Microsatellite instability status determined by next‐generation sequencing and compared with PD‐L1 and tumor mutational burden in 11,348 patients

Abstract

Microsatellite instability (MSI) testing identifies patients who may benefit from immune checkpoint inhibitors. We developed an MSI assay that uses data from a commercially available next‐generation sequencing (NGS) panel to determine MSI status. The assay is applicable across cancer types and does not require matched samples from normal tissue. Here, we describe the MSI‐NGS method and explore the relationship of MSI with tumor mutational burden (TMB) and PD‐L1. MSI examined by PCR fragment analysis and NGS was compared for 2189 matched cases. Mismatch repair status by immunohistochemistry was compared to MSI‐NGS for 1986 matched cases. TMB was examined by NGS, and PD‐L1 was determined by immunohistochemistry. Among 2189 matched cases that spanned 26 cancer types, MSI‐NGS, as compared to MSI by PCR fragment analysis, had sensitivity of 95.8% (95% confidence interval [CI] 92.24, 98.08), specificity of 99.4% (95% CI 98.94, 99.69), positive predictive value of 94.5% (95% CI 90.62, 97.14), and negative predictive value of 99.2% (95% CI, 98.75, 99.57). High MSI (MSI‐H) status was identified in 23 of 26 cancer types. Among 11,348 cases examined (including the 2189 matched cases), the overall rates of MSI‐H, TMB‐high, and PD‐L1 positivity were 3.0%, 7.7%, and 25.4%, respectively. Thirty percent of MSI‐H cases were TMB‐low, and only 26% of MSI‐H cases were PD‐L1 positive. The overlap between TMB, MSI, and PD‐L1 differed among cancer types. Only 0.6% of the cases were positive for all three markers. MSI‐H status can be determined by NGS across cancer types. MSI‐H offers distinct data for treatment decisions regarding immune checkpoint inhibitors, in addition to the data available from TMB and PD‐L1.

Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling

“…Gene copy number variations were assessed in 22 cases by comparing the depth of NGS sequence reads on the Caris panel to reads from a diploid control. Genes harboring with ≥6 copies were considered amplified …”

The current state of molecular testing in the treatment of patients with solid tumors, 2019

“…MSI‐high (MSI‐H) has been found in as many as 24 primary cancer types, most of which are displayed in Table 3, and appears to be a generalized cancer phenotype in about 4% of all adult cancers. Tumor MSI‐H status is prognostic (patients with early‐stage cancers that are MSI‐H have a better prognosis than those with microsatellite stable tumors) as well as predictive—many MSI‐H tumors are exquisitely sensitive to PD‐1/PD‐L1 inhibitors …”

“…Cancer Med . 2018;7:746‐756; and Bonneville R, Krook MA, Kautto EA, et al Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol .…”

“…Microsatellites are lengths of DNA sequence that contain single nucleotide (mononucleotide) or sections of 2 or more nucleotide (dinucleotide, trinucleotide, tetranucleotide, or pentanucleotide) repeats (see Microsatellite instability‐high tumors and DNA mismatch repair). When microsatellites contain a clonal change in several repeated DNA nucleotide units, this results in MSI (tumors with such MSI are characterized as MSI‐H, and this occurs when at least one of the MMR genes— MSH2 , MLH1 , MSH6 , and PMS2 —are inactivated, causing dMMR) . Since MSI‐H was established as a possible biomarker, the MSI status of a tumor has always required microdissection and PCR‐based detection strategies.…”

EUS fine-needle pancreatic core biopsy can determine eligibility for tumor-agnostic immunotherapy

“…Vanderwalde and colleagues recently published their experience evaluating a broad spectrum of 11,348 solid tumors noting the frequency of dMMR based on having MSI-H: PD-L1 expression in endometrial cancer (17 %: 16.2 %), gastric adenocarcinoma (8.7 %: 18.5 %), colorectal adenocarcinoma (5.7 %: 7.2 %), cholangiocarcinoma (2.3 %: 18.6 %), pancreatic ductal adenocarcinoma (PDAC) (1.2 %: 21.6 %), renal cell carcinoma (0.6 %: 29.7 %) and melanoma (0 %: 42.3 %) 2 . The fact that dMMR is rarely present among PDAC patients was further demonstrated in a study of 833 surgically resected PDAC tumors revealing a frequency of 0.8 %, all of whom were patients found to have Lynch syndrome 3 .…”