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A New Genetic Risk Score to Predict the Outcome of Locally Advanced or Metastatic Breast Cancer Patients Treated With First-Line Exemestane: Results From a Prospective Study.

By: Sara Gagno, Mario Rosario D'Andrea, Mauro Mansutti, Chiara Zanusso, Fabio Puglisi, Eva Dreussi, Marcella Montico, Paola Biason, Erika Cecchin, Donatella Iacono, Stefania Russo, Marika Cinausero, Silvana Saracchini, Giampietro Gasparini, Donata Sartori, Mario Bari, Elena Collovà, Rosa Meo, Ghassan Merkabaoui, Ilaria Spagnoletti, Arianna Pellegrino, Lorenzo Gianni, Paolo Sandri, Elisabetta Cretella, Emanuela Vattemi, Andrea Rocca, Patrizia Serra, Maria Agnese Fabbri, Giovanni Benedetti, Laura Foghini, Michele Medici, Umberto Basso, Vito Amoroso, Ferdinando Riccardi, Anna Maria Baldelli, Mario Clerico, Salvatore Bonura, Chiara Saggia, Federico Innocenti, Giuseppe Toffoli

Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano, Italy.
2018-10-01; doi: 10.1016/j.clbc.2018.11.009

Abstract

Introduction

Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival.

Patients

Three hundred two locally advanced or MBC patients treated with first-line exemestane were genotyped for 74 germ line polymorphisms in 39 candidate genes involved in drug activity, hormone balance, DNA replication and repair, and cell signaling pathways. Associations with progression-free survival (PFS) and overall survival (OS) were tested with multivariate Cox regression. Bootstrap resampling was used as an internal assessment of results reproducibility.

Results

Cytochrome P450 19A1-rs10046TC/CC, solute carrier organic anion transporter 1B1-rs4149056TT, adenosine triphosphate binding cassette subfamily G member 2-rs2046134GG, fibroblast growth factor receptor-4-rs351855TT, and X-ray repair cross complementing 3-rs861539TT were significantly associated with PFS and then combined into a risk score (0-1, 2, 3, or 4-6 risk points). Patients with the highest risk score (4-6 risk points) compared with ones with the lowest score (0-1 risk points) had a median PFS of 10 months versus 26.3 months (adjusted hazard ratio [AdjHR], 3.12 [95% confidence interval (CI), 2.18-4.48]; P < .001) and a median OS of 38.9 months versus 63.0 months (AdjHR, 2.41 [95% CI, 1.22-4.79], P = .012), respectively.

Conclusion

In this study we defined a score including 5 polymorphisms to stratify patients for PFS and OS. This score, if validated, might be translated to personalize locally advanced or MBC patient treatment and management.