On-treatment C-reactive Protein Research Articles

C-reactive protein as a response biomarker to immune checkpoint blockade: A meta-analysis.

2559 Background: Tumor-promoting inflammation is a hallmark of cancer pathogenesis and is associated with poor outcomes and treatment resistance. C-reactive protein (CRP) is a routinely measured acute phase reactant whose synthesis is stimulated by cytokines and may thereby represent a surrogate for tumor promoting inflammation. Pre-treatment CRP has been associated with resistance to immune checkpoint blockade (ICB) in several studies. However, whether post-treatment changes in CRP correlate with ICB outcomes has not been systematically examined. Methods: We performed a systematic review to identify cohort studies or clinical trials in solid tumor patients receiving ICB therapy with CRP response comparator pairs (high/low) available. We included studies that had hazard ratio (HR) of overall survival (OS), progression-free survival (PFS), or odds ratio (OR) of objective response rate (ORR) available. We performed a meta-analysis using a random-effect model to evaluate if post-treatment changes in CRP are associated with ORR, PFS, or OS. Subgroup analysis for primary cancer type was performed. Heterogeneity was assessed using the I-squared statistic. Results: We screened 691 eligible studies; 19 met inclusion criteria and 2,101 patients were included. Patients experiencing post-ICB declines in CRP had improved ORR HR=4.67 [95% CI] [2.81-7.78] (p<0.0001, I2=42%), PFS HR=2.47 [1.98-3.09] (p<0.0001, I2=18%), and OS HR=2.28 [1.68-3.08] (p<0.0001, I2=56%). Heterogeneity among subgroups was low in ORR (I2=14.6%) and PFS analysis ( I2=0%), and moderate in OS analysis (I2=64.2%). Conclusions: In patients receiving ICB therapy, post-treatment declines in CRP were associated with improved ORR, PFS, and OS across multiple histologies. These findings support the integration of on-treatment CRP decline as a clinically relevant response biomarker for novel therapies directed at modulating tumor-promoting inflammation. A meta-regression analysis will help determine optimal post-treatment CRP cutpoints. Pooled OR of ORR [95%CI] and HR [95%CI] of PFS and OS with subgroup analysis results and heterogeneity assessment. [Table: see text]

C-reactive protein and immune-related adverse events as prognostic biomarkers in immune checkpoint inhibitor treated metastatic renal cell carcinoma patients

ABSTARCT Background There is an ongoing need to identify biomarkers for correct patient selection for immune-oncology treatments in metastatic renal cell carcinoma (mRCC). The aim of our study was to evaluate the prognostic role of elevated C-reactive protein (CRP) values and immune-related adverse events (irAEs) to indicate immune checkpoint inhibitors’ (ICIs) efficacy in nivolumab-treated mRCC patients. Materials and methods Data from 96 mRCC patients treated with nivolumab at Comprehensive Cancer Center, Helsinki University Hospital in a real-life setting were collected between 2006 and 2020 retrospectively. Patients’ baseline CRP, on-treatment (<12 weeks) CRP, and reported irAE association to median survival and outcome were analyzed using Kaplan–Meier and Cox regression. Results Patients with elevated baseline CRP were associated with worse overall survival (OS) and progression-free survival (PFS) when compared with normal baseline CRP. This significant correlation was also observed with patients with elevated on-treatment CRP. In multivariate survival analyses both elevated baseline and on-treatment CRP had shorter OS and PFS than patients with normal CRP: hazard ratio (HR) 2.84 (95% CI 1.48–5.42), HR 3.68 (95% CI 1.92–7.03) and PFS: HR 1.77 (95% CI 1.06–2.97), HR 2.88 (95% CI 1.75–4.73), respectively. A significant difference in OS was also seen between patients without irAE and with irAE during treatment. In multivariate survival analyses, patients without irAE had shorter OS HR 1.93 (95% CI 1.03–3.62) compared with patients with reported irAE. Conclusions Elevated baseline CRP, on-treatment CRP, and absence of irAE correlate with poor outcome in nivolumb-treated mRCC patients. These results suggest that monitoring CRP values as well as potential irAEs during treatment may be of use in clinical decision making.

C-reactive protein flare predicts response to anti-PD-(L)1 immune checkpoint blockade in metastatic urothelial carcinoma

PurposeRobust biomarkers to predict response to immune checkpoint blockade (ICB) in metastatic urothelial carcinoma (mUC) are still in demand. Recently, early C-reactive protein (CRP) kinetics and especially the novel CRP flare-response phenomenon has been associated with immunotherapy response. MethodsWe conducted a multicentre observational study comprising 154 patients with mUC treated with ICB to evaluate the predictive value of a previously described on-treatment CRP kinetics: CRP flare responders (at least doubling of baseline CRP within the first month after initiation of ICB followed by a decline below baseline within three months), CRP responders (decline in baseline CRP by ≥ 30% within three months without a prior flare) and the remaining patients as CRP non-responders. CRP kinetics groups were correlated with baseline parameters, PD-L1 status, progression-free survival (PFS) and overall survival (OS). ResultsObjective response was observed in 57.1% of CRP responders, 45.8% of CRP flare responders and 17.9% of CRP non-responders (P < 0.001). CRP flare response was associated with prolonged PFS and OS (P < 0.001). In multivariable Cox regression analysis, CRP flare responders showed a risk reduction of ∼70% for tumour progression and death compared to CRP non-responders. Subgroup analysis of CRP flare responders revealed that patients with a long-flare response (completed flare-response kinetics ≥6 weeks on-treatment) showed even more favourable outcomes following ICB (HR = 0.18, 95%-CI: 0.07–0.48, P < 0.001). ConclusionCRP (flare)response robustly predicts immunotherapy response and outcomes in mUC independent of PD-L1 status. Thus, early on-treatment CRP kinetics is a promising low-cost and easy-to-implement biomarker to optimise therapy monitoring in patients with mUC treated with ICB.

On-treatment C-reactive protein control could predict response to subsequent anti-PD-1 treatment in metastatic renal cell carcinoma.

The aim of this study was to evaluate the clinical significance of the on-treatment C-reactive protein (CRP) status during systemic treatment as the predictive marker for the response of subsequent nivolumab monotherapy in patients with refractory metastatic renal cell carcinoma (mRCC). A total of 73 mRCC patients treated with nivolumab were retrospectively reviewed. We evaluated the serum CRP levels before and after molecular-targeted treatments. Patients whose CRP did not exceed baseline value were defined as the CRP-control group and the others were defined as the CRP-progression group. The clinical impact of CRP-control on the efficacy of nivolumab was assessed. Twenty-four patients (33%) were categorized into the CRP-control group. The CRP-control group patients (median PFS not reached) had significantly longer PFS than the CRP-progression group (median PFS 11.9months, 95% confidence interval, CI 4.1-19.8, p = 0.038). The CRP-control group had a tendency of longer OS from nivolumab initiation than the CRP-progression group (p = 0.071). By multivariate analysis, the on-treatment CRP-control was the independent predictive factor for PFS (hazard ratio HR 0.37, 95% CI 0.14-0.99, p = 0.047). The on-treatment CRP-control could be the predictive factor for the efficacy of nivolumab in refractory mRCC patients.

Abstract 5707: On-treatment changes in CRP as a surrogate for overall survival for atezolizumab benefit in 2nd line NSCLC

Abstract Background: Overall survival (OS) is an optimal endpoint for evaluation of checkpoint inhibitors (CPI). Identification of early surrogates of OS is important to inform early clinical signals and treatment decisions. We evaluated C-reactive protein (CRP) in clinical trials with atezolizumab (anti-PD-L1 antibody). CRP is elevated in different inflammatory and malignant conditions and is often considered to be a marker of poor prognosis. Materials and Methods: Serum from patients enrolled in the 2L+ NSCLC studies POPLAR and OAK (randomized phase 2 and phase 3 controlled trials of patients with non-small cell lung cancer (NSCLC) who progressed on post-platinum chemotherapy) was analyzed for CRP levels over time. Patients were binned by changes in CRP at 6 weeks post-treatment (C3D1; Cycle 3 Day 1) as compared to pre-treatment levels, by either greater than 1.5 fold, less than 1.5 fold or unchanged (within +1.5 fold). Results: C3D1 decreases in serum CRP were associated with RECIST1.1 based responses to atezolizumab but not with docetaxel in the POPLAR study, and these findings were further validated in the OAK study. Patients with RECIST based disease progression (PD) demonstrated an increase in serum CRP as early as Cycle 2 (3 weeks post atezolizumab therapy). Notably, decrease in CRP levels was strongly associated with improved PFS and OS. Results from OAK are shown below (table). Furthermore, in patients with RECIST PD or stable disease (SD), decrease in on-treatment CRP also predicted long overall survival. Conclusion: CRP is a soluble biomarker that is modulated post-atezolizumab treatment. This simple lab test may provide utility in informing OS benefit for CPIs and combinations. C3D1 CRP fold change relative to pre-treatmentHRCIp valueHRCIp valueITT0.750.62-0.910.0040.740.6-0.910.0053CRP &amp;lt;1.5 FC0.480.33-0.690.0000950.490.32-0.750.0011CRP +1.5 FC0.850.62-1.150.280.610.43-0.860.0049CRP&amp;gt;=1.5 FC0.960.69-1.340.811.250.86-1.810.25 Citation Format: Namrata Patil, Wei Zou, Simonetta Mocci, Vinita Gupta, Luciana Molinero, Alan Sandler, Marcus Ballinger, Susan Flynn, Marcin Kowanetz, Priti Hegde. On-treatment changes in CRP as a surrogate for overall survival for atezolizumab benefit in 2nd line NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5707.

C-Reactive Protein, but not Low-Density Lipoprotein Cholesterol Levels, Associate With Coronary Atheroma Regression and Cardiovascular Events After Maximally Intensive Statin Therapy

Baseline C-reactive protein (CRP) levels predict major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, coronary revascularization, and hospitalization for unstable angina). The association between changes in CRP levels with plaque progression and MACE in the setting of maximally intensive statin therapy is unknown. The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) used serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. The treatment groups did not differ significantly in the change from baseline of percent atheroma volume on intravascular ultrasound, CRP-modulating effects, or MACE rates, thus allowing for a (prespecified) post hoc analysis to test associations between the changes in CRP levels with coronary disease progression and MACE. Patients with nonincreasing CRP levels (n=621) had higher baseline (2.3 [1.1-4.7] versus 1.1 [0.5-1.8] mg/L; P<0.001) and lower follow-up CRP levels (0.8 [0.5-1.7] versus 1.6 [0.7-4.1] mg/L; P<0.001) versus those with increasing CRP levels (n=364). Multivariable analysis revealed a nonincreasing CRP level to independently associate with greater percent atheroma volume regression (P=0.01). Although the (log) change in CRP did not associate with MACE (hazard ratio, 1.18; 95% confidence interval, 0.93-1.50; P=0.17), the (log) on-treatment CRP associated significantly with MACE (hazard ratio, 1.28; 95% confidence interval, 1.04-1.56; P=0.02). On-treatment low-density lipoprotein cholesterol levels did not correlate with MACE (hazard ratio, 1.09; 95% confidence interval, 0.88-1.35; P=0.45). Following 24 months of potent statin therapy, on-treatment CRP levels associated with MACE. Inflammation may be an important driver of residual cardiovascular risk in patients with coronary artery disease despite aggressive statin therapy. http://clinicaltrials.gov. Unique identifier: NCT000620542.

Evaluation of C-Reactive Protein Before and On-Treatment as a Predictor of Benefit of Atorvastatin: A Cohort Analysis From the Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering Arm

The aim of this study was to determine whether baseline and on-statin C-reactive protein (CRP) are independent predictors of cardiovascular (CV) outcome beyond low-density lipoprotein cholesterol (LDL-C). Use of CRP as a predictor of statin treatment remains controversial. We investigated the relationship of baseline and on-treatment CRP with subsequent CV events in Cox models using a subset of white subjects with no history of CV disease from the UK ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial). During 5.5 years of follow-up, a total of 488 subjects experienced a CV event. CV risk increased with baseline CRP (hazard ratio [HR] per 1 SD: 1.21; 95% confidence interval [CI]: 1.09 to 1.33) in an adjusted model. In ASCOT Lipid-Lowering Arm, the relative statin effect in preventing CV events did not differ according to tertiles of baseline CRP (p= 0.69). After 6 months of atorvastatin therapy, the median LDL-C and CRP were reduced by 38.7% and 25.8%, respectively. Those who achieved LDL-C below the median had a reduced CV risk (HR: 0.58; 95% CI: 0.34 to 0.97) compared with those who did not. In contrast, those who achieved a CRP level below the median did not have a reduced risk of CV events (HR: 0.95; 95% CI: 0.59 to 1.55). Among those who achieved LDL-C below the median, there was no difference in CV risk whether they also achieved a CRP level below (HR: 0.55; 95% CI: 0.30 to 1.02) or above the median (HR: 0.56; 95% CI: 0.30 to 1.03). In these primary prevention patients, although baseline CRP independently predicted CV event risk, the achieved CRP level on while statin therapy did not predict CV events, either alone or in combination with LDL-C.

On-treatment C-reactive protein and HDL cholesterol levels in patients at intermediate cardiovascular risk: Impact on carotid intima-media thickness

AimsStatin therapy is followed by reductions in carotid intima-media thickness (CIMT) and C-reactive protein (CRP) levels, but a significant number of treated patients still have increased CIMT. We investigated whether on-treatment levels of CRP are associated with CIMT in hypercholesterolemic patients receiving statin therapy. The influence of blood pressure and anti-hypertensive therapy on the association between CRP and CIMT was evaluated. Main methodsThe assessment of cardiovascular risk factors, CRP and CIMT, was performed in a cross-sectional study of 240 hypercholesterolemic patients at intermediate cardiovascular risk under statin therapy; 125 patients received only a statin (statin group) and 115 also anti-hypertensive therapy (combined therapy group). Key findingsLogarithmically transformed CRP (β=0.17, p=0.01) and HDL cholesterol levels (β=−0.27, p<0.001) were correlates of CIMT, irrespective of confounders. High CRP levels (>3mg/L) were associated with a 2.7-fold increased risk of having high CIMT (>1.25mm). High CIMT was present in a high percentage of patients not at target for cholesterol and blood pressure levels (61%). Patients in the statin group had lower Framingham risk and CIMT than those in the combined therapy group. In the statin group, logarithmically transformed CRP (β=0.28, p=0.004) and HDL cholesterol (β=−0.21, p=0.03) were associated with CIMT. In the combined therapy group, HDL cholesterol was the only significant CIMT correlate (β=−0.33, p=0.001). SignificanceOn-treatment CRP and HDL cholesterol levels are associated with CIMT among hypercholesterolemic patients under statin therapy. In patients receiving both statin and anti-hypertensive therapy, HDL cholesterol remains the main covariate of CIMT.

Models for the analysis of C‐reactive protein in statin trials

Elevation in C-reactive protein (CRP) is an independent risk factor for cardiovascular disease progression and levels are reduced by treatment with statins. However, on-treatment CRP, given baseline CRP and treatment, is not normally distributed and outliers exist even when transformations are applied. Although classical non-parametric tests address some of these issues, they do not enable straightforward inclusion of covariate information. The aims of this study were to produce a model that improved efficiency and accuracy of analysis of CRP data. Estimation of treatment effects and identification of outliers were addressed using controlled trials of rosuvastatin. The robust statistical technique of MM-estimation was used to fit models to data in the presence of outliers and was compared with least-squares estimation. To develop the model, appropriate transformations of the response and baseline variables were selected. The model was used to investigate how on-treatment CRP related to baseline CRP and estimated treatment effects with rosuvastatin. On comparing least-squares and MM-estimation, MM-estimation was superior to least-squares estimation in that parameter estimates were more efficient and outliers were clearly identified. Relative reductions in CRP were higher at higher baseline CRP levels. There was also evidence of a dose-response relationship between CRP reductions from baseline and rosuvastatin. Several large outliers were identified, although there did not appear to be any relationships between the incidence of outliers and treatments. In conclusion, using robust estimation to model CRP data is superior to least-squares estimation and non-parametric tests in terms of efficiency, outlier identification and the ability to include covariate information.

Eating, vascular biology, and atherosclerosis: a lot to chew onThe opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

This editorial refers to ‘Diet and inflammation: a link to metabolic and cardiovascular diseases’† by K. Esposito et al. , on page 15 Coronary risk factors, such as hypercholesterolaemia and hypertension, are primary causes of atherosclerosis, at least partly due to their adverse impact on vascular biology. Impaired vascular biological states, such as endothelial dysfunction and inflammation, however may be independently atherogenic. Three examples that suggest that vascular indexes need to be considered independent of risk factors are anti-inflammatory effects of statins, hormone replacement therapy (HRT), and post-prandial endothelial dysfunction and inflammation. The REVERSAL and PROVE IT-TIMI 22 trials demonstrated that changes in LDL cholesterol and C-reactive protein independently correlated with coronary atherosclerosis progression and coronary heart events.1,2 On-treatment C-reactive protein was as predictive of subsequent coronary events as was LDL cholesterol. Prior to the recent HRT trials, many clinicians routinely recommended HRT to post-menopausal women to lower their cardiovascular risk. This was not unreasonable because HRT increases HDL cholesterol and decreases LDL cholesterol and lipoprotein(a). At the same time, HRT increases inflammation (e.g. C-reactive protein) and coagulation, two key atherogenic factors.3 Estrogen and HRT improve endothelial function, but this improvement disappears within a few months for as yet unclear reasons. In light of these lipid-independent vascular biological effects, it is not surprising that the recent HRT trials did not find beneficial effects on cardiovascular risk. Esposito et al. review dietary effects on … *Corresponding author. Tel: +1 410 328 8795; fax: +1 410 328 8080. E-mail address : rvogel{at}heart.umaryland.edu