Abstract P4-07-01: Loss of HER2 on residual disease after neoadjuvant therapy in HER2-positive early breast cancer: Clinicopathological characteristics and association with outcomes
Authors: Morganti Stefania , Marra Antonio , Viale Giulia , Zagami Paola , Sajjadi Elham , Corti Chiara , Curigliano Giuseppe , Fusco Nicola , Criscitiello Carmen 
Published: March 2022

Abstract
Background: In HER2-positive (HER2+) early breast cancer (eBC) treated with neoadjuvant therapy (NAT), HER2 loss on residual disease (RD) might be correlated with a dampen survival. Recent data from the KATHERINE trial showed a maintained benefit from post-neoadjuvant trastuzumab emtansine (T-DM1) in patients with HER2 loss on RD, even if clinicopathological variables associated with HER2 loss have not been reported. We aimed to characterize the clinicopathological variables and clinical outcomes associated with HER2 loss after NAT in patients with HER2+ eBC.Methods: We retrieved data from a prospectively collected database including all consecutive HER2+ eBC patients treated with NAT at European Institute of Oncology from September 1999 to May 2018. We collected data on age, menopausal status, NAT regimen, clinical and pathological stage, as well as histological subtype and grade, hormone receptor (HR), HER2, and Ki67 status before and after NAT. HR and HER2 status were re-assessed according to the latest ASCO/CAP guidelines. Invasive disease-free survival (IDFS), distant relapse-free survival (DRFS), and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate (UVA) and multivariate analyses (MVA) were performed to identify variables associated with survival outcomes. Variables considered in UVA included: clinical tumor stage (cT: 1-2 vs 3-4) and nodal status (cN: 0 vs 1-2-3), pre-and post-NAT HR status (neg vs pos), NAT (anti-HER2 agents: yes vs no; endocrine therapy: yes vs no), pathological tumor stage (ypT: is-0-1-2 vs 3-4) and nodal status (ypN: 0 vs 1-2-3). Variables with a p value&lt;0.1 were included in the MVA. Results: Of 920 patients with HER2+ eBC who had received NAT, 106 (11.5%) had RD with HER2 loss and were included in the analysis. Median age was 49 yrs (range 29-76). 55 (51.9%), 48 (45.3%) and 3 (2.8%) patients were post-, pre- and peri-menopausal, respectively. Most patients had cT2 tumors (44.3%, vs cT1 3.8%, cT3 20.8%, cT4 31.1%) and cN+ disease (81% vs 19% N0). 84 patients (79.2%) were HR-pos at diagnosis. All patients received neoadjuvant chemotherapy; 73 patients (69.5%) received also anti-HER2 agents. Pathologic staging was: ypT0-is 9.4%, ypT1 47.2%, ypT2 24.5%, ypT3 17%, ypT4 1.9%; ypN0 42.5%, ypN1 27.4%, ypN2 14.2%, ypN3 16.0%. At a median follow-up of 80.8 months (interquartile range, 43.5-159.4), median IDFS, DRFS, and OS were 100 (95% CI, 61-NA), 183 (95% CI, 157-NA), and 197 months (95% CI, 130-NA), respectively. At UVA, pre-NAT HR status (p=0.088) along with cT (p=0.008) and ypN (p=0.016) status were significantly associated with IDFS. At MVA, only HR status retained significance (HR 0.48, 95% CI 0.24-0.94, p=0.032). Median IDFS in HR-pos and HR-neg patients was 109 (95% CI 68.8-NR) and 61 (95% CI 20.9-NR) months, respectively. None of the considered variables was significantly correlated with DRFS at MVA. cT (p=0.006) and ypN (p=0.003) status were also associated with OS at UVA, with ypN that remained independently associated with OS at MVA (HR 3.6, 95% CI, 1.18-11.3, p=0.025). Median OS in ypN0 vs ypN+ patients was 122 (95% CI, 84-NR) vs NR (95% CI, 213-NR), respectively. Conclusions: HER2 loss on RD can be found in ~10% of HER2+ eBCs treated with NAT. In this subset of patients, HR-negative tumors are associated with worse IDFS, warranting the investigation of escalation treatment strategies. Node-negative disease at surgery was instead associated with a significantly longer OS.
Citation Format: Stefania Morganti, Antonio Marra, Giulia Viale, Paola Zagami, Elham Sajjadi, Chiara Corti, Giuseppe Curigliano, Nicola Fusco, Carmen Criscitiello. Loss of HER2 on residual disease after neoadjuvant therapy in HER2-positive early breast cancer: Clinicopathological characteristics and association with outcomes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-01.