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Title: Clinical validation of a customized multiple signature microarray for breast cancer
Authors: Tan, B.K.T.
Tan, L.K.
Yu, K.
Puay, H.T.
Lee, M.
Lang, H.S.
Chow, Y.W.
Gay, H.H.
Yeo, A.W.Y.
Chow, P.K.H.
Heng, N.K.
Wei, S.Y.
Lim, D.T.H.
Ooi, L.L.P.J.
Khee, C.S.
Tan, P. 
Issue Date: 15-Jan-2008
Citation: Tan, B.K.T., Tan, L.K., Yu, K., Puay, H.T., Lee, M., Lang, H.S., Chow, Y.W., Gay, H.H., Yeo, A.W.Y., Chow, P.K.H., Heng, N.K., Wei, S.Y., Lim, D.T.H., Ooi, L.L.P.J., Khee, C.S., Tan, P. (2008-01-15). Clinical validation of a customized multiple signature microarray for breast cancer. Clinical Cancer Research 14 (2) : 461-469. ScholarBank@NUS Repository.
Abstract: Purpose: Current histopathologic systems for classifying breast tumors require evaluation of multiple variables and are often associated with significant interobserver variability. Recent studies suggest that gene expression profiles may represent a promising alternative for clinical cancer classification. Here, we investigated the use of a customized microarray as a potential tool for clinical practice. Experimental Design: We fabricated custom 188-gene microarrays containing expression signatures for three breast cancer molecular subtypes [luminal/estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2), and "basaloid"], the Nottingham prognostic index (NPI-ES), and low histologic grade (TuM1). The reliability of these multiple-signature arrays (MSA) was tested in a prospective cohort of 165 patients with primary breast cancer. Results: The MSA-ER signature exhibited a high concordance of 90% with ER immunohistochemistry reported on diagnosis (P < 0.001). This remained unchanged at 89% (P < 0.001) when the immunohistochemistry was repeated using current laboratory standards. Expression of the HER2 signature showed a good correlation of 76% with HER2 fluorescence in situ hybridization (FISH; ratio ≥2.2; P < 0.001), which further improved to 89% when the ratio cutoff was raised to ≥5. A proportion of low-level FISH-amplified samples (ratio, 2.2-5) behaved comparably to FISH-negative samples by HER2 signature expression, HER2 quantitative reverse transcription-PCR, and HER2 immunohistochemistry. Luminal/ER+ tumors with high NPI-ES expression were associated with high NPI scores (P = 0.001), and luminal/ER+ TuM1-expressing tumors were significantly correlated with low histologic grade (P = 0.002) and improved survival outcome in an interim analysis (hazard ratio, 0.2; P = 0.019). Conclusion: The consistency of the MSA platform in an independent patient population suggests that custom microarrays could potentially function as an adjunct to standard immunohistochemistry and FISH in clinical practice. © 2008 American Association for Cancer Research.
Source Title: Clinical Cancer Research
ISSN: 10780432
DOI: 10.1158/1078-0432.CCR-07-0999
Appears in Collections:Staff Publications

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