dc.creator | Conroy, Jeffrey M. | es |
dc.creator | Pabla, Sarabjot | es |
dc.creator | Nesline, Mary K. | es |
dc.creator | Glenn, Sean T. | es |
dc.creator | Papanicolau Sengos, Antonios | es |
dc.creator | Burgher, Blake | es |
dc.creator | Cruz Merino, Luis de la | es |
dc.creator | Morrison, Carl | es |
dc.date.accessioned | 2024-03-07T18:09:36Z | |
dc.date.available | 2024-03-07T18:09:36Z | |
dc.date.issued | 2019 | |
dc.identifier.citation | Conroy, J.M., Pabla, S., Nesline, M.K., Glenn, S.T., Papanicolau Sengos, A., Burgher, B.,...,Morrison, C. (2019). Next generation sequencing of PD-L1 for predicting response to immune checkpoint inhibitors. Journal of Immunotherapy of Cancer, 7 (1), 18. https://doi.org/10.1186/s40425-018-0489-5. | |
dc.identifier.issn | 2051-1426 | es |
dc.identifier.uri | https://hdl.handle.net/11441/155952 | |
dc.description.abstract | Background PD-L1 immunohistochemistry (IHC) has been traditionally used for predicting clinical responses to immune checkpoint inhibitors (ICIs). However, there are at least 4 different assays and antibodies used for PD-L1 IHC, each developed with a different ICI. We set to test if next generation RNA sequencing (RNA-seq) is a robust method to determine PD-L1 mRNA expression levels and furthermore, efficacy of predicting response to ICIs as compared to routinely used, standardized IHC procedures.
Methods A total of 209 cancer patients treated on-label by FDA-approved ICIs, with evaluable responses were assessed for PD-L1 expression by RNA-seq and IHC, based on tumor proportion score (TPS) and immune cell staining (ICS). A subset of serially diluted cases was evaluated for RNA-seq assay performance across a broad range of PD-L1 expression levels.
Results Assessment of PD-L1 mRNA levels by RNA-seq demonstrated robust linearity across high and low expression ranges. PD-L1 mRNA levels assessed by RNA-seq and IHC (TPS and ICS) were highly correlated (p < 2e-16). Sub-analyses showed sustained correlation when IHC results were classified as high or low by clinically accepted cut-offs (p < 0.01), and results did not differ by tumor type or anti-PD-L1 antibody used. Overall, a combined positive PD-L1 result (≥1% IHC TPS and high PD-L1 expression by RNA-Seq) was associated with a 2-to-5-fold higher overall response rate (ORR) compared to a double negative result. Standard assessments of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) showed that a PD-L1 positive assessment for melanoma samples by RNA-seq had the lowest sensitivity (25%) but the highest PPV (72.7%). Among the three tumor types analyzed in this study, the only non-overlapping confidence interval for predicting response was for “RNA-seq low vs high” in melanoma.
Conclusions Measurement of PD-L1 mRNA expression by RNA-seq is comparable to PD-L1 expression by IHC both analytically and clinically in predicting ICI response. RNA-seq has the added advantages of being amenable to standardization and avoidance of interpretation bias. PD-L1 by RNA-seq needs to be validated in future prospective ICI clinical studies across multiple histologies. | es |
dc.format | application/pdf | es |
dc.format.extent | 11 p. | es |
dc.language.iso | eng | es |
dc.publisher | BMC | es |
dc.relation.ispartof | Journal of Immunotherapy of Cancer, 7 (1), 18. | |
dc.rights | Atribución 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject | Atezolizumab | es |
dc.subject | Avelumab | es |
dc.subject | Cancer immunotherapy | es |
dc.subject | Durvalumab | es |
dc.subject | Nivolumab | es |
dc.subject | Pembrolizumab | es |
dc.subject | PD-L1 | es |
dc.subject | Biomarker | es |
dc.title | Next generation sequencing of PD-L1 for predicting response to immune checkpoint inhibitors | es |
dc.type | info:eu-repo/semantics/article | es |
dc.type.version | info:eu-repo/semantics/publishedVersion | es |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Medicina | es |
dc.relation.publisherversion | https://jitc.bmj.com/content/7/1/18 | es |
dc.identifier.doi | 10.1186/s40425-018-0489-5 | es |
dc.contributor.group | Universidad de Sevilla. CTS151: Bioquímica médica. | es |
dc.journaltitle | Journal of Immunotherapy of Cancer | es |
dc.publication.volumen | 7 | es |
dc.publication.issue | 1 | es |
dc.publication.initialPage | 18 | es |