Prognostic value of combined glucose and C-reactive protein (CRP) in cervical cancer

Objective: In this study, we aimed to reveal the prognostic importance of glucose and C-reactive protein (CRP) together in cervical cancer, both of which play a critical role in carcinogenesis. Methods: A total of 243 patients who fulfilled the inclusion criteria were included in our study. The effect of fasting blood glucose (FBG) and C-reactive protein (CRP) on survival was evaluated separately as a dichotomous variable by finding the optimal cutoff value. Results: While 31.3% of the patients were in the early stage, 68.7% were in the locally advanced stage. The median follow-up time was 70.2 months (min: 0.57–max: 231). When the locally advanced stage and all stages were included in the analysis, there was a statistically significant difference between the 4 groups in both progression free survival (PFS) and overall survival (OS) (p: 0.026, p: 0.005, p: 0.001 and p: 0.0001, respectively). The HgLc [High fasting blood glucose (FBG) ($\ge$94.5 mg/dL), Low C-reactive protein (CRP) (<0.9585 mg/dL)], HgHc [High FBG (≥94.5 mg/dL) and High CRP ($\ge$0.9585 mg/dL)] groups were found to be independent prognostic risk factors for OS, compared to the LgLc [(Low FBG ($<$94.5 mg/dL) and Low CRP (<0.9585 mg/dL)], in locally advanced stage (HR (Hazard Ratio): 2.95 (95% CI; 1.04–8.40), p: 0.042 and HR: 3.63 (95% CI; 1.39–9.47), p: 0.008, respectively). In the multivariate analysis performed for all stages, among the four groups, only the HgHc group was found to be an independent prognostic risk factor for OS (HR for HgHc group: 2.34 (95% CI; 1.14–4.78), p: 0.019). Conclusions: We found that combined high serum fasting blood glucose (FBG) and C-reactive protein (CRP) levels in cervical cancer, especially in the locally advanced stage, negatively affect the progression free and overall survival, and are independent prognostic risk factors affecting survival. The pre-treatment serum FBG and CRP levels should be carefully evaluated together for each cervical cancer patient. The vital importance of preoperative strict glycemic control for these patients should be considered.

Cervical cancer; Serum fasting blood glucose (FBG) level; Serum C-reactive protein (CRP) level; Locally advanced stage; Survival

[1] Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, et al. Ovarian cancer statistics, 2018. CA: a Cancer Journal for Clinicians. 2018; 68: 284–296.

[2] National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Cervical Cancer. Journal of the National Comprehensive Cancer Network. 2019; 17: 64–84

[3] Salvatici M, Achilarre MT, Sandri MT, Boveri S, Vanna Z, Landoni F. Squamous cell carcinoma antigen (SCC-Ag) during follow-up of cervical cancer patients: Role in the early diagnosis of recurrence. Gynecologic Oncology. 2016; 142: 115–119.

[4] Black S, Kushner I, Samols D. C-reactive Protein. Journal of Biological Chemistry. 2004; 279: 48487–48490.

[5] Fleming JS, Beaugié CR, Haviv I, Chenevix-Trench G, Tan OL. Incessant ovulation, inflammation and epithelial ovarian carcinogenesis: revisiting old hypotheses. Molecular and Cellular Endocrinology. 2006; 247: 4–21.

[6] Elliott RL, Blobe GC. Role of transforming growth factor Beta in human cancer. Journal of Clinical Oncology. 2005; 23: 2078–2093.

[7] Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001; 357: 539–545.

[8] Zahlten-Hinguranage A, Goldschmidt H, Cremer FW, Egerer G, Moehler T, Witte D, et al. Preoperative elevation of serum C-reactive protein is predictive for prognosis in myeloma bone disease after surgery. British Journal of Cancer. 2006; 95: 782–787.

[9] Gockel I, Dirksen K, Messow C, Junginger T. Significance of preoperative C-reactive protein as a parameter of the perioperative course and long-term prognosis in squamous cell carcinoma and adenocarcinoma of the oesophagus. World Journal of Gastroenterology. 2006; 12: 3746–3750.

[10] Hashimoto K, Ikeda Y, Korenaga D, Tanoue K, Hamatake M, Kawasaki K, et al. The impact of preoperative serum C-reactive protein on the prognosis of patients with hepatocellular carci- noma. Cancer. 2005; 103: 1856–1864.

[11] Gunter MJ, Stolzenberg-Solomon R, Cross AJ, Leitzmann MF, Weinstein S, Wood RJ, et al. A prospective study of serum C-reactive protein and colorectal cancer risk in men. Cancer Research. 2006; 66: 2483–2487.

[12] Jones JM, McGonigle NC, McAnespie M, Cran GW, Graham AN. Plasma fibrinogen and serum C-reactive protein are associated with non-small cell lung cancer. Lung Cancer. 2006; 53: 97–101.

[13] Schmid M, Schneitter A, Hinterberger S, Seeber J, Reinthaller A, Hefler L. Association of elevated C-reactive protein levels with an impaired prognosis in patients with surgically treated endometrial cancer. Obstetrics and Gynecology. 2007; 110: 1231–1236.

[14] Hefler LA, Concin N, Hofstetter G, Marth C, Mustea A, Sehouli J, et al. Serum C-reactive protein as independent prognostic variable in patients with ovarian cancer. Clinical Cancer Research. 2008; 14: 710–714.

[15] Polterauer S, Grimm C, Tempfer C, Sliutz G, Speiser P, Reinthaller A, et al. C-reactive protein is a prognostic parameter in patients with cervical cancer. Gynecologic Oncology. 2007; 107: 114–117.

[16] Polterauer S, Grimm C, Zeillinger R, Heinze G, Tempfer C, Reinthaller A, et al. Association of C-reactive protein (CRP) gene polymorphisms, serum CRP levels and cervical cancer prognosis. Anticancer Research. 2011; 31: 2259–2264.

[17] Michaud DS, Fuchs CS, Liu S, Willett WC, Colditz GA, Giovannucci E. Dietary glycemic load, carbohydrate, sugar, and colorectal cancer risk in men and women. Cancer Epidemiology, Biomarkers & Prevention. 2005; 14: 138–147.

[18] Augustin LSA, Gallus S, Negri E, La Vecchia C. Glycemic index, glycemic load and risk of gastric cancer. Annals of Oncology. 2004; 15: 581–584.

[19] Mulholland HG, Murray LJ, Cardwell CR, Cantwell MM. Dietary glycaemic index, glycaemic load and endometrial and ovarian cancer risk: a systematic review and meta-analysis. British Journal of Cancer. 2008; 99: 434–441.

[20] Silvera SA, Rohan TE, Jain M, Terry PD, Howe GR, Miller AB. Glycaemic index, glycaemic load and risk of endometrial cancer: a prospective cohort study. Public Health Nutrition. 2005; 8: 912– 919.

[21] Nomelini RS, Neto ASL, Capuci KA, Murta BMT, Murta EFC. Relationship between plasma glucose levels and malignant uterine cervical neoplasias. Clinical Medicine Insights: Oncology. 2011; 5: 77–82.

[22] Nie D, Zhang L, Wang C, Guo Q, Mao X. A high Glasgow prog- nostic score (GPS) or modified Glasgow prognostic score (mGPS) predicts poor prognosis in gynecologic cancers: a systematic review and meta-analysis. Archives of Gynecology and Obstetrics. 2020; 301: 1543–1551.

[23] Wang H, Wang MS, Zhou YH, Shi JP, Wang WJ. Prognostic Values of LDH and CRP in Cervical Cancer. OncoTargets and Ther- apy. 2020; 13: 1255–1263.

[24] Bhatla N, Berek JS, Cuello Fredes M, Denny LA, Grenman S, Karunaratne K, et al. Revised FIGO staging for carcinoma of the cervix uteri. International Journal of Gynecology & Obstetrics. 2019; 145: 129–135.

[25] Wu M, Guan M, Liu C, Wu J, Rao Q, Li J. The added value of fast- ing blood glucose to serum squamous cell carcinoma antigen for predicting oncological outcomes in cervical cancer patients receiving neoadjuvant chemotherapy followed by radical hysterectomy. Cancer Medicine. 2019; 8: 5068–5078.

[26] Liang S, Shen Y, Wu J, Wang L, Wu M, Li J. Impact of Poor Preoperative Glycemic Control on Outcomes among Patients with Cervical Cancer Undergoing a Radical Hysterectomy. Oncology Research and Treatment. 2020; 43: 10–18.

[27] Li J, Wu M, Lu H, Zhang B, Wang L, Lin Z. Impact of Hyperglycemia on Outcomes among Patients Receiving Neoadjuvant Chemotherapy for Bulky Early Stage Cervical Cancer. PLoS ONE. 2016; 11: e0166612.

[28] Lee Y, Choi CH, Kim CJ, Song TJ, Kim MK, Kim T, et al. Glu- cose as a prognostic factor in non-diabetic women with locally advanced cervical cancer (IIB-IVA). Gynecologic Oncology. 2010; 116: 459–463.

[29] In Choi J, Chang HK, Lee DW, Lee KH, Park JS, Lee HN. Does diabetes mellitus have an impact on the prognosis for patients with cervical cancer? Gynecologic Oncology. 2015; 139: 319–323.

[30] Cui N, Li L, Feng Q, Ma HM, Lei D, Zheng PS. Hexokinase 2 Promotes Cell Growth and Tumor Formation Through the Raf/MEK/ERK Signaling Pathway in Cervical Cancer. Frontiers in Oncology. 2020; 10: 581208.

[31] Ryu TY, Park J, Scherer PE. Hyperglycemia as a Risk Factor for Cancer Progression. Diabetes & Metabolism Journal. 2014; 38: 330–336.

[32] Mueckler M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Molecular Aspects of Medicine. 2013; 34: 121–138.

[33] Dong C, Yuan T, Wu Y, Wang Y, Fan TWM, Miriyala S, et al. Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell. 2013; 23: 316– 331.

[34] Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madar- nas Y, et al. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. Journal of Clinical On- cology. 2002; 20: 42–51.

[35] Deivendran S, Marzook KH, Radhakrishna Pillai M. The role of inflammation in cervical cancer. Advances in Experimental Medicine and Biology. 2014; 816: 377–399.

[36] Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008; 454: 436–444.

[37] Barsoum IB, Smallwood CA, Siemens DR, Graham CH. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Research. 2014; 74: 665–674.

[38] Nozoe T, Korenaga D, Futatsugi M, Saeki H, Maehara Y, Sugimachi K. Immunohistochemical expression of C-reactive protein in squamous cell carcinoma of the esophagus-significance as a tumor marker. Cancer Letters. 2003; 192: 89–95.

[39] Kim MY, Kim YS, Kim M, Choi MY, Roh GS, Lee DH, et al. Metformin inhibits cervical cancer cell proliferation via decreased AMPK O-GlcNAcylation. Animal Cells and Systems. 2019; 23: 302–309.

[40] Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R, et al. A Randomized Trial of Aspirin to Prevent Colorectal Adenomas. New England Journal of Medicine. 2003; 348: 891–899.