A 38-gene expression signature to predict metastasis risk in node-positive breast cancer after systemic adjuvant chemotherapy: a genomic substudy of PACS01 clinical trial

Pascal Jézéquel (1, 2) , Mario Campone (3) , Henri H. Roché (4) , Wilfried Gouraud (1, 5, 6) , Catherine Charbonnel (5, 6, 1) , Gabriel Ricolleau (2) , Florence Magrangeas (5, 1) , Stéphane Minvielle (5, 1) , Jean Genève (7) , Anne-Laure Martin (7) , Régis Bataille (2) , Loïc Campion (5, 6)

1 Unité Mixte de Génomique du Cancer
2 Département de Biologie Oncologique
3 Service d'Oncologie Médicale
4 Département d'oncologie médicale
5 CRCNA - Centre de Recherche en Cancérologie Nantes-Angers
6 Unité de Biostatistique
7 Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC)

Currently, no prognostic gene-expression signature (GES) established from node-positive breast cancer cohorts, able to predict evolution after systemic adjuvant chemotherapy, exists. Gene-expression profiles of 252 node-positive breast cancer patients (median follow-up: 7.7 years), mostly included in a randomized clinical trial (PACS01), receiving systemic adjuvant regimen, were determined by means of cDNA custom array. In the training cohort, we established a GES composed of 38 genes (38-GES) for the purpose of predicting metastasis-free survival. The 38-GES yielded unadjusted hazard ratio (HR) of 4.86 (95% confidence interval = 2.76–8.56). Even when adjusted with the best two clinicopathological prognostic indexes: Nottingham prognostic index (NPI) and Adjuvant!, 38-GES HRs were 3.30 (1.81–5.99) and 3.40 (1.85–6.24), respectively. Furthermore, 38-GES improved NPI and Adjuvant! classification. In particular, NPI intermediate-risk patients were divided into 2/3 close to low-risk group and 1/3 close to high-risk group (HR = 6.97 [2.51–19.36]). Similarly, Adjuvant! intermediate-risk patients were divided into 2/3 close to low-risk group and 1/3 close to high-risk group (HR = 4.34 [1.64–11.48]). The 38-GES was validated on gene-expression datasets from three external node-positive breast cancer subcohorts ( = 224) generated from different microarray platforms, with HR = 2.95 (1.74–5.01). Moreover, 38-GES showed prognostic performance in supplementary cohorts with different lymph-node status and endpoints (1,040 new patients). The 38-GES represents a robust tool able to type systemic adjuvant treated node-positive patients at high risk of metastatic relapse, and is especially powerful to refine NPI and Adjuvant! classification for those patients.

Mots clés: Adjuvant chemotherapy; Breast cancer; Clinicogenomic model; FEC100 regimen; Genomic study; PACS01

Pascal Jézéquel, Mario Campone, Henri H. Roché, Wilfried Gouraud, Catherine Charbonnel, et al.. A 38-gene expression signature to predict metastasis risk in node-positive breast cancer after systemic adjuvant chemotherapy: a genomic substudy of PACS01 clinical trial. Breast Cancer Research and Treatment, 2008, 116 (3), pp.509-520. ⟨10.1007/s10549-008-0250-8⟩. ⟨hal-00478287⟩