Abstract P6-09-49: Three-gene signature predictive of high residual risk of recurrence after adjuvant chemotherapy in ER-positive HER2-negative breast cancer

Background: A proportion of ER-positive, HER2-negative patients treated with both adjuvant endocrine and chemotherapy continue to remain high risk for recurrence. These individuals are the ideal patient population for future adjuvant trials. Methods: We used gene expression data from ER+/HER2- patients who received adjuvant endocrine and chemotherapy. We utilized a training cohort of multiple gene expression datasets (N=131; GSE16391, GSE21653, GSE17907, GSE19615, GSE16716, GSE45255) and a validation cohort (N=277; GSE25066) from similarly treated ER+ patients. All data sets were generated with Affymetrix HGU133 arrays. Cox proportional hazards regression was performed across all genes using all possible cutoff values between the lower and upper quartile. Genes were ranked according to the estimated hazard rates for relapse. The top three genes were combined into a final signature that used the mean expression of these genes as the predictive score. Statistical analyses were performed in the R environment. Results: The final signature capable to predict survival consisted of three genes, MX1, MBD4, and ZWINT. Each of these genes achieved high significance in a univariate analysis: MX1 HR=5.7 (p=1.8E-04) and HR=4.7 (p=1.3E-03), MBD4 HR=3.4 (p=2.8E-04) and HR=4.3 (p=4.4E-04), and ZWINT HR=4.4 (p=1E-03) and HR=3.7 (p=8.5E-03) in the training and validation cohorts, respectively. Using the mean expression of the three genes, the estimated hazard rates for survival were 20.5 (p=2.5E-05) and 17.5 (p=1E-04) in the two cohorts, respectively. Only one patient relapsed in each cohort. In a multivariate analysis including grade and lymph node status as covariates (size was not available), the three-gene signature retained significance (HR=13.2, p=0.011; and HR=13.9, p=0.01 in the two cohorts, respectively), while only lymph node status (HR=3.6, p=0.007) was significant in the validation cohort and no clinical variable was significant in the training cohort. Conclusions: High expression of a 3-gene signature can identify ER+ patients who remain at very high risk for recurrence despite current adjuvant endocrine and chemotherapy. Citation Format: Györffy B, Ocana A, Herman P, Hatzis C, Pandiella A, Pusztai L. Three-gene signature predictive of high residual risk of recurrence after adjuvant chemotherapy in ER-positive HER2-negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-49.