Faculty Collaboration Database

SWI/SNF complex alterations as a biomarker of immunotherapy efficacy in pancreatic cancer. JCI Insight 2021 Sep 22;6(18)

Date

08/11/2021

Pubmed ID

34375311

Pubmed Central ID

PMC8492298

DOI

10.1172/jci.insight.150453

Scopus ID

2-s2.0-85115979107 (requires institutional sign-in at Scopus site)   29 Citations

Abstract

BACKGROUNDImmune checkpoint inhibitors (ICIs) fail to demonstrate efficacy in pancreatic cancer. Recently, genomic biomarkers have been associated with response to ICIs: microsatellite instability high (MSI-H) and tumor mutation burden (TMB) > 10 mutations/Mb. Alterations in Switch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling genes may predispose to improved outcomes with immunotherapy. The current study examined a possible role for SWI/SNF complex abnormalities in pancreatic cancer responsiveness to ICIs.METHODSA database of 6831 cancer patients that had undergone next-generation sequencing (NGS) was filtered for advanced pancreatic cancer, SWI/SNF alterations, and outcomes depending on immunotherapy treatment.RESULTSNine patients had metastatic pancreatic adenocarcinoma harboring SWI/SNF chromatin remodeling gene alterations and had received ICIs: 7 had an ARID1A alteration (77%); 2, ARID1B (22%); 3, SMARCA4 (33%); 1, SMARCB1 (11%); and 1, PBRM1 (11%). Three patients possessed more than 1 SWI/SNF complex alteration. Only 3 tumors were microsatellite unstable. Eight of 9 patients (89%) achieved an objective response, including a complete remission, with the 2 longest responses ongoing at 33+ and 36+ months. Median progression-free and overall survival was 9 and 15 months, respectively. Responses occurred even in the presence of microsatellite stability, low TMB, and/or low PD-L1 expression.CONCLUSIONA small subset of patients with pancreatic cancer have genomic alterations in SWI/SNF chromatin remodeling components and appear to be responsive to ICIs, suggesting the need for prospective trials.TRIAL REGISTRATIONClinicalTrials.gov, NCT02478931.FUNDINGJoan and Irwin Jacobs Fund, NIH P30 CA023100 (RK) and LRP KYGF9753 (GPB), the Gershenson, Duarte, and anonymous patient families (GPB).

Author List

Botta GP, Kato S, Patel H, Fanta P, Lee S, Okamura R, 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

Adenocarcinoma
Aged
Antineoplastic Agents, Immunological
Antineoplastic Combined Chemotherapy Protocols
B7-H1 Antigen
Biomarkers, Tumor
DNA Helicases
DNA-Binding Proteins
Databases, Genetic
Female
Fluorouracil
Humans
Leucovorin
Male
Microsatellite Instability
Middle Aged
Nuclear Proteins
Organoplatinum Compounds
Pancreatic Neoplasms
Retreatment
SMARCB1 Protein
Survival Rate
Transcription Factors