.8 .001

‡30 33.2 21.2

BMI indicates body mass index; SD, standard deviation.a The sum of premenopausal and postmenopausal patients does not match the total sum of the values given because, in

some patients, this information was lacking.

Original Article


TNBC, the sole prognostic factor associated with poorCSS was advanced stage (stage III vs stages I and II;P< .001) (Table 4).

When we conducted a subgroup analysis accordingto breast cancer subtype (HR-positive/HER2-negative,HER2-positive, and TNBC), CSS was longer in patientswith HR-positive/HER2-negative disease compared withthe other 2 groups (P¼ .002) (Fig. 2). Only 10.9% of thewhole population received treatment with trastuzumab,which corresponded to 51.2% of the patients withHER2-positive disease. This was because it was not until2006 that the government covered for trastuzumab ther-apy. We also compared CSS in the HER2-positivepatients who and did not receive trastuzumab treatment.CSS was significantly longer in HER2-positive patientswho received trastuzumab (CSS: 91.6% [95% CI,87.6%-95.5%] vs 75% [95% CI, 63.8%-87.2%];P< .001) (Fig. 3). All data regarding the treatment of dia-betic patients were analyzed according to treatment, andwe did not observe any statistically differences betweenmetformin and other kinds of treatments in terms ofLRFS, DFS, or CSS (insulin, oral hypoglycemic drugs).

DISCUSSIONTo our knowledge, this is the first study to determine theprevalence of TNBC and its risk factors among Hispanicpatients with breast cancer. In our study population, themean age at diagnosis of breast cancer was 11 yearsyounger than the average age reported in the UnitedStates. TNBC prevalence in our study population washigher than that reported in white patients with breastcancer. We identified differences in hormone expressionprofiles of breast cancer according to BMI, menopausalstatus, and parity. TNBC was associated with a higher riskof LRR and with lower DFS and CSS.

Increasing evidence supports the possibility that it isbiologically plausible for specific subtypes of breast cancerto have different etiologies. These findings are based onthe current understanding of the heterogeneity of breastcancer development because of hormone and growth fac-tor receptors status.21 Several studies have demonstratedclear differences in clinical, pathologic, and prognosticcharacteristics between African-American patients andwhite patients.21,26-28 Indeed, gene expression analyses ofseveral breast cancer subtypes have demonstrated differen-ces between African-American patients and non-African-American patients, with a higher prevalence of basal-likebreast tumors and a lower prevalence of luminal tumors in

Figure 1. These Kaplan-Meier plots illustrate (A) locoregionalrecurrence-free survival, (B) disease-free survival, and (C)cancer-specific survival for patients with triple-negativebreast cancer (TNBC) and non-TNBC. HR indicates hazard ra-tio; CI, confidence interval.



the African-American patients.29 These factors may con-tribute to the worse prognosis for African-Americanwomen with breast cancer.29

In our study population, after re-evaluating immu-nohistochemistry results from each sample, we observed

that the prevalence of TNBC was 23.1% in Hispanicpatients at the INCan. This prevalence was higher thanthat reported in white patients (range, 10%-13%) but wascloser to the prevalence reported in African-Americanpatients (range, 23%-30%).14,30 Few studies have been

Table 3. Cancer-Specific Survival Analysis in all Breast Cancer Patients

Variable Five-Year Survival Multivariate Analysis

Rate (95% CI), % P HR (95% CI) P

Menopausal statusPremenopausal 77.60 (72.51-82.69)

Postmenopausal 74.30 (67.25-81.35) .412

HistologyDuctal 77.30 (73.24-81.36)

Lobular 71.30 (54.64-87.96)

Other 71.6 (70.0-73.8) .603

Triple-negative subtypeYes 57.1 (47.3-66.9) <.001 1.66 (1.20-2.30) .002

No 82.80 (79.76-85.84)

ER statusPositive 87.50 (83.58-91.42) <.001

Negative 64.50 (57.45-71.55)

PR statusPositive 86.90 (82.83-91.64)

Negative 68.30 (62.03-74.57) <.001

HER2 statusPositive 69.10 (60.28-77.92)

Negative 76.70 (71.41-81.99) .048 1.30 (1.02-1.80) .031

Scarff-Bloom-Richardson gradeI-II 79.00 (71.16-86.84)

III 75.50 (69.62-81.38) .001 1.30 (0.98-1.77) .062

Lymphovascular invasion statusNo 78.50 (70.86-86.14)

Yes 75.7 (70.8-80.6) .782

StageI 94.20 (88.91-99.49) <.001 2.1 (1.7-2.5) <.001

II 89.90 (84.81-94.99)

III 73.80 (67.53-80.07)

IV 33.80 (32.24-35.36)

Arterial hypertensionNo 77.20 (72.89-81.51) .942

Yes 73.70 (72.53-74.87)

Diabetes mellitusNo 78.30 (73.99-82.61) .259

Yes 65.20 (50.90-79.50)

BMI, kg/m2

<25 72.40 (65.35-79.45) .189

‡25 80.3 (75.4-85.2)

BMI, kg/m2

<30 76.1 (71.4-80.8) .121

‡30 78.10 (69.09-87.11)

CI indicates confidence interval; HR, hazard ratio; ER, estrogen receptor; PR, progesterone receptor; HER2, human epi-

dermal growth factor receptor 2; BMI, body mass index.

Original Article


performed on Hispanics living in the United States. In asmall study of 46 patients, the prevalence of TNBC was10%,14 although this low prevalence may not be represen-tative because of the small sample size. In a subsequentstudy of 255 patients with TNBC, 49 patients (19.2%)were Hispanic Americans.31 The prevalence of TNBCvaries according to ethnicity and has been reported as highas 82% in Ghana,32 39% in Saudi Arabia,33 19.3% inChina,32 and 15.9% in Taiwan.34

The distribution according to clinical disease stagein our study population (localized disease, 44.3%; re-gional disease, 44%; and distant disease, 11.7%) was simi-lar to that reported in African-American patients (51%,37%, and 10%, respectively)1 and Hispanic-Americanpatients (54%, 37%, and 7%, respectively) with breast

cancer.35 All of these distributions differ significantlyfrom those reported in white patients with breast cancer(63%, 29%, and 5%, respectively).1,35 Together, thesefindings suggest a proportional relation between clinicalstage and TNBC prevalence, leading to a worse prognosisfor African-American and Hispanic-American patientscompared with that for white patients with breast cancer.Loss of hormone receptor and HER2 expression has beendescribed as a consequence of tumor progression.36-39

Table 4. Cancer-Specific Survival Analysis in Patients WithTriple-Negative Breast Cancer

Variable Five-Year SurvivalRate (95% CI), %

P

Menopausal statusPremenopausal 63.40 (51.45-75.35) .453

Postmenopausal 42.10 (39.04-45.16)

HistologyDuctal 59.90 (48.14-65.06)

Lobular 72.20 (70.24-74.16) .390

Other 21.60 (18.08-25.12)

Scarff-Bloom-Richardson gradeI-II 68.30 (65.56-71.04) .161

III 55.20 (54.03-56.37)

Lymphovascular invasionNo 57.30 (45.54-69.06) .948

Yes 50.00 (47.26-52.74)

StageI 100 <.001

II 84.3 (74.5-94.1)

III 60.60 (46.88-74.32)

IV 0

Arterial hypertensionNo 56.40 (44.64-68.16) .985

Yes 64.70 (62.43-66.97)

Diabetes mellitusNo 58.00 (46.24-69.76) .58

Yes 39.60 (35.88-43.32)

BMI, kg/m2

<25 46.30 (27.68-64.92) .765

‡25 68.90 (59.89-77.91)

BMI, kg/m2

<30 56.70 (68.46-68.46) .73

‡30 62.50 (46.82-78.18)

CI indicates confidence interval; BMI, body mass index.

Figure 2. Cancer-specific survival is illustrated according tobreast cancer subtypes (hormone [estrogen and/or proges-terone] receptor [HR]-positive/human epidermal growth fac-tor receptor 2 [HER2]-negative [HRþ/HER2�], HR-negative/HER2-positive [HR�/HER2þ], and triple-negative breast can-cer [TNBC]).

Figure 3. Cancer-specific survival is illustrated for patientswith human epidermal growth factor receptor 2-positivebreast cancer who did or did not receive trastuzumab.



We also observed that TNBC was associated withhigh histologic grade, as reported previously.20 Anothersimilar feature between African-American patients withbreast cancer and our study population is the frequency ofhigh histopathologic grade at diagnosis (48% in African-American patients and 51% in our study population),which is higher than that reported in white patients withbreast cancer (32%).14 Several studies have associated highhistologic grade with loss of hormone receptor and HER2expression.40-42 Advanced disease and high grade at diagno-sis in both African-American patients with breast cancerand in our study population may explain the high preva-lence of TNBC. In addition, lack of health education, defi-cient of awareness, and suboptimal access to high-qualitymammography and prompt referral might also justify thehigh rates of advanced disease inMexican patients.

Overweight and obesity have been associated with ahigh risk of developing breast cancer.43 Obesity is relatedto a poor prognosis, possibly secondary to estrogenic activ-ity, advanced or aggressive disease at diagnosis, and ahigh likelihood of both local and systemic treatment fail-ure.43-45 We did not observe a correlation between over-weight or obesity and a diagnosis of TNBC when weconsidered all patients; however, we did observe a signifi-cantly higher prevalence of TNBC in postmenopausalpatients who had a BMI<25 kg/m2 or a BMI<30 kg/m2.

Hormone receptor status has not been linkeddirectly with overweight or obesity. However, severalstudies have yielded conflicting results regarding theassociation between BMI, menopausal status, and hor-mone receptor expression. Similar to our findings, aprospective cohort of >90,000 postmenopausal patientswith breast cancer showed that a higher BMI was asso-ciated with advanced disease and with higher expres-sion of hormone receptors.46 Conversely, in a studythat was conducted in breast cancer patients betweenthe ages of 20 and 50 years, obesity was associatedwith TNBC (HR, 1.89; 95% CI, 1.22-2.92).21 TNBCpatients had a higher incidence of hypertension, diabe-tes, overweight, and obesity compared with their non-TNBC counterparts (58.1% vs 36.7%, respectively).However, BMI was not associated independently withTNBC, consistent with our findings when we analyzedthe entire breast cancer population (a subanalysis inpremenopausal and postmenopausal breast cancerpatients was not carried out by the authors).20 Anotherstudy demonstrated that the association between ER/PR and HER2 expression and BMI varies according tomenopause status.47 In premenopausal women, BMI

was associated inversely with hormone receptor expres-sion; but, in postmenopausal women, BMI had a posi-tive association with hormone receptor and HER2levels. They hypothesized that low serum hormonelevels in overweight or obese, premenopausal womencause up-regulation of ER and PR levels in normalbreast epithelium, leading to an exaggerated hormoneresponse after menopause.47

In our study population, the median age at diagnosisof breast cancer was 11 years younger than that reportedin US patients (50 years vs 61 years).48 Our study sup-ports the finding of Rodriguez-Cuevas et al., who reportedthat the average age at diagnosis of breast cancer was 51years in Mexican patients.49 Another study performed inthe United States indicated that there were differences inage at presentation of breast cancer: 47% of Hispanic-American patients were aged<50 years at diagnosis versus25% of white patients.14 These observations have greatrelevance for evaluating the best screening model forwomen at risk of breast cancer inMexico.50

We observed that there was an association of TNBCwith poor CSS and an increased risk of LRR. Poor prog-nosis was evidenced by low DFS and CSS in HER2-posi-tive patients. This might be related to the fact that only50% of all patients with HER-2 positive breast cancerreceived treatment with trastuzumab, because it was notuntil 2006 that the government paid for this treatment.We believe that, if a higher proportion of HER2-positivepatients received trastuzumab as indicated, then CSS forthe non-TNBC subgroup would have been longer, andmore significant differences in CSS would have beenobserved between the patients with and without TNBC.Studies have reported similar results for CSS and a highLRR rate among patients with TNBC.51-55

Although there are no population-based cancerregistries in Mexico, there are some estimates of breastcancer incidence through mortality-specific analyses. Onthe basis of these findings, the estimated incidence ofbreast cancer in our country is of 27.2 per 100,000 with amortality rate of 10.1 per 100,000.56

Several hormone/reproductive/lifestyle risk factorscan affect the incidence rates of TNBC between popula-tions, and these may be independent of race/ethnicity andmay follow a basic age-related curve.We observed a signif-icant association between TNBC diagnosis and more than1 birth. The increased number of births in Mexicanpatients compared with Caucasian-American women mayexplain the higher incidence of TNBC. The total fertilityrate in the United States is 2.06 per women,57 in contrast

Original Article


to our population, who have a mean number of 3.1 births.Millikan et al. and the Carolina Breast Cancer StudyGroup reported data indicating that reproductive history/parity is a major explanatory factor for race/ethnicity-related differences in the frequency of TNBC.58

In the current univariate analysis, but not in themultivariate analysis, we observed an association betweenhormone contraceptive use and TNBC diagnosis. In pre-vious studies, oral contraceptive use for more than 1 yearwas associated with a 2.5-fold increase in the incidence ofTNBC.59 It has been proposed that the mechanismthrough which oral contraceptives use impacts the risk ofbreast cancer among young women is that estrogen pro-motes the growth of breast cancer-enhancing angiogenesisand stromal cell recruitment.60

In conclusion, in our study population, the medianage at diagnosis of breast cancer was 11 years youngerthan the average age reported in the United States and inother, similar patient populations. Our results suggestthat, in the Hispanic population, screening programs andrecommendations need to be analyzed carefully and eval-uated from the perspective of cost-effectiveness in middle-income countries like Mexico. TNBC prevalence in ourstudy population was higher than that reported in whitepatients with breast cancer. This may be explained byracial differences, a more advanced stage at diagnosis, or ahigher SBR grade, all of which can cause a change inhormone receptor status. We identified differences inhormone expression profiles in breast cancer according toBMI, menopausal status, and parity, suggesting a hetero-geneous etiology. And, as reported in other studies,TNBC was associated a with poor prognosis, a high riskof LRR, and poor DFS and CSS.

CONFLICT OF INTEREST DISCLOSURESThis research is supported in part by the Universal Health Insur-ance Program of the Mexican Government for Breast Cancer.

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Triple-negative breast cancer in Hispanic patients

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