A prognostic signature based on three-genes expression in triple-negative breast tumours with residual disease

Joseph A Pinto; Jhajaira Araujo; Nadezhda K Cardenas; Zaida Morante; Franco Doimi; Tatiana Vidaurre; Justin M Balko; Henry L Gomez

doi:10.1038/npjgenmed.2015.15

A prognostic signature based on three-genes expression in triple-negative breast tumours with residual disease

NPJ Genom Med. 2016 Feb 3:1:15015. doi: 10.1038/npjgenmed.2015.15. eCollection 2016.

Authors

Joseph A Pinto¹, Jhajaira Araujo¹, Nadezhda K Cardenas², Zaida Morante¹, Franco Doimi³, Tatiana Vidaurre⁴, Justin M Balko⁵, Henry L Gomez⁴

Affiliations

¹ Unidad de Investigación Básica y Traslacional, Oncosalud-AUNA, Lima, Peru.
² Escuela de Medicina Humana, Universidad Privada San Juan Bautista, Lima, Peru.
³ Departamento de Patología, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.
⁴ Departamento de Oncología Médica, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.
⁵ Department of Medicine, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, Nashville, TN, USA.

Abstract

Residual disease after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) is related with poor prognosis; however, the risk of recurrence after 3 years from surgery, becomes similar to other breast cancer subtypes indicating that TNBC is composed of tumours of different prognosis. To evaluate genes related to TNBC aggressiveness in the outcome of TNBC resistant to NAC, we profiled 82 samples of residual tumours whose expression for 449 genes was quantified with NanoString. The validation set (GSE25066) consisted of 113 TNBC cases with residual disease. The stepwise multivariate survival analysis performed by the Cox proportional hazards mode selected CCL5, DDIT4 and POLR1C as independent prognostic factors for distant recurrence-free survival (DRFS). We developed a three-genes signature using the regression coefficients for each gene (-0.393×CCL5+0.443×DDIT4+0.490×POLR1C). The median score in the discovery set (0.1494) identified two subgroups with different DRFS (P<0.001). The median score in the validation set was 0.0024 and was able to discriminate patients with different DRFS (P=0.002). In addition, the three-genes signature was a prognostic factor in TNBC patients regardless their response to NAC (data set GSE58812; P=0.001) and in patients with oestrogen-receptor-negative tumours (data set GSE16446; P=0.041). Here we describe a prognostic signature based on expression levels of CCL5, DDIT4 and POLR1C. The knowledge about the involvement of these genes in chemotherapy resistance could improve the therapeutic strategies in TNBC.