Hypermutated Circulating Tumor DNA: Correlation with Response to Checkpoint Inhibitor–Based Immunotherapy

Khagi, Yulian; Goodman, Aaron M.; Daniels, Gregory A.; Patel, Sandip Pravin; Sacco, Assuntina G.; Randall, James M.; Bazhenova, Lyudmila; Kurzrock, Razelle

doi:10.1158/1078-0432.ccr-17-1439

Cited by 183 publications

(151 citation statements)

References 28 publications

(31 reference statements)

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“…Thirteen percent of the patients in this study had HNSCC. This study suggested that higher alteration number on ctDNA liquid biopsy is associated with a significantly improved response to checkpoint inhibitor‐based immunotherapy . This is consistent with findings from primary tissue biopsies.…”

Section: Introductionsupporting

confidence: 87%

Head and Neck Squamous Cell Carcinoma Detection and Surveillance: Advances of Liquid Biomarkers

et al. 2018

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Head and neck squamous cell carcinomas are aggressive tumors that often present at advanced stage in difficult‐to‐biopsy regions of the head and neck. With the rapid move to analyze circulating tumor DNA (ctDNA) to either detect cancer or monitor disease progression and response to therapy, we have designed this article as a primer to understand the recent studies that support a transition to use these circulating biomarkers as a part of routine clinical care. Whereas some technical challenges still need to be overcome, the utility of ctDNA in cancer care is already evident from these early studies. Therefore, it is critical to understand recent advances in this area as well as emerging questions that need to be addressed as these biomarkers move closer to enhancing routine clinical care paradigms.Laryngoscope, 129:1836–1843, 2019

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Section: Introductionsupporting

confidence: 87%

Head and Neck Squamous Cell Carcinoma Detection and Surveillance: Advances of Liquid Biomarkers

et al. 2018

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“…NGS has unveiled useful genomic biomarkers for predicting diagnosis, prognosis, and response to cancer treatment . NGS can be performed on either tissue or blood‐derived ctDNA; these technologies may be complementary.…”

Section: Discussionmentioning

confidence: 99%

Temporal and spatial effects and survival outcomes associated with concordance between tissue and blood KRAS alterations in the pan‐cancer setting

Mardinian

Okamura

Kato

et al. 2019

Intl Journal of Cancer

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We investigated the impact of time interval, primary vs. metastatic biopsy site, variant allele fraction (VAF) and histology on concordance of KRAS alterations in tissue vs. circulating tumor DNA (ctDNA), and association of concordance with survival. Blood and tissue were evaluated by next‐generation sequencing in 433 patients with diverse cancers. Altogether, 101 patients (23.3%) had KRAS alterations: 56, ctDNA (12.9%); 81, tissue (18.7%); and 36, both (8.3%). The overall blood and tissue concordance rate for KRAS alterations was 85%, but was mainly driven by the large negative/negative subset. Therefore, specificity of one test for the other was high (88.1–94.3%), while sensitivity was not high (44.4–64.3%) and was lower still in patients with >6 vs. ≤2 months between blood and tissue sampling (31.0–40.9% vs. 51.2–84.0%; p = 0.14 time interval‐dependent sensitivity of blood for tissue; p = 0.003, tissue for blood). Positive concordance rate for KRAS alterations was 57.1% vs. 27.4% (colorectal vs. noncolorectal cancer; p = 0.01), but site of biopsy (primary vs. metastatic) and VAF (%ctDNA) was not impactful. The presence of KRAS alterations in both tests was independently associated with shorter survival from diagnosis (hazard ratio, 1.72; 95% confidence interval, 1.04–2.86) and from recurrent/metastatic disease (1.70; 1.03–2.81). Positive concordance of KRAS alterations between ctDNA and tissue was negatively affected by a longer time period between blood and tissue sampling and was higher in colorectal cancer than in other malignancies. The presence of KRAS alterations in both tests was an independent prognostic factor for poor survival.

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“…Biomarkers for determining response to PD-1/PD-L1 blockade include PD-L1 expression, 1,2 microsatellite instability (MSI), 3 and a high tumor mutational burden (TMB). 4-6 …”

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Prevalence ofPDL1Amplification and Preliminary Response to Immune Checkpoint Blockade in Solid Tumors

et al. 2018

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IMPORTANCE Copy number alterations in programmed cell death ligand 1 (PDL1 or CD274), programmed cell death 1 ligand 2 (PDCD1LG2 or PDL2), and Janus kinase 2 (JAK2) genes (chromosome 9p24.1) characterize Hodgkin lymphoma, resulting in high response rates to programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade. The prevalence and utility of PDL1 amplification as a response biomarker to PD-1/PD-L1 blockade are unknown in other tumors. OBJECTIVES To examine the prevalence of PDL1 amplification and its utility as a response biomarker to PD-1/PD-L1 blockade in solid tumors. DESIGN, SETTING, AND PARTICIPANTS This retrospective study (October 1, 2012, to October 1, 2017) used a deidentified tumor database from a commercial company and annotated clinical records from a subset of patients treated at a university tertiary referral center. The study analyzed 118 187 tumors from the deidentified database, including a clinically annotated subgroup of 2039 malignant tumors. INTERVENTIONS Comprehensive genomic profiling was performed on all samples to determine PDL1 amplification, microsatellite instability, and tumor mutational burden (TMB). A subset of patients was treated with PD-1/PD-L1 blockade. MAIN OUTCOMES AND MEASURES The prevalence of PDL1 amplification was determined among 118 187 patient samples that underwent next-generation sequencing. Solid tumors treated with checkpoint blockade were evaluated for response and progression-free survival (PFS). RESULTS Of the 118 187 deidentified tumor samples, PDL1 amplifications were identified in 843 (0.7%), including more than 100 types of solid tumors. Most PDL1-amplified tumors (84.8%) had a low to intermediate TMB. PDL1 amplification did not always correlate with high-positive PD-L1 expression by immunohistochemical analysis. Six of 9 patients (66.7%) from 1 center with PDL1-amplified solid tumors had objective responses after checkpoint blockade administration. The median PFS among all treated patients was 15.2 months. Responders included 1 patient with glioblastoma (PFS, ≥5.2 months), 2 patients with head and neck squamous cell cancer (PFS, ≥9 and 15.2 months), 2 patients with metastatic basal cell cancer (PFS, 3.8 and ≥24.1 months), and 1 patient with urothelial cancer (PFS, ≥17.8 months). CONCLUSIONS AND RELEVANCE The results of this study suggest that PDL1 amplification occurs in a small subset of malignant tumors. Additional large-scale, prospective studies of PDL1-amplified cancers are warranted to confirm the responses to checkpoint blockade described herein, even in the absence of microsatellite instability, high PD-L1 expression, and a high TMB.

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Hypermutated Circulating Tumor DNA: Correlation with Response to Checkpoint Inhibitor–Based Immunotherapy

Cited by 183 publications

References 28 publications

Head and Neck Squamous Cell Carcinoma Detection and Surveillance: Advances of Liquid Biomarkers

Head and Neck Squamous Cell Carcinoma Detection and Surveillance: Advances of Liquid Biomarkers

Temporal and spatial effects and survival outcomes associated with concordance between tissue and blood KRAS alterations in the pan‐cancer setting

Prevalence ofPDL1Amplification and Preliminary Response to Immune Checkpoint Blockade in Solid Tumors

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