Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond

Abstract Background: Papillary renal cell carcinoma (PRCC) is the second most prevalent subtype of renal cell carcinoma (RCC), accounting for 15% of all RCCs. Tumor mutational burden (TMB) is a promising prognostic factor in many types of cancers. The present study aimed to investigate the association between TMB and patient survival in PRCC patients.Methods: Genomic and clinical data of 281 PRCC patients were collected from The Cancer Genome Atlas. Overall survival (OS) was compared between patients with high and low TMB using the Kaplan-Meier method with log-rank tests. Gene expression comparison and immune cell fraction comparison were performed using Student’s t test or Wilcoxon’s rank-sum test. Results: Patients with high TMB tumors had longer OS than those with low TMB tumors. Among tumor-infiltrating immune cells, high TMB tumors were associated with high levels of CD4+ T-cell infiltration, which were further associated with better survival. Furthermore, low TMB tumors were associated with a high level of infiltration of regulatory T-cells and dendritic cells. Among immune checkpoint genes, low TMB tumors expressed high levels of CD274, PDCD1LG2, LAG3, and TGFB1, and these genes were associated with a poor prognosis in PRCC. Among cytokine-related genes, low TMB tumors were associated with a high expression of IL6, whereas high TMB tumors were associated with a high expression of IFNA1.Conclusions: High TMB indicated better survival outcomes in PRCC patients. High TMB was associated with anti-tumor immune cell infiltration, whereas low TMB was associated with high expression of checkpoint genes that indicated a worse prognosis in RCC. Moreover, TMB was associated with the expression of immune cytokines. Thus, TMB may be a novel prognostic factor in PRCC.

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Loss-of-function of PBRM1 to predict response to anti-PD-1/PD-L1 therapy in metastatic renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3016 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3016-3016 ◽

Cited By ~ 2

Author(s):

Diana Miao ◽

Claire Margolis ◽

Dylan Martini ◽

Stephanie Anne Mullane ◽

Dana Cullen ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

Cell Carcinoma ◽

Chromatin Remodeling ◽

Immune Checkpoint ◽

Clinical Benefit ◽

Renal Cell ◽

Functional Characterization ◽

Mutational Burden ◽

Tumor Mutational Burden

3016 Background: Immune checkpoint inhibitors targeting programmed cell death-1 (PD-1) substantially improve patient survival in clear-cell renal cell carcinoma (ccRCC), but predictive biomarkers for efficacy have not yet been identified. Methods: We analyzed whole exome sequencing (WES) from a clinical trial of anti-PD-1 monotherapy (nivolumab) for ccRCC (N = 34) to discover genomic predictors of response to immune checkpoint therapy, and validated our findings in 28 ccRCC patients from 2 institutions treated with anti-PD-1 or anti-PD-L1 therapies. We defined 3 response groups: clinical benefit (CB) – complete or partial response by RECIST or stable disease with objective decrease in tumor burden and progression free survival (PFS) > 6 months - and no clinical benefit (NCB) – progressive disease with PFS < 3 months, with all other patients in intermediate benefit (IB). We further validated our findings in WES from 212 melanoma patients treated with immune checkpoint therapies in 3 published cohorts. Results: Biallelic loss of the chromatin remodeling subunit PBRM1, mutated in 34/62 (55%) patients across both cohorts and up to 41% of ccRCC overall, was the only gene mutation associated with CB in both the training (p = 0.0064; Pearson’s chi-squared) and validation cohorts (p = 0.043), and predicted both PFS and overall survival (OS) (p = 0.042 and 0.014, respectively; Kaplan-Meier). In 212 melanomas, truncating alterations in ARID2 – a closely related chromatin remodeler - were also enriched in responders after correcting for tumor mutational burden (p = 0.036), and having a truncating alteration in either PBRM1 or ARID2 significantly predicted overall survival (p = 0.022). In this ccRCC cohort, tumor mutational burden and loss of antigen presentation machinery were not associated with CB or NCB. Conclusions: Loss of chromatin remodeling subunits may impact response to immune checkpoint therapy in both ccRCC and melanoma. Further study in larger cohorts of immunotherapy-treated patients and functional characterization of ARID2 and PBRM1 in the context of the tumor-immune microenvironment will help to determine potential for further biomarker development.

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Comparison of tumor mutational burden (TMB) in PBRM1/BAP1-based subsets of advanced renal cell carcinoma (aRCC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.634 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 634-634

Author(s):

Sumanta K. Pal ◽

Russell Madison ◽

Jon Chung ◽

Neeraj Agarwal ◽

Paulo Gustavo Bergerot ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Genomic Profiling ◽

Coverage Depth ◽

Mutational Burden ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden ◽

Clear Cell Rcc

634 Background: Using IHC, Joseph et al (J Urol 2016) propose that 40.1%, 48.6%, 8.7% and 1.8% of patients (pts) can be characterized as PBRM1+BAP1+, PRBM1-BAP1+, PBRM1+BAP1- and PBRM1-BAP1-, respectively. We sought to confirm consistency of the frequency of genomic alterations (GAs) and IHC data and to compare TMB across subsets. Methods: DNA was extracted from 40 microns of FFPE sections from pts with aRCC. Comprehensive genomic profiling (CGP) was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 688X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. TMB was determined on 1.2 million Mb of sequenced DNA; results are reported in subsets segregated by presence or absence of PBRM1 and BAP1 alteration. Results: 648 consecutive pts (459:189 M:F) with clear cell RCC (ccRCC) were assessed with a median age of 58, and 368 consecutive pts (254:114 M:F) with non-clear cell RCC (nccRCC) were assessed with a median age of 57. Mutations in BAP1 and PBRM1 were found more frequently in ccRCC vs nccRCC (P < 0.05 for both). In pts with ccRCC, average TMB was highest in pts with co-occurring PBRM1 and BAP1 GAs (4.87 muts/Mb), and lowest in pts lacking both GAs (2.77 muts/Mb) (P < 0.05). TMB was similar across PBRM1/BAP1-based subsets amongst pts with nccRCC. Conclusions: As anticipated, the frequency of PBRM1/BAP1-mutated subsets by CGP is inversely related to the frequency of subsets with PBRM1/BAP1 loss by IHC from previous reports. In addition to these confirmatory findings, this large series identifies that pts with dual PBRM1/ BAP1 GAs (associated with the worst prognosis) had the highest TMB. [Table: see text]

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Tumor mutational burden and immune signatures interplay in renal cell carcinoma

Annals of Translational Medicine ◽

10.21037/atm.2020.02.81 ◽

2020 ◽

Vol 8 (6) ◽

pp. 269-269

Author(s):

Evgeny Yakirevich ◽

Nimesh R. Patel

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Mutational Burden ◽

Immune Signatures ◽

Tumor Mutational Burden

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Tumour mutational burden and immune infiltrates in primary renal cell carcinoma and matched brain metastases

Annals of Oncology ◽

10.1093/annonc/mdz243.013 ◽

2019 ◽

Vol 30 ◽

pp. v148

Author(s):

A. Steindl ◽

E.S. Bergen ◽

D. Alpar ◽

B. Gatterbauer ◽

K. Dieckmann ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Brain Metastases ◽

Cell Carcinoma ◽

Renal Cell ◽

Primary Renal Cell Carcinoma ◽

Mutational Burden

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Immunotherapy in Renal Cell Carcinoma: The Future Is Now

International Journal of Molecular Sciences ◽

10.3390/ijms21072532 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2532 ◽

Cited By ~ 2

Author(s):

Antoine Deleuze ◽

Judikaël Saout ◽

Frédéric Dugay ◽

Benoit Peyronnet ◽

Romain Mathieu ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

New Technologies ◽

Treatment Options ◽

Unmet Need ◽

Tumour Microenvironment ◽

High Rate ◽

Programmed Death ◽

Tumor Mutational Burden

Renal cell carcinoma is the third type of urologic cancer and has a poor prognosis with 30% of metastatic patients at diagnosis. The antiangiogenics and targeted immunotherapies led to treatment remodeling emphasizing the role of the tumour microenvironment. However, long-term responses are rare with a high rate of resistance. New strategies are emerging to improve the efficacy and the emerging drugs are under evaluation in ongoing trials. With the different treatment options, there is an urgent need to identify biomarkers in order to predict the efficacy of drugs and to better stratify patients. Owing to the limitations of programmed death-ligand 1 (PD-L1), the most studied immunohistochemistry biomarkers, and of the tumor mutational burden, the identification of more reliable markers is an unmet need. New technologies could help in this purpose.

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Burden of tumor mutations, neoepitopes, and other variants are dubious predictors of cancer immunotherapy response and overall survival

10.1101/665026 ◽

2019 ◽

Cited By ~ 2

Author(s):

Mary A. Wood ◽

Benjamin R. Weeder ◽

Julianne K. David ◽

Abhinav Nellore ◽

Reid F. Thompson

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

Cell Carcinoma ◽

Renal Cell ◽

Intrinsic Variability ◽

Clinical Value ◽

Sufficient Cause ◽

Tumor Mutational Burden ◽

Checkpoint Inhibitor Therapy ◽

Cancer Types

ABSTRACTBackgroundTumor mutational burden (TMB, the quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy and is gaining broad acceptance as a result. However, TMB harbors intrinsic variability across cancer types, and its assessment and interpretation are poorly standardized.MethodsUsing a standardized approach, we quantify the robustness of TMB as a metric and its potential as a predictor of immunotherapy response and survival among a diverse cohort of cancer patients. We also explore the additive predictive potential of RNA-derived variants and neoepitope burden, incorporating several novel metrics of immunogenic potential.ResultsWe find that TMB is a partial predictor of immunotherapy response in melanoma and non-small cell lung cancer, but not renal cell carcinoma. We find that TMB is predictive of overall survival in melanoma patients receiving immunotherapy, but not in an immunotherapy-naive population. We also find that it is an unstable metric with potentially problematic repercussions for clinical cohort classification. We finally note minimal additional predictive benefit to assessing neoepitope burden or its bulk derivatives, including RNA-derived sources of neoepitopes.ConclusionsWe find sufficient cause to suggest that the predictive clinical value of TMB should not be overstated or oversimplified. While it is readily quantified, TMB is at best a limited surrogate biomarker of immunotherapy response. The data do not support isolated use of TMB in renal cell carcinoma.

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