Faculty Collaboration Database

Microsatellite-Stable Tumors with High Mutational Burden Benefit from Immunotherapy. Cancer Immunol Res 2019 Oct;7(10):1570-1573

Date

08/14/2019

Pubmed ID

31405947

Pubmed Central ID

PMC6774837

DOI

10.1158/2326-6066.CIR-19-0149

Scopus ID

2-s2.0-85072849285 (requires institutional sign-in at Scopus site)   182 Citations

Abstract

Programmed death receptor-1/ligand 1 (PD-1/L1) antibodies can induce durable remissions in malignancies. However, response rates are only approximately 10% to 20% in unselected patients versus approximately 50% in microsatellite instability-high (MSI-high) tumors, probably related to high tumor mutational burden (TMB). Pembrolizumab is approved for MSI-high or deficient mismatch repair tumors. However, outside of colorectal and endometrial carcinoma, only a small subset of tumors were MSI-high, making this treatment option unavailable to most patients. It is not known if MS-stable tumors with high TMB respond to PD-1/PD-L1 blockade. Next-generation sequencing (NGS) was performed on 60 patients (14 different histologies) treated with checkpoint blockade using the FoundationOne assay to determine TMB and MSI status. TMB was dichotomized into two groups: low-to-intermediate (0-19 mutations/mb) versus high (≥20 mutations/mb). Benefit rate (stable disease for ≥6 months and partial or complete response) was determined: 2,179 of 148,803 samples (1.5%) were MSI-high and 9,762 (6.6%) TMB-high (7,972, MS-stable/TMB-high). The majority (82.1%) of MSI-H tumors were TMB-high; however, only 18.3% of TMB-high tumors were MSI-H. Median progression-free survival for MS-stable/TMB-high versus MS-stable/TMB-low/TMB-intermediate tumors was 26.8 versus 4.3 months (P = 0.0173). Thus, our data demonstrate that MS-stable/TMB-high tumors are more common than MSI-high cancers and may benefit from immunotherapy.

Author List

Goodman AM, Sokol ES, Frampton GM, Lippman SM, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Antineoplastic Agents, Immunological
B7-H1 Antigen
CTLA-4 Antigen
Female
High-Throughput Nucleotide Sequencing
Humans
Immunotherapy
Male
Microsatellite Repeats
Middle Aged
Mutation
Neoplasms
Programmed Cell Death 1 Receptor
Survival Rate