Abstract P4-02-14: Gain of HER2 Amplification in Patients with HR+/HER2- and Triple Negative Early Breast Cancer Treated with Neoadjuvant Chemotherapy
Authors: Ferraro Emanuela , Minmin Sonya Chew , Safonov Anton , Barrio Andrea V. , Modi Shanu , Seidman Andrew D , Wen Hanna Y , Brogi Edi , Robson Mark E. , Dang Chau T 
Published: March 2023

Abstract
Background: Neoadjuvant chemotherapy (NAC) is standard of care for the majority of patients with clinical stage II-III triple negative breast cancer (TNBC) and is considered in high-risk patients with hormone receptor positive (HR+)/human epidermal growth factor receptor 2 (HER2) negative (-) tumors, with expected pathological complete response (pCR) rates of 40-60% and 10-12%, respectively. In HER2- patients with residual disease (RD) after NAC, there is limited data on rates of gain of HER2 amplification. The biological and clinical significance of this phenomenon is unknown and determining the best adjuvant therapy for these patients remains a challenge. We sought to determine the rate of HER2 gain in a cohort of consecutive patients with HER2- breast cancer (BC) treated with NAC.
Methods: From 01/2021 to 12/2021, we identified patients with HER2- breast cancer treated with NAC followed by surgery at our institution. Patients who received neoadjuvant endocrine therapy were excluded. The rates of pCR (ypT0/is ypN0) and HER2 status pre- and post-NAC were assessed. Estrogen receptor (ER), progesterone receptor (PR) and HER2 status on surgery specimens were internally determined for all patients using ASCO/CAP 2020 guidelines. ER-low was defined as ER expression by immunohistochemistry (IHC) 1-10%.
Results: We included 256 patients, 130 (51%) HR+/HER2- [13/130(10%) ER-low] and 126 (49%) TNBC. Median age was 48 years (range 25-82) and the majority presented with clinical T2 (57%) and N1 (59%). Of 130 patients with HR+/HER2-tumors, 120 (92%) received dose-dense (dd) doxorubicin/cyclophosphamide-paclitaxel (AC-T). Of 126 TNBC patients, 46 (37%) received ddAC followed by carboplatin in combination with paclitaxel +/- pembrolizumab. Centralized HER2 status assessment on the core biopsy was performed in 22% of samples. Overall, pCR was achieved in 40% of TNBC and 11% of HR+/HER2-. Among the 192 patients with RD, the rate of HER2 gain was 8/192 (4%), including 3% (2/76) of TNBC and 5% (6/116) of HR+/HER2- patients. 7 of the 8 patients (88%) converted from IHC 1+ or 2+ fluorescence in situ hybridization (FISH) not amplified on core biopsy to IHC 2+ FISH amplified on the surgical specimen. In only 1 case, the HER2 status converted from IHC2+ FISH not amplified to IHC3+. 3/8 patients had multifocal disease. All 6 patients with HR+/HER2- BC and HER2 gain had high (&gt;90%) ER expression (Table 1). All but one patient with HER2 gain received adjuvant anti-HER2 therapy. After a median follow-up of 10 months, no recurrence events occurred in this group.12 of the remaining 184 patients experienced a recurrence [11 distant recurrences (8 and 3, in the TNBC and HR+/HER2- groups, respectively), and there was 1 local event (localized chest wall recurrence) in the HR+/HER2- group].
Conclusions: At a single center, we found that in patients with HER2- BC treated with NAC, HER2 gain in patients with RD was uncommon and occurred more frequently in those with HR+ tumors. Analysis of a larger cohort is ongoing to corroborate these results. It is remains to be determined if this phenomenon represents a true HER2 status conversion or tumor heterogeneity.
Table 1: Clinico-pathological characteristics of patients with HER2 gain on residual disease
Citation Format: Emanuela Ferraro, Sonya Chew Minmin, Anton Safonov, Andrea V. Barrio, Shanu Modi, Andrew D Seidman, Hanna Y Wen, Edi Brogi, Mark E. Robson, Chau T Dang. Gain of HER2 Amplification in Patients with HR+/HER2- and Triple Negative Early Breast Cancer Treated with Neoadjuvant Chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-14.