PD-L1 Negative Status is Associated with Lower Mutation Burden, Differential Expression of Immune-Related Genes, and Worse Survival in Stage III Melanoma

Madore, Jason; Strbenac, Dario; Vilain, Ricardo E.; Menzies, Alexander M.; Yang, Yee Hwa; Thompson, John F.; Long, Georgina V.; Mann, Graham J.; Scolyer, Richard A.; Wilmott, James S.

doi:10.1158/1078-0432.ccr-15-1714

Cited by 93 publications

(84 citation statements)

References 40 publications

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“…Our analysis suggests that combinations of anti-PD-1/PD-L1/CTLA4-blocking antibodies can induce responses regardless of the TMB level. This observation is supported by prior studies reporting that combined ipilimumab and nivolumab produced similar response rates in PD-L1-expressing and non-expressing tumors,(49) which is relevant because increased PD-L1 expression correlates with higher TMB(50). The number of patients treated with combination therapy was, however, small in our study, and the implications of TMB level for combination therapy requires validation in larger cohorts.…”

Section: Discussionsupporting

confidence: 81%

Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers

Goodman

Kato

Bazhenova

et al. 2017

Molecular Cancer Therapeutics

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Immunotherapy induces durable responses in a subset of patients with cancer. High TMB may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free and overall survival (PFS, OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥ 20 mutations/mb) vs. low to intermediate TMB was 22/38 (58%) vs. 23/113 (20%) (P = 0.0001); median PFS, 12.8 vs. 3.3 months (P = <0.0001); median OS, not reached vs. 16.3 months (P = 0.0036). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders vs. non-responders treated with anti-PD-1/PD-L1 monotherapy was 18.0 vs. 5.0 mutations/mb (P < 0.0001). Interestingly, anti-CTLA4/anti-PD-1/PD-L1 combinations vs. anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%) (P = 0.004) and PFS (P = 0.024). Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB.

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Section: Discussionsupporting

confidence: 81%

Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers

Goodman

Kato

Bazhenova

et al. 2017

Molecular Cancer Therapeutics

1,861

1,554

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“…Mutation load has been shown to correlate with response to anti-PD1 immunotherapy [22]. Rizvi et al performed whole exome sequencing of non-small cell lung cancers treated with pembrolizumab and showed that higher mutation load correlated with better response rate (63% vs 0%), more durable clinical benefit (73% vs 13%), and better progression-free survival (14.5 vs 3.7 months)[23].…”

Section: Discussionmentioning

confidence: 99%

PD-L1 expression in tonsillar cancer is associated with human papillomavirus positivity and improved survival: implications for anti-PD1 clinical trials

et al. 2016

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In this study, we examined PD-L1 expression by immunohistochemistry in 99 patients with tonsillar cancer and known human papillomavirus (HPV) status to assess its clinical significance. We showed that the pattern of PD-L1 expression is strongly related to HPV status. The PD-L1 positivity rate was 83.3% in HPV-positive cases and 56.9% in HPV-negative cases (p < 0.05). Patients with HPV-positive/PD-L1-positive cancer had significantly better event free survival and overall survival compared with patients with HPV-negative/PD-L1-negative cancer. Relative to those patients with HPV-negative/PD-L1-negative disease who had the highest risk of death, patients with HPV-positive/PD-L1-positive cancers had a 2.85 fold lower risk of developing an event (HR 0.35, 95% CI: 0.16–0.79) and a 4.5 fold lower risk of death (HR =0.22, 95% CI: 0.09–0.53). Our findings will help to guide future clinical trial design in immunotherapy based on PD-L1 expression in tonsillar cancer.

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“…Hypermutated tumors with more than 500 SNVs showed obviously higher PD-L1 expression than tumors with low mutation. The specific co-rrelation of PD-L1 expression with high mutations has been reported, and PD-L1 expression may be one parameter responsible for good responses in the clinic to anti-immune checkpoint antibody therapy (12). In the future, the immune-response gene profiling of hypermutated tumors should be performed to identify better biomarkers to predict good responders to antibody treatment.…”

Section: Discussionmentioning

confidence: 99%

<b>Immune response-associated gene analysis of 1,000 cancer patients using whole-exome sequencing and gene expression profiling—Project </b><b>HOPE— </b>

et al. 2016

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Project HOPE (High-tech Omics-based Patient Evaluation) has been progressing since its implementation in 2014 using whole-exome sequencing (WES) and gene expression profiling (GEP). With the aim of evaluating immune status in cancer patients, a gene panel consisting of 164 immune response-associated genes (56 antigen-presenting cell and T-cell-associated genes, 34 cytokine-and metabolism-associated genes, 47 TNF and TNF receptor superfamily genes, and 27 regulatory T-cell-associated genes) was established, and its expression and mutation status were investigated using 1,000 cancer patient-derived tumors. Regarding WES, sequencing and variant calling were performed using the Ion Proton system. The average number of single-nucleotide variants (SNVs) detected per sample was 183 ± 507, and the number of hypermutators with more than 500 total SNVs was 51 cases. Regarding GEP, seven immune response-associated genes (VTCN1, IL2RA, ULBP2, TREM1, MSR1, TNFSF9 and TNFRSF12A) were more than 2-fold overexpressed compared with normal tissues in more than 2 organs. Specifically, the positive rate of PD-L1 expression in all patients was 25.8%, and PD-L1 expression was significantly upregulated in hypermutators. The simultaneous analyses of WES and GEP based on immune response-associated genes are very intriguing tools to screen cancer patients suitable for immune checkpoint antibody therapy.Cancer immunotherapy has a long history originating from innovating events in the 1970's, such as biological response modifier and hybridoma technology, and moving to the recent renaissance stage in which peptide or dendritic cell (DC)-based vaccines have been applied. Throughout history, even the most powerful modality has not demonstrated a response rate more than 20% in clinical trials, which is referred to as the glass ceiling phenomenon (9, 21).However, since the recent success of immune checkpoint antibodies, such as ipilimumab and nivolumab, reported in metastatic melanoma patients, many ongoing clinical trials have been underway to evaluate their efficacy in various solid cancers other than melanomas (2,8,26,31,33). Specifically, a promising combination therapy of ipilimumab and nivolumab has demonstrated a very high response rate of up to 40% and long-term survival benefit in patients with advanced cancers, including non-small cell lung cancer (18,25,29).

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PD-L1 Negative Status is Associated with Lower Mutation Burden, Differential Expression of Immune-Related Genes, and Worse Survival in Stage III Melanoma

Cited by 93 publications

References 40 publications

Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers

Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers

PD-L1 expression in tonsillar cancer is associated with human papillomavirus positivity and improved survival: implications for anti-PD1 clinical trials

<b>Immune response-associated gene analysis of 1,000 cancer patients using whole-exome sequencing and gene expression profiling—Project </b><b>HOPE— </b>

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