Abstract 6439: Next-generation sequencing based detection of HER2 copy number predicts pathological response to neoadjuvant therapy in HER2 positive breast cancer

Abstract Purpose: Achieving pathologic complete response (pCR) following neoadjuvant chemotherapy is associated with better prognosis for HER2 positive breast cancer. However, clinical and biological heterogeneity of HER2 positive disease significantly affect prognosis and treatment response. Early prediction of treatment benefit could enable tailored anti-HER2 therapy. Next-generation sequencing (NGS) based genomic tests including copy number (CN) detection are widely used in breast cancer patients. We aim to evaluate the association of HER2 copy number detected by NGS with pCR rate of HER2 positive breast cancer after neoadjuvant chemotherapy. Methods: HER2 positive breast cancer patients underwent neoajuvant chemotherapy in Henan Cancer Hospital From January 2022 to March 2023 were included in the study. Pretreatment tumour specimens were subjected to pan-cancer 1021-gene panel genomic sequencing. Copy number of HER2 was obtained from the panel. Copy number of >=4 was classified as HER2 amplified and HER2 copy number <4 was classified as HER2 non-amplified. All patients underwnt definitive surgery after receieveing neoadjuvant chemotherapy containing taxanes, trastuzumab and pertuzumab. pCR was defined as pathological stage ypT0/Tis ypN0. Results: In total, 299 HER2 positive breast cancer patients were eligible for the analysis. 87 were classified as HER2 non-amplified (29.1%) by copy number and 212 patients were classified as amplified group (70.9%). The HER2 non-amplified group tends to have a higher proportion of hormone receptor positive (HR+) patients (71.3% vs. 50.5%, p=0.002). Other clinicopathological parameters were well distributed between the groups. 91.3% of patients in HER2 amplified group had strong positive HER2 expression (IHC 3+), while only 10.5% of patients in HER2 non-amplified group had HER2 expression of IHC 3+. Patients with HER2 IHC 3+ had a PCR rate of 75.8% and Patients with HER2 IHC 2+ had a pCR rate of 20.0% (20.0% vs. 75.8% p<0.001). Patients in the amplified group had a pCR rate of 76.9% and pCR rate of the non-amplified group was12.6% (12.6% vs. 76.9% p<0.001). In a multivariable logistic regression with HER2 copy number by NGS, HR status and HER2 IHC, the HER2 copy number predicted pCR rate independently of HER2 IHC and HR status. Conclusions: NGS based detection of HER2 copy number could predict response to neoadjuvant therapy in HER2 positive patients. The discordance between IHC/FISH and NGS based detection of HER2 amplification may reflect HER2 heterogeneity. HER2 heterogeneity promotes resistance to anti-HER2 therapy. Noval antibody-drug conjugates (ADC) with bystander effect, such as Trastuzumab deruxtecan, have shown anti-tumor effect even in HER2 low expression tumors. Thus, prospective study is needed to optimize anti-HER2 therapy for patients with HER2 heterogeneity. Citation Format: Hao Dai, Dechuang Jiao, Xuhui Guo, Jianghua Qiao, anfang Li, Zhenduo Lu, Xiuchun Chen, Chengzheng Wang, Min Yan, Zhenzhen Liu. Next-generation sequencing based detection of HER2 copy number predicts pathological response to neoadjuvant therapy in HER2 positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6439.