Abstract P3-09-26: Efficacy of trastuzumab deruxtecan (T-DXd) in patients with metastatic lobular breast cancer with or without HER2 mutations: the MSKCC experience

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Abstract Background: In patients with HER2-low metastatic breast cancer (MBC), T-DXd improves outcomes compared to chemotherapy. Metastatic invasive lobular carcinoma (mILC) is associated with lower rates of HER2 amplification compared to invasive ductal carcinoma, but higher rates of HER2 (ERBB2) mutations, which are found in 14-15% of mILC. The SUMMIT trial demonstrated meaningful activity of neratinib + fulvestrant + trastuzumab in patients with HR+, HER2 non-amplified, HER2-mutant MBC. In DESTINY-PanTumor01, patients with solid tumors with HER2 mutations, 20% of whom had MBC, received T-DXd; median progression-free survival (PFS) was 5.4 months (95%CI 2.7-7.1). The activity of T-DXd in HER2-low is not well described by histology, nor for HER2-mutant ILC. Methods: This single-center retrospective cohort study identified patients with HER2-negative mILC treated with T-DXd from 2018-2024 at Memorial Sloan Kettering Cancer Center (MSKCC). We abstracted patient demographics, clinicopathologic characteristics, T-DXd treatment history, and dates of disease progression (defined as radiographic or clinical progression leading to treatment change) from medical records. Presence or absence of HER2 or PIK3CA/AKT/PTEN mutations was determined using the MSK-IMPACT next generation sequencing platform from tissue samples taken prior to initiation of T-DXd. Median time to progression was computed using the Kaplan-Meier method. Results: Among 41 patients, 34 (83%) had HR+ disease and 7 (17%) had TNBC. The median number of prior therapies in the metastatic setting was 5 (range 2-21); median number of prior chemotherapies was 1 (range 0-6). Among HR+ patients, the number of median prior endocrine therapies was 3 (range 1-10), 31/34 (91%) had prior CDK4/6 inhibitor, and median duration of CDK4/6 inhibitor was 11 months (range 1-72). Across all metastatic site biopsies, the highest degree of HER2 expression per IHC was 0 in 3 patients (7%), 1+ in 23 patients (56%), and 2+ in 14 patients (34%). 10 (24%) patients had HER2 mutations and 18 (44%) had PIK3CA/AKT/PTEN mutations. Median time to progression (TTP) in the total cohort was 7.2 months (95%CI 4.6-13.1). In patients with HER2 mutations, TTP was not reached (95%CI 6.6-NR) vs. 6.4 months (95%CI 4.0-12.4) in patients without HER2 mutations (p=0.09). In patients with PIK3CA/AKT/PTEN mutations, TTP was 4.6 months (95%CI 3.6-8.7) vs. 9.2 (95%CI 6.6-NR) in patients without pathway mutations (p=0.01). There were no significant differences for HR+ vs. TNBC or HER2 IHC 0/1+ vs. 2+. 27 (66%) patients discontinued T-DXd for disease progression, 3 (7%) for toxicity, and T-DXd treatment was ongoing in 11 (27%). Median overall survival in the total cohort was 18.2 months (95%CI 15.8-NR). 1 patient with HER2 mutation and HER2 IHC 0 on all biopsies in the early-stage and metastatic setting has been on T-DXd for 32 months; treatment is ongoing. Additional data on prior neratinib use in this cohort will be presented at the meeting. Conclusions: In patients with mILC and HER2 mutation, there was a trend toward longer TTP with T-DXd. Genomic data could aid in prognostication in patients with mILC treated with T-DXd. These findings warrant confirmation in larger cohorts. Citation Format: Sherry Shen, Anton Safonov, Jimmitti Teysir, Mithat Gonen, Mehnaj Ahmed, Pedram Razavi, Komal Jhaveri. Efficacy of trastuzumab deruxtecan (T-DXd) in patients with metastatic lobular breast cancer with or without HER2 mutations: the MSKCC experience [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-09-26.

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