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

By M. Cheang, S. Chia, D. Voduc, D. Gao, S. Leung, J. Snider, M. Watson, S. Davies, P. Bernard, J. Parker and 3 more. Journal of the National Cancer Institute, 2009

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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.

Subfields: Cancer Research, Genetics, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/60a5e17db2ebec70ad7ebb9addd7b2a5f3bf9992

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Citations in the corpus

Molecular biology in breast cancer: intrinsic subtypes and signaling pathways. (2012, methodology): “From the immunohistochemical point of view, there have been attempts to differentiate between luminal A and B using the protein expression of Ki67 as a possible marker.(22) The luminal A subtype has been defined as ER+/ HER2 and low Ki67, while the luminal B subtype has tumors with ER+/HER2 and high”
Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype (2011, methodology): “The Ki67 index was based on the study published by Cheang and colleagues, 40 in which its expression was considered as a continuous variable and the cut point was determined by the receiver operating characteristic method, using gene expression pro ﬁ le as the gold standard.”
FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer (2010, positive): “Of tumors with high proliferation [≥14% Ki67 as a surrogate for luminal B subtype (2)], 16% have FGFR1 overexpression compared with 3.”
Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. (2011, methodology): “This scoring system has been developed and validated for this very large TMA, and has been used previously to demonstrate prognostic significance for breast cancer biomarkers such as HER-2 and Ki67 (33, 35).”
Deconstructing the molecular portraits of breast cancer (2010, methodology): “(Millikan et al., 2008; Carey et al., 2006), survival (Perou et al., 2000; Sorlie et al., 2001; Cheang et al., 2009; Hu et al., 2006), and response to treatment (Prat et al., 2010; Nielsen et al., 2010; Parker et al., 2009b; Hugh et al., 2009; Carey et al., 2007; Rouzier et al., 2005a).”
Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 (2013, neutral): “hybridization confirmation, where appropriate [23].”
Subtyping of Breast Cancer by Immunohistochemistry to Investigate a Relationship between Subtype and Short and Long Term Survival: A Collaborative Analysis of Data for 10,159 Cases from 12 Studies (2010, background): “There is also some nonrandom error as the luminal 1 tumours that express proliferation markers are likely to behave more like luminal 2 tumours [6].”
Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011 (2011, methodology): “[7], has been adopted as a useful shorthand.”
Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry (2013, background): “In former studies, Ki-67 has also been valued as a prognostic factor being associated with breast cancer outcomes [3, 30, 36, 45–49].”
Breast cancer intrinsic subtype classification, clinical use and future trends. (2015, background): “[ER+|PR+] HER2+KI67+ |Poor 14% [p1] [10]”
Predicting breast tumor proliferation from whole‐slide images: The TUPAC16 challenge (2018, methodology): “Two other more objective methods that assess tumor proliferation in the breast include immunohistochemical staining for Ki67 protein (Cheang et al., 2009) and the molecular gene expression based PAM50 proliferation score (Heng et al., 2017; Nielsen et al., 2010; The Cancer Genome Atlas Network,…”