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

Abstract

Micro‐Abstract Currently there are no reliable biomarkers to predict outcome of exemestane treatment. We designed a prospective study to investigate whether constitutive genetic background might affect response to therapy. In a population of 302 advanced breast cancer patients treated with exemestane we showed that a 5–polymorphism‐based genetic score could be used to identify patients with different risks of progression and death. 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 and Methods: 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. Graphical abstract Figure. No caption available.