Abstract HER2-10: HER2-10 Dynamics of HER2-low expression in triple-negative breast cancer
Authors: Garrido-Castro Ana C. , Ngo Lan D. , Richardson Edward T. , Frangieh Allison , Mohammed-Abreu Ayesha , Hughes Melissa E. , Zanudo Jorge Gomez Tejada , Navarro John , Tarantino Paolo , Mittendorf Elizabeth A. , Tolaney Sara , King Tari , Winer Eric , Lin Nancy U. , Wagle Nikhil 
Published: March 2023

Abstract
Background: With the development of novel antibody drug conjugates (ADC), it is increasingly important to understand the changes that occur in cell-surface targets over time from early-stage to metastatic breast cancer. Discordance in HER2 expression per immunohistochemistry (IHC) has been reported between primary and metastatic tumors in patients (pts) with HER2-negative breast cancer defined per ASCO/CAP guidelines, with both gain and loss of expression described. Representation of HR-negative (TNBC) tumors has been limited in these studies, and HER2 status at multiple time points in TNBC has not been described. Here we report changes in HER2 IHC in patients diagnosed with TNBC, using a collection of matched tumor samples over time. Methods: Pts were identified from two sources: 1) an institutional database including all consecutive pts who underwent surgery for stage I-III breast cancer at Dana-Farber/Brigham Cancer Center between 2015-2018, and 2) a prospective research biopsy protocol for pts with known or suspected metastatic breast cancer. Pts were included in the present analysis if they received neoadjuvant chemotherapy (NAC) for stage I-III TNBC (eTNBC), or if they were diagnosed with any stage TNBC and ultimately developed metastatic TNBC (mTNBC). Clinical pathology records were reviewed for HER2 IHC results of samples collected at: initial diagnosis (DX); residual disease (RD) post-NAC, if applicable; and at recurrence (M). HER2 IHC was classified as HER2-0 if HER2 IHC 0, and HER2-low if 1+ or 2+ (and ISH non-amplified). For matched comparisons, if IHC was performed in more than one DX sample (e.g., breast, node), only the breast was considered; if more than one M sample, only the first M biopsy with available IHC was considered. Results: Among 110 pts in this cohort, 101 were initially diagnosed with eTNBC (79 received NAC; 22 underwent surgery as first intervention) and 9 with de novo mTNBC. Median age was 48.7 years (range 19.8-71.6). Among all pts, a total of 292 samples (136 DX, 53 RD, 103 M) had available HER2 IHC scores. When restricting to one sample per time point, HER2-low prevalence was 49/102 (48.0%) in DX breast tumors, 21/53 (39.6%) in RD, and 13/58 (22.4%) in first M samples (with all remaining samples HER2-0, except one HER2 3+ sample). In eTNBC pts, HER2 IHC scores were available for 50 paired DX and RD, and 48 paired DX and M samples. Among 50 pts with paired DX and RD, HER2 IHC was discordant in 56% (28/50) (Table 1). Of the 21 HER2-0 DX tumors, 23.8% (5/21) became HER2-low at RD. Of the 29 HER2-low DX tumors, 51.7% (15/29) became HER2-0 at RD. Among 48 eTNBC pts who recurred and had paired DX and M samples, HER2 IHC was discordant in 50% (24/48) (Table 1). Change from HER2-0 to low was 12.5% (3/24), and from HER2-low to HER2-0 was 66.7% (16/24). Among 9 de novo mTNBC pts, 5 had HER2 IHC available in paired DX breast and M prior to starting therapy; 3 were concordant (IHC 0, n=2; IHC 1+, n=1), one had IHC 0 in DX breast and IHC 2+ in M (liver), one had IHC 1+ in DX breast and IHC 0 in M (node). Conclusions: HER2 IHC classification was discordant in about half of the TNBC cases we examined, with more frequent rates of conversion from HER2-low to HER2-0 in both paired DX/RD post-NAC, and paired DX/M samples. Additional analyses will be presented exploring HER2 IHC changes among multiple metastases per patient. Genomic and molecular analysis, including whole exome sequencing, RNA sequencing, and methylation profiling, are underway in these samples to further elucidate HER2 evolutionary dynamics.
Citation Format: Ana C. Garrido-Castro, Lan D. Ngo, Edward T. Richardson, Allison Frangieh, Ayesha Mohammed-Abreu, Melissa E. Hughes, Jorge Gomez Tejada Zanudo, John Navarro, Paolo Tarantino, Elizabeth A. Mittendorf, Sara Tolaney, Tari King, Eric Winer, Nancy U. Lin, Nikhil Wagle. HER2-10 Dynamics of HER2-low expression in triple-negative breast cancer [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 HER2-10.