Elevated CRP levels indicate poor progression-free and overall survival on cancer patients treated with PD-1 inhibitors

Iivanainen, Sanna; Ahvonen, Jarkko; Knuuttila, Aija; Tiainen, Satu; Koivunen, Jussi

doi:10.1136/esmoopen-2019-000531

Cited by 69 publications

(65 citation statements)

References 45 publications

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“…We found that elevated pretreatment CRP levels were associated with poor disease outcome as indicated with shortened PFS and OS. This is in line with previous studies investigating the prognostic impact of pretreatment CRP levels in cancer patients treated with ICI [ 27 , 28 , 29 , 36 , 37 ]. Suzuki et al showed a strong association between elevated pretreatment CRP levels and worse OS in patients with metastatic renal cell carcinoma treated with nivolumab.…”

Section: Discussionsupporting

confidence: 92%

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C-Reactive Protein (CRP) Levels in Immune Checkpoint Inhibitor Response and Progression in Advanced Non-Small Cell Lung Cancer: A Bi-Center Study

Riedl

Barth

Brückl

et al. 2020

Cancers

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Background: Biomarkers for predicting response to immune checkpoint inhibitors (ICI) are scarce and often lack external validation. This study provides a comprehensive investigation of pretreatment C-reactive protein (CRP) levels as well as its longitudinal trajectories as a marker of treatment response and disease outcome in patients with advanced non-small cell lung cancer (NSCLC) undergoing immunotherapy with anti PD-1 or anti PD-L1 agents. Methods: We performed a retrospective bi-center study to assess the association between baseline CRP levels and anti PD-(L)1 treatment outcomes in the discovery cohort (n = 90), confirm these findings in an external validation cohort (n = 101) and explore the longitudinal evolution of CRP during anti PD-(L)1 treatment and the potential impact of dynamic CRP changes on treatment response and disease outcome in the discovery cohort. Joint models were implemented to evaluate the association of longitudinal CRP trajectories and progression risk. Primary treatment outcomes were progression-free survival (PFS) and overall survival (OS), while the objective response rate (ORR) was a secondary outcome, respectively. Results: In the discovery cohort, elevated pretreatment CRP levels emerged as independent predictors of worse PFS (HR per doubling of baseline CRP = 1.37, 95% CI: 1.16–1.63, p < 0.0001), worse OS (HR per doubling of baseline CRP = 1.42, 95% CI: 1.18–1.71, p < 0.0001) and a lower ORR ((odds ratio (OR) of ORR per doubling of baseline CRP = 0.68, 95% CI: 0.51–0.92, p = 0.013)). In the validation cohort, pretreatment CRP could be fully confirmed as a predictor of PFS and OS, but not ORR. Elevated trajectories of CRP during anti PD-(L)1 treatment (adjusted HR per 10 mg/L increase in CRP = 1.22, 95% CI: 1.15–1.30, p < 0.0001), as well as a faster increases of CRP over time (HR per 10 mg/L/month faster increase in CRP levels = 13.26, 95% CI: 1.14–154.54, p = 0.039) were strong predictors of an elevated progression risk, whereas an early decline of CRP was significantly associated with a reduction in PFS risk (HR = 0.91, 95% CI: 0.83–0.99, p = 0.036), respectively. Conclusion: These findings support the concept that CRP should be further explored by future prospective studies as a simple non-invasive biomarker for assessing treatment benefit during anti PD-(L)1 treatment in advanced NSCLC.

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Section: Discussionsupporting

confidence: 92%

“…Importantly, recent studies have indicated that pretreatment CRP may represent a valuable prognostic marker in the immunotherapy setting of advanced NSCLC [ 27 , 28 , 29 ]. However, these studies were either limited by a very small sample size or the lack of an external validation.…”

Section: Introductionmentioning

confidence: 99%

C-Reactive Protein (CRP) Levels in Immune Checkpoint Inhibitor Response and Progression in Advanced Non-Small Cell Lung Cancer: A Bi-Center Study

Riedl

Barth

Brückl

et al. 2020

Cancers

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“…It is important to understand the mechanisms behind treatment responses to expand the proportion of patients benefiting from these treatments. A high NLR has been reported to be a marker of poor prognosis also in cancer patients treated with PD-1/PD-L1 inhibitors [24]. Thus, trastuzumab's possible ability to modulate the blood lymphocyte and neutrophil counts provides a rationale for combining trastuzumab with IO-treatments.…”

Section: Discussionmentioning

confidence: 99%

The prognostic and predictive role of the neutrophil-to-lymphocyte ratio and the monocyte-to-lymphocyte ratio in early breast cancer, especially in the HER2+ subtype

Tiainen

Rilla

Hämäläinen

et al. 2020

Breast Cancer Res Treat

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Purpose The aim of this study was to investigate the prognostic impact of two systemic inflammatory markers, the neutrophil-to-lymphocyte ratio (NLR) and the monocyte-to-lymphocyte ratio (MLR), and their possible predictive role regarding the efficacy of adjuvant trastuzumab, in 209 early breast cancer cases, 107 of which were HER2-positive. Methods Baseline NLR and MLR values were divided into two groups, high and low, according to cut-off-points determined from the ROC curve (2.2 for NLR and 0.22 for MLR). Cox’s model was utilized for survival analyses. Results High NLR and MLR correlated with poor overall survival (OS) and breast cancer specific survival (BCSS) among all the patients (p ≤ 0.030). Among the HER2+ patients whose adjuvant treatment did not include trastuzumab (n = 64), the survival rates were remarkably lower in patients with a high NLR as compared to those with low; 31% vs. 71% for OS and 42% vs. 74% for BCSS (p ≤ 0.014). Similarly, high MLR correlated with poor survival among these patients (p ≤ 0.020). On the contrary, among the patients who had received adjuvant trastuzumab (n = 43), NLR or MLR did not correlate with survival. Furthermore, trastuzumab was beneficial for the HER2+ patients with high NLR/MLR, while the survival of the HER2+ patients with low NLR/MLR was good irrespective if they received adjuvant trastuzumab. Conclusions Our results suggest that trastuzumab modulates the systemic inflammatory conditions and overcomes the poor prognostic impact of high NLR/MLR. This finding may also provide a rationale for combining trastuzumab with immuno-oncological treatments in HER2+ breast cancer.

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“…There are several reports, including our report, that ICI treatment has less efficacy in patients with poor PS or high CRP. It is thought that these are due to immunosuppression and the relationship with inflammatory cytokines [31][32][33], but the reasons are not clear. Therefore, CRP is not a clear biomarker.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Immune Checkpoint Inhibitor Monotherapy for Advanced Non-Small-Cell Lung Cancer with ALK Rearrangement

Oya

Kuroda

Nakada

et al. 2020

IJMS

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Programmed death-ligand 1 (PD-L1) expression is a predictor of immune checkpoint inhibitor (ICI) treatment efficacy. The clinical efficacy of ICIs for non-small-cell lung cancer (NSCLC) patients harboring major mutations, such as EGFR or ALK mutations, is limited. We genotyped 190 patients with advanced lung adenocarcinomas who received nivolumab or pembrolizumab monotherapy, and examined the efficacy in NSCLC patients with or without major mutations. Among the patients enrolled in the genotyping study, 47 patients harbored EGFR mutations, 25 patients had KRAS mutations, 5 patients had a HER2 mutation, 6 patients had a BRAF mutation, and 7 patients had ALK rearrangement. The status of PD-L1 expression was evaluated in 151 patients, and the rate of high PD-L1 expression (≥50%) was significantly higher in patients with ALK mutations. The progression-free survival was 0.6 (95% CI: 0.2-2.1) months for ALK-positive patients and 1.8 (95% CI: 1.2-2.1) months for EGFR-positive patients. All patients with ALK rearrangement showed disease progression within three months from the initiation of anti-PD-1 treatment. Our data suggested that ICI treatment was significantly less efficacious in patients with ALK rearrangement than in patients with EGFR mutations, and PD-L1 expression was not a critical biomarker for ICI treatment for patients with one of these mutations.

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Elevated CRP levels indicate poor progression-free and overall survival on cancer patients treated with PD-1 inhibitors

Cited by 69 publications

References 45 publications

C-Reactive Protein (CRP) Levels in Immune Checkpoint Inhibitor Response and Progression in Advanced Non-Small Cell Lung Cancer: A Bi-Center Study

C-Reactive Protein (CRP) Levels in Immune Checkpoint Inhibitor Response and Progression in Advanced Non-Small Cell Lung Cancer: A Bi-Center Study

The prognostic and predictive role of the neutrophil-to-lymphocyte ratio and the monocyte-to-lymphocyte ratio in early breast cancer, especially in the HER2+ subtype

Efficacy of Immune Checkpoint Inhibitor Monotherapy for Advanced Non-Small-Cell Lung Cancer with ALK Rearrangement

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