Germline variants predictive of tumor mutational burden and immune checkpoint inhibitor efficacy.
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ABSTRACT:
SUBMITTER: Chatrath A
PROVIDER: S-EPMC7988326 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundImpaired DNA damage response (DDR) can affect immune checkpoint inhibitors (ICI) efficacy and lead to heightened immune activation. We assessed the impact of pathogenic or likely pathogenic (P/LP) germline DDR mutations on ICI response and toxicity.Materials and methodsA retrospective analysis of 131 cancer patients with germline DNA testing and ICI treatment was performed.ResultsNinety-two patients were DDR-negative (DDR-), and 39 had ≥1 DDR mutation (DDR+). DDR+ patients showed higher objective response rates (ORRs) compared to DDR- in univariate and multivariable analyses, adjusting for age and metastatic disease (62% vs. 23%, unadjusted OR = 5.41; 95% CI, 2.41-12.14; adjusted OR 5.94; 95% CI, 2.35-15.06). Similar results were seen in mismatch repair (MMR), DDR pathways with intact MMR (DDR+MMRi), and homologous recombination (HR) subgroups versus DDR- (adjusted OR MMR = 24.52; 95% CI 2.72-221.38, DDR+MMRi = 4.26; 95% CI, 1.57-11.59, HR = 4.74; 95% CI, 1.49-15.11). DDR+ patients also had higher ORRs with concurrent chemotherapy (82% vs. 39% DDR-, p=0.03) or concurrent tyrosine kinase inhibitors (50% vs. 5% DDR-, p=0.03). No significant differences in immune-related adverse events were observed between DDR+ and DDR- cohorts.ConclusionP/LP germline DDR mutations may enhance ICI response without significant additional toxicity.
| S-EPMC10859432 | biostudies-literature
Project description:Tumor mutational burden (TMB) is a genomic biomarker that predicts favorable responses to immune checkpoint inhibitors (ICIs). Here, we set out to assess the predictive value of TMB on long-term survival outcomes in patients undergoing ICIs. We systematically searched PubMed, Embase, CENTRAL and clinicaltrials.gov from inception to 6 August 2019. We included retrospective studies or clinical trials of ICIs that reported hazard ratios (HRs) for overall survival (OS) and/or progression-free survival (PFS) according to TMB. Data on 5712 patients from 26 studies were included. Among patients who received ICIs, high TMB groups showed better OS (HR 0.53, 95% CI 0.42 to 0.67) and PFS (HR 0.52, 95% CI 0.40 to 0.67) compared to low TMB groups. In patients with high TMB, those who received ICIs had a better OS (HR 0.69, 95% CI 0.50 to 0.95) and PFS (HR = 0.66, 95% CI = 0.47 to 0.92) compared to those who received chemotherapy alone, while in patients with low TMB, such ICI benefits of OS or PFS were not statistically significant. In conclusion, TMB may be an effective biomarker to predict survival in patients undergoing ICI treatment. The role of TMB in identifying patient groups who may benefit from ICIs should be determined in future randomized controlled trials.
| S-EPMC6895916 | biostudies-literature
Project description:Treatment with immune checkpoint inhibitors (ICPIs) extends survival in a proportion of patients across multiple cancers. Tumor mutational burden (TMB)-the number of somatic mutations per DNA megabase (Mb)-has emerged as a proxy for neoantigen burden that is an independent biomarker associated with ICPI outcomes. Based on findings from recent studies, TMB can be reliably estimated using validated algorithms from next-generation sequencing assays that interrogate a sufficiently large subset of the exome as an alternative to whole-exome sequencing. Biological processes contributing to elevated TMB can result from exposure to cigarette smoke and ultraviolet radiation, from deleterious mutations in mismatch repair leading to microsatellite instability, or from mutations in the DNA repair machinery. A variety of clinical studies have shown that patients with higher TMB experience longer survival and greater response rates following treatment with ICPIs compared with those who have lower TMB levels; this includes a prospective randomized clinical trial that found a TMB threshold of ?10 mutations per Mb to be predictive of longer progression-free survival in patients with non-small cell lung cancer. Multiple trials are underway to validate the predictive values of TMB across cancer types and in patients treated with other immunotherapies. Here we review the rationale, algorithm development methodology, and existing clinical data supporting the use of TMB as a predictive biomarker for treatment with ICPIs. We discuss emerging roles for TMB and its potential future value for stratifying patients according to their likelihood of ICPI treatment response. IMPLICATIONS FOR PRACTICE: Tumor mutational burden (TMB) is a newly established independent predictor of immune checkpoint inhibitor (ICPI) treatment outcome across multiple tumor types. Certain next-generation sequencing-based techniques allow TMB to be reliably estimated from a subset of the exome without the use of whole-exome sequencing, thus facilitating the adoption of TMB assessment in community oncology settings. Analyses of multiple clinical trials across several cancer types have demonstrated that TMB stratifies patients who are receiving ICPIs by response rate and survival. TMB, alongside other genomic biomarkers, may provide complementary information in selecting patients for ICPI-based therapies.
| S-EPMC6964127 | biostudies-literature
Project description:More than 2000 immuno-oncology agents are being tested or are in use as a result of the cancer immunotherapy revolution. Manipulation of co-inhibitory receptors has achieved tumor eradication in a minority of patients, but widespread immune-related adverse events (irAEs) compromised tolerance to healthy self-tissues in the majority. We have proposed that a major mechanism of irAEs is similar to a graft-versus-malignancy effect of graft-versus-host disease. To verify our hypothesis, we retrieved post-marketing data of adverse events from the U.S. Food and Drug Administration Adverse Event Reporting System. A significant positive correlation was revealed in 7677 patients between the reporting odds ratio of irAEs during immune checkpoint inhibitor therapy and the corresponding tumor mutational burden across 19 cancer types. These results can be interpreted to mean that the ICI drugs unleashed T cells against "altered-self," self, and tumors resulting in better overall survival.
| S-EPMC7183506 | biostudies-literature
Project description:BACKGROUND:Clinically-available biomarkers to identify the fraction of patients with small cell lung cancer (SCLC) who respond to immune-checkpoint inhibitors (ICIs) are lacking. High nonsynonymous tumor mutational burden (TMB), as assessed by whole exome sequencing, correlates with improved clinical outcomes for patients with SCLC treated with ICIs. Whether TMB as assessed by targeted next generation sequencing (NGS) is associated with improved efficacy of ICIs in patients with SCLC is currently unknown. Here we determined whether TMB by targeted NGS is associated with efficacy of ICIs in patients with SCLC. METHODS:We collected clinicopathologic data from patients with relapsed or refractory SCLC which underwent targeted NGS with TMB assessment by the Dana-Farber Cancer Institute OncoPanel platform. The relationship between TMB and clinical outcomes after treatment with ICIs was investigated. RESULTS:Among the 52 patients treated with ICIs, we found no significant difference in the objective response rate (ORR) between patients with a TMB above the 50th percentile ("TMB high") and those with a TMB at or below the 50th percentile ("TMB low"). The median progression-free survival (mPFS) and median overall survival (mOS) were significantly longer in patients with a high TMB compared to those with a low TMB (mPFS: 3.3 versus 1.2 months, HR: 0.37 [95% CI: 0.20-0.69], P < 0.01; mOS: 10.4 versus 2.5 months, HR: 0.38 [95% CI: 0.19-0.77], P < 0.01). The one-year PFS and OS rates improved with increasing mutational load when TMB was divided into tertiles. CONCLUSIONS:These findings show that targeted NGS, a readily available clinical diagnostic test, can be used to identify patients with SCLC who are most likely to benefit from treatment with immune checkpoint inhibitors.
| S-EPMC6437848 | biostudies-literature
Project description:Background: Despite an increasing understanding about tumor mutation burden (TMB) in cancer immunity and cancer immunotherapy, the comprehensive cognition between TMB and efficiency of immune checkpoint inhibitors (ICIs) is still lacking. A systematic review and meta-analysis was conducted to evaluate the predictive value of TMB on efficacy of ICIs. Methods: Systematic literature search was conducted on PubMed, EMBASE, Web of Science and Cochrane Library up to June 16, 2019. Pooled odds ratio (OR) of objective response rate (ORR), hazard ratio (HR) of progression-free survival (PFS) and overall survival (OS) were estimated by inverse variance weighted fixed-effects model (I 2 ≤ 50%) or DerSimonian-Laird random-effects model (I 2 > 50%). In addition, heterogeneity analysis, sensitivity analysis, publication bias and subgroup analysis were conducted. Moreover, fractional polynomial regression was conducted to investigate the dose-response relationship between TMB cutoffs and efficacy of ICIs. Furthermore, we assessed ORR by TMB and programmed cell death ligand 1 (PD-L1) expression after layering each other in studies which the two could be both acquired. Results: Three thousand six hundred fifty-seven records were retrieved through database searching, and 29 studies with 4,431 patients were finally included in the meta-analysis. TMB high group had significantly improved ORR (pooled OR 3.31, 95% CI 2.61, 4.19, P < 0.001), PFS (pooled HR 0.59, 95% CI 0.49, 0.71, P < 0.001) and OS (pooled HR 0.68, 95% CI 0.53, 0.89, P = 0.004). Sensitivity analyses illustrated the results were stable, and publication bias was identified in ORR. Subgroup analyses showed the predictive value of TMB was significant in non-small-cell lung cancer (except for the OS) and melanoma. In addition, heterogeneity was substantial in targeted next generation sequencing group but tiny in whole exome sequencing group. Furthermore, TMB and PD-L1 expression were capable to predict improved ORR of ICIs after stratification of each other, with tiny heterogeneity. Conclusions: High tumor mutation burden predicted improved efficacy of immune checkpoint inhibitors in cancers, and targeted next generation sequencing for estimating tumor mutation burden in clinic should be standardized to eliminate heterogeneity in the future. Moreover, tumor mutation burden and programmed cell death ligand 1 expression were independent factors on predicting efficacy of immune checkpoint inhibitors.
| S-EPMC6848266 | biostudies-literature
Project description:BackgroundThis study aimed to explore the prognostic value of tumor mutational burden (TMB) combined with smoking status in advanced non-small cell lung cancer (NSCLC) patients who received immune checkpoint inhibitor therapy (anti PD-1/PD-L1 therapy) combined with chemotherapy or anti-angiogenesis therapy.MethodsWe conducted a retrospective analysis of NSCLC patients who underwent next-generation sequencing test (either 295-gene panel NGS or 1021-gene panel NGS) from September 2017 to November 2020. The relationship between TMB and smoking status was investigated. Kaplan-Meier survival analysis was used to compare progression-free survival (PFS) of the NSCLC patients who received combination immunotherapy grouped by TMB value and smoking status.ResultsWe enrolled 323 cases and 388 cases of NSCLC patients in the 295-gene panel cohort and 1021-gene panel cohort, respectively. Positive correlation between TMB and smoking status was found in lung adenocarcinoma, but not in lung squamous cell carcinoma. Participants with both high TMB and smoking status who received immune checkpoint therapy combined with chemotherapy or anti-angiogenesis therapy had longer PFS than other participants (p < 0.05).ConclusionsThe combination of TMB with smoking status might be a potential predictor for the efficacy of combination immunotherapy in advanced NSCLC.
| S-EPMC8495280 | biostudies-literature
Project description:Tumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, varies across malignancies. Panel sequencing-based estimates of TMB have largely replaced whole-exome sequencing-derived TMB in the clinic. Retrospective evidence suggests that TMB can predict the efficacy of immune checkpoint inhibitors, and data from KEYNOTE-158 led to the recent FDA approval of pembrolizumab for the TMB-high tumor subgroup. Unmet needs include prospective validation of TMB cutoffs in relationship to tumor type and patient outcomes. Furthermore, standardization and harmonization of TMB measurement across test platforms are important to the successful implementation of TMB in clinical practice. SIGNIFICANCE: Evaluation of TMB as a predictive biomarker creates the need to harmonize panel-based TMB estimation and standardize its reporting. TMB can improve the predictive accuracy for immunotherapy outcomes, and has the potential to expand the candidate pool of patients for treatment with immune checkpoint inhibitors.
| S-EPMC7710563 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICIs) have yielded remarkable responses but often lead to immune-related adverse events (irAEs). Although germline causes for irAEs have been hypothesized, no individual variant associated with developing irAEs has been identified. We carried out a genome-wide association study of 1,751 patients on ICIs across 12 cancer types. We investigated two irAE phenotypes: (1) high-grade (3-5) and (2) all-grade events. We identified 3 genome-wide significant associations (P < 5 × 10-8) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined P = 3.6 × 10-11; hazard ratio (HR) = 2.1); rs75824728 near IL22RA1 (combined P = 3.5 × 10-8; HR = 1.8); and rs113861051 on 4p15 (combined P = 1.2 × 10-8, HR = 2.0); rs16906115 was replicated in 3 independent studies. The association near IL7 colocalized with the gain of a new cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation, which was itself predictive of downstream irAEs and improved survival.
| S-EPMC10958775 | biostudies-literature
Project description:Endocrine treatment plus CDK4/6 inhibitors have become standard of care for estrogen receptor positive (ER+) breast cancer. Although immune checkpoint inhibitors (ICIs) have shown promising antitumor activity in a variety of cancer types, only limited success has been achieved for metastatic breast cancer (mBC) patients, especially the ER+ subtype, which usually exhibit lower tumor mutation burden (TMB) compared with other subtypes and therefore perceived as immunologically quiescent. Here we present a case of an ER+/HER2- but TMB-high mBC patient who had significant response to combination therapy with anti-PD-1 antibody camrelizumab and vinorelbine and obtained partial response (PR) with a progression-free survival (PFS) of 5 months after failure of multiple lines of therapy. Our case indicates that TMB may serve as a potential biomarker in immunotherapy selection for normally immunologically "cold" tumors such as ER+ mBC, also molecular monitoring during the whole treatment course plays an important role in patient management.
| S-EPMC7900143 | biostudies-literature