Predictive role of serum C-Reactive protein, albumin, and monocyte level in advanced stage solid tumors treated with immunotherapy

Authors

Abstract

Aim The goal of this study was to find out easily applicable laboratory parameters to predict the response and outcome of patients receiving immunotherapy treatments in routine oncology clinics.
Materials and Methods Patients who were followed up in the oncology outpatient clinic, diagnosed with CA, and received immunotherapy were included in this study. Demographic, diagnostic, laboratory, pathology, treatment, and duration of ımmunotherapy response data were extracted from the medical history of patients, radiological assessments, and pathology reports in both patient files and electronic records. The obtained data were analyzed in the SPSS program, and the significance level was taken as p<0.05.
Results This study recruited 80 patients, 21 females and 59 males, diagnosed with advanced-stage solid tumors treated with immunotherapy with or without chemotherapy. Statistically significant longer median response duration in patients with serum CRP level <10 mg/L was detected when compared to patients with higher CRP ≥10 mg/L (372 and 227 days, respectively, p=0.000). Moreover, there was a statistically significant difference between serum albumin and monocyte levels of patients with CRP level <10 mg/L and patients with CRP ≥10 mg/L in terms of immunotherapy response duration (p=0.000 and 0.017, respectively). Peripheral blood albumin < 4mg/dl and monocyte >0.6x103L were related to decreased duration of response to immunotherapies.
Discussion Routine peripheral blood C-reactive protein, albümin, and monocyte levels may predict who will get more benefit from novel immunotherapeutic agents.

Keywords

Introduction

Immun checkpoint inhibitors (ICIs) have emerged as both efficient and novel treatment options in various metastatic cancers such as lung, gastric, genitourinary system cancers, and malignant melanoma [1]. Histological markers like programmed death ligand 1 (PD L1) expression, tumor mutation burden (TMB), microsatellite instability (MSI) and T cell receptors (TCRs) have been found effective to predict the efficacy of immunotherapy treatments, however there may be a debate over deriving tumor response according to existance of these well known markers. For instance, it was reported that only about 20–25% of non-small cell lung cancer (NSCLC) patients respond well to immunotherapy treatments [2]. Secondly, different PDL-1 positivity rates ranging from 1% to 50% have been observed in various current studies, as well as TMB with different cut-off values. In general, high TMB is accepted as >10 mutations/megabase. Pembrolizumab has been widely used for patients with high TMB despite some contradictory results in clinical settings [3]. Lastly, the presence of high MSI (MSI-H) may predict improved outcomes with utilizing pembrolizumab therapy for most solid tumors, while several other studies have claimed that colorectal cancer patients with microsatellite stability (MSS) may also have an essential clinical response to PD-1 inhibitors [4].
Cancer patients have mostly poor nutritional status with low levels of albumin levels which indicates poor prognosis in gastric cancer due to various reasons such as poor appetite, abnormal protein metabolism, and digestive dysfunction [5, 6]. Xuanxuan Yang et al confirmed that serum CRP, alongside albumin level, measured before initiating treatments, were suitable markers for predicting prognosis in gastric cancer patients [7].
Serum monocytes, which can be diverted into tumor-associated macrophages (TAMs), dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs), are one of the most crucial blood cells that can halt tumor progression. Many studies have proved that monocytes play important roles in tumor cell phagocytosis, secretion of tumoricidal mediators, angiogenesis, remodeling of the extracellular matrix, and clustering of lymphocytes [3]. Unfortunately, there is also evidence showing TAMs may decrease the efficiency of cancer treatments. In many cancers like breast, lung, prostate, and ovarian cancer, TAMs can contrıbute to tumor growth in unclear ways [8, 9].
It is worth noting that affordable and easily accessible predictive and/or prognostic biomarkers have been required to determine which disease group will benefit most from ICIs in clinical settings. For these reasons, we aimed to explore the relationship between serum CRP, albumin, and monocyte count levels with the duration of response to immunotherapy in advanced-stage cancer patients who received immunotherapy with or without chemotherapy treatments.

Materials and Methods

Study Design And Eligibility Criteria
This multi-center, retrospective study comprised 90 patients having histologically and radiologically proven advanced-stage cancers according to the American Joint Committee on Cancer, 8th edition Tumor, lymph node, and metastasis (TNM) Staging Classifications for Carcinomas. Other inclusion criteria were patients older than 18 years who received immunotherapy either alone or with chemotherapy, with reported serum baseline CRP and albumin levels measured within 1 month of initiating their treatment. All patients were administered at least one of the following immune checkpoint inhibitors (ICIs): Pembrolizumab, Nivolumab, or Atezolizumab. Patients reported with any other illnesses, such as hematological, nephrological, and liver diseases, patients younger than 18 years old, and patients with missing data were excluded. The demographic data included gender and age. The clinical data included pathological cancer type, leucocyte, platelet, granulocyte, and monocyte counts, baseline CRP, and albumin levels. Patients followed up between 01 January 2020 and 31 May 2024 were recruited.
Data Collection
In this study, our hospital management was consulted with the ethics committee report, and access to the database was provided for data collection. Demographic, diagnostic, laboratory, pathology, treatment, and duration of ımmunotherapy response data were extracted from the medical history of patients, radiological assessments, and pathology reports in both patient files and electronic records.
Radiological Response and Follow-up Criteria
Patients staged before their immunotherapy treatments with or without chemotherapy regimens were followed up with 3 to 4 months intervals based on thorax and abdominal computed tomography (CT) and/or positron emission tomography (PET-CT) results during their treatment periods. RECIST 1.1 (Response Evaluation Criteria In Solid Tumors) criteria were used to assess radiological response.
Statistical Analysis
SPSS 22.0 (Statistical Package for Social Sciences, IBM, Armonk, NY, USA) package program was used for statistical analysis of the data. The study data were presented as frequency distribution (number, percentage) for categorical variables, and descriptive statistics (mean, standard deviation, median, interquartile range) for numerical variables. The conformity of the data to normal distribution was assessed using the Kolmogorov-Smirnov test (p>0.05). Since our data did not show normal distribution, the significance level between groups was assessed using the Mann-Whitney U test and the Kruskal-Wallis test. The Spearman Correlation Coefficient was used to determine whether there was a relationship between the variables. The role of CRP, monocyte, and albumin levels in predicting the day of immunotherapy was analyzed using the “Receiver Operating Characteristic (ROC)” curve analysis. When evaluating the area under the curve, a 5% type 1 error level was used to accept a statistically significant predictive value of the test variables. The significance level was taken as p<0.05.
Ethical Approval
This study was approved by the Ethics Committee of Yalova University (Date: 2024-12-04, No: 2024/283).

Results

Of the patients included in the study, 26.3% were female, and the mean age was 64.63±8.25 years. When the distribution of patients according to cancer type was examined; 57.5% of the patients had non-small cell lung cancer, 20.0% had small cell lung cancer, 8.8% had kidney cancer, 5.0% had head and neck cancer, 3.8% had malignant melanoma, 2.5% had mesothelioma and 2.5% had bladder cancer. When the status of the patients who received immunotherapy was evaluated according to the cancer treatment line, it was seen that 27.5% were in the 1st line, 52.5% in the 2nd line, 12.5% in the 3rd line, 3.8% in the 4th line, and 2.5% in the 5th line. Of the patients who received immunotherapy, 35.0% died and 65.0% were alive (Table 1). Data on laboratory parameters of the patients are shown in Table 1.When the laboratory parameters of patients receiving immunotherapy were examined according to their CRP levels; it was found that there was a significant difference between the laboratory parameters of albumin and monocyte levels of patients with CRP <10 mg/L and below and those with CRP >10 mg/L and above, while there was no significant difference between WBC, neutrophil, and platelet levels (Table 1). In addition, when the immunotherapy response time of patients with CRP <10 mg/L and below and those with CRP >10 mg/L and above was evaluated; the median immunotherapy response time of patients with CRP <10 mg/L and below was 372 days, and the median immunotherapy response time of patients with CRP >10 mg/L and above was 227 days; there was a statistically significant difference between these values (p=0.000, Table 1). It was found that there was a significant negative correlation between CRP and monocyte levels and the duration of response to immunotherapy, and that as CRP and monocyte levels increased, the duration of response to immunotherapy decreased (p=0.000, r=-0.563; p=0.008; r=-0.296, respectively). A positive significant correlation was found between albumin level and the duration of response to immunotherapy (p=0.000; r=0.386).
The results of the correlation analysis performed to determine the relationship between CRP, albumin, and monocyte levels and the duration of response to immunotherapy are shown in Table 2. Receiver Operating Characteristics (ROC) Curve Analysis was performed for the immunotherapy response day. The AUC value for immunotherapy response day was 0.779 (95% CI 0.677- 0.880, p=0.000), and was found to be significantly associated with CRP. The cut-off value defining immunotherapy response day was 289.5 (71% sensitivity and 29% specificity) (Figure 1a, Table 3).ROC Curve Analysis was evaluated for monocyte level and albumin level. The AUC value for monocyte level was 0.655 (95% CI 0.535-0.775, p=0.017) and the AUC value for albumin level was 0.746 (95% CI 0.636-0.857, p=0.000), and was found to be significantly associated with CRP and monocyte, and albumin levels (p<0.05).
The defining cut-off value for monocyte level was 0.6 for immunotherapy response day and 4.0 for albumin level (64% sensitivity and 43% specificity; 76% sensitivity and 39% specificity, respectively) (Figures 1b and 1c, Table 3).

Discussion

Serum CRP, also known as an acute phase reactant biomarker, not only increases in the inflammation occurring in the formation of cancer, but also promotes DNA damage and tumor progression. Moreover, tumors can escape from immune surveillance by developing inflammatory and anti-inflammatory signals. Therefore, there has been a presumption that CRP contributes to worsening prognosis. MinDong Sung et al explored the prognostic value of baseline and early treatment response of CRP in non-cell lung cancer patients undergoing immunotherapy. This study confirmed that high levels of CRP at the beginning of immunotherapy predicted worse survival (p<0.001) [10].
Yilun Wei et al evaluated the prognostic value of baseline CRP level in patients with advanced non-small cell lung cancer treated with immun checkpoint inhibitors. In this research, serum CRP levels 8 mg/L and above were related to decreased mPFS [11]. Consistent with these findings, our study revealed a statistically significant relationship between increased (≥10 mg/L) baseline serum CRP level and shortened response duration with immunotherapy treatments shown in Table 2. Patients with lower (<10 mg/L) plasma CRP levels responded to immunotherapy significantly longer period than patients with higher (≥10 mg/L) CRP levels in this study (372 versus 227 days, p=0.000). Serum albumin drops in inflammatory conditions where CRP rises. In addition, low plasma albumin levels in inflammatory processes like malignancies due to poor nutritional, immunocompromised, and myelosuppression conditions are associated with worse cancer outcomes in many studies. Therefore, albumin can have an important prognostic accuracy for cancer survival [12, 12]. Liu XY et al have demonstrated a 1-year improvement in all survival in cachectic cancer patients with higher level serum albümin [14]. Our study, supporting these findings, revealed that reduced peripheral blood albumin (<4 mg/dl) level was associated with lessened response duration time to immunotherapy treatments (p=0.000) demonstrated in Table 2. Peripheral blood albumin level was found to rise as the duration of immunotherapy treatment increased (p = 0.000; r = 0.386).Inflammation due to tumor progression is one of the main factors that attracts monocytes from the peripheral blood to the tumor site. Therefore, elevated serum monocyte count can be expected in cancer patients due to inflammatory regulators, including angiogenic and apoptotic factors [15].
Although peripheral blood monocytes are one of the mainstay components of tumor control, they can also have complex effects. Tumor-associated macrophages (TAMs) derived from monocytes can enhance tumor growth by releasing multiple growth factors such as S100, extracellular matrix, and chitinase- like proteins in breast, lung, prostate, and ovarian cancers [16, 17, 18]. However, it remains unclear within solid tumors how monocytes preferentially differentiate into immunosuppressive TAMs rather than immunostimulatory dendritic cells. In addition, TAMs may impair the effects of cancer treatments. Some research found out a low lymphocyte monocyte ratio (LMR) predicted poor OS in gastric cancer and correlated with shorter PFS in gallbladder cancer [19, 20]. Furthermore, other studies also revealed that rising levels of monocytes could be indicative of worse outcomes in multiple myeloma and lymphoma patients [21, 22]. Following these findings, elevated peripheral blood monocyte count (>0.6x103/L) was associated with decreased immunotherapy response duration in this study (p=0.008; r=- 0.296) displayed in Table 3. Finally, statistically significant differences among serum monocyte levels of patients with CRP level <10 mg/L and patients with CRP ≥10 mg/L (p=0.000 and 0.017, respectively) in our study are shown in Table 2.

Limitations

Limiting factors of our study can be explained as a small sample size, as immunotherapeutic agents could not be administered to the patients based on guidelines easily due to a lack of financial support for these expensive options. Other factors were tumor and treatment heterogenities. Fınally, patients with different malignant tumor types received immunotherapy in different lines. Despite these limiting factors, it seems like peripheral blood CRP, albumin, and monocyte levels can predict treatment response duration in different solid malign tumors treated with immunotherapies in routine oncology clinics. This study may differ from the results of other scientists at home and abroad, and should be further developed in clinical cases. Due to the limitations highlighted above, more comprehensive, prospective, randomized controlled studies with bigger patient populations are needed to replicate these investigations at various phases of the disease.

Conclusion

In conclusion, our study found that there was a significant difference in the duration of response to immunotherapy, monocyte and albumin levels between patients with CRP <10 mg/L and CRP >10 mg/L. Current evidence suggests that increased baseline CRP levels are associated with poor overall survival and progression-free survival in patients receiving ICIs compared with patients with low baseline CRP levels. Moreover, CRP≥10 mg/L indicates a worse prognosis. Additionally, peripheral blood albumin < 4mg/dl and monocyte > 0.6 × 10^3L levels were related to decreased duration of response to immunotherapies. Therefore, baseline CRP, monocyte, and albumin levels may serve as markers for the prognosis of certain solid tumor patients treated with ICIs. Due to the limited quality and quantity of the included studies, more prospective, well- designed studies are needed to confirm the current findings.

References

1. Duan J, Cui L, Zhao X, Bai H, Cai S, et al. Use of Immunotherapy With Programmed Cell Death 1 vs Programmed Cell Death Ligand 1 Inhibitors in Patients With Cancer: A Systematic Review and Meta-analysis. JAMA Oncol. 2020;6(3):375-84.
   PubMed Google Scholar
2. Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015;5(9):2892-911.
   PubMed Google Scholar
3. Xu Y, Ma K, Zhang F, et al. Association between baseline C-reactive protein level and survival outcomes for cancer patients treated with immunotherapy: A meta-analysis. Exp Ther Med. 2023;26(2):361.
   PubMed Google Scholar
4. Sahin IH, Akce M, Alese O, et al. Immune checkpoint inhibitors for the treatment of MSI-H/MMR-D colorectal cancer and a perspective on resistance mechanisms. Br J Cancer. 2019;121(10):809-18.
   PubMed Google Scholar
5. Lin JX, Lin JP, Xie JW, et al. Prognostic importance of the preoperative modified systemic inflammation score for patients with gastric cancer. Gastric Cancer. 2019;22(2):403-12.
   PubMed Google Scholar
6. Saito H, Kono Y, Murakami Y, et al. Postoperative Serum Albumin is a Potential Prognostic Factor for Older Patients with Gastric Cancer. Yonago Acta Med. 2018;61(1):72-8.
   PubMed Google Scholar
7. Yang X, Song X, Zhang L, Wu C. Prognostic role of the pretreatment C-reactive protein/albumin ratio in gastric cancer: A systematic review and meta-analysis. Medicine (Baltimore). 2020;99(10):e19362.
   PubMed Google Scholar
8. Patysheva M, Frolova A, Larionova I, et al. Monocyte programming by cancer therapy. Front Immunol. 2022;13:994319.
   PubMed Google Scholar
9. Larionova I, Tuguzbaeva G, Ponomaryova A, et al. Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian, and Prostate Cancers. Front Oncol. 2020;10:566511.
   PubMed Google Scholar
10. Sung M, Jang WS, Kim HR, et al. Prognostic value of baseline and early treatment response of neutrophil-lymphocyte ratio, C-reactive protein, and lactate dehydrogenase in non-small cell lung cancer patients undergoing immunotherapy. Transl Lung Cancer Res. 2023;12(7):1506-16.
    PubMed Google Scholar
11. Wei Y, Xu J, Huang X, et al. C-reactive protein and lactate dehydrogenase serum levels potentially predict the response to checkpoint inhibitors in patients with advanced non-small cell lung cancer. J Thorac Dis. 2023;15(4):1892-900.
    PubMed Google Scholar
12. Sheinenzon A, Shehadeh M, Michelis R. Serum albumin levels and inflammation. Int J Biol Macromol. 2021;184:857-62.
    PubMed Google Scholar
13. Nakashima K, Hata K, Hotta T, et al. Ability of the Glasgow Prognostic Score to predict the tolerability and efficacy of platinum-combination chemotherapy among elderly patients with advanced non-small cell lung cancer. J Med Invest. 2021;68(3.4):260-4.
    PubMed Google Scholar
14. Liu XY, Zhang X, Ruan GT, et al. One-Year Mortality in Patients with Cancer Cachexia: Association with Albumin and Total Protein. Cancer Manag Res. 2021;13:6775-83.
    PubMed Google Scholar
15. Ziegler-Heitbrock L, Ancuta P, Crowe S, et al. Nomenclature of monocytes and dendritic cells in blood. Blood. 2010;116(16):e74-80.
    PubMed Google Scholar
16. Larionova I, Kazakova E, Patysheva M. Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages. Cancers (Basel). 2020;12(6):1411.
    PubMed Google Scholar
17. Larionova I, Tuguzbaeva G, Ponomaryova A, et al. Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian, and Prostate Cancers. Front Oncol. 2020;10:566511.
    PubMed Google Scholar
18. Larionova I, Kazakova E, Gerashchenko T. New Angiogenic Regulators Produced by TAMs: Perspective for Targeting Tumor Angiogenesis. Cancers (Basel). 2021;13(13):3253.
    PubMed Google Scholar
19. Pan YC, Jia ZF, Cao DH, et al. Preoperative lymphocyte-to-monocyte ratio (LMR) could independently predict overall survival of resectable gastric cancer patients. Medicine (Baltimore). 2018;97(52):e13896.
    PubMed Google Scholar
20. Xu BB, Xu Y, Lu J, et al. Prognostic significance of combined Lymphocyte- monocyte Ratio and Tumor-associated Macrophages in Gastric Cancer Patients after Radical Resection. J Cancer. 2020;11(17):5078-87.
    PubMed Google Scholar
21. Becker C, Wirtz S, Ma X. Regulation of IL-12 p40 promoter activity in primary human monocytes: roles of NF-kappaB, CCAAT/enhancer-binding protein beta, and PU.1 and identification of a novel repressor element (GA-12) that responds to IL-4 and prostaglandin E(2). J Immunol. 2001;167(5):2608-18.
    PubMed Google Scholar
22. Olingy CE, Dinh HQ, Hedrick CC. Monocyte heterogeneity and functions in cancer. J Leukoc Biol. 2019;106(2):309-22.
    PubMed Google Scholar

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