Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer

• Published in: Nature communications 2021-09, Vol.12 (1), p.5563-13, Article 5563
• Main Authors: Keenan, Tanya E., Guerriero, Jennifer L., Barroso-Sousa, Romualdo, Li, Tianyu, O’Meara, Tess, Giobbie-Hurder, Anita, Tayob, Nabihah, Hu, Jiani, Severgnini, Mariano, Agudo, Judith, Vaz-Luis, Ines, Anderson, Leilani, Attaya, Victoria, Park, Jihye, Conway, Jake, He, Meng Xiao, Reardon, Brendan, Shannon, Erin, Wulf, Gerburg, Spring, Laura M., Jeselsohn, Rinath, Krop, Ian, Lin, Nancy U., Partridge, Ann, Winer, Eric P., Mittendorf, Elizabeth A., Liu, David, Van Allen, Eliezer M., Tolaney, Sara M.
• Format: Article
• Language: English
• Subjects: 38/39; 38/91; 45/23; 631/67/1347; 692/699/67/1347; Adult; Aged; Antibodies, Monoclonal, Humanized - therapeutic use; Antigen presentation; Antigen Presentation - genetics; Antigens; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; B7-H1 Antigen - metabolism; Biomarkers; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Breast Neoplasms - mortality; Cytokines; Cytokines - blood; Cytokines - immunology; Drug Resistance, Neoplasm - genetics; Estrogens; Estrogens - metabolism; Female; Furans - therapeutic use; Gene Expression Profiling; Genetic Heterogeneity; Genome, Human - genetics; Genomics; Heterogeneity; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - therapeutic use; Immunoregulation; Immunotherapy; Ketones - therapeutic use; Lymphocytes, Tumor-Infiltrating - immunology; Metastases; Metastasis; Middle Aged; Monoclonal antibodies; multidisciplinary; Mutation; Neoplasm Metastasis; Patients; Pembrolizumab; Receptors; Receptors, Estrogen - metabolism; Receptors, Progesterone - metabolism; Science; Science (multidisciplinary); Signal Transduction - genetics; Survival Rate; Targeted cancer therapy; Toxicity; Treatment Outcome; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25769-z

Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results ( n  = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors ( n  = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity ( n  = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59–1.55, p  = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659. A randomized phase 2 clinical trial has recently shown no benefit of the combination eribulin and pembrolizumab over pembrolizumab alone in HR + metastatic breast cancer patients (NCT03051659). Here, the authors are reporting the final OS data and biomarker analyses on a subset of samples to analyze molecular correlates