Abstract P2-09-03: Identifying clinically relevant subgroups of women with HER2-positive breast cancer: An analysis of Neo-ALTTO using the 41-gene TRAR score
Authors: Di Cosimo S , Triulzi T , De Cecco L , Pizzamiglio S , de Azambuja E , Fumagalli D , Pusztai L , Harbeck N , Izquierdo M , de la Pena L , Huober J , Baselga J , Piccart M , Verderio P , Tagliabue E 
Published: February 2018

Abstract
BACKGROUND: As a neoadjuvant regimen for HER2-positive early breast cancer (BC), the use of two HER2-directed agents is more effective in producing pathological complete (pCR) responses than trastuzumab alone. Nevertheless, highly effective dual anti-HER2 combination may be unnecessary in patients who already benefit from a single agent. We previously reported that our 41-gene TRAR score is an accurate predictor of response to trastuzumab, with low scores being predictive of response to trastuzumab and favorable prognosis (Triulzi T. et al., 2015).
PATIENTS AND METHODS: Tissue specimens from HER2-positive BC patients of Neo-ALTTO trial who received neoadjuvant trastuzumab and/or lapatinib plus paclitaxel were included in this study. Analysing RNA from fresh tissue using the 41-gene signature test, the area under the ROC curve (AUC) and the corresponding 95% confidence interval was computed to evaluate the predictive ability of TRAR score with respect to pCR, the primary endpoint of Neo-ALTTO. The prognostic role of TRAR score was investigated using a Cox regression model in univariate fashion. The patterns of Event Free Survival (EFS) according to the dichotomized TRAR score were estimated using the Kaplan–Meier method.
RESULTS: The TRAR score was assessed for 226 of the 455 (49.7%) patients enrolled in the Neo-ALTTO study: 136 (60%) presented with T2 tumors, 188 (83%) with N0/1 and 128 (56.6%) with estrogen receptor negative BC. In details, basal TRAR score was available for 69, 79 and 78 patients assigned to neoadjuvant trastuzumab, lapatinib, and their combination, respectively. Overall, patients achieving a pCR showed significantly lower levels of TRAR score than those with residual disease (p &lt;.0001). According to treatment arm, the classifier highly performed in discriminating responders (pCR) from non responders (no pCR) (trastuzumab: AUC = 0.74, 95% CI: 0.60–0.88; lapatinib: AUC = 0.76, 95% CI: 0.65–0.87; trastuzumab + lapatinib: AUC = 0.71, 95% CI: 0.59–0.83). Of note, the predictive value of the TRAR score was confirmed after adjustment for hormone receptor status. An AUC value of 0.70 (95% CI: 0.59–0.81) and 0.71 (95% CI: 0.62–0.80) was obtained in estrogen receptor positive and negative patients, respectively. We also evaluated the contribution to the predictive capability of TRAR levels and PAM50 by implementing a multivariate logistic regression model including both classifiers and clinically relevant variables. In this model the most predictive variable was TRAR. At a median follow-up of 7 years, with a total of 64 events, no statistically significant association was found between the TRAR score and EFS.
CONCLUSION: Overall, we show that our 41-gene signature is accurate in predicting patient response to neoadjuvant HER2 targeted therapy in terms of pCR. In particular, low levels of TRAR score can identify a HER2-positive breast cancer subgroup highly responsive to trastuzumab as monotherapy for whom combination with other HER2-targeted drugs does not appear justified and may be one tool used for exploring de-escalating strategies without sacrificing outcomes.
Citation Format: Di Cosimo S, Triulzi T, De Cecco L, Pizzamiglio S, de Azambuja E, Fumagalli D, Pusztai L, Harbeck N, Izquierdo M, de la Pena L, Huober J, Baselga J, Piccart M, Verderio P, Tagliabue E. Identifying clinically relevant subgroups of women with HER2-positive breast cancer: An analysis of Neo-ALTTO using the 41-gene TRAR score [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-03.