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Journal of Ovarian Research
Published in: Journal of Ovarian Research 1/2017

Open Access 01-12-2017 | Research

Correlates of circulating ovarian cancer early detection markers and their contribution to discrimination of early detection models: results from the EPIC cohort

Authors: Renée T. Fortner, Allison F. Vitonis, Helena Schock, Anika Hüsing, Theron Johnson, Raina N. Fichorova, Titilayo Fashemi, Hidemi S. Yamamoto, Anne Tjønneland, Louise Hansen, Kim Overvad, Marie-Christine Boutron-Ruault, Marina Kvaskoff, Gianluca Severi, Heiner Boeing, Antonia Trichopoulou, Vassiliki Benetou, Carlo La Vecchia, Domenico Palli, Sabina Sieri, Rosario Tumino, Giuseppe Matullo, Amalia Mattiello, N. Charlotte Onland-Moret, Petra H. Peeters, Elisabete Weiderpass, Inger Torhild Gram, Mie Jareid, J. Ramón Quirós, Eric J. Duell, Maria-Jose Sánchez, María Dolores Chirlaque, Eva Ardanaz, Nerea Larrañaga, Björn Nodin, Jenny Brändstedt, Annika Idahl, Kay-Tee Khaw, Naomi Allen, Marc Gunter, Mattias Johansson, Laure Dossus, Melissa A. Merritt, Elio Riboli, Daniel W. Cramer, Rudolf Kaaks, Kathryn L. Terry

Published in: Journal of Ovarian Research | Issue 1/2017

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Abstract

Background

Ovarian cancer early detection markers CA125, CA15.3, HE4, and CA72.4 vary between healthy women, limiting their utility for screening.

Methods

We evaluated cross-sectional relationships between lifestyle and reproductive factors and these markers among controls (n = 1910) from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Improvements in discrimination of prediction models adjusting for correlates of the markers were evaluated among postmenopausal women in the nested case-control study (n = 590 cases). Generalized linear models were used to calculate geometric means of CA125, CA15.3, and HE4. CA72.4 above vs. below limit of detection was evaluated using logistic regression. Early detection prediction was modeled using conditional logistic regression.

Results

CA125 concentrations were lower, and CA15.3 higher, in post- vs. premenopausal women (p ≤ 0.02). Among postmenopausal women, CA125 was higher among women with higher parity and older age at menopause (ptrend ≤ 0.02), but lower among women reporting oophorectomy, hysterectomy, ever use of estrogen-only hormone therapy, or current smoking (p < 0.01). CA15.3 concentrations were higher among heavier women and in former smokers (p ≤ 0.03). HE4 was higher with older age at blood collection and in current smokers, and inversely associated with OC use duration, parity, and older age at menopause (≤ 0.02). No associations were observed with CA72.4. Adjusting for correlates of the markers in prediction models did not improve the discrimination.

Conclusions

This study provides insights into sources of variation in ovarian cancer early detection markers in healthy women and informs about the utility of individualizing marker cutpoints based on epidemiologic factors.
Appendix
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Literature
1.
Haridas D, Ponnusamy MP, Chugh S, Lakshmanan I, Seshacharyulu P, Batra SK. MUC16: molecular analysis and its functional implications in benign and malignant conditions. FASEB J. 2014;28(10):4183–99.CrossRefPubMed
2.
Nath S, Mukherjee P. MUC1: a multifaceted oncoprotein with a key role in cancer progression. Trends Mol Med. 2014;20(6):332–42.CrossRefPubMed
3.
Ferraro S, Braga F, Lanzoni M, Boracchi P, Biganzoli EM, Panteghini M. Serum human epididymis protein 4 vs carbohydrate antigen 125 for ovarian cancer diagnosis: a systematic review. J Clin Pathol. 2013;66(4):273–81.CrossRefPubMed
4.
Guadagni F, Roselli M, Cosimelli M, Ferroni P, Spila A, Cavaliere F, Casaldi V, Wappner G, Abbolito MR, Greiner JW, et al. CA 72-4 serum marker—a new tool in the management of carcinoma patients. Cancer Invest. 1995;13(2):227–38.CrossRefPubMed
5.
Terry KL, Schock H, Fortner RT, Husing A, Fichorova RN, Yamamoto HS, Vitonis AF, Johnson T, Overvad K, Tjonneland A, et al. A Prospective Evaluation of Early Detection Biomarkers for Ovarian Cancer in the European EPIC Cohort. Clin Cancer Res. 2016;22(18):4664–75.CrossRefPubMed
6.
Johnson CC, Kessel B, Riley TL, Ragard LR, Williams CR, Xu J-L, Buys SS, Prostate L. Colorectal and ovarian cancer project team: the epidemiology of CA-125 in women without evidence of ovarian cancer in the prostate, lung, colorectal and ovarian cancer (PLCO) screening trial. Gynecol Oncol. 2008;110(3):383–9.CrossRefPubMedPubMedCentral
7.
Pauler DK, Menon U, McIntosh M, Symecko HL, Skates SJ, Jacobs IJ. Factors influencing serum CA125II levels in healthy postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2001;10(5):489–93.PubMed
8.
Skates SJ, Mai P, Horick NK, Piedmonte M, Drescher CW, Isaacs C, Armstrong DK, Buys SS, Rodriguez GC, Horowitz IR, et al. Large prospective study of ovarian cancer screening in high-risk women: CA125 cut-point defined by menopausal status. Cancer Prev Res. 2011;4(9):1401–8.CrossRef
9.
Ferraro S, Borille S, Caruso S, Boggio A, Muzio F, Rizzi A, Panteghini M. Body mass index does not influence human epididymis protein 4 concentrations in serum. Clin Chim Acta. 2015;446:163–4.CrossRefPubMed
10.
Ferraro S, Schiumarini D, Panteghini M. Human epididymis protein 4: factors of variation. Clin Chim Acta. 2015;438:171–7.CrossRefPubMed
11.
Urban N, Thorpe J, Karlan BY, McIntosh MW, Palomares MR, Daly MB, Paley P, Drescher CW. Interpretation of single and serial measures of HE4 and CA125 in asymptomatic women at high risk for ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2012;21(11):2087–94.CrossRefPubMedPubMedCentral
12.
Urban N, Thorpe JD, Bergan LA, Forrest RM, Kampani AV, Scholler N, O’Briant KC, Anderson GL, Cramer DW, Berg CD, et al. Potential role of HE4 in multimodal screening for epithelial ovarian cancer. J Natl Cancer Inst. 2011;103(21):1630–4.CrossRefPubMedPubMedCentral
13.
Takami M, Sakamoto H, Ohtani K, Takami T, Satoh K. An evaluation of CA125 levels in 291 normal postmenopausal and 20 endometrial adenocarcinoma-bearing women before and after surgery. Cancer Lett. 1997;121(1):69–72.CrossRefPubMed
14.
Nguyen H, Jacobson A, Patino-Paul R. New reference levels for CA125 in pre- and postmenopausal women. Prim Care Update Ob Gyns. 1998;5(4):157.CrossRefPubMed
15.
Crump C, McIntosh MW, Urban N, Anderson G, Karlan BY. Ovarian cancer tumor marker behavior in asymptomatic healthy women: implications for screening. Cancer Epidemiol Biomarkers Prev. 2000;9(10):1107–11.PubMed
16.
Bon GG, Kenemans P, Verstraeten R, van Kamp GJ, Hilgers J. Serum tumor marker immunoassays in gynecologic oncology: establishment of reference values. Am J Obstet Gynecol. 1996;174(1 Pt 1):107–14.CrossRefPubMed
17.
Bjerner J, Høgetveit A, Wold Akselberg K, Vangsnes K, Paus E, Bjøro T, Børmer OP, Nustad K. Reference intervals for carcinoembryonic antigen (CEA), CA125, MUC1, Alfa‐foeto‐protein (AFP), neuron‐specific enolase (NSE) and CA19.9 from the NORIP study. Scand J Clin Lab Invest. 2008;68(8):703–13.CrossRefPubMed
18.
Riboli E, Hunt KJ, Slimani N, Ferrari P, Norat T, Fahey M, Charrondiere UR, Hemon B, Casagrande C, Vignat J, et al. European Prospective Investigation into Cancer and Nutrition (EPIC): study populations and data collection. Public Health Nutr. 2002;5(6B):1113–24.CrossRefPubMed
19.
Rosner B. Percentage Points for a Generalized Esd Many-Outlier Procedure. Technometrics. 1983;25(2):165–72.CrossRef
20.
Stemp M, Roberts P, McClements A, Chapple V, Natalwala MB, Black M, Matson P. Serum concentrations of the biomarkers CA125, CA15-3, CA72-4, tPSA and PAPP-A in natural and stimulated ovarian cycles. Asian Pacific J Reprod. 2014;3(2):90–6.CrossRef
21.
McLemore MR, Aouizerat BE, Lee KA, Chen L, Cooper B, Tozzi M, Miaskowski C. A comparison of the cyclic variation in serum levels of CA125 across the menstrual cycle using two commercial assays. Biol Res Nurs. 2012;14(3):250–6.CrossRefPubMed
22.
Li K, Husing A, Fortner RT, Tjonneland A, Hansen L, Dossus L, Chang-Claude J, Bergmann M, Steffen A, Bamia C, et al. An epidemiologic risk prediction model for ovarian cancer in Europe: the EPIC study. Br J Cancer. 2015;112(Suppl(7)):1257–65.CrossRefPubMedPubMedCentral
23.
Dehaghani AS, Ghiam AF, Hosseini M, Mansouri S, Ghaderi A. Factors influencing serum concentration of CA125 and CA15-3 in Iranian healthy postmenopausal women. Pathol Oncol Res. 2007;13(4):360–4.CrossRefPubMed
24.
Yu S, Lee JK, Kim JH, Park H, Lee MY, Ryu S, Kwon MJ, Woo HY. Diagnostic performance and establishment of reference limits of HE4 in Korean healthy women. Gynecol Oncol. 2016;143(1):128–34.CrossRefPubMed
25.
Hallamaa M, Suvitie P, Huhtinen K, Matomaki J, Poutanen M, Perheentupa A. Serum HE4 concentration is not dependent on menstrual cycle or hormonal treatment among endometriosis patients and healthy premenopausal women. Gynecol Oncol. 2012;125(3):667–72.CrossRefPubMed
26.
Galgano MT, Hampton GM, Frierson Jr HF. Comprehensive analysis of HE4 expression in normal and malignant human tissues. Mod Pathol. 2006;19(6):847–53.PubMed
27.
Group ECW. Ovarian and endometrial function during hormonal contraception. Hum Reprod. 2001;16(7):1527–35.CrossRef
28.
Morrison C, Fichorova RN, Mauck C, Chen PL, Kwok C, Chipato T, Salata R, Doncel GF. Cervical inflammation and immunity associated with hormonal contraception, pregnancy, and HIV-1 seroconversion. J Acquir Immune Defic Syndr. 2014;66(2):109–17.PubMed
29.
Karabacak O, Ilgin N, Tiras B, Gursoy R, Himmetoglu O. Influence of exogenous estrogen administration on serum CA-125 originating from the endometrium. Int J Gynaecol Obstet. 2002;76(2):169–72.CrossRefPubMed
30.
Okon MA, Lee S, Laird SM, Li TC. A prospective randomized controlled study comparing the morphological and biochemical responses of the endometrium to two different forms of ‘period-free’ hormone replacement therapy. Hum Reprod. 1998;13(8):2261–5.CrossRefPubMed
31.
Cengiz B, Atabekoglu C, Cetinkaya E, Cengiz SD. Effect of hormone replacement therapy on serum levels of tumor markers in healthy postmenopausal women. Maturitas. 2003;46(4):301–6.CrossRefPubMed
32.
Szecsi PB, Andersen MR, Bjørngaard B, Hedengran KK, Stender S. Cancer antigen 125 after delivery in women with a normal pregnancy: a prospective cohort study. Acta Obstet Gynecol Scand. 2014;93(12):1295–301.CrossRefPubMed
33.
Haga Y, Sakamoto K, Egami H, Yoshimura R, Akagi M. Evaluation of serum CA125 values in healthy individuals and pregnant women. Am J Med Sci. 1986;292(1):25–9.CrossRefPubMed
34.
Aslam N, Ong C, Woelfer B, Nicolaides K, Jurkovic D. Serum CA125 at 11–14 weeks of gestation in women with morphologically normal ovaries. BJOG. 2000;107(5):689–90.CrossRefPubMed
35.
Kobayashi F, Takashima E, Sagawa N, Mori T, Fujii S. Maternal serum CA125 levels in early intrauterine and tubal pregnancies. Arch Gynecol Obstet. 1993;252(4):185–9.CrossRefPubMed
36.
Ercan Ş, Kaymaz Ö, Yücel N, Orçun A. Serum concentrations of CA 125, CA 15–3, CA 19–9 and CEA in normal pregnancy: a longitudinal study. Arch Gynecol Obstet. 2012;285(3):579–84.CrossRefPubMed
37.
Westhoff C, Gollub E, Patel J, Rivera H, Bast R. CA 125 levels in menopausal women. Obstet Gynecol. 1990;76(3 Pt 1):428–31.PubMed
38.
Dalton CF, Laird SM, Estdale SE, Saravelos HG, Li TC. Endometrial protein PP14 and CA-125 in recurrent miscarriage patients; correlation with pregnancy outcome. Hum Reprod. 1998;13(11):3197–202.CrossRefPubMed
39.
Lowe KA, Shah C, Wallace E, Anderson G, Paley P, McIntosh M, Andersen MR, Scholler N, Bergan L, Thorpe J, et al. Effects of personal characteristics on serum CA125, mesothelin, and HE4 levels in healthy postmenopausal women at high-risk for ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2008;17(9):2480–7.CrossRefPubMedPubMedCentral
40.
Atoum M, Nimer N, Abdeldayem S, Nasr H. Relationships among serum CA15-3 tumor marker, TNM staging, and estrogen and progesterone receptor expression in benign and malignant breast lesions. Asian Pac J Cancer Prev. 2012;13(3):857–60.CrossRefPubMed
41.
Bolstad N, Oijordsbakken M, Nustad K, Bjerner J. Human epididymis protein 4 reference limits and natural variation in a Nordic reference population. Tumour Biol. 2012;33(1):141–8.CrossRefPubMed
42.
Green PJ, Ballas SK, Westkaemper P, Schwartz HG, Klug TL, Zurawski VR. CA 19–9 and CA 125 levels in the sera of normal blood donors in relation to smoking history. J Natl Cancer Inst. 1986;77(2):337–41.PubMed
43.
Hornstein MD, Goodman HM, Thomas PP, Knapp RC, Harlow BL. Use of a second-generation CA125 assay in gynecologic patients. Gynecol Obstet Invest. 1996;42(3):196–200.CrossRefPubMed
44.
Marom-Haham L, Shulman A. Cigarette smoking and hormones. Curr Opin Obstet Gynecol. 2016;28(4):230–5.CrossRefPubMed
45.
Schoenaker DA, Jackson CA, Rowlands JV, Mishra GD. Socioeconomic position, lifestyle factors and age at natural menopause: a systematic review and meta-analyses of studies across six continents. Int J Epidemiol. 2014;43(5):1542–62.CrossRefPubMedPubMedCentral
46.
Davies JR, Kirkham S, Svitacheva N, Thornton DJ, Carlstedt I. MUC16 is produced in tracheal surface epithelium and submucosal glands and is present in secretions from normal human airway and cultured bronchial epithelial cells. Int J Biochem Cell Biol. 2007;39(10):1943–54.CrossRefPubMed
47.
van Altena AM, Holtsema H, Hendriks JC, Massuger LF, de Hullu JA. Cancer antigen 125 level after a bilateral salpingo-oophorectomy: what is the contribution of the ovary to the cancer antigen 125 level? Menopause (New York, NY). 2011;18(2):133–7.
48.
Zeimet AG, Müller-Holzner E, Marth C, Daxenbichler G, Dapunt O. Tumor marker CA-125 in tissues of the female reproductive tract and in serum during the normal menstrual cycle. Fertil Steril. 1993;59(5):1028–35.CrossRefPubMed
Metadata
Title
Correlates of circulating ovarian cancer early detection markers and their contribution to discrimination of early detection models: results from the EPIC cohort
Authors
Renée T. Fortner
Allison F. Vitonis
Helena Schock
Anika Hüsing
Theron Johnson
Raina N. Fichorova
Titilayo Fashemi
Hidemi S. Yamamoto
Anne Tjønneland
Louise Hansen
Kim Overvad
Marie-Christine Boutron-Ruault
Marina Kvaskoff
Gianluca Severi
Heiner Boeing
Antonia Trichopoulou
Vassiliki Benetou
Carlo La Vecchia
Domenico Palli
Sabina Sieri
Rosario Tumino
Giuseppe Matullo
Amalia Mattiello
N. Charlotte Onland-Moret
Petra H. Peeters
Elisabete Weiderpass
Inger Torhild Gram
Mie Jareid
J. Ramón Quirós
Eric J. Duell
Maria-Jose Sánchez
María Dolores Chirlaque
Eva Ardanaz
Nerea Larrañaga
Björn Nodin
Jenny Brändstedt
Annika Idahl
Kay-Tee Khaw
Naomi Allen
Marc Gunter
Mattias Johansson
Laure Dossus
Melissa A. Merritt
Elio Riboli
Daniel W. Cramer
Rudolf Kaaks
Kathryn L. Terry
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Ovarian Research / Issue 1/2017
Electronic ISSN: 1757-2215
DOI
https://doi.org/10.1186/s13048-017-0315-6

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