Cancer Chemotherapy and Pharmacology

, Volume 72, Issue 2, pp 437–444 | Cite as

A high serum level of M65 is associated with tumour aggressiveness and an unfavourable prognosis for epithelial ovarian cancer

  • Ibrahim YildizEmail author
  • Faruk Tas
  • Leyla Kilic
  • Fatma Sen
  • Pinar Saip
  • Yesim Eralp
  • Serkan Keskin
  • Senem Karabulut
  • Rumeysa Ciftci
  • Murat Serilmez
  • Vildan Yasasever
  • Adnan Aydiner
Original Article



This study was conducted to determine the clinical significance of serum M30 and M65 in epithelial ovarian cancer (EOC).


A total of 56 patients with EOC and 56 healthy women were included in the study. All of the patients received platinum-based chemotherapy. Pretreatment levels of M30 and M65 were measured using the quantitative ELISA method.


The median M30 and M65 serum levels were significantly elevated in the EOC patients compared with the healthy controls (96.7 vs. 69.5, p = 0.028 and 436.4 versus 166.3, p < 0.001, respectively). The cut-off value of 423.4 U/L for M65 determined with ROC analysis, predicted progression with 75.1 % sensitivity and 65.6 % specificity (AUC = 0.708, p = 0.008). Patients with higher M65 levels had shorter progression-free survival (PFS) (p = 0.021). Both M30 and M65 serum levels were significantly higher for serous-type histology (p = 0.001 and p < 0.001, respectively). Increased M65 serum levels were associated with advanced disease (p = 0.005) and higher grade (p = 0.005). Moreover, M65 levels were higher for chemotherapy-resistant patients (p = 0.04). Multivariate analysis revealed that an elevated serum M65 level was the only significant independent prognostic factor (p = 0.039, HR 3.792).


These results indicated that serum M30 and M65 levels were significantly elevated in patients with EOC compared with healthy women. Particularly, high serum M65 levels were associated with poor prognosis and resistance to platinum-based chemotherapy.


Serum M65 Biomarker Epithelial ovarian cancer Apoptosis Prognostic 



We thank all of our patients and their families for their participation in this study, as well as the investigators and staff from the participating sites. No financial support was received for this work.

Conflict of interest



  1. 1.
    Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62(1):10–29. doi: 10.3322/caac.20138 PubMedCrossRefGoogle Scholar
  2. 2.
    Cannistra SA (2004) Cancer of the ovary. N Engl J Med 351(24):2519–2529. doi: 10.1056/NEJMra041842 PubMedCrossRefGoogle Scholar
  3. 3.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. doi: 10.3322/caac.20107 PubMedCrossRefGoogle Scholar
  4. 4.
    Gadducci A, Cosio S, Tana R, Genazzani AR (2009) Serum and tissue biomarkers as predictive and prognostic variables in epithelial ovarian cancer. Crit Rev Oncol Hematol 69(1):12–27. doi: 10.1016/j.critrevonc.2008.05.001 PubMedCrossRefGoogle Scholar
  5. 5.
    Baekelandt M, Holm R, Nesland JM, Trope CG, Kristensen GB (2000) Expression of apoptosis-related proteins is an independent determinant of patient prognosis in advanced ovarian cancer. J Clin Oncol 18(22):3775–3781PubMedGoogle Scholar
  6. 6.
    Codegoni AM, Bertoni F, Colella G, Caspani G, Grassi L, D’Incalci M, Broggini M (1999) Microsatellite instability and frameshift mutations in genes involved in cell cycle progression or apoptosis in ovarian cancer. Oncol Res 11(7):297–301PubMedGoogle Scholar
  7. 7.
    Baekelandt M, Kristensen GB, Nesland JM, Trope CG, Holm R (1999) Clinical significance of apoptosis-related factors p53, Mdm2, and Bcl-2 in advanced ovarian cancer. J Clin Oncol 17(7):2061PubMedGoogle Scholar
  8. 8.
    Demiray M, Ulukaya EE, Arslan M, Gokgoz S, Saraydaroglu O, Ercan I, Evrensel T, Manavoglu O (2006) Response to neoadjuvant chemotherapy in breast cancer could be predictable by measuring a novel serum apoptosis product, caspase-cleaved cytokeratin 18: a prospective pilot study. Cancer Invest 24(7):669–676. doi: 10.1080/07357900600981307 PubMedCrossRefGoogle Scholar
  9. 9.
    Ulukaya E, Yilmaztepe A, Akgoz S, Linder S, Karadag M (2007) The levels of caspase-cleaved cytokeratin 18 are elevated in serum from patients with lung cancer and helpful to predict the survival. Lung Cancer 56(3):399–404. doi: 10.1016/j.lungcan.2007.01.015 PubMedCrossRefGoogle Scholar
  10. 10.
    Olofsson MH, Ueno T, Pan Y, Xu R, Cai F, van der Kuip H, Muerdter TE, Sonnenberg M, Aulitzky WE, Schwarz S, Andersson E, Shoshan MC, Havelka AM, Toi M, Linder S (2007) Cytokeratin-18 is a useful serum biomarker for early determination of response of breast carcinomas to chemotherapy. Clin Cancer Res 13(11):3198–3206. doi: 10.1158/1078-0432.CCR-07-0009 PubMedCrossRefGoogle Scholar
  11. 11.
    Ausch C, Buxhofer-Ausch V, Olszewski U, Hinterberger W, Ogris E, Schiessel R, Hamilton G (2009) Caspase-cleaved cytokeratin 18 fragment (M30) as marker of postoperative residual tumor load in colon cancer patients. Eur J Surg Oncol 35(11):1164–1168. doi: 10.1016/j.ejso.2009.02.007 PubMedCrossRefGoogle Scholar
  12. 12.
    Oyama K, Fushida S, Kinoshita J, Okamoto K, Makino I, Nakamura K, Hayashi H, Inokuchi M, Nakagawara H, Tajima H, Fujita H, Takamura H, Ninomiya I, Kitagawa H, Fujimura T, Ohta T (2012) Serum cytokeratin 18 as a biomarker for gastric cancer. Clin Exp Med. doi: 10.1007/s10238-012-0202-9
  13. 13.
    Bilici A, Ustaalioglu BB, Ercan S, Orcun A, Seker M, Salepci T, Gumus M (2011) Is there any impact of plasma M30 and M65 levels on progression-free survival of patients with advanced gastric cancer? Cancer Chemother Pharmacol 68(2):309–316. doi: 10.1007/s00280-010-1480-0 PubMedCrossRefGoogle Scholar
  14. 14.
    Yaman E, Coskun U, Sancak B, Buyukberber S, Ozturk B, Benekli M (2010) Serum M30 levels are associated with survival in advanced gastric carcinoma patients. Int Immunopharmacol 10(7):719–722. doi: 10.1016/j.intimp.2010.03.013 PubMedCrossRefGoogle Scholar
  15. 15.
    Bodenmuller H, Donie F, Kaufmann M, Banauch D (1994) The tumor markers TPA, TPS, TPACYK and CYFRA 21–1 react differently with the keratins 8, 18 and 19. Int J Biol Markers 9(2):70–74PubMedGoogle Scholar
  16. 16.
    Gadducci A, Ferdeghini M, Cosio S, Fanucchi A, Cristofani R, Genazzani AR (2001) The clinical relevance of serum CYFRA 21–1 assay in patients with ovarian cancer. Int J Gynecol Cancer 11(4):277–282. doi: 10.1046/j.1525-1438.2001.011004277.x PubMedCrossRefGoogle Scholar
  17. 17.
    Tempfer C, Hefler L, Heinzl H, Loesch A, Gitsch G, Rumpold H, Kainz C (1998) CYFRA 21–1 serum levels in women with adnexal masses and inflammatory diseases. Br J Cancer 78(8):1108–1112PubMedCrossRefGoogle Scholar
  18. 18.
    Behbakht K, Sill MW, Darcy KM, Rubin SC, Mannel RS, Waggoner S, Schilder RJ, Cai KQ, Godwin AK, Alpaugh RK (2011) Phase II trial of the mTOR inhibitor, temsirolimus and evaluation of circulating tumor cells and tumor biomarkers in persistent and recurrent epithelial ovarian and primary peritoneal malignancies: a Gynecologic Oncology Group study. Gynecol Oncol 123(1):19–26. doi: 10.1016/j.ygyno.2011.06.022 PubMedCrossRefGoogle Scholar
  19. 19.
    Cummings J, Ranson M, Lacasse E, Ganganagari JR, St-Jean M, Jayson G, Durkin J, Dive C (2006) Method validation and preliminary qualification of pharmacodynamic biomarkers employed to evaluate the clinical efficacy of an antisense compound (AEG35156) targeted to the X-linked inhibitor of apoptosis protein XIAP. Br J Cancer 95(1):42–48. doi: 10.1038/sj.bjc.6603220 PubMedCrossRefGoogle Scholar
  20. 20.
    Karlsen MA, Sandhu N, Hogdall C, Christensen IJ, Nedergaard L, Lundvall L, Engelholm SA, Pedersen AT, Hartwell D, Lydolph M, Laursen IA, Hogdall EV (2012) Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass. Gynecol Oncol 127(2):379–383. doi: 10.1016/j.ygyno.2012.07.106 PubMedCrossRefGoogle Scholar
  21. 21.
    Gagnon A, Ye B (2008) Discovery and application of protein biomarkers for ovarian cancer. Curr Opin Obstet Gynecol 20(1):9–13. doi: 10.1097/GCO.0b013e3282f226a5 PubMedCrossRefGoogle Scholar
  22. 22.
    Bast RC Jr, Badgwell D, Lu Z, Marquez R, Rosen D, Liu J, Baggerly KA, Atkinson EN, Skates S, Zhang Z, Lokshin A, Menon U, Jacobs I, Lu K (2005) New tumor markers: CA125 and beyond. Int J Gynecol Cancer 15(Suppl 3):274–281. doi: 10.1111/j.1525-1438.2005.00441.x PubMedCrossRefGoogle Scholar
  23. 23.
    Hogdall E (2008) Cancer antigen 125 and prognosis. Curr Opin Obstet Gynecol 20(1):4–8. doi: 10.1097/GCO.0b013e3282f2b124 PubMedCrossRefGoogle Scholar
  24. 24.
    Greystoke A, Cummings J, Ward T, Simpson K, Renehan A, Butt F, Moore D, Gietema J, Blackhall F, Ranson M, Hughes A, Dive C (2008) Optimisation of circulating biomarkers of cell death for routine clinical use. Ann Oncol 19(5):990–995. doi: 10.1093/annonc/mdn014 PubMedCrossRefGoogle Scholar
  25. 25.
    Holdenrieder S, Stieber P, VONP J, Raith H, Nagel D, Feldmann K, Seidel D (2006) Early and specific prediction of the therapeutic efficacy in non-small cell lung cancer patients by nucleosomal DNA and cytokeratin-19 fragments. Ann N Y Acad Sci 1075:244–257. doi: 10.1196/annals.1368.033 PubMedCrossRefGoogle Scholar
  26. 26.
    Pichon MF, Labroquere M, Rezai K, Lokiec F (2006) Variations of soluble Fas and cytokeratin 18-Asp 396 neo-epitope in different cancers during chemotherapy. Anticancer Res 26(3B):2387–2392PubMedGoogle Scholar
  27. 27.
    Barczyk K, Kreuter M, Pryjma J, Booy EP, Maddika S, Ghavami S, Berdel WE, Roth J, Los M (2005) Serum cytochrome c indicates in vivo apoptosis and can serve as a prognostic marker during cancer therapy. Int J Cancer 116(2):167–173. doi: 10.1002/ijc.21037 PubMedCrossRefGoogle Scholar
  28. 28.
    Wu YX, Wang JH, Wang H, Yang XY (2003) Study on expression of Ki-67, early apoptotic protein M30 in endometrial carcinoma and their correlation with prognosis. Zhonghua Bing Li Xue Za Zhi 32(4):314–318PubMedGoogle Scholar
  29. 29.
    de Haas EC, di Pietro A, Simpson KL, Meijer C, Suurmeijer AJ, Lancashire LJ, Cummings J, de Jong S, de Vries EG, Dive C, Gietema JA (2008) Clinical evaluation of M30 and M65 ELISA cell death assays as circulating biomarkers in a drug-sensitive tumor, testicular cancer. Neoplasia 10(10):1041–1048PubMedGoogle Scholar
  30. 30.
    Kramer G, Schwarz S, Hagg M, Havelka AM, Linder S (2006) Docetaxel induces apoptosis in hormone refractory prostate carcinomas during multiple treatment cycles. Br J Cancer 94(11):1592–1598. doi: 10.1038/sj.bjc.6603129 PubMedGoogle Scholar
  31. 31.
    Koelink PJ, Lamers CB, Hommes DW, Verspaget HW (2009) Circulating cell death products predict clinical outcome of colorectal cancer patients. BMC Cancer 9:88. doi: 10.1186/1471-2407-9-88 PubMedCrossRefGoogle Scholar
  32. 32.
    Bilici A, Ustaalioglu BB, Ercan S, Seker M, Yilmaz BE, Orcun A, Gumus M (2012) The prognostic significance of the increase in the serum M30 and M65 values after chemotherapy and relationship between these values and clinicopathological factors in patients with advanced gastric cancer. Tumour Biol. doi: 10.1007/s13277-012-0481-5
  33. 33.
    Brandt D, Volkmann X, Anstatt M, Langer F, Manns MP, Schulze-Osthoff K, Bantel H (2010) Serum biomarkers of cell death for monitoring therapy response of gastrointestinal carcinomas. Eur J Cancer 46(8):1464–1473. doi: 10.1016/j.ejca.2010.01.037 PubMedCrossRefGoogle Scholar
  34. 34.
    Oven Ustaalioglu B, Bilici A, Ercan S, Orcun A, Seker M, Ozkan A, Ustaalioglu R, Gumus M (2012) Serum M30 and M65 values in patients with advanced stage non-small-cell lung cancer compared with controls. Clin Transl Oncol 14(5):356–361. doi: 10.1007/s12094-012-0808-0 PubMedCrossRefGoogle Scholar
  35. 35.
    Ozturk B, Coskun U, Sancak B, Yaman E, Buyukberber S, Benekli M (2009) Elevated serum levels of M30 and M65 in patients with locally advanced head and neck tumors. Int Immunopharmacol 9(5):645–648. doi: 10.1016/j.intimp.2009.02.004 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Ibrahim Yildiz
    • 1
    Email author
  • Faruk Tas
    • 1
  • Leyla Kilic
    • 1
  • Fatma Sen
    • 1
  • Pinar Saip
    • 1
  • Yesim Eralp
    • 1
  • Serkan Keskin
    • 1
  • Senem Karabulut
    • 1
  • Rumeysa Ciftci
    • 1
  • Murat Serilmez
    • 2
  • Vildan Yasasever
    • 2
  • Adnan Aydiner
    • 1
  1. 1.Department of Medical Oncology, Institute of OncologyIstanbul UniversityIstanbulTurkey
  2. 2.Department of Basic Oncology, Institute of OncologyIstanbul UniversityIstanbulTurkey

Personalised recommendations