Dataset Information

Integrin signaling gene alterations and outcomes of cancer patients receiving immune checkpoint inhibitors.

ABSTRACT:

Background

Immune evasion is a hallmark of cancer and is associated with resistance to PD-1/PD-L1 and CTLA-4 inhibitors. Several interactions between tumor and immune cells within the tumor microenvironment are effected through integrin signaling; however the latter has been underrecognized as a pathway that could have an impact on oncological outcomes after treatment with immune checkpoint inhibitors (ICIs). This study aimed to assess the clinical relevance of genomic alterations in the integrin signaling pathway in ICI-treated patients with advanced cancers.

Methods

Next generation sequencing (NGS) data from tumor samples of patients with advanced cancers treated with ICIs (anti-PD-1/PD-L1, anti-CTLA4 or both) were queried from four independent publicly available cohorts for mutations and structural variations in 72 integrin signaling pathway genes (Gene Set: GOBP_CELL_ADHESION_MEDIATED_BY_INTEGRIN). The Kaplan Meier method was used to assess the association between mutated and unmutated genes with overall (OS) and progression-free survival (PFS). All results were reported at the 0.05 significance level.

Results

The largest cohort included 1662 patients (discovery set) and comprised 350 non-small cell lung cancer (NSCLC), 321 melanoma, 214 bladder, 151 renal cell carcinoma (RCC), 138 head neck (HN), 126 esophageal/gastric (EG), 117 glioma, 110 colorectal (CRC), 90 cancer of unknown primary (CUP), and 45 breast cancer patients. ICI treatments included PD-1 or PD-L1 inhibitors (n=1256), anti-CTLA4 inhibitors (n=146) or both (n=260). 170 patients (10% of the entire cohort) harbored mutations in PIK3CG (6%), RET (3%), SYK (1.4%), LYN (1.4%), PTPN11 (1.3%), and CRKL (0.1%) genes. Presence of these mutations was more frequent in melanoma (18%), followed by CRC (14.5%), CUP (11%), and NSCLC (11%). Patients with mutated tumors experienced a significantly longer median OS (41 months) compared to those without alterations (16 months, log-rank P<0.001). The favorable prognostic value of PIK3CG, RET, SYK, LYN, PTPN11, and CRKL alterations was confirmed in three melanoma cohorts (validation set, n=212, P=0.024). Assessment of mutation status of these genes in a fourth cohort of NSCLC patients (n=75) revealed a predictive significance as well, with regard to PFS after treatment with ipilimumab and nivolumab combination (P=0.048).

Conclusion

Mutations and/or structural variations in integrin signaling genes may have prognostic and predictive value in patients with metastatic malignancies who receive ICIs. Although confirmation in larger studies with concurrent investigation of underlying immunologic mechanisms is needed, these findings pose therapeutic implications for co-targeted approaches to overcome immune evasion and resistance.

SUBMITTER: Vlachostergios PJ

PROVIDER: S-EPMC8661141 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundAs indications for immune checkpoint inhibitor (ICI) therapy have increased in recent years, so has the proportion of patients eligible for this type of therapy. However, a lack of data exists about the risks and benefits of ICI therapy in hospitalized patients, who tend to be frailer and sicker than patients enrolled in clinical trials.Material and methodsWe conducted a retrospective cohort study among hospitalized patients with metastatic solid tumors who received ICI therapy at a large academic cancer center over the course of 4 years. We analyzed the characteristics and outcomes of these patients and identified demographic and clinical factors that could be used to predict mortality.ResultsDuring the 4-year study period, 106 patients were treated with ICI therapy while admitted to the hospital; 70 (66%) had Eastern Cooperative Oncology Group Performance Status ≥2, which would have prevented them from enrolling in most clinical trials of ICIs. Fifty-two patients (49%) died either during admission or within 30 days of discharge; median overall survival was 1.0 month from discharge, and 16 patients (15%) were alive 6 months after discharge. Independent predictors of death following receipt of inpatient ICI included a diagnosis of non-small cell lung cancer relative to melanoma and prior treatment with two or more lines of therapy.ConclusionThe poor overall outcomes observed in this study may give clinicians pause when considering ICI therapy for hospitalized patients, particularly those with characteristics that are associated with a greater risk of mortality.Implications for practiceImmunotherapy strategies for patients with cancer are rapidly evolving and their use is expanding, but not all patients will develop a response, and secondary toxicity can be significant and challenging. This is especially evident in hospitalized patients, where the economic cost derived from inpatient immune checkpoint inhibitor (ICI) administration is important and the clinical benefit is sometimes unclear. The poor overall outcomes evidenced in the ICI inpatient population in this study highlight the need to better identify the patients that will respond to these therapies, which will also help to decrease the financial burden imposed by these highly priced therapies.

Project description:BACKGROUND:Influenza vaccination (FV) is recommended for patients with cancer. Recent data suggested that the administration of the FV was associated with an increase in immune-related adverse events (irAEs) among patients on immune checkpoint inhibitors (ICIs). Myocarditis is an uncommon but serious complication of ICIs and may also result from infection with influenza. There are no data testing the relationship between FV and the development of myocarditis on ICIs. METHODS:Patients on ICIs who developed myocarditis (n?=?101) (cases) were compared to ICI-treated patients (n?=?201) without myocarditis (controls). A patient was defined as having the FV if they were administered the FV from 6?months prior to start of ICI to anytime during ICI therapy. Alternate thresholds for FV status were also tested. The primary comparison of interest was the rate of FV between cases and controls. Patients with myocarditis were followed for major adverse cardiac events (MACE), defined as the composite of cardiogenic shock, cardiac arrest, hemodynamically significant complete heart block and cardiovascular death. RESULTS:The FV was administered to 25% of the myocarditis cases compared to 40% of the non-myocarditis ICI-treated controls (p?=?0.01). Similar findings of lower rates of FV administration were noted among myocarditis cases when alternate thresholds were tested. Among the myocarditis cases, those who were vaccinated had 3-fold lower troponin levels when compared to unvaccinated cases (FV vs. No FV: 0.12 [0.02, 0.47] vs. 0.40 [0.11, 1.26] ng/ml, p?=?0.02). Within myocarditis cases, those administered the FV also had a lower rate of other irAEs when compared to unvaccinated cases (36 vs. 55% p?=?0.10) including lower rates of pneumonitis (12 vs. 36%, p?=?0.03). During follow-up (175 [IQR 89, 363] days), 47% of myocarditis cases experienced a MACE. Myocarditis cases who received the FV were at a lower risk of cumulative MACE when compared to unvaccinated cases (24 vs. 59%, p?=?0.002). CONCLUSION:The rate of FV among ICI-related myocarditis cases was lower than controls on ICIs who did not develop myocarditis. In those who developed myocarditis related to an ICI, there was less myocardial injury and a lower risk of MACE among those who were administered the FV.

Project description:BackgroundHyponatremia due to endocrinopathies such as adrenal insufficiency and hypothyroidism has been reported in patients receiving immune checkpoint inhibitors (ICIs). We determined the risk and predictors of hyponatremia and other electrolyte abnormalities in a 'real-world' sample of patients receiving ICIs to treat advanced malignancies.MethodsThis was a retrospective observational study of all patients who received ICIs from a single cancer center between 2011 and 2018. Patients were followed for 12 months after initiation of ICIs or until death. Common Terminology for Cancer Adverse Events version 5.0 criteria were used to grade the severity of hyponatremia and other electrolyte abnormalities. The predictors of severe (Grade 3 or 4) hyponatremia were determined using a multivariable logistic regression model. The etiology of Grade 3 or 4 hyponatremia was determined by chart review.ResultsA total of 2458 patients were included. Their average age was 64 years [standard deviation (SD) 13], 58% were male and 90% were white. In the first year after starting ICIs, 62% experienced hyponatremia (sodium <134 mEq/L) and 136 (6%) experienced severe hyponatremia (<124 mEq/L). Severe hyponatremia occurred on average 164 days (SD 100) after drug initiation. Only nine cases of severe hyponatremia were due to endocrinopathies (0.3% overall incidence). Risk factors for severe hyponatremia included ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor) use, diuretic use and non-White race. Other severe electrolyte abnormalities were also commonly observed: severe hypokalemia (potassium <3.0 mEq/L) occurred in 6%, severe hyperkalemia (potassium ≥6.1 mEq/L) occurred in 0.6%, severe hypophosphatemia (phosphorus <2 mg/dL) occurred in 17% and severe hypocalcemia (corrected calcium <7.0 mg/dL) occurred in 0.2%.ConclusionsHyponatremia is common in cancer patients receiving ICIs. However, endocrinopathies are an uncommon cause of severe hyponatremia.

Project description:BackgroundWith increased use of immune checkpoint inhibitors (ICIs) among patients with cancer, there is substantial interest in understanding clinical and economic outcomes and management of immune-related adverse events (irAEs).Patients, materials, and methodsA retrospective study was conducted using Premier Healthcare Database, a U.S. national hospital discharge database, from March 1, 2015, through December 31, 2017. The database comprises more than 880 million inpatient and hospital-based outpatient encounters, with more than 200 million unique patients reported by 966 hospitals. Patients with four solid tumors known to benefit from ICI therapy were included. The list of irAEs assessed was defined a priori per American Society of Clinical Oncology clinical guidelines for irAE management. Baseline irAE-related inpatient and outpatient visits were defined as the first inpatient or hospital-based outpatient visit with discharge diagnosis of any irAE of interest following confirmed ICI usage within 90 days prior to the baseline visit. Patients were followed for 90 days after baseline irAE-related inpatient discharge date or outpatient visit date to assess irAE-related inpatient admissions, all-cause in-hospital mortality, ICI reinitiation, and to determine costs and health care resource utilization.ResultsRecords from 673,957 patients with four tumor types were reviewed for ICI therapy. Of 13,030 patients receiving ICIs, approximately 40% experienced at least one irAE, with a total of 10,121 irAEs occurring within 90 days of the ICI visit. The most frequent (>1,000 events) irAEs were anemia, impaired ventricular function with heart failure and vasculitis, thrombocytopenia, thyroid conditions, and peripheral edema. As might be expected, compared with those with baseline irAE-related outpatient visits, patients with baseline irAE-related inpatient visits had a significantly higher percentage of irAE-related inpatient admissions (23% vs. 14%) and all-cause in-hospital mortality (22% vs. 6%) and lower reinitiation of ICI therapy (31% vs. 71%). Baseline irAE-related inpatient visits had significantly higher mean costs ($29,477 vs. $5,718) with longer hospital stays (12.6 vs. 7.8 days).ConclusionFindings from a U.S. national hospital discharge database suggest that irAEs in patients treated with ICIs are common, occur in multiples and with greater frequency in those with pre-existing comorbidities. Those with inpatient admissions have poorer outcomes.Implications for practiceThe present work addressed the knowledge gap in understanding real-world outcomes of immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs). Patients who experienced irAEs had significantly higher baseline comorbidities and were more likely to have immune-related or immune-compromised comorbid conditions. Patients with baseline irAE-related hospitalizations were more likely to be rehospitalized and to experience in-hospital mortality and less likely to reinitiate ICI treatment. Real-world patients are more diverse than clinical trials, and clinicians should consider both the efficacy and safety profile of ICI treatments, especially for patients with comorbidity conditions. Close monitoring is needed after patients have experienced an irAE.

Project description:BackgroundImmune checkpoint inhibitors (ICI) have revolutionized the treatment of metastatic renal cell carcinoma (mRCC). Biomarkers for mRCC patients treated with ICI are limited, and body composition is underutilized in mRCC. We investigated the association between body composition and clinical outcomes in ICI-treated mRCC patients.MethodsWe performed a retrospective analysis of 79 ICI-treated mRCC patients at Winship Cancer Institute from 2015-2020. Baseline CT images were collected at mid-L3 and segmented using SliceOMatic v5.0 (TomoVision). Density of skeletal muscle (SM), subcutaneous fat, inter-muscular fat, and visceral fat were measured and converted to indices by dividing by height(m)2 (SMI, SFI, IFI, and VFI, respectively). Total fat index (TFI) was defined as the sum of SFI, IFI, and VFI. Patients were characterized as high versus low for each variable at gender-specific optimal cuts using overall survival (OS) as the primary outcome. A prognostic risk score was created based on the beta coefficient from the multivariable Cox model after best subset variable selection. Body composition risk score was calculated as IFI + 2*SM mean + SFI and patients were classified as poor (0-1), intermediate (2), or favorable risk (3-4). Kaplan-Meier method and Log-rank test were used to estimate OS and PFS and compare the risk groups. Concordance statistics (C-statistics) were used to measure the discriminatory magnitude of the model.ResultsMost patients were male (73%) and most received ICI as first (35%) or second-line (51%) therapy. The body composition poor-risk patients had significantly shorter OS (HR: 6.37, p<0.001), PFS (HR: 4.19, p<0.001), and lower chance of CB (OR: 0.23, p=0.044) compared to favorable risk patients in multivariable analysis. Patients with low TFI had significantly shorter OS (HR: 2.72, p=0.002), PFS (HR: 1.91, p=0.025), and lower chance of CB (OR: 0.25, p=0.008) compared to high TFI patients in multivariable analysis. The C-statistics were higher for body composition risk groups and TFI (all C-statistics ≥ 0.598) compared to IMDC and BMI.ConclusionsRisk stratification using the body composition variables IFI, SM mean, SFI, and TFI may be prognostic and predictive of clinical outcomes in mRCC patients treated with ICI. Larger, prospective studies are warranted to validate this hypothesis-generating data.