Serum HE4, CA125, YKL-40, bcl-2, cathepsin-L and prediction optimal debulking surgery, response to chemotherapy in ovarian cancer

Journal of Ovarian Research

Izabella Anna Rzepka-Górska²  Aleksandra Izabela Tołoczko-Grabarek³  Agnieszka Monika Sompolska-Rzechuła¹  Janusz Leszek Menkiszak²  Aneta Alicja Cymbaluk-Płoska²  Anita Monika Chudecka-Głaz² 

[1] Department of Mathematics Applications in Economy, West Pomeranian University of Technology, Szczecin, Poland;Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland;International Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland

关键词: Ovarian cancer;    Debulking surgery;    Neoadjuvant chemotherapy;    Cathepsin-L;    YKL-40;    CA125;    HE4;   

Others  :  1151828
DOI  :  10.1186/1757-2215-7-62

 received in 2014-01-04, accepted in 2014-05-30,  发布年份 2014

【 摘 要 】

Background

The most important prognostic factor in the ovarian cancer is optimal cytoreduction. The neoadjuvant chemotherapy, an only optional method of treatment in this case and is still the subject of debate. The object of this study was to evaluate the usefulness of markers: CA 125, HE4, YKL-40 and bcl-2 as well as cathepsin L in predicting optimal cytoreduction and response to chemotherapy.

Methods

Sera were secured preoperatively. The division into groups was performed retrospectively depending on the method of treatment (surgery vs neoadjuvant chemotherapy) as well as on response to chemotherapy (sensitive vs resistant vs refractory). Comparisons were made between groups, and the diagnostic usefulness of tested proteins was examined.

Results

We found that statistically significant differences between primary operated patients and patients undergoing neoadjuvant chemotherapy were applicable only to the tumour markers (CA125 1206.79 vs 2432.38, p = 0.000191; HE4 78.87 vs 602.45, p = 0.000004; YKL-40 108.13 vs 203.96, p = 0.003991). Cathepsin-L and Bcl-2 were statistically insignificant. The cut-off point values were determined for the CA 125 (345 mIU/ml), HE4 (218.43 pmol/L) and YKL-40 (140.9 ng/ml). The sensitivity, specificity, PPV and NPV were as follows: CA125 (83.3%; 75%; 80.6%; 78.3%), HE4 (86.6%; 91.3%; 92.9%; 84%) and YKL-40 (75%; 83.3%; 84%; 74.1%).

Conclusion

Among the tested proteins the HE4 marker appears to be helpful in forecasting of optimal cytoreduction and possibly also of the prediction of response to platinum analogues used in first-line treatment of ovarian cancer.

【 授权许可】

   
2014 Chudecka-Głaz et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Bristow R, Tamacruz R, Armstrong D, Trimble EL, Montz FJ: Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta analysis. J Clin Oncol 2002, 20:1248-1259.
• [2]Piccart M, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, Stuart G, Kaye S, Vergote I, Blom R, Grimshaw R, Atkinson RJ, Swenerton KD, Trope C, Nardi M, Kaern J, Tumolo S, Timmers P, Roy JA, Lhoas F, Lindvall B, Bacon M, Birt A, Andersen JE, Zee B, Paul J, Baron B, Pecorelli S: Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamid in women with advanced epithelial ovarian cancer: three years results. J Natl Cancer Inst 2000, 92:699-708.
• [3]Whitney CW, Spirtos N: Gynecologic oncology group surgical procedures manual. Philadelphia: gynecologic oncology group. 2009. https://gogmember.gog.org/manuals/pdf/surgamn.pdf webcite
• [4]Harter P, Muallem ZM, Buhrmann C, Lorenz D, Kaub C, Hils R, Kommoss S, Heitz F, Traut A, du Bois A: Impact of a structured quality management program on surgical outcome in primary advanced ovarian cancer: redefining “optimal residual disease. Gynecol Oncol 2012, 25:483-492.
• [5]Tangjitgamol S, Manusirivithaya S, Laopaibon M, Lumbiganon P, Bryant A: Interval debulking surgery for advanced epithelilal ovarian cancer. Cochrane Database Syst Rev 2013, 30(4):CD006014. doi:10.1002/14651858.CD006014.pub6
• [6]McLean K, Shah C, Thompson S, Gray H, Swensen R, Goff B: Ovarian cancer in elderly: outcomes with neoadajuvant chemotherapy or primary cytoreduction. Gynecol Oncol 2010, 118:43-46.
• [7]Steed H, Oza A, Murphy J, Laframboise S, Lockwood G, DE Petrillo D, Sturgeon J, Rosen B: A retrospective analysis of neoadjuvant platinum based chemotherapy versus up front surgery in advanced ovarian cancer. Int J Gynecol Cancer 2006, 16:47-53.
• [8]van Meurs HS, Tajik P, Hof MH, Vergote I, Kenter GG, Mol BW, Buist MR, Bossuyt PM: Which patients benefit most from primary surgery or neoadjuvant chemotherapy in stage IIC or IV ovarian cancer? an exploratory analysis of the European Organisation Research and Treatment of Cancer 55971 randomised trial. Eur J Cancer 2013. (Epub ahead of print)
• [9]Vergote I, Trope C, Amant F, Kristensen GB, Ehlen T, Johnson N, Verheijen RH, van der Burg ME, Lacave AJ, Panici PB, Kenter GG, Casado A, Mendiola C, Coens C, Verleye L, Stuart GC, Pecorelli S, Reed NS, European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group; NCIC Clinical Trials Group: Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010, 363:943-953.
• [10]Brun JL, Rouzier R, Selle F, Houry S, Uzan S, Darai E: Neoadjuvant chemotherapy or primary surgery for stage II/IV ovarian cancer: contribution of diagnostic laparoscopy. BMC Cancer 2009, 9:171.
• [11]Mousavi SA, Mazhari MM, Guilani MM, Ghaemmaghami F, Bentash N, Akhavan S: Can primary optimal cytoreduction be predicted in advanced epithelial ovarian cancer preoperatively? World J Surg Oncol 2010, 8:11.
• [12]Fujwara K, Yoshino K, Enomoto T, Fujita M, Ueda Y, Miyatake T, Kimura T, Muraji M, Fujita H, Kimura T, Hori M: Usefulness of computed tomography in predicting cytoreductive surgical outcomes for ovarian cancer. Arch Gynecol Obstet 2011, 284:1501-1507.
• [13]Freedman OC, Dodge J, Shaw P, Oza AM, Bernadini M, Klachook S, Murphy KJ, Lo E, Rosen B, Mackay H: Diagnosis of epithelial ovarian carcinoma prior to neoadjuvant chemotherapy. Gynecol Oncol 2010, 119:22-25.
• [14]Kang S, Kim T, Seo S, Kim B, Bae D, Park S: Interaction between preoperative CA 125 level and survival benefit of neoadjuvant chemotherapy in advanced epithelial ovarian cancer. Gynecol Oncol 2011, 120:18-22.
• [15]Angioli R, Plotti F, Capriglione E, Aloisi A, Montera R, Luvero D, Miranda A, Cafà EV, Damiani P, Benedetti-Panici P: Can the preoperative HE 4 level predict optimal cytoreduction in patients with advanced ovarian carcinoma? Gynecol Oncol 2013, 128:579-583.
• [16]Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J: New response evaluation criteria in solid tumors : revised RECIST guideline (version 1.1). Eur J Cancer 2009, 45:228-247.
• [17]DeLong ER, DeLong DM, Clarke-Pearson DL: Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988, 44:837-845.
• [18]Gąsowska-Bodnar A, Bodnar L, Wcisło B, Jerzak M, Szczylik C, Baranowski W: CA 125 regression after two cycles of neoadjuvant chemotherapy as prognostic factor in patients with advanced ovarian cancer and primary peritoneal serous cancer who underwent interval surgical cytoreduction. Ginekol Pol 2008, 79:108-114.
• [19]Yildrim Y, Ertas IE, Dogan A, Gultekin OE, Gultekin E: The predictors of response to neoadjuvant chemotherapy in advanced epithelial ovarian cancer. J Surg Oncol 2012, 105:200-205.
• [20]Le T, Hopkins L, Faught W, Fung-Kee-Fung M: The lack of significance of CA 125 response in epithelial ovarian cancer patients with neoadjuvant chemotherapy and delayed primary surgical debulking. Gynecol Oncol 2007, 105:712-715.
• [21]Rocconi RP, Matthews KS, Kemper MK, Hoskins KE, Huh WK, Straugh JM Jr: The timing of normalization of CA 125 levels during primary chemotherapy is predictive of survival in patients with epithelial ovarian cancer. Gynecol Oncol 2009, 114:242-245.
• [22]Vasudev NS, Trigonis I, Cairns DA, Hall GD, Jackson DP, Broadhead T, Buxton J, Hutson R, Nugent D, Perren TJ: The prognostic and predictive value of CA 125 regression during neoadjuvant chemotherapy for advanced ovarian primary peritoneal carcinoma. Arch Gynecol Obstet 2011, 284:221-227.
• [23]Bingle L, Cross SS, High AS, Wallace WA, Rassl D, Yuan G, Hellstrom I, Campos MA, Bingle CD, WFDC2 (HE4): A potential role in the innate immunity of the oral cavity and respiratory tract and the development of adenocarcinomas of the lung. Respir Res 2006. doi:10.1186/1465-9921-7-61
• [24]Bingle L, Singleton V, Bingle CD: The putative ovarian tumor marker gene HE4 (WFDC2), is expressed in normal tissues and undergoes complex alternative splicing to yield multiple protein isoforms. Oncogene 2002, 21:2768-2777.
• [25]Galgano MT, Hampton GM, Frierson HF Jr: Comprehensive analysis of HE4 expression in normal and malignant human tissues. Mod Pathol 2006, 19:847-853.
• [26]Gao L, Cheng HY, Dong L, Ye X, Liu YN, Chang XH, Cheng YX, Chen J, Ma RQ, Cui H: The role of HE4 in ovarian cancer : inhibiting tumour cell proliferation and metastasis. J Int Med Res 2011, 39:1645-1660.
• [27]Zou S, Chang X, Ye X, Cheng HY, Cheng YX, Tang ZJ, Zhang ZJ, Gao L, Chen XH, Cui H: Effect of human epididymis protein 4 gene silencing on the malignant phenotype in ovarian cancer. Chin Med J 2011, 124:3133-3140.
• [28]Lu R, Sun X, Xiao R, Zhou L, Gao X, Guo L: Human epididymis protein 4 (HE4) plays a key role in ovarian cancer cell adhesion and motility. Biochem Biophys Res Commun 2012, 419:274-280.
• [29]Steffensen KD, Waldstrom M, Brandslund I, Petzold M, Jacobsen A: The prognostic and predictive value of combined HE4 and CA125 in ovarian cancer patients. Int J Gynecol Cancer 2012, 22:1474-1482.
• [30]Chudecka-Głaz A, Cymbaluk-Płoska A, Menkiszak J, Sompolska Rzechuła A, Strojna A, Byra E, Tołoczko-Grabarek A, Rzepka-Górska I: Preoperative diagnostic performance of ROMA (Risk of Ovarian Malignancy Algorithm) in relation to etiopathogenesis of epithelial ovarian tumors. J Mol Biomark Diagn 2013, S 4:003.
• [31]Kalpotharacos G, Asciutto C, Henic E, Casslen B, Borgfeldt C: High preoperative blood levels of HE4 predicts poor prognosis in patients with ovarian cancer. J Ov Res 2012, 5:20.
• [32]Chudecka-Głaz A, Rzepka-Górska I, Wojciechowska I: Human epididymal protein 4 (HE4) is a novel biomarker and promising prognostic factor in ovarian cancer patients. Eur J Gynaecol Oncol 2012, 33:382-390.
• [33]Yang Z, Luo Z, Zhao B, Zhang W, Zhang J, Li Z: Diagnosis and preoperative value of serum HE4 concentrations for optimal debulking in epithelial ovarian cancer. Oncol Lett 2013, 6:28-34.
• [34]Braicu EI, Fotopoulou C, Van Gorp T, Richter R, Chekerov R, Hall C, Butz H, Castillo-Tong DC, Mahner S, Zeillinger R, Concin N, Vergote I, Sehouli J: Preoperative HE4 expression in plasma predicts surgical outcome in primary ovarian cancer patients. Results from the OVCA study. Gynecol Oncol 2013, 128:245-251.
• [35]Allin KH, Bojesen SE, Johansen JS, Nordestgaard BG: Cancer risk by combined levels of YKL-40 and C-reactive protein in the general population. Br J Cancer 2012, 106:199-205.
• [36]Stawerski P, Wągrowska–Danilewicz M, Stasikowska-Kanicka O, Danilewicz M: Increased tissue immunoexpression of YKL-40 protein in high grade serous ovarian cancers. Pathol Res Pract 2011, 207:573-576.
• [37]Yip P, Chen TH, Seshaiah P, Stephen LL, Michael-Ballard KL, Mapes JP, Mansfield BC, Bertenshaw GP: Comperhesive serum profiling for the discovery of epithelial ovarian biomarkers. PLoS One 2011, 6:e 29533.
• [38]Chudecka-Głaz A, Górski B, Zielińska D, Błogowski W, Wojciechowska I, Bedner R, Rzepka-Górska I: Serum YKL 40 levels in patients with ovarian cancer and women with BRCA 1 gene mutation – comparison to CA 125. Eur J Gynaecol Oncol 2009, 30:668-671.
• [39]Karczmarek–Borowska B, Zmorzyński S, Filip A, Wojcierowski J: BCL-XL as a tumour prognostic factor? Contemp Oncol 2010, 14:7-10.
• [40]Avraam K, Pavlakis K, Papadimitrou C, Vrekoussis T, Panoskaltsis T, Messini I, Patsouris E: The prognostic and predictive value of ERCC-1, p53, bcl-2 and bax in epithelial ovarian cancer. Eur J Gynecol Oncol 2011, 32:516-520.
• [41]Onan O, Sisman A, Gallant ND, Kruk P, Guldiken R: A urinary bcl-2 surface acoustic wave biosensor for early ovarian cancer detection. Sensors 2012, 12:7423-7437.
• [42]Heubner M, Wimberger P, Otterbach F, Kasimir-Bauer S, Siffert W, Kimmig R, Nückel H: Association of the AA genotype of bcl-2 (−938C > A) promoter polymorphism with better survival ovarian cancer. Int J Biol Markers 2009, 24:223-229.
• [43]Protopapas A, Diakomanolis E, Bamias A, Milingos S, Markaki S, Papadimitriou C, Dimopoulos AM, Michalas S: The prognostic significance of the immunohistochemical expression of p53, bcl-2, c-erb B-2 and cathepsin –D in ovarian cancer patients receiving platinum with cyclophosphamide or paclitaxel chemotherapy. Eur J Gynecol Oncol 2003, 25:225-229.
• [44]Crasta JA, Mishra S, Vallikad E: Ovarian serous carcinoma : relationship of p53 and bcl-2 with tumor angiogenesis and VEGF expression. Int J Gynecol Pathol 2011, 30:521-526.
• [45]Dutta T, Sharma H, Kumar L, Dinda AK, Kumar S, Bhatla N, Singh N: Neoadjuvant chemotherapy for epithelial ovarian cancer – role of apoptosis. Cancer Chemother Pharmacol 2005, 56:427-435.
• [46]Kupryjańczyk J, Szymańska T, Mądry R, Timorek A, Stelmachów J, Karpińska G, Rembiszewska A, Ziółkowska I, Kraszewska E, Debniak J, Emerich J, Ułańska M, Płuzańska A, Jedryka M, Goluda M, Chudecka-Głaz A, Rzepka-Górska I, Klimek M, Urbański K, Breborowicz J, Zieliński J, Markowska J: Evaluation of clinical significance of TP 53, BCL-2, BAX and MEKI expression in 229 ovarian carcinomas treated with platinum based regimen. Br J Cancer 2003, 88:848-854.
• [47]Camlica H, Duranyildiz D, Tas F, Yasasever V: Statistical interpretation of CA 125 and bcl-2 in serum of patients with late stage ovarian cancer. Am J Clin Oncol 2008, 31:585-588.
• [48]Berdowska I: Cysteine proteases as disease markers. Clin Chim Acta 2004, 342:41-69.
• [49]Nishida Y, Kohno K, Kawamata T, Morimitsu K, Kuwano M, Miyakawa I: Increased cathepsin L levels in serum in some patients with ovarian cancer : comparison with CA 125 and CA 72.4. Gynecol Oncol 1995, 56:357-361.
• [50]Zhang W, Yang HC, Wang Q, Yang ZJ, Chen H, Wang SM, Pan ZM, Tang BJ, Li QQ, Li L: Clinical value of combined detection of serum matrix metalloproteinase 9, heparinase, and cathepsin for determining ovarian cancer invasion and metastasis. Anticancer Res 2011, 31:3423-3428.
• [51]Chai Y, Wu W, Zhou C, Zhou J: The potential prognostic value of cathepsin D protein in serous ovarian cancer. Arch Gynecol Obstet 2012, 286:465-471.
• [52]Wang SM, Li L, Zhang W, Li DR, Tang BJ: Relationship between cathepsin L and invasion and metastasis of ovarian carcinoma cells. Zhonghua Fu Chan Ke Za Zhi 2010, 45:598-602.
• [53]Kolwijck E, Massuger L, Thomas C, Span PN, Krasovec M, Kos J, Sweep FC: Cathepsin B, L and cystatin C in cyst fluid of ovarian carcinoma. J Cancer Res Clin Oncol 2010, 136:771-778.