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Age-Based Disparities in Metastatic Melanoma Patients Treated in the Immune Checkpoint Inhibitors (ICI) Versus Non-ICI Era: A Population-Based Study.

ABSTRACT: Immune checkpoint inhibitors (ICIs) have revolutionized metastatic melanoma treatment, but our knowledge of ICI activity across age groups is insufficient. Patients in different age groups with advanced melanoma were selected based on the ICI approval time in this study. Patients with melanoma were identified in the Surveillance, Epidemiology, and End Result (SEER) database program 2004-2016. The results showed that 4,040 patients had advanced melanoma before the advent of ICI (referred to as the "non-ICI era"), whereas there were 6,188 cases after ICI approval (referred to as the "ICI era"). In all age groups, the cases were dominated by men. The differences between the first (20-59 years) and second (60-74 years) age groups in both eras were significant in terms of surgery performance and holding of insurance policies (p = 0.05). The first and second groups (20-59 and 60-70 years old, respectively) showed no difference in survival (median = 8 months) during the non-ICI era, but the difference was evident in the first, second, and third age groups in the ICI era, with the younger group (20-59 years) having significantly better survival (median = 18, 14, and 10 months, respectively, p = 0.0001). Multivariate analysis of the first group (the youngest) in the ICI era revealed that surgery was significantly associated with an increase in survival among patients compared with those who did not undergo surgery (p < 0.0001). Furthermore, having an insurance policy among all age groups in the ICI era was associated with favorable survival in the first (20-59 years) and second (60-74 years) age groups (p = 0.0001), while there were no survival differences in the older ICI group (>74 years). Although there were differences in survival between the ICI era and the non-ICI era, these results demonstrate that ICI positively affected the survival of younger patients with advanced melanoma (first age group) than it had beneficial effects on older patients. Moreover, having had cancer surgery and holding an insurance policy were positive predictors for patient survival. This study emphasizes that adequate clinical and preclinical studies are important to enhance ICI outcomes across age groups.

SUBMITTER: Safi M

PROVIDER: S-EPMC8650702 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCancer diagnoses and deaths among the elderly (65 +) are expected to increase significantly over the next decade. Immune checkpoint inhibitors specifically target ICI genes and enhance immune system function. However, poor outcomes may be associated with aging.MethodsWe downloaded the Genomic Data Commons from the Cancer Genome Atlas (TCGA) and collected gene expression data from malignant melanoma (MM) tissues, the third level as the primary site. The CKTTD ICI genes database were applied and validated using the GEO database and lab experiments.ResultsIn 414 patients, 13 ICI genes were obtained as risk gene signature by univariate and multivariate Cox hazard models and were associated with poor survival in the older group. At 1, 3, and 5 years (79%, 76%, and 76%, respectively), we investigate TNFRFS4 gene and age prediction using novel nomogram-associated aging (HR = 1.79, P 0.001, CI = 1.32-2.45) with higher sensitivity testing.TNFRSF4 gene expression was significantly high in younger (15 years interval) MM patients (P < 0.001). By correlation analysis, a significant negative association was determined (P < 0.001). The validation of gene correlation from GEO (GSE59455) and (GSE22153) was obtained as external validation. We tested the TNFRSF4 protein levels by IHC in 14 melanoma tissue samples. TNFRSF4 expression was observed to be lower expressed in the older of melanoma tissues, and higher in the younger age group (P = 0.02). Besides the connectivity of ICI gene proteins, the biological processes of cell aging, aging, and the immune system were found to be highly related.ConclusionsAlong with the risk score evaluation, the ICI gene (TNFRSF4) was identified as a tumor suppressor gene related to inequalities in age survival and associated with immune cell infiltrations. The aging responses of melanoma patients and related gene expression need further investigation in order to identify potential therapeutic targets.

Project description:PurposeThis study evaluated pretreatment 2[18F]fluoro-2-deoxy-D-glucose (FDG)-PET/CT-based radiomic signatures for prediction of hyperprogression in metastatic melanoma patients treated with immune checkpoint inhibition (ICI).Material and methodFifty-six consecutive metastatic melanoma patients treated with ICI and available imaging were included in the study and 330 metastatic lesions were individually, fully segmented on pre-treatment CT and FDG-PET imaging. Lesion hyperprogression (HPL) was defined as lesion progression according to RECIST 1.1 and doubling of tumor growth rate. Patient hyperprogression (PD-HPD) was defined as progressive disease (PD) according to RECIST 1.1 and presence of at least one HPL. Patient survival was evaluated with Kaplan-Meier curves. Mortality risk of PD-HPD status was assessed by estimation of hazard ratio (HR). Furthermore, we assessed with Fisher test and Mann-Whitney U test if demographic or treatment parameters were different between PD-HPD and the remaining patients. Pre-treatment PET/CT-based radiomic signatures were used to build models predicting HPL at three months after start of treatment. The models were internally validated with nested cross-validation. The performance metric was the area under receiver operating characteristic curve (AUC).ResultsPD-HPD patients constituted 57.1% of all PD patients. PD-HPD was negatively related to patient overall survival with HR=8.52 (95%CI 3.47-20.94). Sixty-nine lesions (20.9%) were identified as progressing at 3 months. Twenty-nine of these lesions were classified as hyperprogressive, thereby showing a HPL rate of 8.8%. CT-based, PET-based, and PET/CT-based models predicting HPL at three months after the start of treatment achieved testing AUC of 0.703 +/- 0.054, 0.516 +/- 0.061, and 0.704 +/- 0.070, respectively. The best performing models relied mostly on CT-based histogram features.ConclusionsFDG-PET/CT-based radiomic signatures yield potential for pretreatment prediction of lesion hyperprogression, which may contribute to reducing the risk of delayed treatment adaptation in metastatic melanoma patients treated with ICI.

Project description:ImportanceThe development of new primary cutaneous melanoma (CM) after starting immune checkpoint inhibitor (ICI) therapy is poorly characterized.ObjectiveTo determine the incidence of new CM in patients treated with ipilimumab, nivolumab, and/or pembrolizumab for metastatic melanoma.Design, setting, and participantsSingle-center, retrospective, observational cohort study using an institutional database to identify patients diagnosed with melanoma at a tertiary care cancer hospital in New York, New York.ExposuresIpilimumab, nivolumab, and/or pembrolizumab treatment for metastatic melanoma.Main outcomes and measuresPrimary outcomes were the incidence proportion, the incidence rate, and the 5-year cause-specific cumulative risk.ResultsA total of 2251 patients were included in the study; mean (SD) age at the time of ICI start was 62.8 (14.4) years. The majority were male (63.8%, n = 1437), White (92.7%, n = 2086), and non-Hispanic (92.1%, n = 2073). Forty-two of 2251 patients who received ipilimumab, nivolumab, and/or pembrolizumab were diagnosed with 48 new CMs at a median (range) of 397.5 (39-2409) days after ICI initiation. The median age of affected patients at the time of ICI first dose was 66.5 years. The majority were male (66.7%, n = 28), White (92.9%, n = 39), and non-Hispanic (100.0%, n = 42). There were no differences in age, sex, race, and ethnicity among patients who did and did not develop a new CM. Patients who developed a new CM were more likely to have a family history of melanoma (23.8% vs 16.3%, P = .02). Most new CMs (n = 30, 62.5%) were diagnosed after the last date of ICI administration. Twenty-seven (56.3%) new CMs were in situ and 21 (43.8%) were invasive. Of the invasive CMs with a reported Breslow thickness (n = 20), the median (range) thickness was 0.4 (0.1-8.4) mm. The overall incidence proportion of new CM was 1.9% (95% CI, 1.4%-2.5%) and the incidence rate was 1103 cases per 100 000 person-years (95% CI, 815-1492). The 5-year cumulative cause-specific risk of new CM was 4.9% (95% CI, 3.3%-7.4%).Conclusions and relevancePatients treated with ICI therapy for metastatic melanoma remain at risk for the development of new CM.

Project description:BackgroundThe utilization of modern-immunotherapies, notably immune checkpoint inhibitors (ICIs), has increased markedly in patients with metastatic melanoma over the past decade and are recommended as standard treatment. Given their increasing adoption in routine care for melanoma, understanding patient access to immunotherapy and patterns of its use in Texas is crucial as it remains one of the few states without Medicaid expansion and with high rates of the uninsured population. The objectives of this study were to examine the trend in the utilization of immunotherapy and to determine factors associated with immunotherapy utilization among patients with metastatic melanoma in the era of ICIs in Texas.MethodsA retrospective cohort study was conducted using the Texas Cancer Registry (TCR) database. The cohort comprised of adult (≥ 18 years) patients with metastatic melanoma diagnosed between June 2011 and December 2018. The trend in immunotherapy utilization was assessed by determining the proportion of patients receiving immunotherapy each year. The Average Annual Percent Change (AAPC) in immunotherapy utilization was assessed using joinpoint regression, while multivariable logistic regression was used to determine the association between patient characteristics and immunotherapy receipt.ResultsA total of 1,795 adult patients with metastatic melanoma were identified from the TCR. Immunotherapy utilization was higher among younger patients, those with no comorbidities, and patients with private insurance. Multivariable analysis showed that the likelihood of receipt of immunotherapy decreased with older age [(adjusted Odds Ratio (aOR), 0.92; 95% CI, 0.89- 0.93, p = 0.001], living in high poverty neighborhood (aOR, 0.52; 95% CI, 0.44 - 0.66, p < 0.0001), having Medicaid (aOR, 0.58; 95% CI, 0.44 - 0.73, p = 0.02), being uninsured (aOR, 0.49; 95% CI, 0.31 - 0.64, p = 0.01), and having comorbidities (CCI score 1: aOR, 0.48; 95% CI, 0.34 - 0.71, p = 0.003; CCI score ≥ 2: aOR, 0.32; 95% CI, 0.16 - 0.56, p < 0.0001).Conclusions and relevanceThis cohort study identified sociodemographic and socioeconomic disparities in access to immunotherapy in Texas, highlighting the need for policies such as Medicaid expansion that would increase equitable access to this innovative therapy.

Project description:Emerging evidence supports the important role of the tumor microbiome in oncogenesis, cancer immune phenotype, cancer progression, and treatment outcomes in many malignancies. In this study, we investigated the metastatic melanoma tumor microbiome and its potential roles in association with clinical outcomes, such as survival, in patients with metastatic disease treated with immune checkpoint inhibitors (ICI). Baseline tumor samples were collected from 71 patients with metastatic melanoma before treatment with ICIs. Bulk RNA sequencing (RNA-seq) was conducted on the formalin-fixed, paraffin-embedded and fresh frozen tumor samples. Durable clinical benefit (primary clinical endpoint) following ICIs was defined as overall survival >24 months and no change to the primary drug regimen (responders). We processed RNA-seq reads to carefully identify exogenous sequences using the {exotic} tool. The age of the 71 patients with metastatic melanoma ranged from 24 to 83 years, 59% were male, and 55% survived >24 months following the initiation of ICI treatment. Exogenous taxa were identified in the tumor RNA-seq, including bacteria, fungi, and viruses. We found differences in gene expression and microbe abundances in immunotherapy-responsive versus nonresponsive tumors. Responders showed significant enrichment of bacteriophages in the phylum Uroviricota, and nonresponders showed enrichment of several bacteria, including Campylobacter jejuni. These microbes correlated with immune-related gene expression signatures. Finally, we found that models for predicting prolonged survival with immunotherapy using both microbe abundances and gene expression outperformed models using either dataset alone. Our findings warrant further investigation and potentially support therapeutic strategies to modify the tumor microbiome in order to improve treatment outcomes with ICIs.SignificanceWe analyzed the tumor microbiome and interactions with genes and pathways in metastatic melanoma treated with immunotherapy and identified several microbes associated with immunotherapy response and immune-related gene expression signatures. Machine learning models that combined microbe abundances and gene expression outperformed models using either dataset alone in predicting immunotherapy responses.

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Age-Based Disparities in Metastatic Melanoma Patients Treated in the Immune Checkpoint Inhibitors (ICI) Versus Non-ICI Era: A Population-Based Study.

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