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

Abstract

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.

• Authors: S Y Cindy Yang, Scott C Lien, Ben X Wang, Derek L Clouthier, Youstina Hanna, Iulia Cirlan, Kelsey Zhu, Jeffrey P Bruce, Samah El Ghamrasni, Marco A J Iafolla, Marc Oliva, Aaron R Hansen, Anna Spreafico, Philippe L Bedard, Stephanie Lheureux, Albiruni Razak, Vanessa Speers, Hal K Berman, Alexey Aleshin, Benjamin Haibe-Kains, David G Brooks, Tracy L McGaha, Marcus O Butler, Scott V Bratman, Pamela S Ohashi, Lillian L Siu, Trevor J Pugh
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 5137 (08 26 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34446728 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• BRCA2 Protein
• BRCA2 protein, human
• Circulating Tumor DNA
• pembrolizumab
• Group II Phospholipases A2
• PLA2G2D protein, human

Topics

• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• BRCA2 Protein (genetics, immunology)
• Circulating Tumor DNA (genetics, metabolism)
• DNA Copy Number Variations
• Drug Resistance, Neoplasm
• Group II Phospholipases A2 (genetics, immunology)
• Humans
• Neoplasms (drug therapy, genetics, immunology)
• Prospective Studies
• Tumor Burden
• Tumor Escape (drug effects)
• Exome Sequencing