A Population-Based Study From the California Cancer Registry. BACKGROUND. Tumor markers are becoming increasingly important in breast cancer

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1 1721 Descriptive Analysis of Estrogen Receptor (ER)- Negative, Progesterone Receptor (PR)-Negative, and HER2-Negative Invasive Breast Cancer, the So-called Triple-Negative Phenotype A Population-Based Study From the California Cancer Registry Katrina R. Bauer, MS CTR 1 Monica Brown, PhD 2 Rosemary D. Cress, DrPH 1,3 Carol A. Parise, PhD 4 Vincent Caggiano, MD 4,5 1 Public Health Institute/California Cancer Registry, Sacramento, California. 2 Public Health Institute/Cancer Surveillance Program, Sacramento, California. 3 Department of Health Sciences, Division of Epidemiology, UC Davis, California. 4 Sutter Institute for Medical Research, Sacramento, California. 5 Sutter Cancer Center/Cancer Surveillance Program, Sacramento, California. The collection of cancer incidence data used in the study was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section ; the National Cancer Institute s Surveillance, Epidemiology, and End Results Program under contract N01-PC awarded to the Northern California Cancer Center, contract N01- PC awarded to the University of Southern California, and contract N02-PC awarded to the Public Health Institute; and the Centers for Disease Control and Prevention s National Program of Cancer Registries, under agreement U55/CCR awarded to the Public Health Institute. BACKGROUND. Tumor markers are becoming increasingly important in breast cancer research because of their impact on prognosis, treatment, and survival, and because of their relation to breast cancer subtypes. The triple-negative phenotype is important because of its relation to the basal-like subtype of breast cancer. METHODS. Using the population-based California Cancer Registry data, we identified women diagnosed with triple-negative breast cancer between 1999 and We examined differences between triple-negative breast cancers compared with other breast cancers in relation to age, race/ethnicity, socioeconomic status (SES), stage at diagnosis, tumor grade, and relative survival. RESULTS. A total of 6370 women were identified as having triple-negative breast cancer and were compared with the 44,704 women with other breast cancers. Women with triple-negative breast cancers were significantly more likely to be under age 40 (odds ratio [OR], 1.53), and non-hispanic black (OR, 1.77) or Hispanic (OR, 1.23). Regardless of stage at diagnosis, women with triple-negative breast cancers had poorer survival than those with other breast cancers, and non-hispanic black women with late-stage triplenegative cancer had the poorest survival, with a 5-year relative survival of only 14%. CONCLUSIONS. Triple-negative breast cancers affect younger, non-hispanic black and Hispanic women in areas of low SES. The tumors were diagnosed at later stage and were more aggressive, and these women had poorer survival regardless of stage. In addition, non-hispanic black women with late-stage triple-negative breast cancer had the poorest survival of any comparable group. Cancer 2007;109: Ó 2007 American Cancer Society. KEYWORDS: breast neoplasms, estrogen receptors, progesterone receptors, HER2/ neu, continental population groups, ethnic groups, health disparities. Breast cancer is the most common cancer among women in California, accounting for approximately one-third of newly diagnosed cancers. 1 Racial disparities in breast cancer outcomes have been well documented, 2 7 with African American women having a The ideas and opinions expressed herein are those of the author(s) and endorsement by the State of California, Department of Health Services, the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors is not intended nor should be inferred. Address for reprints: Katrina R. Bauer, MS, Research Associate IV, California Cancer Registry, Public Health Institute, 1700 Tribute Rd. Ste. 100, Sacramento, CA ; Fax: (916) kbauer@ccr.ca.gov Received September 26, 2006; revision received December 7, 2006; accepted January 23, ª 2007 American Cancer Society DOI /cncr Published online 26 March 2007 in Wiley InterScience (

2 1722 CANCER May 1, 2007 / Volume 109 / Number 9 lower incidence of breast cancer compared with whites but a higher overall mortality. 2,8 In California the relative burden of invasive breast cancer varies by age and by race/ethnicity. Thus, breast cancer comprises nearly one-quarter (24.4%) of all new invasive cancers in black women aged 20 to 29 years, whereas it only represents 9.1% in non-hispanic whites. Similarly, average age-adjusted mortality rates for African American women less than 50 years of age are reported at 11.9 deaths per 100,000, or nearly twice the rate in non-hispanic whites (6.0 deaths per 100,000). Even after age 50, black women continue to have the highest mortality rate. 2 Determination of estrogen receptor (ER) status of invasive breast carcinoma is useful as a prognostic and predictive factor and has become standard practice in the management of this neoplasm. ER positivity predicts for response to endocrine therapy such as antiestrogen (tamoxifen) administration or ovarian suppression. Similarly, human epidermal growth factor receptor 2 (HER2) positivity is useful for selecting targeted therapy with monoclonal antibody (trastuzumab) against HER2. Recently, microarray profiling of invasive breast carcinoma has identified 5 distinct subtypes of morphologically similar breast cancers (luminal A, luminal B, normal breast-like, HER2-overexpressing, and basal-like). 9 The basal-like subtype, accounting for about 15% of breast cancer cases and characterized by negativity for ER, progesterone receptor (PR), and HER2, is associated with aggressive histology, poor prognosis, and unresponsiveness to the usual endocrine therapies, shorter survival, and BRCA1-related breast cancer Because basal-like breast cancers are ER-, PR-, and HER2-negative, they are sometimes called triplenegative, although it should be noted that only about 85% of triple-negative phenotypic breast cancers are deemed to be basal-like when tested by appropriate immunohistochemical means. 13,14 To help develop treatment strategies for this subtype of breast cancer, we undertook the present study to better characterize the triple-negative phenotype with respect to age, race/ethnicity, socioeconomic status, and survival. MATERIALS AND METHODS Case Identification Data included in this study were identified using the California Cancer Registry (CCR), a population-based registry composed of 8 regional registries collecting cancer incidence and mortality data for the entire population of California. A state law passed in 1985 mandated the reporting of all newly diagnosed cancers in California, and statewide implementation began January 1, Cases are reported to the Cancer Surveillance Section of the California Department of Health Services from hospitals and any other facilities providing care or therapy to cancer patients residing in California. 15 First primary cases of invasive, female breast cancer (ICDO-3 sites C50.0-C50.9) 16 diagnosed between January 1, 1999, and December 31, 2003, and reported to the CCR as of April 2006, are presented in these analyses. A case was defined as triple-negative if ER, PR, and HER2 were negative and the remaining breast cancer cases, where tumor marker status was known, were defined as other breast cancers. The CCR requires the collection of tumor marker information from the medical record on the status of ER and PR for breast cancers diagnosed on or after January 1, 1990, and the status of HER2 for breast cancers diagnosed on or after January 1, ER and PR status are recorded according to the pathologist s interpretation of the assays. ER and PR are considered negative if immunoperoxidase staining of tumor cell nuclei is less than 5%. ER and PR status can also be determined by examining cytosol protein. ER is considered negative if there are fewer than 3 femtomoles per milligram of cytosol protein and PR is considered negative if there are fewer than 5 femtomoles per milligram of cytosol protein. 17 HER2 was assessed through immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH). IHC is scored on a qualitative scale from 0 to 31, based on interpretation of staining intensity, with 0 and 11 classified as negative, 21 as borderline, and 31 as positive. 18 FISH is scored on a quantitative scale with less than 2 copies of the HER2 gene classified as negative. 19 Variables Race/ethnicity was classified into 4 mutually exclusive categories of Asian-Pacific Islander, Hispanic, non- Hispanic black, and non-hispanic white. Race/ethnicity was based on information obtained from the medical record, which can be derived from patient self-identification, assumptions based on personal appearance, or inferences based on the race/ethnicity of the parents, birthplace, surname, or maiden name. Hispanic ethnicity was based on information from the medical record and computerized comparisons to the 1980 US census list of Hispanic surnames. Patients identified as Hispanic on the medical record, or patients identified as white, black, or of unknown race with a Hispanic surname were classified as Hispanic. Cases with unknown race/ethnicity, age, or sex were excluded from these analyses. Quintile of socioeconomic status (SES) was derived from a principle component analysis using data

3 Triple-Negative Breast Cancers/Bauer et al from the 2000 US census. 20 SES was assigned at the census block group level (2000 US census) and based on address at time of initial diagnosis as reported in the medical record. Stage at diagnosis was collected from the patient s medical record and coded according to the American Joint Commission on Cancer (AJCC) Cancer Staging Manual, 6th ed. 21 The CCR collected Surveillance, Epidemiology, and End Results (SEER) extent of disease (EOD) 22 for breast cancer cases diagnosed from 1988 through December EOD was converted to AJCC stage at diagnosis using SEER guidelines. 23 For logistic regression and survival analyses, stage III and stage IV were combined owing to small cell counts. Tumor grade was collected from the medical record and coded according to ICDO Tumor size in millimeters was collected from the medical record according to SEER EOD. 22 Statistical Analysis Proportions and 95% confidence intervals (CI) were calculated for age, race, SES, and tumor characteristic comparisons, including AJCC stage and tumor grade. T-tests were used to detect differences in average age and tumor size between the 2 breast cancer groups. Tests of independent proportions were used to detect differences for age group, race, SES, AJCC stage, and tumor grade. 24 Bivariate and multiple logistic regression analyses were performed to calculate odds ratios (OR) and 95% CIs for demographic differences between triple-negative breast cancers and other breast cancers. ORs from the multiple logistic regression were adjusted for age, race, SES, AJCC stage, and tumor grade. Counts and 5-year relative cumulative survival, a type of overall survival, were calculated using SEER*Stat The actuarial method was used for relative survival calculations. SAS (Cary, NC) was used for logistic regression analyses. RESULTS Of the 92,358 women with first primary breast cancer diagnosed between 1999 and 2003, 51,074 (55.3%) were found to have the 3 markers and 41,284 (44.7%) were missing 1 or more of the markers. We performed 2 sets of analyses, first comparing triple-negatives to other breast cancers with known tumor marker status, and second comparing triple-negatives to other breast cancers including cases with at least 1 unknown tumor marker. The bivariate and multivariate comparisons were nearly identical, with no differences in statistical significance with regard to median age, age groupings, stage, race/ethnicity, SES, and overall relative 5-year survival. Only those cases with known tumor marker status were included in these analyses. The triple-negative phenotype was observed in 6370 (12.5%) of the eligible breast cancer cases, and the remaining 44,704 cases were classified as other breast cancers. Table 1 shows the demographic characteristics of the 51,074 women with known tumor marker status. The median age at diagnosis for the triple-negative group was 54 years, significantly less than 60 years for the other breast cancer group. Approximately 63% of women with triple-negative breast cancer were diagnosed before age 60, whereas fewer than half of women with other breast cancer were diagnosed in that age range. Although the majority of women with breast cancer were non-hispanic white, a smaller proportion (62%) was observed among the triple-negative group when compared with women with other breast cancers (73%). The percent of non-hispanic black women among the triple-negative group was twice that of the other breast cancer group (P <.001). The proportion of Hispanic women in the triple-negative group was also significantly higher than the proportion in the other breast cancer group. No significant difference was noted for Asian-Pacific Islanders. In addition, one-quarter of non-hispanic blacks (24.6%) were found to have the triple-negative phenotype, whereas the percent of non-hispanic whites or Asian- Pacific Islanders with triple-negative features was low, 10.8% and 11.7%, respectively (data not shown). Hispanics were intermediate at 17.2%. Among both groups of women the percent of all breast cancers increased as SES increased, although women with triple-negative breast cancer had a larger proportion diagnosed in areas of low SES. Stage at diagnosis was significantly different between the 2 groups, with the triple-negative patients presenting at a more advanced stage. Median tumor size was significantly larger for the triple-negative group (22 mm versus 17 mm, P <.001). The vast majority of triplenegative breast cancers (76%) were classified as poorly differentiated or undifferentiated, whereas only 28% of the other breast cancer group were so categorized (P <.001). Table 2 shows the adjusted ORs and 95% CIs from the multiple logistic regression analyses for patient demographics of triple-negative breast cancers compared with other breast cancers. The odds of having triple-negative breast cancer increased with younger age, with women less than age 40 being 1.53 times more likely than 60 to 69-year-olds to be diagnosed with triple-negative breast cancer. Non-Hispanic black women were nearly twice as likely to be diagnosed with triple-negative breast cancer when compared with non-hispanic whites, and Hispanic women were slightly more likely to be diagnosed with

4 1724 CANCER May 1, 2007 / Volume 109 / Number 9 TABLE 1 Characteristics of Invasive Breast Cancer Cases in Women in California With Known Tumor Marker Status, Triple negative N = 6370 Other breast cancers N = 44,704 Characteristics No. (%) No. (%) P * Total Age at diagnosis, median <.001 < (12.2) 2534 (5.7) < (24.4) 8359 (18.7) < (26.5) 11,415 (25.5) (17.4) 9616 (21.5) < (12.8) 8671 (19.4) < (6.7) 4109 (9.2).027 Race/ethnicity Non-Hispanic white 3959 (62.2) 32,712 (73.2) <.001 Non-Hispanic black 636 (10.0) 1951 (4.4) <.001 Hispanic 1187 (18.6) 5714 (12.8) <.001 Asian/Pacific Islander 537 (8.4) 4043 (9.0).319 Other 51 (0.8) 284 (0.6).44 SES SES 1, Low 830 (13.0) 4344 (9.7) <.001 SES (18.5) 6701 (15.0) <.001 SES (21.1) 8969 (20.1).2 SES (23.2) 11,014 (24.6).116 SES 5, High 1536 (24.1) 13,676 (30.6) <.001 Tumor size in mm, median <.001 AJCC stage at diagnosis Stage I 2088 (32.8) 20,439 (45.7) <.001 Stage II 3099 (48.6) 17,919 (40.1) <.001 Stage III 686 (10.8) 3016 (6.7).001 Stage IV 248 (3.9) 1440 (3.2) <.001 Unknown 249 (3.9) 1887 (4.2).409 Tumor grade Well differentiated 195 (3.1) 10,091 (22.6) <.001 Moderately differentiated 1003 (15.7) 18,786 (42.0) <.001 Poorly differentiated 4526 (71.1) 11,825 (26.5) <.001 Undifferentiated 333 (5.2) 773 (1.7).004 Unknown 313 (4.9) 3229 (7.2).039 SES indicates socioeconomic status. * t-tests were used to test for differences in means for age and tumor size, and tests of independent proportions were used to test for differences for race, SES, stage, and grade. triple-negative breast cancer. Compared with women living in areas of the highest quintile of SES, women living in areas of lower SES were more likely to be diagnosed with triple-negative breast cancer than other breast cancers. However, women in the lowest level of SES were only marginally significantly more likely to be triple-negative. Relative survival for women with triple-negative breast cancer was poorer than for women with other types of breast cancer, with 77% of women surviving 5 years after diagnosis, compared with 93% survival for other breast cancers (Fig. 1). Figure 2 demonstrates these differences in relative survival by stage at diagnosis and by race/ethnicity. Women with triple-negative breast cancer had consistently poorer survival when compared with women with other breast cancers for each stage and race group. For women diagnosed at AJCC stage I (Fig. 2, top), Hispanic women with triple-negative breast cancers had the worst 5-year cumulative relative survival, although their survival rates were just over 90%, and the difference was not statistically significant. For women diagnosed at stage II (Fig. 2, middle), non-hispanic whites, Hispanics, and non-hispanic blacks with triple-negative breast cancer had statistically significant lower survival than all race groups among the women with other breast cancers. In addition, among women with stage II breast cancers, non-hispanic black women had the poorest survival, although the difference was not significant when compared with other stage II tri-

5 Triple-Negative Breast Cancers/Bauer et al TABLE 2 Adjusted Odds Ratios* and 95% Confidence Intervals for Patient Characteristics and Triple-Negative Phenotype Among Women With Breast Cancer in California, No. (%) Adjusted odds ratio 95% CI Age group at diagnosis < (6.5) (19.4) (25.7) ,724 (21.0) (18.6) (8.9) Race/ethnicity Non-Hispanic white 36,671 (71.8) Non-Hispanic black 2587 (5.1) Hispanic 6901 (13.5) Asian/Pacific Islander 4580 (9.0) Other 335 (0.7) SES SES1, Low 5174 (10.1) SES (15.4) SES3 10,314 (20.2) SES4 12,493 (24.5) SES5, High 15,212 (29.8) SES indicates socioeconomic status. * Adjusted for age, race, SES, AJCC stage, and tumor grade. ple-negative breast cancers. Non-Hispanic black women diagnosed at late stage (Fig. 2, bottom) with triple-negative breast cancer had the poorest survival of any other comparable group, with only 14% surviving 5 years after diagnosis, compared with 49% 5-year relative survival among non-hispanic black women with other breast cancers diagnosed at late stage, as well as 36% survival among non-hispanic white and 37% among Hispanic women with late stage triplenegative breast cancer. DISCUSSION In this large population-based study of invasive breast cancer, we found the triple-negative phenotype to be significantly associated with younger age, African American race/ethnicity, more advanced stage at diagnosis, poorly differentiated histology, lower SES, and shortened survival. Racial disparities in breast cancer incidence and mortality have been well documented in the past, and numerous studies have shown that African American women have a lower incidence of breast cancer but worse survival when compared with white women. 2 8 Possible explanations advanced for this disparity in breast cancer mortality include lack of access to health insurance and medical care, 25 differences in FIGURE 1. Five-year relative survival of triple-negative breast cancers compared with other breast cancers by stage at diagnosis, California, treatment, 26,27 or socioeconomic factors. 7,28,29 Other investigations have shown that equal access to medical care does not eliminate completely the survival disadvantage for African American women, and race alone has been suggested as an independent predictor for survival African American women were noted to have significantly earlier age at diagnosis, high grade tumors, and a higher proportion of ERnegative and PR-negative cancers, 3,6,37 42 suggesting that breast cancer is biologically different in African American women. The molecular classification of breast cancer, based on DNA microarray technology, into luminal, basal, and HER2 subtypes with distinct differences in prognosis and response to therapy, is a vivid illustration of the heterogeneity of breast cancer. The basallike subtype, characterized by lack of expression of ER and PR, low or absent expression of HER2, and IHC expression for cytokeratins usually expressed in the basal cells of the breast (CK5 and CK14), is associated with aggressive histology, poor clinical outcomes, and BRCA1-related breast cancer First presented during the 2004 American Society of Clinical Oncology annual meeting, 43 Carey et al. 44 have shown that the basal-like breast cancer subtype is more prevalent among premenopausal African American women and is a contributing factor to the poor prognosis of young African American women with breast cancer. The present study, based solely on populationbased registry data without the benefit of microarray or IHC confirmation of the basal-like subtype, illustrates the value of the triple-negative phenotype as a surrogate marker for basal-like cancer. Age less than 40 years, being non-hispanic black and, to a lesser extent, being Hispanic, are clearly the most powerful

6 1726 CANCER May 1, 2007 / Volume 109 / Number 9 FIGURE 2. Top: Five-year relative survival for women with breast cancer diagnosed at AJCC stage I, triple-negative breast cancers versus other breast cancers, California, Middle: Five-year relative survival for women with breast cancer diagnosed at AJCC stage II, triple-negative breast cancers versus other breast cancers, California, Bottom: Five-year relative survival for women with breast cancer diagnosed at AJCC stage III-IV, triplenegative breast cancers versus other breast cancers, California, risk factors for this poor prognosis subtype of breast cancer. Because the triple-negative phenotype is not amenable to any form of endocrine therapy, efforts are underway to develop appropriate targeted therapies. 45 We acknowledge the limitations of this study. First, this is strictly a population-based cancer registry investigation. Second, histologic grading of tumors, as well as tests for ER, PR, and HER2, were performed by a wide variety of laboratories without central review. Third, almost half the initial study population lacked information about ER, PR, and HER2, with the latter constituting the bulk of missing data. In 1999 the CCR began collection of HER2 results but over 50% of newly diagnosed breast cancers lacked this test result. By 2003, HER2 testing of primary breast cancer was more common and more than 70% of breast cancer cases were found to have HER2 on record. The results from our analysis comparing triple-negative cases to other breast cancers with at least 1 tumor marker coded as unknown were nearly identical to the comparisons between triple-negatives and other breast cancers with known tumor marker status. Thus, we feel confident that these 2 groups were fairly comparable. Fourth, our study examined the triple-negative phenotype without confirmatory microarray or IHC assays. We recognize that triple-negativity does not automatically equate with the basal-like breast cancer. However, the proportion of the triple-negative phenotype found in the present study (12.5%) corresponds well to the reported incidence of the basal-like breast cancer. 12,45,46 Despite these shortcomings, our study is of value because 1) it includes a sufficiently adequate number of breast cancer cases; 2) it reflects real-world experience of a large, statewide cancer registry in an ethnically diverse population; 3) it highlights the importance of the triple-negative phenotype, now readily available for all new breast cancer cases, as a surrogate marker for basal-like breast cancer; 4) it emphasizes the role of younger age and race/ethnicity (African American and Hispanic) as important risk factors; and 5) it clearly reveals the survival disadvantage of the triple-negative phenotype and may help hasten the development of specific targeted therapy for this subtype of breast cancer. Further research regarding the contribution of each of the tumor markers is underway with survival analyses adjusting for multiple risk factors. REFERENCES 1. American Cancer Society. California Facts and Figures Oakland, CA: California Division and Public Health Institute, California Cancer Registry; Campleman S, Curtis R. Demographic aspects of breast cancer incidence and mortality in California, In: Morris C, Kwong SL, eds. Breast Cancer in California, 2003 Sacramento, CA: California Department of Health Services, Cancer Surveillance Section, July 2004.

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8 1728 CANCER May 1, 2007 / Volume 109 / Number 9 in an urban community hospital. Ann Surg Oncol. 1997;4: Shavers VL, Harlan LC, Stevens JL. Racial/ethnic variation in clinical presentation, treatment, and survival among breast cancer patients under age 35. Cancer. 2003;97: Carey LA, Perou CM, Dressler LG, et al. Race and the poor prognosis basal breast tumor (BBT) phenotype in the population-based Carolina Breast Cancer Study (CBCS). J Clin Oncol (Meeting Abstracts). 2004;22(14 Suppl): Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295: Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10: Rodriguez-Pinilla SM, Sarrio D, Honrado E, et al. Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin Cancer Res. 2006;12: