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PD-L1 expression and survival in p16-negative and -positive squamous cell carcinomas of the vulva.

ABSTRACT: AIM:Programmed death-ligand 1 (PD-L1) has become a widely used predictive biomarker for therapy with checkpoint inhibitors in a variety of cancers. Here, we studied the expression of PD-L1 in squamous cell carcinomas of the vulva (SCCV) with regard to HPV status via its surrogate marker p16. Additionally, the status of PD-L1 and p16 were analyzed for prognostic information and potential correlation to tumor-infiltrating lymphocytes (TILs). METHODS:PD-L1 was analyzed in 128 cases of SCCV using the tumor proportion score (TPS), the immune cell score (ICS) and the combined positive score (CPS). Cases were immunostained for p16 and analyzed for stromal TILs. PD-L1, p16, and TILs were compared to clinico-pathological parameters and patient's survival. RESULTS:TPS???50% and CPS???50 were correlated to a worse grading (p?=?0.028 and p?=?0.031), but not to FIGO-stage. CPS???50 was associated to a worse prognosis with overall survival (p?=?0.021) but was not correlated to the progression-free survival. P16-positivity was correlated to a longer progression-free survival (p?=?0.006) and overall survival (p?=?0.023). PD-L1 expression was independent from p16 status. TILs???50% were present in 24% of the cases and were strongly correlated to PD-L1 (TPS p?=?0.02, ICS p?

SUBMITTER: Czogalla B

PROVIDER: S-EPMC7040065 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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PD-L1 expression and survival in p16-negative and -positive squamous cell carcinomas of the vulva.

Czogalla Bastian B Pham Deborah D Trillsch Fabian F Rottmann Miriam M Gallwas Julia J Burges Alexander A Mahner Sven S Kirchner Thomas T Jeschke Udo U Mayr Doris D Schmoeckel Elisa E

Journal of cancer research and clinical oncology 20200205 3

<h4>Aim</h4>Programmed death-ligand 1 (PD-L1) has become a widely used predictive biomarker for therapy with checkpoint inhibitors in a variety of cancers. Here, we studied the expression of PD-L1 in squamous cell carcinomas of the vulva (SCCV) with regard to HPV status via its surrogate marker p16. Additionally, the status of PD-L1 and p16 were analyzed for prognostic information and potential correlation to tumor-infiltrating lymphocytes (TILs).<h4>Methods</h4>PD-L1 was analyzed in 128 cases o ...[more]

PMID: 32025868

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Project description:Importance:Clinical trials that deintensify treatment for patients with suspected human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) use p16 expression to identify HPV-mediated tumors and guide treatment. While p16 staining has a strong correlation with good outcomes, approximately 12% of p16-positive patients have recurrent disease. Biomarkers that reveal tumor-specific characteristics, such as nodal involvement, may change therapy decisions. Objective:To assess whether if a tumor-specific genetic signature exists for node-negative vs node-positive HPV 16-positive/p16-positive OPSCCs. Design, Setting, and Participants:This was a retrospective cohort study with randomized case selection for p16 OPSCCs undertaken at a university-based, tertiary care cancer center. Samples were collected from patients with p16-positive OPSCC. A total of 21 HPV 16/p16-positive tumors were used in this study. Main Outcomes and Measures:Gene expression profiles of node-negative vs node-positive tumor samples were evaluated using a differential expression analysis approach and the sensitivity and specificity of a molecular signature was determined. Results:Among the 21 patients in the study (3 women, 18 men; mean [SD] age, 54.6 [9.6] years), 6 had node-negative disease and 15 had node-positive disease. Using differential expression analysis, we found 146 genes that were significantly different in patients with node-negative disease vs those with node-positive disease, of which 15 genes were used to create a genetic signature that could distinguish node-negative-like from node-positive-like disease. The resultant molecular signature has a sensitivity of 88.2% (95% CI, 63.6%-98.5%) and specificity of 85.7% (95% CI, 42.1%-99.6%). The positive likelihood ratio of this signature was 6.1 (95% CI, 1.0-38.2) and the negative likelihood ratio was 0.1 (95% CI, 0.04-0.5). Given this population's prevalence of node-positive disease of 70.8%, the positive- and negative-predicative values for this gene signature were 93.7% (95% CI, 70.8%-98.9%) and 75.0% (95% CI, 44.1%-92.0%), respectively. In addition, we developed a gene signature using agnostic, machine learning software that identified a 40-gene profile that predicts node-negative disease from node-positive disease (area under the curve, 0.93; 95% CI, 0.63-1.00). Conclusions and Relevance:Many HPV-16 and p16-positive tumors are treated as "lower-risk," but they do not have similar genetic compositions at the biological level. The identification of subgroups with unique expression patterns, such as those with nodal metastases, may guide physicians toward alternative or more aggressive therapies. In our study, unguided clustering suggested that that the larger biological characteristics of a tumor could be a better prognostic biomarker.

Project description:IntroductionPembrolizumab 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 programmed death-ligand 1 (PD-L1) positive.Materials and methodsThe cohort of this study consisted of a total of 528 consecutive UC patients with PD-L1 immunohistochemistry (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 ≥ 10.ResultsA total of 44.5% (235/528) patients with UC were PD-L1positive . A lower PD-L1 positivity rate was detected in primary (42.3%, 148/350) versus metastatic sites (48.9%, 87/178). PD-L1 positivity was dependent on the location of the metastatic sites. CGP revealed PD-L1positive patients had more frequent genomic alterations (GAs) in TP53 (p = .006) and RB1 (p = .003) and less frequent GAs in FGFR3 (p = .001) and MTAP (p = .028). The APOBEC mutational signature and tumor mutational burden (TMB)-high were more common in PD-L1positive patients. By testing patients with UC with CGP, in addition to PD-L1 IHC, an additional 97 patients (18.4%) in the total cohort were eligible for immunotherapy based on TMB status.ConclusionPD-L1positive and PD-L1negative urothelial carcinomas are genomically different. Also, our study provides the framework for future clinical investigation with regard to specimen site selection for PD-L1 testing as well as candidate biomarker genomic alterations that may predict for better response or lack of response to immune checkpoint inhibitors.Implications for practiceIn this study, a higher prevalence of TP53 and RB1 alterations and APOBEC mutational signatures in the PD-L1positive urothelial carcinoma disease subset and enrichment of FGFR3 alterations in the PD-L1negative disease subset were found. These data provide the basis for future investigation into the role of these genomic changes as positive and negative predictors of immunotherapy response. Also, differences wer seen in PD-L1 positivity based on the collection site of the sample, which can provide a framework for future clinical trial design and could influence sample selection for PD-L1 testing in patients with urothelial carcinoma when multiple samples are available.

Dataset Information

PD-L1 expression and survival in p16-negative and -positive squamous cell carcinomas of the vulva.

Publications

PD-L1 expression and survival in p16-negative and -positive squamous cell carcinomas of the vulva.

Similar Datasets

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