A pan-cancer analysis of PD-L1 immunohistochemistry and gene amplification, tumor mutation burden and microsatellite instability in 48,782 cases

Huang, Richard S.P.; Haberberger, James; Severson, Eric Allan; Duncan, Daniel; Hemmerich, Amanda; Edgerly, Claire; Ferguson, N. Lynn; Williams, Erik; Elvin, Julia A.; Vergilio, Jo‐Anne; Killian, Jonathan Keith; Lin, Douglas I.; Tse, Julie Y; Hiemenz, Matthew; Owens, Clarence; Danziger, Natalie; Hegde, Priti S.; Venstrom, Jeffrey M.; Alexander, Brian M.; Ross, Jeffrey S.; Ramkissoon, Shakti

doi:10.1038/s41379-020-00664-y

Cited by 93 publications

(84 citation statements)

References 38 publications

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“…This could be attributed to methodological differences and to the fact that in the majority of cases the patients analyzed have received more than one treatment lines, commonly chemotherapy, which is known to increase tumor's mutation load (69). Similarly, to our study a TMB positivity rate of 21.1% was observed in a recent study analyzing immunotherapy biomarkers in 48.782 clinical samples (70). TMB has emerged as a promising biomarker of response to such treatments, and several clinical trials have shown that both blood and tissue samples TMB can effectively be used (15,17,19,71).…”

Section: Immunotherapy Biomarkerssupporting

confidence: 67%

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A Comprehensive Tumor Molecular Profile Analysis in Clinical Practice: A Single Center’s Experience

Özdoğan¹,

Papadopoulou²,

Tsoulos³

et al. 2020

Preprint

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Background: Tumor molecular profile is of great importance for the detection of biomarkers of response to targeted treatment due to the increased availability, with concomitant reduction of cost, of Next Generation Sequencing technology (NGS). In parallel to targeted therapies’, immunotherapies are also evolving, revolutionizing cancer therapy, with Programmed Death-ligand 1 (PD-L1), Microsatellite Instability (MSI), and Tumor Mutational Burden (TMB) analysis being the biomarkers employed most commonly.Methods: In the present study, a 161 gene NGS panel, containing the majority of clinically significant genes for cancer treatment selection, was used for tumor molecular profile analysis. A variety of tumor types have been analyzed, including aggressive and hard to treat cancers such as pancreatic cancer. Besides, the clinical utility of immunotherapy biomarkers (TMB, MSI, PD-L1), was also studied.Results: Molecular profile analysis was conducted in 610 cancer patients, while in 393 of them a at least one biomarker for immunotherapy response was requested. At least one actionable alteration was detected in 77.70% of the patients. 54.59% of them received information related to on-label or off-label treatment (Tiers 1A.1, 1A.2, 2B, and 2C.1) and 21.31% received a variant that could be used for clinical trial inclusion. The addition to immunotherapy biomarker to targeted biomarkers’ analysis in 191 cases increased the number of patients with an on-label treatment recommendation by 22.40%, while an option for on-label or off-label treatment was provided in 71.35% of the cases. Conclusions: Tumor molecular profile analysis by NGS is a first-tier methodology for a variety of tumor types, which provides critical information for treatment decision making in cancer patients. Importantly, simultaneous analysis for targeted therapy and immunotherapy biomarkers could lead to a better tumor characterization and provide actionable information in the majority of patients. Moreover, our results indicate that one in two patients is eligible for ICI treatment based on the biomarkers’ analysis. However, when these analyses are performed, the challenge is their implementation in clinical practice. Multidisciplinary patient management is critical to the refinement of the strategy incorporating such information.

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Section: Immunotherapy Biomarkerssupporting

confidence: 67%

“…However, in accordance to a recent study, a higher TMB positivity rate was observed in the TMB high group. (70). The TMB positivity rate among the PD-L1 positive patients was 33.77% (26/77) compared to 15.79% (18/114) in the PD-L1 negative group (p=0.005).…”

Section: Immunotherapy Biomarkersmentioning

confidence: 86%

A Comprehensive Tumor Molecular Profile Analysis in Clinical Practice: A Single Center’s Experience

Özdoğan¹,

Papadopoulou²,

Tsoulos³

et al. 2020

Preprint

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“…As TMB and MSI are also CPI biomarkers, the higher expression of PD-L1 in ROS1 fusion pos tumors contrasts with the lower median and mean TMB and no MSI-H cases in the ROS1 fusion pos cohort. While patients with TMB-High and/or MSI-H are eligible for CPIs, PD-L1 expression identifies a subset of low TMB/ Microsatellite Stable patients that are still eligible for CPIs as previously described 30,31. While the exact mechanism for higher PD-L1 and lower TMB-H/MSI-H remains elusive, these data suggest that CPIs could be further explored in tumors with ROS1 fusion.Overall, the amount of driver mutations in the ROS1 fusion positive cohorts is low when compared to the ROS1 fusion negative patient cohorts and suggests that, when identified, ROS1 fusion is an important driver genomic alteration in both the NSCLC and non-NSCLC ROS1 fusion pos patients.…”

mentioning

confidence: 62%

“…While patients with TMB-High and/or MSI-H are eligible for CPIs, PD-L1 expression identifies a subset of low TMB/ Microsatellite Stable patients that are still eligible for CPIs as previously described. 30,31 While the exact mechanism for higher PD-L1 and lower TMB-H/MSI-H remains elusive, these data suggest that CPIs could be further explored in tumors with ROS1 fusion.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic, genomic and protein expression characterization of 356ROS1fusion driven solid tumors cases

Huang¹,

Haberberger²,

Sokol³

et al. 2020

Intl Journal of Cancer

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Based on the approvals of crizotinib and entrectinib by the Food and Drug Administration for the treatment of ROS1 positive nonsmall cell lung cancer (NSCLC), we sought to examine the mutational profile of a variety of solid tumors (excluding sarcomas) with ROS1 fusions that underwent comprehensive genomic profiling. A review of our database was performed to extract all nonsarcoma patients with ROS1 fusions that were discovered by the hybrid capture‐based DNA only sequencing assays. We examined the coalterations representing potentially targetable biomarkers, resistance alterations and other alterations in these cases. In addition, we examined the histologic characteristics and protein expression with immunohistochemistry (IHC). From a series of clinically advanced nonsarcoma solid tumors, 356 unique cases with ROS1 fusions included 275 (77.2%) NSCLC and 81 (22.8%) non‐NSCLC. Ten novel ROS1 fusions were discovered. Importantly, the NSCLC ROS1 fusionpos tumors had a higher PD‐L1 IHC expression positivity when compared to the NSCLC ROS1 fusionneg population (P = .012, Chi‐squared). The frequency of known and likely anti‐ROS1 targeted therapy resistance genomic alterations in NSCLC was 7.3% (20/275) and in non‐NSCLC was 4.9% (4/81). Overall, the coalteration profile of ROS1 fusionpos NSCLC and non‐NSCLC was similar with only three genes altered significantly more frequently in non‐NSCLC vs NSCLC: TERT, PTEN, APC. In our study, we characterized a large cohort of ROS1 fusionpos NSCLC and non‐NSCLC solid tumors and discovered 10 novel ROS1 fusions.

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“…While the relationship of PD-L1 IHC, TMB, MSI, and CD274 amplification has been recently studied by Huang et al in >48,000 samples tested with both PD-L1 IHC and CGP, the investigation of clinicopathologic and genomic features of PD-L1 positive tumors in most tumor types is lacking in the literature. [20,21] To the best of our knowledge, this is the first study that examined the clinicopathologic and genomic features of PD-L1 pos and PD-L1 neg (as defined by the DAKO 22C3 CDx assay) UC patients in a large cohort of clinical samples. In our PD-L1 pos disease subset, we saw an increased association with GA in RB1 and TP53.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic and Genomic Characterization of PD-L1 Positive Urothelial Carcinomas

Huang¹,

Haberberger²,

Harries³

et al. 2021

The Oncologist

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Introduction. Pembrolizumab was approved with an accompanying companion diagnostic (CDx) assay (PD-L1 DAKO 22C3) for urothelial carcinoma (UC). In this study, we further characterize the clinicopathologic and genomic features of UC that are PD-L1 positive. Materials and Methods. The cohort of this study consisted of a total of 528 consecutive UC patients with PD-L1 IHC and comprehensive genomic profiling (CGP). All PD-L1 IHC testing was performed using the DAKO 22C3 CDx assay for UC. PD-L1 positivity was determined at a combined positive score (CPS) ≥ 10. Results. 44.5% of 528 consecutive UC patients were PD-L1 positive. A lower PD-L1 positivity rate was detected in primary (42.3%, 148/350) vs metastatic sites (48.9%, 87/178). PD-L1 positivity was dependent on the location of the metastatic sites with PD-L1 positivity rate. CGP revealed PD

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A pan-cancer analysis of PD-L1 immunohistochemistry and gene amplification, tumor mutation burden and microsatellite instability in 48,782 cases

Cited by 93 publications

References 38 publications

A Comprehensive Tumor Molecular Profile Analysis in Clinical Practice: A Single Center’s Experience

A Comprehensive Tumor Molecular Profile Analysis in Clinical Practice: A Single Center’s Experience

Clinicopathologic, genomic and protein expression characterization of 356ROS1fusion driven solid tumors cases

Clinicopathologic and Genomic Characterization of PD-L1 Positive Urothelial Carcinomas

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