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Leptomeningeal metastases (LM) are a devastating complication of HER2 + metastatic breast cancer (MBC), with no effective treatments. In a case series of 8 patients with heavily pretreated HER2 + MBC and progressing LM, all 8 patients (100%) derived clinical benefit from Trastuzumab deruxtecan (TDXd), and 4 patients (50%) had an objective partial response based on formal neuroradiology MRI reads using the EORTC/RANO-LM Revised-Scorecard. T-DXd warrants further study in LM in HER2 + MBC and solid tumors where T-DXd may be active.

PURPOSE APOBEC mutagenesis underlies somatic evolution and accounts for tumor heterogeneity in several cancers, including breast cancer (BC). In this study, we evaluated the characteristics of a real-world cohort for time-to-treatment discontinuation (TTD) and overall survival on CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) and immune checkpoint inhibitors. METHODS Comprehensive genomic profiling results from 29,833 BC samples were analyzed for tumor mutational burden and APOBEC signatures. For clinical outcomes, a deidentified nationwide (United States–based) BC Clinico-Genomic Database (CGDB) was evaluated with log-rank and Cox models. Patients with hormone receptor–positive (HR+) human epidermal growth factor receptor 2–negative (HER2–) BC who received first-line ET and CDK4/6i were included. Eligible patients from Mayo Clinic and Duke University were HR+ HER2– BC with sequencing data between September 2013 and July 2020. RESULTS Of 29,833 samples sequenced, 7.9% were APOBEC+ with a high rate in invasive lobular carcinoma (16.7%) and in metastatic tumors (9.7%) relative to locally biopsied BC (4.3%; P < .001). In CGDB, 857 patients with HR+ HER2– BC received ET plus CDK4/6i in the first line. APOBEC+ patients had significantly shorter TTD on ET plus CDK4/6i than APOBEC– patients, 7.8 (95% CI, 4.3 to 14.6) versus 12.4 months (95% CI, 11.2 to 14.1; hazard ratio, 1.6; 95% CI, 1.03 to 2.39; P = .0036). Clinical benefit to immune checkpoint inhibitors was observed in HR+ HER2–, APOBEC+, tumor mutational burden–high patients, with four of nine CGDB patients (TTD 0.3-11.3 months) and four of six patients in Duke/Mayo cohorts (TTD 0.9-40.5 months) with a TTD of ≥ 3 months. CONCLUSION APOBEC+ HR+ HER2– patients had shorter TTD on first-line ET plus CDK4/6i relative to APOBEC– patients. Further research is needed to optimize the treatment of APOBEC+ HR+ HER2– BC and to investigate the efficacy of immunotherapeutic strategies in this population.

Background: LMD is a devastating clinical outcome of advanced BC with a median survival of 4.4 months for the HER2+ subtype. There are few effective treatments for LMD. T-DXd has shown excellent extracranial efficacy in the DESTINY-Breast01/03 trials for metastatic HER2+ BC, including the stable brain metastases (BrM) subgroups. The efficacy of T-DXd in HER2+ untreated BrM and LMD is unknown. We present a case series of 6 patients with HER2+ LMD treated with T-DXd. Methods: Six patients with HER2+ BC with LMD (based on imaging +/- positive cytology) who had received T-DXd prior to 10/18/21 and had undergone at least 1 restaging evaluation were identified at Duke Cancer Institute and Dana Farber Cancer Institute. Data was extracted from patients’ electronic medical records and entered into a secure, patient de-identified database. Objective MRI response was defined as neuroimaging with definitive improvement assessed by neuroradiologist review without signs of clinical progression. Clinical benefit (CB) is defined as stable disease or objective response by neuroimaging without clinical progression. Results: Of the 6 patients included, median age was 42.5 years with 5 median lines of prior therapy. All 6 patients (100%) derived CB and 5/6 (83.3%) had objective response on MRI. Patients were treated with a median 6.5 (5-23) cycles. Median duration of T-DXd therapy was 5.3 months (4.1-16.9) with 4/6 patients receiving ongoing treatment. The median survival from initial diagnosis of LMD to death or last follow-up was 12.5 months. Results are summarized in Table 1. Conclusion: In this case series, 5/6 patients had radiographic responses without clinical progression, with median duration of treatment nearing 6 months and 4/6 patients continuing T-DXd at data cutoff. This series provides rationale for prospective evaluation of T-DXd in HER2+ LMD patients across tumor types. Table 1. Demographic and clinical information T-DXd in HER2+ BC LMD - Demographic and Clinical Information*Data cut-off: 10/18/21 Demographic Characteristic (n=6) # (%) or median (range) Median age at T-DXd, years (range) 42.5 (37 - 56) ER Status Positive Negative 4 (66.7%)2 (33.3%) Site DFCI Duke 4 (66.7%)2 (33.3%) Clinical Information (n=6) # (%) or median (range) Median # of therapies prior to T-DXd Prior HER2 TKI 5 (4-6)6 (100%) T-DXd Treatment Median # cycles Total time on DS-8201 (months) 6.5 (5-23)5.3 (4.1-16.9) Response on first MRI post-C1D1 T-DXd Yes No 5 (83.3%)1 (16.6%) Still on T-DXd Treatment Yes No 4 (66.7%)2 (33.3%) Median survival since LMD diagnosis (months) 12.5 (6.8 - 20.6) Citation Format: Laura Alder, Dario Trapani, Amanda Van Swearingen, Mustafa Khasraw, Carey Anders, Nancy Lin, Sarah Sammons. Durable clinical and radiographic responses in a series of patients with HER2+ Breast Cancer (BC) Leptomeningeal Disease (LMD) treated with trastuzumab deruxtecan (T-DXd) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5257.

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