Journal of the National Cancer Institute Advance Access published online on May 12, 2009
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djp082
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Ki67 Index, HER2 Status, and Prognosis of Patients With Luminal B Breast Cancer
Affiliations of authors: Genetic Pathology Evaluation Centre, Vancouver Coastal Health Research Institute, British Columbia Cancer Agency, and University of British Columbia, Vancouver, BC, Canada (MCUC, DV, DG, SL, TON); Department of Medical Oncology (SKC) and Department of Radiation Oncology (DV), British Columbia Cancer Agency, Vancouver, BC, Canada; Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St Louis, MO (JS, MW, SD, MJE); Department of Pathology, University of Utah Health Sciences Center, Salt Lake, UT (PSB); Lineberger Comprehensive Cancer Center and Department of Genetics and Department of Pathology & Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC (JSP, CMP)
Correspondence to: Torsten O. Nielsen, MD, PhD, Anatomical Pathology, JP 1401, Vancouver Hospital and Health Sciences Centre, 855 West 12th Ave, Vancouver, BC, Canada V5Z 1M9 (e-mail: torsten{at}interchange.ubc.ca).
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.
| CONTEXT AND CAVEATS Prior knowledge Two biologically distinct estrogen receptor–positive subtypes of breast cancer have been identified by gene expression profiling of breast cancers: luminal A and luminal B, with luminal B tumors having a higher rate of tumor cell proliferation and poorer prognosis than luminal A tumors. Study design A group of tumors from patients with invasive cancer was subjected to gene expression profiling to determine the breast cancer subtype. Another group of hormone receptor–positive breast cancers was assessed by immunohistochemistry for the expression of a panel of four biomarkers for breast cancer (ie, estrogen receptor, progesterone receptor, HER2, and Ki67); patients in this group were separated by subtype determined by immunohistochemistry, and their survival was analyzed. Contribution Luminal A and B breast cancers appear to be distinguished by the expression of estrogen receptor, progesterone receptor, HER2, and Ki67 proteins. Implications An immunohistochemistry test of four biomarkers appears to be able to separate breast cancer patients by subtype. Additional research is warranted to determine whether this assay could have clinical utility. Limitations This study has limitations typical of immunohistochemical approaches, including limited technical reproducibility, subjective interpretation, and qualitative readouts. The false-positive and false-negative rates of the assay were approximately 25%. From the Editors
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Dr P. S. Bernard owns founding stock in University Genomics, Inc. Dr C. M. Perou owns stock in University Genomics, Inc., which makes assays for breast cancer patient prognosis prediction. Dr M. J. Ellis is a founder of University Genomics, Inc. and owns stock in this company. Dr T. O. Nielsen is a codirector of the tissue microarray unit of the Genetic Pathology Evaluation Centre, which has an unrestricted educational grant from sanofi-aventis, Canada.
Manuscript received August 8, 2008; revised February 27, 2009; accepted March 11, 2009.
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  S. J. Howell, A. M. Wardley, and A. C. Armstrong Re: Ki67 Index, HER2 Status, and Prognosis of Patients With Luminal B Breast Cancer J Natl Cancer Inst, November 5, 2009; (2009) djp390v1. [Full Text] [PDF]
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