The interplay between cancer type, panel size and tumor mutational burden threshold in patient selection for cancer immunotherapy.
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ABSTRACT:
SUBMITTER: Golkaram M
PROVIDER: S-EPMC7676656 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
Publications
The interplay between cancer type, panel size and tumor mutational burden threshold in patient selection for cancer immunotherapy.
Golkaram Mahdi M Zhao Chen C Kruglyak Kristina K Zhang Shile S Bilke Sven S
PLoS computational biology 20201109 11
The tumor mutational burden (TMB) is increasingly recognized as an emerging biomarker that predicts improved outcomes or response to immune checkpoint inhibitors in cancer. A multitude of technical and biological factors make it difficult to compare TMB values across platforms, histologies, and treatments. Here, we present a mechanistic model that explains the association between panel size, histology, and TMB threshold with panel performance and survival outcome and demonstrate the limitations ...[more]
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Project description:Objective: Panel-based sequencing is widely used to measure tumor mutational burden (TMB) in clinical trials and is ready to enter routine diagnostics. However, cut-off points to distinguish "TMB-high" from "TMB-low" tumors are not consistent and the clinical implications of TMB in predicting responses to immune checkpoint blockade (ICB) in gastric cancer are not clearly defined. We aimed to assess whether TMB is associated with the response to immunotherapy and to examine its relation with other biomarkers of immunotherapy response in advanced gastric cancer. Design: In total, 63 patients with advanced gastric cancer treated with ICB were included in the study. Panel-based TMB in gastric tumor samples, treatment responses to ICB, clinicopathological data, and time to progression were retrospectively analyzed. Microsatellite instability (MSI) status, Epstein-Barr virus (EBV) positivity, and programmed death-ligand 1 (PD-L1) combined positive score (CPS) were also analyzed. Results: TMB ranged from 0 to 446 mutations/megabase (mt/mb) and was significantly associated with MSI (P < 0.001), PD-L1 CPS (P = 0.022), response to ICB (P = 0.04), chemotherapy (P = 0.02) and older patient age (?65 years; P = 0.0014). The cut-off point of 14.31 mt/mb determined by log-rank statistics for progression-free survival divided the tumors into eight (12.7%) TMB-high and 55 (87.3%) TMB-low tumors. The median TMB of the chemo-refractory group was significantly higher (8.43 mt/mb) compared to that of chemo-naïve group (3.42 mt/mb) (P = 0.02). Patients with TMB-high tumors showed prolonged progression-free survival in univariate [HR, 0.32; 95% confidence interval (CI), 0.12-0.90] and multivariate (HR, 0.21; 95% CI, 0.07-0.69) analyses. In area under the receiver operating curve (AUC) analysis of TMB, PD-L1, EBV, MSI, and their combination, the AUC value was the highest for EBV (0.97), followed by MSI (0.96), PD-L1 (0.81), the combination (0.78), and TMB (0.56). Conclusion: In addition to EBV, MSI, and PD-L1 CPS, TMB could be used as a predictive biomarker in patients with advanced gastric cancer treated with ICB and may aid clinical decision making.
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Project description:Tumor mutational burden (TMB) is a promising tool to help define patients with triple-negative breast cancer (TNBC) most likely to benefit from immune checkpoint blockade (ICB) therapies. Roughly reflecting the degree of neo-antigens that tumors present to immune cells, TMB associates with multiple measures of tumoral immunogenicity and has proven clinically useful in cancers with relatively high mutation burden. TNBC carries higher TMB than other breast cancer subtypes, and recent data suggest that high-TMB TNBC cases may derive particular benefit from ICB in combination with chemotherapy (GeparNuevo, IMpassion130) or even ICB alone (KEYNOTE-119, TAPUR). Given the recent approval of pembrolizumab and atezolizumab in combination with chemotherapy for PD-L1-positive, metastatic TNBC, standardizing TMB calculation methods and cut-off values is of critical importance to deploy this clinical biomarker.
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Project description:Purpose: Tumor mutational burden (TMB) calculated by whole-exome sequencing (WES) is proved to be effective to predict the clinical benefit of immune checkpoint blockades. However, WES is not commonly used in China. We aimed to determine if a 381-caner-gene panel (CGP) could be used to estimate TMB, delineate the landscape of TMB of Chinese patients and identify mutated genes and pathways related to higher TMB. Methods: We first evaluated the correlation between the TMB estimated by a 381-cancer-gene panel MasterView and WES using the data from the melanoma sample cohort. 3023 formalin fixed, paraffin-embedded tumor specimens from 2932 Chinese patients with advanced solid tumor were profiled for 381 gene sequencing, the baits of which covered 4,557 exons of 365 cancer-related genes and 47 introns of 25 genes frequently rearranged in cancer (All performed in a lab who achieved full marks five times in the external quality assessment by College of American Pathologists [CAP]). Using the sequencing data, we estimated the TMB of Chinese advanced solid tumor and identified mutated genes and pathways related to higher TMB level. Results: 381-CGP-mutational burden was strongly associated with those calculated by WES (R2 = 0.978). The median TMB for each tumor type was 5.65 (colorectal cancer), 4.84 (lung cancer), 4.03 (hepatobiliary cancer), 4.03 (gastric carcinoma), 4.03 (breast cancer) mutations/mb respectively. No correlation was observed between TMB level and age (P = 0.577) or gender (P = 0.307). The TMB of patients with mismatch repair (MMR) or DNA repair response (DDR) pathway deficiency was significantly higher than that without MMR or DDR pathway deficiency (P < 0.001). Conclusion: The 381-cancer gene panel is a clinical practicable method to assess tumor mutational burden compared with whole exome sequencing. MMR and DDR deficiency are correlated with higher tumor mutational burden of Chinese patients with advanced solid tumors.
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Project description:Cancer is instigated by mutator phenotypes, including deficient mismatch repair and p53-associated chromosomal instability. More recently, a distinct class of cancers was identified with unusually high mutational loads due to heterozygous amino acid substitutions (most commonly P286R) in the proofreading domain of DNA polymerase ?, the leading strand replicase encoded by POLE. Immunotherapy has revolutionized cancer treatment, but new model systems are needed to recapitulate high mutational burdens characterizing human cancers and permit study of mechanisms underlying clinical responses. Here, we show that activation of a conditional LSL-PoleP286R allele in endometrium is sufficient to elicit in all animals endometrial cancers closely resembling their human counterparts, including very high mutational burden. Diverse investigations uncovered potentially novel aspects of Pole-driven tumorigenesis, including secondary p53 mutations associated with tetraploidy, and cooperation with defective mismatch repair through inactivation of Msh2. Most significantly, there were robust antitumor immune responses with increased T cell infiltrates, accelerated tumor growth following T cell depletion, and unfailing clinical regression following immune checkpoint therapy. This model predicts that human POLE-driven cancers will prove consistently responsive to immune checkpoint blockade. Furthermore, this is a robust and efficient approach to recapitulate in mice the high mutational burdens and immune responses characterizing human cancers.
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Project description:Programmed death receptor-1/ligand 1 (PD-1/L1) antibodies can induce durable remissions in malignancies. However, response rates are only approximately 10% to 20% in unselected patients versus approximately 50% in microsatellite instability-high (MSI-high) tumors, probably related to high tumor mutational burden (TMB). Pembrolizumab is approved for MSI-high or deficient mismatch repair tumors. However, outside of colorectal and endometrial carcinoma, only a small subset of tumors were MSI-high, making this treatment option unavailable to most patients. It is not known if MS-stable tumors with high TMB respond to PD-1/PD-L1 blockade. Next-generation sequencing (NGS) was performed on 60 patients (14 different histologies) treated with checkpoint blockade using the FoundationOne assay to determine TMB and MSI status. TMB was dichotomized into two groups: low-to-intermediate (0-19 mutations/mb) versus high (≥20 mutations/mb). Benefit rate (stable disease for ≥6 months and partial or complete response) was determined: 2,179 of 148,803 samples (1.5%) were MSI-high and 9,762 (6.6%) TMB-high (7,972, MS-stable/TMB-high). The majority (82.1%) of MSI-H tumors were TMB-high; however, only 18.3% of TMB-high tumors were MSI-H. Median progression-free survival for MS-stable/TMB-high versus MS-stable/TMB-low/TMB-intermediate tumors was 26.8 versus 4.3 months (P = 0.0173). Thus, our data demonstrate that MS-stable/TMB-high tumors are more common than MSI-high cancers and may benefit from immunotherapy.
| S-EPMC6774837 | biostudies-literature
Project description:Characterization of tumors utilizing next-generation sequencing methods, including assessment of the number of somatic mutations (tumor mutational burden [TMB]), is currently at the forefront of the field of personalized medicine. Recent clinical studies have associated high TMB with improved patient response rates and survival benefit from immune checkpoint inhibitors; hence, TMB is emerging as a biomarker of response for these immunotherapy agents. However, variability in current methods for TMB estimation and reporting is evident, demonstrating a need for standardization and harmonization of TMB assessment methodology across assays and centers. Two uniquely placed organizations, Friends of Cancer Research (Friends) and the Quality Assurance Initiative Pathology (QuIP), have collaborated to coordinate efforts for international multistakeholder initiatives to address this need. Friends and QuIP, who have partnered with several academic centers, pharmaceutical organizations, and diagnostic companies, have adopted complementary, multidisciplinary approaches toward the goal of proposing evidence-based recommendations for achieving consistent TMB estimation and reporting in clinical samples across assays and centers. Many factors influence TMB assessment, including preanalytical factors, choice of assay, and methods of reporting. Preliminary analyses highlight the importance of targeted gene panel size and composition, and bioinformatic parameters for reliable TMB estimation. Herein, Friends and QuIP propose recommendations toward consistent TMB estimation and reporting methods in clinical samples across assays and centers. These recommendations should be followed to minimize variability in TMB estimation and reporting, which will ensure reliable and reproducible identification of patients who are likely to benefit from immune checkpoint inhibitors.
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Project description:ImportanceTumor mutational burden (TMB), as measured by whole-exome sequencing (WES) or a cancer gene panel (CGP), is associated with immunotherapy responses. However, whether TMB estimated by circulating tumor DNA in blood (bTMB) is associated with clinical outcomes of immunotherapy remains to be explored.ObjectivesTo explore the optimal gene panel size and algorithm to design a CGP for TMB estimation, evaluate the panel reliability, and further validate the feasibility of bTMB as a clinical actionable biomarker for immunotherapy.Design, setting, and participantsIn this cohort study, a CGP named NCC-GP150 was designed and virtually validated using The Cancer Genome Atlas database. The correlation between bTMB estimated by NCC-GP150 and tissue TMB (tTMB) measured by WES was evaluated in matched blood and tissue samples from 48 patients with advanced NSCLC. An independent cohort of 50 patients with advanced NSCLC was used to identify the utility of bTMB estimated by NCC-GP150 in distinguishing patients who would benefit from anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1) therapy. The study was performed from July 19, 2016, to April 20, 2018.Main outcomes and measuresAssessment of the Spearman correlation coefficient between bTMB estimated by NCC-GP150 and tTMB calculated by WES. Evaluation of the association of bTMB level with progression-free survival and response to anti-PD-1 and anti-PD-L1 therapy.ResultsThis study used 2 independent cohorts of patients with NSCLC (cohort 1: 48 patients; mean [SD] age, 60 [13] years; 15 [31.2%] female; cohort 2: 50 patients; mean [SD] age, 58 [8] years; 15 [30.0%] female). A CGP, including 150 genes, demonstrated stable correlations with WES for TMB estimation (median r2 = 0.91; interquartile range, 0.89-0.92), especially when synonymous mutations were included (median r2 = 0.92; interquartile range, 0.91-0.93), whereas TMB estimated by the NCC-GP150 panel found higher correlations with TMB estimated by WES than most of the randomly sampled 150-gene panels. Blood TMB estimated by NCC-GP150 correlated well with the matched tTMB calculated by WES (Spearman correlation = 0.62). In the anti-PD-1 and anti-PD-L1 treatment cohort, a bTMB of 6 or higher was associated with superior progression-free survival (hazard ratio, 0.39; 95% CI, 0.18-0.84; log-rank P = .01) and objective response rates (bTMB ≥6: 39.3%; 95% CI, 23.9%-56.5%; bTMB <6: 9.1%; 95% CI, 1.6%-25.9%; P = .02).Conclusions and relevanceThe findings suggest that established NCC-GP150 with an optimized gene panel size and algorithm is feasible for bTMB estimation, which may serve as a potential biomarker of clinical benefit in patients with NSCLC treated with anti-PD-1 and anti-PD-L1 agents.
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Project description:BackgroundImmune checkpoint blockade (ICB) with antibodies inhibiting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) (or its ligand (PD-L1)) can stimulate immune responses against cancer and have revolutionized the treatment of tumors. The influence of host germline genetics and its interaction with tumor neoantigens remains poorly defined. We sought to determine the interaction between tumor mutational burden (TMB) and the ability of a patient's major histocompatibility complex class I (MHC-I) to efficiently present mutated driver neoantigens in predicting response ICB.MethodsComprehensive genomic profiling was performed on 83 patients with diverse cancers treated with ICB to determine TMB and human leukocyte antigen-I (HLA-I) genotype. The ability of a patient's MHC-I to efficiently present mutated driver neoantigens (defined by the Patient Harmonic-mean Best Rank (PHBR) score (with lower PHBR indicating more efficient presentation)) was calculated for each patient.ResultsThe median progression-free survival (PFS) for PHBR score < 0.5 vs. ≥ 0.5 was 5.1 vs. 4.4 months (P = 0.04). Using a TMB cutoff of 10 mutations/mb, the stable disease > 6 months/partial response/complete response rate, median PFS, and median overall survival (OS) of TMB high/PHBR high vs. TMB high/PHBR low were 43% vs. 78% (P = 0.049), 5.8 vs. 26.8 months (P = 0.03), and 17.2 months vs. not reached (P = 0.23), respectively. These findings were confirmed in an independent validation cohort of 32 patients.ConclusionsPoor presentation of driver mutation neoantigens by MHC-I may explain why some tumors (even with a high TMB) do not respond to ICB.
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Project description:Anti-programmed death (ligand)-1 [anti-PD-(L)1] therapies such as pembrolizumab, nivolumab or atezolizumab have become standard of care for non-small cell lung cancer (NSCLC) patients either in first line or beyond. PD-L1 expression level allows enriching the treated population with responders, but it is still not an optimal biomarker. Even in patients with PD-L1 tumor proportion score (TPS) levels of ?50% treated with first line pembrolizumab overall response rate (ORR) is only 44.8% and overall survival at one year is 70%. Moreover, in combination trials with chemotherapy and anti-PD-(L)1 therapy, a significant proportion of patients does not respond (ORR ranges from 45.3% to 64.0%), regardless of PD-L1 expression. Furthermore, PD-L1 expression level is not associated with improved benefit in patients treated with combinations of anti-PD-(L)1 and anti-cytotoxic T-lymphocyte-associated antigen (anti-CTLA4) therapy. One of the new promising biomarkers is tumor mutational burden (TMB). It has been discovered that especially tumor types with a known high mutation rate such as NSCLC and melanoma respond best to immune checkpoint inhibitors (ICIs). An explanation is that this high mutation rate makes it more likely that neoantigens arise that are targeted by activated immune cells, but it is not feasible to determine neoantigen load in daily practice. However, TMB of a certain tumor type is associated with neoantigen load and outcome on ICIs. In this comprehensive review, we discuss the TMB analysis methods, the rationale to use TMB as a predictive biomarker and the clinical utility of TMB in NSCLC patients treated with ICIs.
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Project description:Metastatic gastric cancer (GC) is an incurable and aggressive disease with a poor prognosis. Immunotherapy is an attractive approach for treating patients with cancer, and studies using immunotherapy have shown promising results in melanoma, kidney and non-small cell lung cancers, among others.We present a case of a 50-year-old woman with metastatic GC whose cancer had progressed after first-line chemotherapy and who received pembrolizumab as an experimental treatment. Molecular analyses showed that her tumor was negative for PD-L1 expression, contained microsatellite stability and several focal somatic copy number alterations. The patient experienced an almost complete response after eleven cycles of treatment. Her symptoms related to the disease disappeared, and the medication was well tolerated.Despite reports of promising responses in some patients, immunotherapy is not suitable for all patients; therefore, we explored the molecular characteristics that could explain the exceptional response and clinical benefits observed in our patient.
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