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      Breast Cancer Survival Defined by the ER/PR/HER2 Subtypes and a Surrogate Classification according to Tumor Grade and Immunohistochemical Biomarkers

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      Journal of Cancer Epidemiology
      Hindawi Publishing Corporation

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          Abstract

          Introduction. ER, PR, and HER2 are routinely available in breast cancer specimens. The purpose of this study is to contrast breast cancer-specific survival for the eight ER/PR/HER2 subtypes with survival of an immunohistochemical surrogate for the molecular subtype based on the ER/PR/HER2 subtypes and tumor grade. Methods. We identified 123,780 cases of stages 1–3 primary female invasive breast cancer from California Cancer Registry. The surrogate classification was derived using ER/PR/HER2 and tumor grade. Kaplan-Meier survival analysis and Cox proportional hazards modeling were used to assess differences in survival and risk of mortality for the ER/PR/HER2 subtypes and surrogate classification within each stage. Results. The luminal B/HER2− surrogate classification had a higher risk of mortality than the luminal B/HER2+ for all stages of disease. There was no difference in risk of mortality between the ER+/PR+/HER2− and ER+/PR+/HER2+ in stage 3. With one exception in stage 3, the ER-negative subtypes all had an increased risk of mortality when compared with the ER-positive subtypes. Conclusions. Assessment of survival using ER/PR/HER2 illustrates the heterogeneity of HER2+ subtypes. The surrogate classification provides clear separation in survival and adjusted mortality but underestimates the wide variability within the subtypes that make up the classification.

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          Most cited references39

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          Ki67 Index, HER2 Status, and Prognosis of Patients With Luminal B Breast Cancer

          Background Gene expression profiling of breast cancer has identified two biologically distinct estrogen receptor (ER)-positive subtypes of breast cancer: luminal A and luminal B. Luminal B tumors have higher proliferation and poorer prognosis than luminal A tumors. In this study, we developed a clinically practical immunohistochemistry assay to distinguish luminal B from luminal A tumors and investigated its ability to separate tumors according to breast cancer recurrence-free and disease-specific survival. Methods Tumors from a cohort of 357 patients with invasive breast carcinomas were subtyped by gene expression profile. Hormone receptor status, HER2 status, and the Ki67 index (percentage of Ki67-positive cancer nuclei) were determined immunohistochemically. Receiver operating characteristic curves were used to determine the Ki67 cut point to distinguish luminal B from luminal A tumors. The prognostic value of the immunohistochemical assignment for breast cancer recurrence-free and disease-specific survival was investigated with an independent tissue microarray series of 4046 breast cancers by use of Kaplan–Meier curves and multivariable Cox regression. Results Gene expression profiling classified 101 (28%) of the 357 tumors as luminal A and 69 (19%) as luminal B. The best Ki67 index cut point to distinguish luminal B from luminal A tumors was 13.25%. In an independent cohort of 4046 patients with breast cancer, 2847 had hormone receptor–positive tumors. When HER2 immunohistochemistry and the Ki67 index were used to subtype these 2847 tumors, we classified 1530 (59%, 95% confidence interval [CI] = 57% to 61%) as luminal A, 846 (33%, 95% CI = 31% to 34%) as luminal B, and 222 (9%, 95% CI = 7% to 10%) as luminal–HER2 positive. Luminal B and luminal–HER2-positive breast cancers were statistically significantly associated with poor breast cancer recurrence-free and disease-specific survival in all adjuvant systemic treatment categories. Of particular relevance are women who received tamoxifen as their sole adjuvant systemic therapy, among whom the 10-year breast cancer–specific survival was 79% (95% CI = 76% to 83%) for luminal A, 64% (95% CI = 59% to 70%) for luminal B, and 57% (95% CI = 47% to 69%) for luminal–HER2 subtypes. Conclusion Expression of ER, progesterone receptor, and HER2 proteins and the Ki67 index appear to distinguish luminal A from luminal B breast cancer subtypes.
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            A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen.

            Tamoxifen significantly reduces tumor recurrence in certain patients with early-stage estrogen receptor-positive breast cancer, but markers predictive of treatment failure have not been identified. Here, we generated gene expression profiles of hormone receptor-positive primary breast cancers in a set of 60 patients treated with adjuvant tamoxifen monotherapy. An expression signature predictive of disease-free survival was reduced to a two-gene ratio, HOXB13 versus IL17BR, which outperformed existing biomarkers. Ectopic expression of HOXB13 in MCF10A breast epithelial cells enhances motility and invasion in vitro, and its expression is increased in both preinvasive and invasive primary breast cancer. The HOXB13:IL17BR expression ratio may be useful for identifying patients appropriate for alternative therapeutic regimens in early-stage breast cancer.
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              Socioeconomic status and breast cancer incidence in California for different race/ethnic groups.

              The majority of research on breast cancer risk and socioeconomic status (SES) has been conducted for blacks and whites. This study evaluates the relationship between SES and breast cancer incidence in California for four race/ethnic groups. Principal component analysis was used to create an SES index using 1990 Census data. Untracted cases were randomly allocated to census block groups within their county of residence. A total of 97,227 female breast cancer cases diagnosed in California between 1988 and 1992 were evaluated. Incidence rates and rate ratios (RRs) were estimated and a chi2 test for trend across SES levels was performed. SES was positively related to breast cancer incidence, and this effect was stronger for Hispanics and Asian/others than for whites and blacks. Adjusting by SES did not eliminate the differences in breast cancer rates among race/ethnic groups. RR differences between the race/ethnic groups were greatest in the lowest SES category and attenuated with increasing SES. An increasing trend over SES was statistically significant for all race/ethnic groups. Including randomly allocated cases affected RR estimates for white women only. Our results are consistent with similar findings for the Los Angeles area but differ from previous results for the San Francisco Bay area.
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                Author and article information

                Journal
                J Cancer Epidemiol
                J Cancer Epidemiol
                JCE
                Journal of Cancer Epidemiology
                Hindawi Publishing Corporation
                1687-8558
                1687-8566
                2014
                26 May 2014
                : 2014
                : 469251
                Affiliations
                Sutter Institute for Medical Research, 2801 Capitol Avenue, Suite 400, Sacramento, CA 95816, USA
                Author notes

                Academic Editor: P. Vineis

                Author information
                http://orcid.org/0000-0002-8351-7309
                Article
                10.1155/2014/469251
                4058253
                9dafe0a8-7b72-4cb4-af4f-f8400b8e1784
                Copyright © 2014 C. A. Parise and V. Caggiano.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 January 2014
                : 18 April 2014
                : 2 May 2014
                Funding
                Funded by: California Health and Safety Code Section
                Award ID: 103885
                Funded by: Northern California Cancer Center
                Award ID: N01-PC-35136
                Funded by: http://dx.doi.org/10.13039/100006034 University of Southern California
                Award ID: N01-PC-35139
                Funded by: http://dx.doi.org/10.13039/100001808 Public Health Institute
                Award ID: N01-PC-54404
                Funded by: http://dx.doi.org/10.13039/100001808 Public Health Institute
                Award ID: 1U58DP00807-01
                Categories
                Clinical Study

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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