title: 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.
abstract: 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 (n = 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.
authors.affiliation: Unité Mixte de Génomique du Cancer, Hôpital Laënnec, 44805 Nantes, Saint Herblain Cedex, France. p-jezequel@nantes.fnclcc.fr
authors.forename: Pascal
authors.initials: P
authors.lastname: Jézéquel
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.forename: Henri
authors.initials: H
authors.lastname: Roché
authors.forename: Wilfried
authors.initials: W
authors.lastname: Gouraud
authors.forename: Catherine
authors.initials: C
authors.lastname: Charbonnel
authors.forename: Gabriel
authors.initials: G
authors.lastname: Ricolleau
authors.forename: Florence
authors.initials: F
authors.lastname: Magrangeas
authors.forename: Stéphane
authors.initials: S
authors.lastname: Minvielle
authors.forename: Jean
authors.initials: J
authors.lastname: Genève
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Martin
authors.forename: Régis
authors.initials: R
authors.lastname: Bataille
authors.forename: Loïc
authors.initials: L
authors.lastname: Campion
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary*; D017024:Chemotherapy, Adjuvant; D017326:Clinical Trials, Phase III as Topic; D003520:Cyclophosphamide / Q000008:administration & dosage; D004311:Double-Blind Method; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D020869:Gene Expression Profiling; D006801:Humans; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology*; D008207:Lymphatic Metastasis; D015337:Multicenter Studies as Topic; D020411:Oligonucleotide Array Sequence Analysis; D017698:Postmenopause; D011379:Prognosis; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil