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Human Epidermal Growth Factor Receptor 2 Status Correlates With Lymph Node Involvement in Patients With Estrogen Receptor (ER) –Negative, but With Grade in Those With ER-Positive Early-Stage Breast Cancer Suitable for Cytotoxic Chemotherapy

John M.S. Bartlett, Ian O. Ellis, Mitch Dowsett, Elizabeth A. Mallon, David A. Cameron, Stephen Johnston, Emma Hall, Roger A'Hern, Clare Peckitt, Judith M. Bliss, Lindsay Johnson, Peter Barrett-Lee, Paul Ellis

From the Endocrine Cancer Group, Edinburgh Cancer Research Centre, Western General Hospital; Department of Oncology, Western General Hospital, Lothian University Hospitals Trust, Edinburgh; Molecular Medical Sciences, Department of Histopathology, University of Nottingham, Nottingham City Hospital, Nottingham; Department of Pathology, Western Infirmary, Glasgow; Department of Medicine, Breast Unit, Royal Marsden Hospital, London; Section of Clinical Trials—The Institute of Cancer Research Section of Clinical Trials Clinical Trials & Statistics Unit, Sutton, Surrey; Velindre National Health Service Trust, Whitchurch, Cardiff; and the Guys & St Thomas Hospital NHS Trust, London, United Kingdom

Address reprint requests to John Bartlett, PhD, Endocrine Cancer Research Group, Edinburgh University Cancer Research Centre, Western General Hospital, Crewe Rd South, Edinburgh, EH4 2XR United Kingdom; e-mail: John.Bartlett{at}ed.ac.uk

Purpose Human epidermal growth factor receptor 2 (HER-2) expression is associated with increased risk of high-grade disease, nodal metastasis, and absence of estrogen receptors (ERs) in early breast cancer. We tested interactions between ER and HER-2 to determine if they may modulate breast cancer nodal metastasis and proliferation.

Patients and Methods Tumors from the Cancer Research UK Taxotere as Adjuvant Chemotherapy phase III trial were tested for HER-2 using current diagnostic procedures. ER status, progesterone status, clinicopathologic characteristics, and patient age were included in a logistic regression analysis to identify associations with HER-2 status (positive v negative).

Results A total of 841 (23.6%) of 3,565 samples were HER-2 positive (3+ by immunohistochemistry or positive by fluorescent in situ hybridization). ER-negative tumors were more likely to be HER-2 positive than were ER-positive tumors (odds ratio [OR] = 1.87, ER negative v ER positive; P < .001). For ER-positive tumors, risk of HER-2 positivity increased by grade (OR = 7.6, grade 3 v grade 1; P < .001) but not nodal status (OR = 1.3, four or more positive nodes v node negative; P = .08). Conversely, ER negative node-positive tumors were markedly more frequently HER-2 positive than node-negative cases (OR = 3.05, four or more positive nodes v node negative; P < .001) but independent of grade (OR = 0.82, grade 3 v grade 1; P = .76).

Conclusion In early breast cancer patients selected for cytotoxic chemotherapy, we identified significant interactions between HER-2 and ER expression that correlate with tumor pathology. In ER-positive breast cancers, HER-2 expression correlates with grade, not nodal metastasis. In ER-negative breast cancers, HER-2 expression correlates with increased nodal positivity, not grade. ER and HER-2 expression may modify tumor pathology via ER/HER-2–mediated cross talk.

Supported by Cancer Research UK and educational grants from Aventis, Roche, and Pharmacia Upjohn. Storage, construction of microarrays, and tissue HER-2 testing was funded by an educational grant from Roche.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Related Correspondence

• In Early-Stage Breast Cancer, the Estrogen Receptor Interacts With Correlation Between Human Epidermal Growth Factor Receptor 2 Status and Age at Diagnosis, Tumor Grade, and Lymph Node Involvement
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  JCO 2008 26: 1768-1769 [Full Text]

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