Journal Article

Pan-cancer analysis of longitudinal metastatic tumors reveals genomic alterations and immune landscape dynamics associated with pembrolizumab sensitivity

Butler, Marcus O., Pugh, Trevor J., Clouthier, Derek L., Bruce, Jeffrey P., El Ghamrasni, Samah, Lheureux, Stephanie, Hanna, Youstina, Hansen, Aaron R., Bratman, Scott V., Speers, Vanessa, Haibe-Kains, Benjamin, Spreafico, Anna, Razak, Albiruni, Cindy Yang, S. Y., Cirlan, Iulia, Aleshin, Alexey, Ohashi, Pamela S., Lien, Scott C., Zhu, Kelsey, Brooks, David G., Siu, Lillian L., Iafolla, Marco A. J., Oliva, Marc, Bedard, Philippe L., Wang, Ben X., Berman, Hal K., McGaha, Tracy L.

2021

Overview

Serial circulating tumor DNA (ctDNA) monitoring is emerging as a non-invasive strategy to predict and monitor immune checkpoint blockade (ICB) therapeutic efficacy across cancer types. Yet, limited data exist to show the relationship between ctDNA dynamics and tumor genome and immune microenvironment in patients receiving ICB. Here, we present an in-depth analysis of clinical, whole-exome, transcriptome, and ctDNA profiles of 73 patients with advanced solid tumors, across 30 cancer types, from a phase II basket clinical trial of pembrolizumab (NCT02644369) and report changes in genomic and immune landscapes (primary outcomes). Patients stratified by ctDNA and tumor burden dynamics correspond with survival and clinical benefit. High mutation burden, high expression of immune signatures, and mutations in BRCA2 are associated with pembrolizumab molecular sensitivity, while abundant copy-number alterations and B2M loss-of-heterozygosity corresponded with resistance. Upon treatment, induction of genes expressed by T cell, B cell, and myeloid cell populations are consistent with sensitivity and resistance. We identified the upregulated expression of PLA2G2D , an immune-regulating phospholipase, as a potential biomarker of adaptive resistance to ICB. Together, these findings provide insights into the diversity of immunogenomic mechanisms that underpin pembrolizumab outcomes. Although circulating tumour DNA (ctDNA) can predict immune checkpoint blockade (ICB) responses, its association with tumour biomarkers remains unknown. Here, the authors use ctDNA to inform exome and transcriptome profiling of >100 patients with 30 cancer types on a single clinical ICB trial and identify tumour microenvironment features associated with response.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 45 / 45/23 / 45/91 / 631/250/251 / 631/67/69 / 692/4028/67/1857 / Antibodies, Monoclonal, Humanized - therapeutic use / Antineoplastic Agents - therapeutic use / Biomarkers / BRCA2 protein / BRCA2 Protein - genetics / BRCA2 Protein - immunology / Breast cancer / Cancer / Circulating Tumor DNA - genetics / Circulating Tumor DNA - metabolism / Deoxyribonucleic acid / DNA / DNA Copy Number Variations / Drug Resistance, Neoplasm / Exome Sequencing / Genomics / Group II Phospholipases A2 - genetics / Group II Phospholipases A2 - immunology / Heterozygosity / Humanities and Social Sciences / Humans / Immune checkpoint / Immune system / Immunotherapy / Lymphocytes / Lymphocytes T / Metastases / Microenvironments / Monoclonal antibodies / multidisciplinary / Mutation / Neoplasms - drug therapy / Neoplasms - genetics / Neoplasms - immunology / Patients / Pembrolizumab / Prospective Studies / Science / Science (multidisciplinary) / Sensitivity / Solid tumors / Targeted cancer therapy / Transcriptomes / Tumor Burden / Tumor Escape - drug effects / Tumor microenvironment / Tumors