ABSTRACT
Talimogene laherparepvec (T-VEC) is an immunotherapy that generates local tumor lysis and systemic antitumor immune response. We studied the efficacy of intratumoral administration of T-VEC as monotherapy for inoperable locoregional recurrence of breast cancer. T-VEC was injected intratumorally at 106 PFU/mL on day 1 (cycle 1), 108 PFU/mL on day 22 (cycle 2), and 108 PFU/mL every 2 weeks thereafter (cycles ≥ 3). Nine patients were enrolled, 6 with only locoregional disease and 3 with both locoregional and distant disease. No patient completed the planned 10 cycles or achieved complete or partial response. The median number of cycles administered was 4 (range, 3-8). Seven patients withdrew prematurely because of uncontrolled disease progression, 1 withdrew after cycle 3 because of fatigue, and 1 withdrew after cycle 4 for reasons unrelated to study treatment. Median progression-free survival and overall survival were 77 days (95% CI, 63-NA) and 361 days (95% CI, 240-NA). Two patients received 8 cycles with clinically stable disease as the best response. The most common grade 2 or higher adverse event was injection site reaction (n = 7, 78%). Future studies could examine whether combining intratumoral T-VEC with concurrent systemic therapy produces better outcomes.
Subject(s)
Biological Products/therapeutic use , Breast Neoplasms/therapy , Genetic Therapy , Oncolytic Virotherapy , Adult , Aged , Biological Products/administration & dosage , Biological Products/adverse effects , Biomarkers , Breast Neoplasms/diagnosis , Breast Neoplasms/etiology , Breast Neoplasms/mortality , Combined Modality Therapy , Female , Genetic Therapy/methods , Herpesvirus 1, Human , Humans , Immunophenotyping , Immunotherapy , Lymphocyte Count , Middle Aged , Oncolytic Virotherapy/adverse effects , Oncolytic Virotherapy/methods , Prognosis , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , Treatment OutcomeABSTRACT
PURPOSE: Androgen receptor (AR) is frequently detected in breast cancers, and AR-targeted therapies are showing activity in AR-positive (AR+) breast cancer. However, the role of AR in breast cancers is still not fully elucidated and the biology of AR in breast cancer remains incompletely understood. Circulating tumor cells (CTCs) can serve as prognostic and diagnostic tools, prompting us to measure AR protein expression and conduct genomic analyses on CTCs in patients with metastatic breast cancer. METHODS: Blood samples from patients with metastatic breast cancer were deposited on glass slides, subjected to nuclear staining with DAPI, and reacted with fluorescent-labeled antibodies to detect CD45, cytokeratin (CK), and biomarkers of interest (AR, estrogen receptor [ER], and HER2) on all nucleated cells. The stained slides were scanned and enumerated by non-enrichment-based non-biased approach independent of cell surface epithelial cell adhesion molecule (EpCAM) using the Epic Sciences CTC platform. Data were analyzed using established digital pathology algorithms. RESULTS: Of 68 patients, 51 (75%) had at least 1 CTC, and 49 of these 51 (96%) had hormone-receptor-positive (HR+)/HER2-negative primary tumors. AR was expressed in CK+ CTCs in 10 patients. Of these 10 patients, 3 also had ER expression in CK+ CTCs. Single cell genomic analysis of 78 CTCs from 1 of these 3 patients identified three distinct copy number patterns. AR+ cells had a lower frequency of chromosomal changes than ER+ and HER2+ cells. CONCLUSIONS: CTC enumeration and analysis using no enrichment or selection provides a non-biased approach to detect AR expression and chromosomal aberrations in CTCs in patients with metastatic breast cancer. The heterogeneity of intrapatient AR expression in CTCs leads to the new hypothesis that patients with AR+ CTCs have heterogeneous disease with multiple drivers. Further studies are warranted to investigate the clinical applicability of AR+ CTCs and their heterogeneity.