Gene signature evaluation as a prognostic tool: challenges in the design of the MINDACT trial

Bogaerts, Jan; Cardoso, Fátima; Buyse, Marc; Braga, Sofía; Loi, Sherene; Ja, Harrison; Bines, José; Mook, Stella; Decker, Nuria; Ravdin, Peter M.; Therasse, Patrick; Rutgers, Emiel J.; Lj, van 't Veer; Piccart, Martine

doi:10.1038/ncponc0591

Cited by 209 publications

(128 citation statements)

References 17 publications

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“…Based on the results of this study the inclusion criteria of the MINDACT trial (EORTC 10041 BIG 3-04), which is currently prospectively validating the 70-gene signature in node-negative patients, will be enlarged to include patients with 1-3 positive nodes [21]. Furthermore, our validation study shows that the signature adds independent prognostic information to that provided by traditional clinicopathological factors and can accurately identify patients with node-positive breast cancer and an excellent disease outcome, which would allow a more tailored approach for adjuvant systemic therapy in this patient group.…”

Section: Discussionmentioning

confidence: 99%

The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1–3 positive lymph nodes in an independent validation study

Mook

Schmidt

Viale

et al. 2008

Breast Cancer Res Treat

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263

152

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Section: Discussionmentioning

confidence: 99%

The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1–3 positive lymph nodes in an independent validation study

Mook

Schmidt

Viale

et al. 2008

Breast Cancer Res Treat

Self Cite

263

152

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“…The 70-gene prognosis signature has been used in the Dutch RASTER-study (Netherlands Cancer Institute in collaboration with the Dutch Health Care Insurance Board) [41] and is currently used in the international MINDACT-trial (TRANSBIG consortium in collaboration with the European Organisation for Research and Treatment of Cancer) [42].…”

Section: Discussionmentioning

confidence: 99%

Validation of 70-gene prognosis signature in node-negative breast cancer

Bueno-de-Mesquita

Linn

Keijzer

et al. 2008

Breast Cancer Res Treat

150

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International audienceThe 70-gene prognosis signature (van't Veer et al., Nature 415(6871):530–536, 2002) may improve the selection of lymph node-negative breast cancer patients for adjuvant systemic therapy. Optimal validation of prognostic classifiers is of great importance and we therefore wished to evaluate the prognostic value of the 70-gene prognosis signature in a series of relatively recently diagnosed lymph node negative breast cancer patients. We evaluated the 70-gene prognosis signature in an independent representative series of patients with invasive breast cancer ( = 123; <55 years; pT1-2N0; diagnosed between 1996 and 1999; median follow-up 5.8 years) by classifying these patients as having a good or poor prognosis signature. In addition, we updated the follow-up of the node-negative patients of the previously published validation-series (Van de Vijver et al., N Engl J Med 347(25):1999–2009, 2002; = 151; median follow-up 10.2 years). The prognostic value of the 70-gene prognosis signature was compared with that of four commonly used clinicopathological risk indexes. The endpoints were distant metastasis (as first event) free percentage (DMFP) and overall survival (OS). The 5-year OS was 82 ± 5% in poor (48%) and 97 ± 2% in good prognosis signature (52%) patients (HR 3.4; 95% CI 1.2–9.6; = 0.021). The 5-years DMFP was 78 ± 6% in poor and 98 ± 2% in good prognosis signature patients (HR 5.7; 95% CI 1.6–20; = 0.007). In the updated series ( = 151; 60% poor vs. 40% good), the 10-year OS was 51 ± 5% and 94 ± 3% (HR 10.7; 95% CI 3.9–30; < 0.01), respectively. The DMFP was 50 ± 6% in poor and 86 ± 5% in good prognosis signature patients (HR 5.5; 95% CI 2.5–12; < 0.01). In multivariate analysis, the prognosis signature was a strong independent prognostic factor in both series, outperforming the clinicopathological risk indexes. The 70-gene prognosis signature is also an independent prognostic factor in node-negative breast cancer patients for women diagnosed in recent years

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“…Indeed, the utility of tumor expression profiling is currently being investigated in clinical trials (e.g. TAILORx, MINDACT [38]). We believe that further studies like the current work that reveal novel expression signatures not only serve to enhance our understanding of human breast cancer progression, but more importantly hold the promise of improving upon assessment of prognosis at the time of presentation.…”

Section: Discussionmentioning

confidence: 99%

The Diasporin Pathway: a tumor progression-related transcriptional network that predicts breast cancer survival

Crawford

Walker

Lukes

et al. 2008

Clin Exp Metastasis

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Microarray expression signature analyses have suggested that extracellular matrix (ECM) gene dysregulation is predictive of metastasis in both mouse mammary tumorigenesis and human breast cancer. We have previously demonstrated that such ECM dysregulation is influenced by hereditary germline-encoded variation. To identify novel metastasis efficiency modifiers, we performed expression QTL (eQTL) mapping in recombinant inbred mice by characterizing genetic loci modulating metastasis-predictive ECM gene expression. Three reproducible eQTLs were observed on chromosomes 7, 17 and 18. Candidate genes were identified by correlation analyses and known associations with metastasis. Seven candidates were identified (Ndn, Pi16, Luc7l, Rrp1b, Brd4, Centd3 and Csf1r). Stable transfection of the highly metastatic Mvt-1 mouse mammary tumor cell line with expression vectors encoding each candidate modulated metastasis-predictive ECM gene expression. Implantation of these cells into mice demonstrated that candidate gene ectopic expression impacts tumor progression. Gene expression analyses facilitated the construction of a transcriptional network that we have termed the 'Diasporin Pathway'. This pathway contains the seven candidates, as well as metastasis-predictive ECM genes and metastasis suppressors. Brd4 and Rrp1b appear to form a central node within this network, which likely is a consequence of their physical interaction with the metastasis efficiency modifier Sipa1. Furthermore, we demonstrate that the microarray gene expression signatures induced by activation of ECM eQTL genes in the Mvt-1 cell line can be used to accurately predict survival in a human breast cancer cohort. These data imply that the Diasporin Pathway may be an important nexus in tumor progression in both mice and humans.

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Gene signature evaluation as a prognostic tool: challenges in the design of the MINDACT trial

Cited by 209 publications

References 17 publications

The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1–3 positive lymph nodes in an independent validation study

The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1–3 positive lymph nodes in an independent validation study

Validation of 70-gene prognosis signature in node-negative breast cancer

The Diasporin Pathway: a tumor progression-related transcriptional network that predicts breast cancer survival

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