Serum cell division cycle 42 reflects the treatment response and survival in patients with advanced cervical cancer who receive immune checkpoint inhibitor treatment
- Authors:
- Published online on: August 8, 2023 https://doi.org/10.3892/ol.2023.14000
- Article Number: 414
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Copyright: © Guo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Introduction
Cervical cancer is one of the most common types of gynecological cancer, with an incidence of 7.7 per 100,000 population and mortality of 2.2 per 100,000 population worldwide according to the Cancer Statistics (2023) (1,2). Despite multi-therapy choice (such as surgery and chemoradiation) for early and locally advanced-stage cervical cancer, treatment options for patients with advanced cervical cancer patients are limited and primarily include platinum-based chemotherapy regimens (3–6). There are few therapeutic options beyond first-line chemotherapy.
Immune checkpoint inhibitors (ICIs) provide another therapeutic option for advanced cervical cancer (7–9). ICI regimens have promising treatment outcomes [for example, 13.3–17.0% of patients achieved objective response rate (ORR) in the KEYNOTE-028 and KEYNOTE-158 trials (10,11)], however ~80% of patients exhibit no response (10,11). Hence, to minimize ineffective treatment, avoid the adverse reactions of ICI regimens and reduce the consumption of medical resources, it is urgent to find a potential biomarker to achieve individualized ICI treatment in patients with advanced cervical cancer.
Cell division cycle 42 (CDC42) is a small hydrolase that regulates immune escape by several mechanisms, such as regulating antigen-specific cytotoxic T lymphocyte-mediated cytotoxicity and differentiation of macrophages into M2 phenotype (12–14). For example, CDC42-deficient naïve T cells preferentially differentiate to CD8+ effector cells both in vitro and in vivo (15). Clinically, CDC42 could predict the response of ICI treatment in several types of cancer, such as hepatocellular carcinoma and colorectal cancer (16,17). However, the effect of CDC42 on response of ICI treatment have not been verified in patients with advanced cervical cancer. Hence, the present study aimed to evaluate the potential of serum CDC42 in predicting ICI treatment outcome in patients with advanced cervical cancer.
Materials and methods
Patients
From July 2020 to December 2022, 46 patients (age, 36.0–70.0 years) with advanced cervical cancer who planned to receive ICI treatment with or without antiangiogenic agents were enrolled at Tongji Hospital (Wuhan, China). The inclusion criteria were as follows: i) Histopathologically diagnosed as cervical cancer; ii) confirmed as recurrent, persistent or metastatic cervical cancer; iii) aged >18 years; iv) progression after at least once standardized systemic chemotherapy; v) Eastern Cooperative Oncology Group Performance Status (ECOG PS) (18) 0–1; vi) at least one measurable lesion by the Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 (19); vii) scheduled to receive ICI treatment with or without antiangiogenic agents. The exclusion criteria were as follows: i) Presence of other primary malignant disease; ii) inadequate liver, kidney, heart, bone marrow, and blood coagulation function; iii) history of ICI treatment; iv) complicated with autoimmune disease; v) presence of hematological diseases; vi) pregnancy or breastfeeding. The patients provided written informed consent. The study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (Wuhan, China; approval no. ChiECRCT20200180).
Clinical characteristics
Clinical characteristics of patients were collected from medical records, including age, International Federation of Gynecology and Obstetrics (FIGO) (20) stage, ECOG PS, histology type, target lesion size, metastasis, programmed death-ligand 1 combined positive score [PD-L1 CPS; as previously described (21)] and treatment history.
Treatment
Patients received ICI treatment with or without antiangiogenic agents according to their willingness, disease condition and doctor's advice. The treatment was given in 3-week cycles. ICI was given continually until intolerable toxicity occurred or the disease progressed (up to 24 months) and included camrelizumab (200 mg/cycle), sintilimab (200 mg/cycle), pembrolizumab (200 mg/cycle) and atezolizumab (1,200 mg/cycle). For patients who received ICI treatment combined with antiangiogenic agents, antiangiogenic agents were given until the occurrence of intolerable toxicity or disease progression and included bevacizumab (15 mg/kg/cycle) and apatinib (250 mg/day). The dosing adjustments were allowed based on conditions such as intolerance.
Blood samples
Peripheral blood (5 ml) of patients was collected before treatment (at baseline) and following two treatment cycles. The serum was isolated (centrifugation at 1,800 × g for 10 min) and serum CDC42 was detected by ELISA using commercial kits (cat. no. JM-1116H1; Jiangsu Jingmei Biotechnology Co., Ltd.) according to the manufacturer's instructions.
Assessment
Patients were routinely followed up until May 2023 and underwent imaging examinations (computed tomography or nuclear magnetic resonance) after every two cycles of treatment. Based on the imaging results after four cycles of treatment, the tumor response was assessed via RECIST V.1.1 (19). Progression-free survival (PFS) and overall survival (OS) were recorded for prognosis analysis.
CDC42 cutoff value
To explore the association of CDC42 with PFS and OS, the CDC42 levels (baseline and following two treatment cycles) were divided based on the cutoff value of 600 pg/ml (approximate median value of CDC42 at baseline).
Statistical analysis
SPSS V.24.0 (IBM Corp.) was used for data processing. Data are presented as median and interquartile range (IQR). Comparisons were performed by the Wilcoxon or Kruskal-Wallis H rank sum or Wilcoxon signed-rank test. Correlation analysis was performed by Spearman's rank correlation test. PFS and OS were determined by Kaplan-Meier curves and analyzed by log-rank test. Factors associated with PFS and OS were determined by univariate and backward-stepwise multivariate Cox's proportional hazard regression models. A total of three independent experimental repeats was performed. P<0.05 was considered to indicate a statistically significant difference.
Results
Clinical characteristics
The median (IQR) age of patients was 49.5 (45.8–52.0) years. A total of 15 (32.6%), 11 (23.9%), 8 (17.4%) and 12 (26.1%) patients had FIGO stage I, II, III and IV, respectively. A total of 28 (60.9%) patients had squamous cell carcinoma; 15 (32.6%) patients had adenocarcinoma, while 3 (6.5%) patients had adenosquamous carcinoma. The baseline median (IQR) CDC42 expression was 599.0 (422.8–973.3) pg/ml. Baseline characteristics are shown in Table I.
High CDC42 at baseline is associated with target lesion ≥5 cm and pelvis and lung metastases
CDC42 at baseline was increased in patients with target lesion size ≥5 cm (P=0.020), the presence of pelvis metastasis (P=0.031) and lung metastasis (P=0.043). However, CDC42 at baseline was not significantly different between patients with other clinical characteristics including age (based on median cutoff value of 50 years), ECOG PS and histology type (all P>0.05; Table II). Furthermore, CDC42 was not correlated with FIGO stage at initial diagnosis or treatment line (both P>0.05) (Table SI).
CDC42 at baseline is associated with worse treatment response
No patients with advanced cervical cancer achieved the complete response (CR), 14 (30.4%) patients achieved the partial response (PR), 22 (47.8%) patients exhibited stable disease (SD), while 10 (21.7%) patients exhibited progressive disease (PD). Therefore, ORR was 30.4%, and disease control rate (DCR) was 78.3% (Table III). CDC42 at baseline was decreased in patients who achieved the ORR compared with non-ORR (P=0.042; Fig. 1A) but remained unchanged between patients who achieved DCR and non-DCR (P=0.055; Fig. 1B).
CDC42 at baseline is associated with worse survival profile
The median [95% confidential interval (CI)] PFS was 5.8 (4.0–7.6) months (Fig. 2A) and the median OS was 13.1 (11.0–15.2) months (Fig. 2B) in all patients. PFS (P=0.006; Fig. 2C) and OS (P=0.019; Fig. 2D) were reduced in patients with baseline CDC42 ≥600 pg/ml compared with those with baseline CDC42 <600 pg/ml.
CDC42 following two treatment cycles is associated with unfavorable treatment response
Following two treatment cycles, CDC42 expression decreased (P<0.001; Fig. 3). CDC42 following two treatment cycles showed a significant difference between patients with ORR and non-ORR (P=0.032; Fig. 4A), as well as patients with DCR and non-DCR (P=0.019; Fig. 4B).
CDC42 following two treatment cycles is associated with unfavorable prognosis
PFS (P=0.004; Fig. 4C) and OS (P=0.005; Fig. 4D) were also worse in patients with CDC42 ≥600 pg/ml compared with CDC42 <600 pg/ml following two treatment cycles.
CDC42 following two treatment cycles was an independent factors for shorter PFS and OS
After adjusting the confounders by the multivariate Cox's regression analysis, CDC42 following two treatment cycles (≥600 vs. <600 pg/ml) was independently associated with a shorter PFS [P=0.022, hazard ratio (HR)=2.469]. Furthermore, ECOG PS (1 vs. 0; P=0.007, HR=2.709) and lung metastasis (yes vs. no; P=0.025, HR=2.517) independently predicted shorter PFS, while PD-L1 CPS (positive vs. negative or unknown; P=0.002, HR=0.284) and treatment type (ICI + antiangiogenic therapy vs. ICI-alone; P<0.001, HR=0.259) were associated with prolonged PFS (Table IV).
Multivariate cox's regression analysis for OS showed that CDC42 following two treatment cycles (≥600 vs. <600 pg/ml) was also associated with a shorter OS (P=0.013, HR=4.166). Age (≥50 vs. <50 years; P=0.003, HR=4.175), higher FIGO stage at initial diagnosis (P=0.008, HR=1.621), ECOG PS (1 vs. 0; P=0.033, HR=2.619), target lesion size (≥5 vs. <5 cm; P=0.001, HR=5.628) and higher treatment line (P<0.001, HR=3.809) were linked with a shorter OS, while PD-L1 CPS (positive vs. negative or unknown) was associated with prolonged OS (P=0.001, HR=0.197; Table V).
Discussion
CDC42 is a key protein responsible for progression of cervical cancer (22,23). Knockdown of CDC42 increases C-terminal domain Ser phosphatases RNA polymerase II associated protein 2 and F-cell production 1 (FCP1) in cervical cancer cells, thus controlling cell proliferation (22). Another study reported that activation of CDC42/p21-activated kinases 1 is associated with the tumorigenic and invasive properties of tumorsphere cells enriched from cervical cancer cell line HeLa (23). Nevertheless, the association between CDC42 and the clinicopathological features of patients with cervical cancer needs exploration. Here, serum CDC42 was elevated in patients with advanced cervical cancer with larger tumor size, pelvis metastasis and lung metastasis. These findings might be explained by the proliferation- and invasion-enhancing property of CDC42 in cervical cancer cells, (24–26). However, CDC42 was not significantly different between patients with PD-L1 CSP positive and those with PD-L1 CSP negative or known. The potential reason is that the sample size was too small, which resulted in low statistical power. CDC42 might participate in regulation of immune escape via modulating CD8+ T cells, rather than modulating the expression of PD-L1 (27).
In recent years, clinical investigations have revealed that ICI is a potential treatment modality for patients with advanced cervical cancer (28–30). A recent phase II, single-arm study showed that in previously treated patients with PD-L1-positive cervical cancer, serplulimab + nab-paclitaxel achieves ORR of 51.7%, median PFS is 5.7 months and the median OS is 15.5 months (28). Balstilimab achieves ORR of 15% in patients with recurrent/metastatic cervical cancer who receive prior platinum-based treatment (31). Another phase III trial revealed that in patients with cervical cancer and disease progression after first-line platinum-based chemotherapy, ORR (16.4 vs. 6.3%) and median OS (12.0 vs. 8.5 months) are both improved following treatment with cemiplimab compared with chemotherapy (29). In the present study, the ORR and DCR were 30.4 and 78.3%, respectively, after ICI treatment in patients with advanced cervical cancer. Median PFS and OS were 5.8 and 13.1 months, respectively. These findings are in line with previous studies and support application of ICI treatment in these patients (28,29,31).
CDC42 is reported to predict treatment response and survival in patients with cancer who receive ICI treatment (16,17). The present study revealed that serum CDC42 at baseline was not significantly decreased in patients with objective response achievement and disease control achievement; PFS and OS after ICI treatment in patients with advanced cervical cancer were decreased in patients with baseline CDC42 ≥600 pg/ml. These findings might be because CDC42 negatively modulated the differentiation of CD8+ T cells, which killed tumor cells following suppression of immune escape by ICI treatment (15,32). As aforementioned, CDC42 was associated with larger tumor size, pelvis metastasis and lung metastasis, which represent higher tumor burden. Patients with a higher tumor burden might have worse survival. Patients with better treatment responses tended to have better survival. Another key finding of this study was that serum CDC42 was decreased following two cycles of treatment and showed stronger prognostic value for treatment response and survival in patients with advanced cervical cancer compared with serum CDC42 at baseline. Moreover, the association of serum CDC42 with survival was confirmed by multivariate Cox's proportional hazard regression model. These findings provide a potential prognostic tool for patients with advanced cervical cancer, thus improving the management of these patients.
Nevertheless, the present study had limitations. First, the present study only enrolled patients with advanced cervical cancer who received ICI treatment with or without antiangiogenic agents. Therefore, the findings might not be applicable in patients with cervical cancer who receive surgical resection of the tumor. Second, the present study only detected serum CDC42, however, the prognostic value of CDC42 from other sources, such as tumors, should be explored in future. Third, the sample size was not large enough to draw a definitive conclusion. Further studies with larger sample sizes should be conducted to verify the prognostic value of serum CDC42.
In conclusion, serum CDC42 was reduced after treatment and its high expression reflected a lower possibility of achieving treatment response and worse survival in patients with advanced cervical cancer.
Supplementary Material
Supporting Data
Acknowledgements
Not applicable.
Funding
The present study was supported by National Science Foundation of China (grant no. 81802612).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
LLG and CYW conceived the study. YS, XYL, WX and SLM collected data and drafted the manuscript. LLG, YHL, WJW, XFL and CYW analyzed data and revised the manuscript. LLG and CYW confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.
Ethics approval and consent to participate
The patients provided written informed consent to participate. Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (Wuhan, China) provided ethics approval (approval no. ChiECRCT20200180).
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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