Abstract P2-09-04: Association of intrinsic subtype and immune genes with pathological complete response in the OPTIHER-HEART phase II clinical trial following neoadjuvant trastuzumab/pertuzumab-based chemotherapy in HER2-positive breast cancer
Authors: Gavila J , Oliveira M , Pascual T , Pérez J , Canes J , González X , Paré L , Calvo I , Ciruelos E , Muñoz M , Virizuela JA , Ruiz I , Andrés R , Perelló A , Martínez J , Morales S , Marín M , Martínez D , Quero JC , Llombart-Cussac A , Prat A 
Published: February 2018

Abstract
Background. In HER2-positive early breast cancer, neoadjuvant therapy based on dual HER2 blockade with trastuzumab and pertuzumab in combination with chemotherapy is associated with high rates of pCR. The OPTIHER-HEART trial examined the safety of the neoadjuvant dual blockade added to paclitaxel and liposomal doxorubicin (Gávila et al, SABCS 2016). In this analysis, we examined the intrinsic subtypes and immune genes in baseline and surgical samples from the OPTIHER-HEART trial.
Methods.OPTIHER-HEART was a multicenter single-arm phase II study of 18 weeks of neoadjuvant pertuzumab, weekly trastuzumab, liposomal doxorubicin (50 mg/m2 every 21 days) and weekly paclitaxel 80 mg/m2 in patients with stage II-IIIB HER2-positive breast cancer. pCR was defined as absence of infiltrating tumor in the breast and axilla. The expression of 55 breast cancer-related and immune genes in baseline samples and surgical specimens was measured using the nCounter platform. Intrinsic subtypes were determined by the PAM50 gene expression predictor. Univariate and multivariable logistic regression models adjusted for tumor size, ER status, age and nodal status was performed.
Results. A total of 58 of the 83 (69.8%) baseline tumor samples were available. 51.7% (n=30) were classified as HER2 enriched (HER2-E) followed by Normal-like (15.5%; n=9), Basal-like (12.0%; n=7), Luminal A (10.3%; n=6), and Luminal B (10.3%; n=6). HER2-E was the most frequent subtype in both hormone receptor (HR)-negative (50.0%) and HR-positive (52.0%) tumors. The pCR rates varied according to intrinsic subtype (p&lt;0.001). The highest rate of pCR was observed in Basal-like (85.7%) and HER2-E (83.3%), followed by Normal-like (44.4%), Luminal A (33.3%) and Luminal B (16.6%). HER2-E tumors were associated with higher pCR rates compared to non-HER2-E tumors (83.3% vs 46.5%, unadjusted odds ratio = 5.76, 95% CI 1.71 – 19.42, P=0.004), even after adjusting for HR status, size, age and lymph node involvement (odds ratio = 13.50, 95% CI2.51 – 72.52, P=0.002). Among the 55 genes, 14 (25.5%) were statistically significantly associated with pCR in univariate analysis (false discovery rate &lt; 1%). Genes associated with pCR were 17q12-21 amplicon genes (e.g. GRB7 and ERBB2) and immune genes (e.g. CD8A and PD1). Genes associated with residual disease were luminal-related genes (e.g. ESR1 and PGR). Among the 14 genes, only 7 (i.e. CDH3, CD8A, PD1, EGFR, ESR1, SLC39A6, NAT1) were significantly associated with pCR beyond intrinsic subtype (HER2-E vs non-HER2-E). Finally, a total of 58 of the 80 (72.5%) surgical specimens were profiled. 77% of the samples were classified as Normal-like, followed by Luminal A (20%), Luminal B (2%) and HER2-E (2%). Normal-like was identified in a higher proportion in pCR samples (90%) compared to samples with residual disease (47%) (p&lt;0.001).
Conclusion. HER2-E subtype and immune genes are independently associated with pCR after dual HER2 blockade and multi-agent chemotherapy. Subtyping of surgical specimens might provide additional response and outcome data and warrants further evaluation.
Citation Format: Gavila J, Oliveira M, Pascual T, Pérez J, Canes J, González X, Paré L, Calvo I, Ciruelos E, Muñoz M, Virizuela JA, Ruiz I, Andrés R, Perelló A, Martínez J, Morales S, Marín M, Martínez D, Quero JC, Llombart-Cussac A, Prat A. Association of intrinsic subtype and immune genes with pathological complete response in the OPTIHER-HEART phase II clinical trial following neoadjuvant trastuzumab/pertuzumab-based chemotherapy in HER2-positive breast cancer [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 P2-09-04.