Abstract P2-01-01: Genetic alterations detected by circulating tumor DNA (ctDNA) in HER2-low metastatic breast cancer (MBC)
Authors: Hensing Whitney L , Gerratana Lorenzo , Clifton Katherine , Velimirovic Marko , Shah Ami , D'Amico Paolo , Reduzzi Carolina , Zhang Qiang , Dai Charles S , Bagegni Nusayba A , Opyrchal Mateusz , Ademuyiwa Foluso O , Ron Bose , Behdad Amir , Ma Cynthia X , Bardia Aditya , Cristofanilli Massimo , Davis Andrew A 
Published: March 2022

Introduction: Approximately 40-50% of breast cancers are characterized by low HER2 expression (HER2-low), defined as immunohistochemistry (IHC) 1+ or 2+ and HER2 fluorescence in situ hybridization (FISH) unamplified, encompassing a large and heterogeneous subgroup that may confer benefit from novel HER2 directed therapies. Circulating tumor DNA (ctDNA) has emerged as a minimally invasive technique to detect cancer-specific gene aberrations. Genetic alterations in ctDNA of HER2-low MBC have not been well described, and we hypothesized that HER2-low MBC may have a distinct genomic profile, beyond standard histopathologic features. Methods: This retrospective cohort study included patients with MBC treated at Washington University in St. Louis, Northwestern University (Chicago, IL) and Massachusetts General Hospital (Boston, MA) who had undergone ctDNA analysis during the course of treatment using the commercially available Guardant360® assay. HER2 expression was evaluated by IHC/FISH according to ASCO/CAP guidelines on metastatic tissue biopsies (or primary breast tumor tissue if a metastatic site biopsy was not available). Tumors were classified as HER2-low (IHC 1+ or 2+/FISH negative), HER2-0 (IHC 0) or HER2-positive (IHC 3+ or IHC 2+/FISH amplified). Clinicopathologic characteristics and ctDNA genetic alterations for HER2-low MBC were described and compared with the HER2-0 and HER2-positive subgroups. Chi-square and Fisher’s exact tests were used for categorical variables. Logistical regression was performed for multivariable analyses. Results: A total of 991 patients with MBC were analyzed, including 160 (16.1%) HER2-positive, 351 (35.4%) HER2-0, and 480 (48.4%) HER2-low MBC. The majority (89.2%) of HER2-low MBC were estrogen-receptor positive (ER+). Compared with HER2-0 MBC, HER2-low MBC had a significantly higher incidence of PIK3CA mutations (OR 1.54, p=0.027). PDGFRA and MYC amplifications were also more common among HER2-low MBC (2.3% vs 0.28% and 8.1% vs 4.6%, respectively), although not significantly associated with this subtype in multivariable analysis. Within the ER+ MBC cohort, those with HER2-low also had higher rates of PIK3CA mutations (OR 1.66, p=0.012) and MYC amplification (OR 2.29, p=0.034), as compared to HER2-0. Compared with HER2-positive, HER2-low MBC had significantly lower rates of ERBB2 alterations (OR 0.26, p=0.0076 for ERBB2 mutations and OR 0.022, p&lt;0.001 for ERBB2 amplification). ESR1, AKT1, and RB1 mutations were more common in HER2-low compared with HER2-positive MBC (14.0% vs 6.9%; 3.1% vs none; 3.1% vs none, respectively), but were not significant in multivariable analysis. Conclusions: Among patients with ER+ MBC, HER-low had a higher incidence of PIK3CA mutations and MYC amplification compared to HER2-0 MBC, and both of these alterations have been implicated as mechanisms of endocrine resistance. We did not demonstrate a high incidence of ERBB2 alterations in patients with HER2-low MBC. To our knowledge, this is the first study to describe genetic alterations detected by ctDNA in patients with HER2-low MBC. Given the emergence of novel HER2-targeted antibody drug conjugates with clinical activity in HER2-low MBC, these findings may guide combination treatment strategies and patient selection for future studies. Further studies are needed to confirm whether HER2-low MBC represents a truly unique biologic subtype.

Citation Format: Whitney L Hensing, Lorenzo Gerratana, Katherine Clifton, Marko Velimirovic, Ami Shah, Paolo D'Amico, Carolina Reduzzi, Qiang Zhang, Charles S Dai, Nusayba A Bagegni, Mateusz Opyrchal, Foluso O Ademuyiwa, Bose Ron, Amir Behdad, Cynthia X Ma, Aditya Bardia, Massimo Cristofanilli, Andrew A Davis. Genetic alterations detected by circulating tumor DNA (ctDNA) in HER2-low metastatic breast cancer (MBC) [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 P2-01-01.