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. 2008 Nov 21:8:339.
doi: 10.1186/1471-2407-8-339.

Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature

Andrew Tutt  1 , Alice Wang, Charles Rowland, Cheryl Gillett, Kit Lau, Karen Chew, Hongyue Dai, Shirley Kwok, Kenneth Ryder, Henry Shu, Robert Springall, Paul Cane, Blair McCallie, Lauren Kam-Morgan, Steve Anderson, Horst Buerger, Joe Gray, James Bennington, Laura Esserman, Trevor Hastie, Samuel Broder, John Sninsky, Burkhard Brandt, Fred Waldman
Affiliations

Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature

Andrew Tutt et al. BMC Cancer. .

Abstract

Background: Given the large number of genes purported to be prognostic for breast cancer, it would be optimal if the genes identified are not confounded by the continuously changing systemic therapies. The aim of this study was to discover and validate a breast cancer prognostic expression signature for distant metastasis in untreated, early stage, lymph node-negative (N-) estrogen receptor-positive (ER+) patients with extensive follow-up times.

Methods: 197 genes previously associated with metastasis and ER status were profiled from 142 untreated breast cancer subjects. A "metastasis score" (MS) representing fourteen differentially expressed genes was developed and evaluated for its association with distant-metastasis-free survival (DMFS). Categorical risk classification was established from the continuous MS and further evaluated on an independent set of 279 untreated subjects. A third set of 45 subjects was tested to determine the prognostic performance of the MS in tamoxifen-treated women.

Results: A 14-gene signature was found to be significantly associated (p < 0.05) with distant metastasis in a training set and subsequently in an independent validation set. In the validation set, the hazard ratios (HR) of the high risk compared to low risk groups were 4.02 (95% CI 1.91-8.44) for the endpoint of DMFS and 1.97 (95% CI 1.28 to 3.04) for overall survival after adjustment for age, tumor size and grade. The low and high MS risk groups had 10-year estimates (95% CI) of 96% (90-99%) and 72% (64-78%) respectively, for DMFS and 91% (84-95%) and 68% (61-75%), respectively for overall survival. Performance characteristics of the signature in the two sets were similar. Ki-67 labeling index (LI) was predictive for recurrent disease in the training set, but lost significance after adjustment for the expression signature. In a study of tamoxifen-treated patients, the HR for DMFS in high compared to low risk groups was 3.61 (95% CI 0.86-15.14).

Conclusion: The 14-gene signature is significantly associated with risk of distant metastasis. The signature has a predominance of proliferation genes which have prognostic significance above that of Ki-67 LI and may aid in prioritizing future mechanistic studies and therapeutic interventions.

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Figures

Figure 1
Figure 1
Kaplan-Meier analysis for distant-metastasis-free survival (DMFS) and overall survival (OS). a) DMFS of training set, b) OS of training set, c) DMFS of validation set, d) OS of validation set, e) DMFS of tamoxifen-treated set.
Figure 2
Figure 2
Metastasis Score as a continuous predictor of probability of distant- metastasis-free survival (DMFS) (5 and 10 year estimates with dashed lines as 95% CI).
Figure 3
Figure 3
Receiver operating characteristic (ROC) curves of 14-gene signature and of Adjuvants! software. ROC curves for distant metastasis (a) and for death (b) within 10 years.
See this image and copyright information in PMC

References

    1. van 't Veer LJ, Dai H, Vijver MJ van de, He YD, Hart AA, Mao M, Peterse HL, Kooy K van der, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530–536. doi: 10.1038/415530a. - DOI - PubMed
    1. van de Vijver MJ, He YD, van't Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, Velde T van der, Bartelink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999–2009. doi: 10.1056/NEJMoa021967. - DOI - PubMed
    1. Buyse M, Loi S, van't Veer L, Viale G, Delorenzi M, Glas AM, d'Assignies MS, Bergh J, Lidereau R, Ellis P, Harris A, Bogaerts J, Therasse P, Floore A, Amakrane M, Piette F, Rutgers E, Sotiriou C, Cardoso F, Piccart MJ, TRANSBIG Consortium Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006;98:1183–1192. - PubMed
    1. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T, Hiller W, Fisher ER, Wickerham DL, Bryant J, Wolmark N. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817–2826. doi: 10.1056/NEJMoa041588. - DOI - PubMed
    1. Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, Cronin M, Baehner FL, Watson D, Bryant J, Costantino JP, Geyer CE, Jr, Wickerham DL, Wolmark N. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:3726–32. doi: 10.1200/JCO.2005.04.7985. - DOI - PubMed

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