Clinical Use of Cancer Biomarkers in Epithelial Ovarian Cancer: Updated Guidelines From the European Group on Tumor Markers

Sölétormos, György MD, DMSc*; Duffy, Michael J. MD, PhD; Othman Abu Hassan, Suher MD*; Verheijen, René H.M. MD, PhD; Tholander, Bengt MD, PhD§; Bast, Robert C. Jr MD, PhD; Gaarenstroom, Katja N. MD, PhD; Sturgeon, Catharine M. MD, PhD#; Bonfrer, Johannes M. MD, PhD**; Petersen, Per Hyltoft Msc††; Troonen, Hugo PhD, MSc‡‡; CarloTorre, Gian MD, PhD§§; Kanty Kulpa, Jan MD, PhD∥∥; Tuxen, Malgorzata K. MD, PhD¶¶; Molina, Raphael MD, PhD##

International Journal of Gynecological Cancer: January 2016 - Volume 26 - Issue 1 - p 43–51
doi: 10.1097/IGC.0000000000000586
Ovarian Cancer

Objective: To present an update of the European Group on Tumor Markers guidelines for serum markers in epithelial ovarian cancer.

Methods: Systematic literature survey from 2008 to 2013. The articles were evaluated by level of evidence and strength of recommendation.

Results: Because of its low sensitivity (50–62% for early stage epithelial ovarian cancer) and limited specificity (94–98.5%), cancer antigen (CA) 125 (CA125) is not recommended as a screening test in asymptomatic women. The Risk of Malignancy Index, which includes CA125, transvaginal ultrasound, and menopausal status, is recommended for the differential diagnosis of a pelvic mass. Because human epididymis protein 4 has been reported to have superior specificity to CA125, especially in premenopausal women, it may be considered either alone or as part of the risk of ovarian malignancy algorithm, in the differential diagnosis of pelvic masses, especially in such women. CA125 should be used to monitor response to first-line chemotherapy using the previously published criteria of the Gynecological Cancer Intergroup, that is, at least a 50% reduction of a pretreatment sample of 70 kU/L or greater. The value of CA125 in posttherapy surveillance is less clear. Although a prospective randomized trial concluded that early administration of chemotherapy based on increasing CA125 levels had no effect on survival, European Group on Tumor Markers state that monitoring with CA125 in this situation should occur, especially if the patient is a candidate for secondary cytoreductive surgery.

Conclusions: At present, CA125 remains the most important biomarker for epithelial ovarian cancer, excluding tumors of mucinous origin.

*Department of Clinical Biochemistry, University of Copenhagen North Zealand Hospital, Hillerød, Denmark; †Clinical Research Centre, St Vincent’s University Hospital and UCD School of Medicine and Medical Science, Conway Institute of Bimolecular and Biomedical, Research, University College Dublin, Dublin, Ireland; ‡Department of Gynecological Oncology, University Medical, Centre Utrecht, Utrecht, the Netherlands; §Department of Oncology, Gynecologic Oncology Unit, Uppsala, University Hospital, Uppsala, Sweden; ∥Division of Cancer Medicine, Department of Gynecologic Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; ¶Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands; #Department of Clinical Biochemistry, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; **Senior Expert Clinical Laboratories, PUM Netherlands Senior Experts, Heemstede, the Netherlands; ††Norwegian Quality Improvement of Primary Care Laboratories (NOKLUS), Section for General Practice, University of Bergen, Bergen, Norway; ‡‡Emeritus Scientist from Abbott, Limburg, Germany; §§Consultant, Centro Ippocrate, Bogliasco, Italy; ∥∥Department of Clinical Biochemistry, Center of Oncology - M. Sklodowska-Curie Memorial Institute, Cracow Division, Poland; ¶¶Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev, Denmark; and ##Laboratory of Biochemistry, Hospital Clinico, Barcelona, Spain.

Address correspondence and reprint requests to György Sölétormos, MD, DMSc, Department of Clinical Biochemistry, University of Copenhagen North Zealand Hospital, Dyrehavevej 29, DK-3400, Hillerød, Denmark. E-mail: Georg.Soeletormos@regionh.dk.

R.C.B. receives royalties for CA125 from Fujirebio Diagnostics Inc. and serves on the Scientific Advisory Board of Vermillion.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

Received August 22, 2014

Received in revised form August 14, 2015

Accepted September 4, 2015

Article Outline

Cancer antigen 125 (CA125) is currently the only serological biomarker in routine use for the management of patients with epithelial ovarian/fallopian tube or primary serous peritoneal cancer.1 The reference interval for CA125 is 35 kU/L or less.2 Elevated concentrations can occur in healthy premenopausal women during menses, in pregnancy, and in nonmalignant gynecologic diseases, such as ovarian cysts, endometriosis, adenomyosis, and uterine leiomyomas. High serum concentrations may also occur in several nonmalignant nongynecological diseases, such as peritoneal, pleural, and musculoskeletal inflammatory disorders as well as pelvic inflammatory disease, liver, and renal as well as cardiac disease (Fig. 1). Additionally, elevated concentrations can occur in most types of advanced adenocarcinomas, including breast, colorectal, pancreas, lung, endometrium, and cervix (Fig. 2).4–6 In women with epithelial ovarian cancer, approximately 80% have concentrations above 35 kU/L, with elevations in 50% to 60% of patients with clinical stage I disease, 80% to 90% in stage II, and greater than 90% in stages III to IV.4,5 However, the frequency of elevated concentrations is highest in patients with serous epithelial ovarian cancer followed by endometrioid and clear cell types.4,5 The CA125 is not expressed in pure mucinous tumors and is not useful among patients with this histological type of epithelial ovarian cancer.4,7,8 Carcinoembryonic antigen or CA19.9 may be better markers in these patients.7,9

Back to Top | Article Outline

METHODS

Literature was searched in the Medline Database, using the following criteria: human epididymis protein 4 (HE4), ovarian carcinoma, CA125; and screening or diagnosis or prognosis or monitoring; and ovarian carcinoma or HE4 or human epididymis protein 4, or CA125. Filters are publication dates from January 1, 2008, to December 31, 2013. All of the titles were generated by the search, and the abstracts were reviewed for relevance, after which the full articles were obtained for those selected. The articles were evaluated by level of evidence (LOE) and strength of recommendation (SOR) according to the classifications provided in Tables 1 and 2, respectively.10,11 Earlier guideline articles and their references were also searched.4,8 The results of the literature search were structured according to the types of marker utility as presented in Table 3.

Back to Top | Article Outline

RESULTS

CA125 Screening

The Prostate, Lung, Colorectal, and Ovarian Cancer trial in the United States was a randomized controlled trial in which 78,216 women aged 55 to 74 years were included between 1993 and 2001. There was no evidence of a shift to early-stage disease associated with screening using CA125 and transvaginal ultrasound. Furthermore, ovarian cancer mortality was equivalent in both groups.12 An earlier multicenter randomized controlled trial was conducted in Japan between 1985 and 1999, in which postmenopausal women were assigned to either a screening group (n = 41,688) or a control group (n = 40,799). The screening group was assigned to pelvic examination, transvaginal ultrasound, and CA125. No tests were applied in women allocated to the control group. The study showed a decrease in stage at detection; however, analysis of mortality in the screening and control group has not yet been reported.13 In a single-arm prospective study, the University of Kentucky Ovarian Cancer Screening Trial conducted from 1987 to 2011, 37,293 women were screened annually with ultrasound and CA125.14 Eligibility criteria included all asymptomatic women aged 50 years or older and women aged 25 years or older with a documented family history of ovarian cancer. Although there was no randomization against a control group, a historic control group was available, consisting of 380 patients diagnosed with ovarian cancer during the study period. The trial suggested a decrease in stage at detection as well as a survival benefit.14 Another single-arm, prospective multicenter study, also from the United States, investigated the utility of a 2-stage ovarian cancer screening strategy using a risk of ovarian cancer algorithm among 4051 postmenopausal women. Rising concentrations of CA125 above cutoff 35 kU/L prompted ultrasound investigation. The study showed a specificity and positive predictive value of 99.9% and 40%, respectively.15 The United Kingdom Collaborative Trial of Ovarian Cancer Screening is ongoing.16 From 2001 to 2005, 202,638 postmenopausal women, aged 50 to 74 years were randomly assigned to annual transvaginal ultrasound alone (N = 50,639) or annual CA125 with transvaginal ultrasound performed at rising CA125 concentrations (N = 50,640) or no investigative procedures (N = 101,359). The trial is expected to conclude in 2015, and the effect of diagnosis at early stage of disease on ovarian cancer mortality awaits analysis of these data.16

At present, the conclusion from these major trials is that owing to limitations of CA125 sensitivity and specificity, its use among asymptomatic women outside the context of a clinical trial cannot be recommended for general population screening (Table 4).4 However, CA125, in combination with transvaginal ultrasound, may have a role in early detection of ovarian cancer in women with hereditary alterations in the BRCA1 and BRCA2 tumor suppressor genes, where the lifetime risk of developing ovarian cancer is approximately 40% for BRCA1 carriers and 18% for BRCA2 carriers.22 However, there is as yet no evidence that ovarian cancer screening results in a stage shift to earlier stage disease, or that it reduces morbidity or mortality from ovarian cancer. The best prevention in these women is bilateral salpingooophorectomy.23–25

European Group on Tumor Markers Statement

• Screening for ovarian cancer based on CA125 is not recommended among asymptomatic women due to lack of sensitivity both for stage I disease and for mucinous epithelial ovarian tumors. CA125 also lacks specificity, especially for premenopausal women.

(LOE I, SOR B)

Back to Top | Article Outline

Differential Diagnosis

Postmenopausal women with CA125 concentrations greater than 35 kU/L should be considered for transvaginal ultrasound examination as well as a computed tomography scan. The CA125 concentrations greater than 95 kU/L has been reported to discriminate malignant from nonmalignant pelvic masses with a positive predictive value of 95%.8 For premenopausal women, the American College of Obstetrics and Gynecologists suggested that patients with a pelvic mass and CA125 concentrations greater than 200 kU/L should be referred to a gynecologist for consultation.26

Algorithms to calculate the Risk of Malignancy Index (RMI) have been developed by Jacobs et al27 and by Tingulstad et al28 as RMI 1 and RMI 2, respectively. Both RMI scoring systems are the product of ultrasound score × menopausal score × CA125 concentration in kU/L (Table 5). The difference between the RMI 1 and the RMI 2 scores is the number of ultrasound findings considered. Three studies have compared the 2 RMI systems using score values above 200 to indicate malignancy. The validity of the RMI 1 and the RMI 2 scores was similar.28–30 Another algorithm was developed and validated in co-operation with a number of European centers specialized in ultrasound of the pelvis (International Ovarian Tumor Analysis group). The algorithm challenged the suggestion that the CA125 concentration added to ultrasound in distinguishing nonmalignant from malignant ovarian masses.31 In the hands of these expert centers, the ultrasound criteria only performed better than the RMI 1.32 The same group has, however, reintroduced CA125 in the latest version of their algorithm, Assessment of Different NEoplasias in the adneXa.33 The National Institute for Health and Care Excellence has introduced guidelines for early detection of ovarian cancer in symptomatic women for use by general practitioners.34 The potential advantages and disadvantages of the guidelines have been discussed with focus on the use of CA125 among premenopausal women where its increasing use may lead to waste of health care resources.35 The recommendations from different scientific societies are provided in Table 4.

European Group on Tumor Markers Statement

• The RMI calculated either as RMI 1 or as RMI 2 is recommended for differential diagnosis of non-malignant and malignant pelvic masses in postmenopausal women.

(LOE II-III, SOR B)

Back to Top | Article Outline

Prognosis

Prognosis Based on a Single Measurement

Preoperatively, the initial stage of disease is an important prognostic factor. However, it has been suggested that in patients who had a preoperative CA125 concentration greater than 65 kU/L, the 5-year survival rates in univariate and multivariate analyses were found to be significantly lower as compared to patients who had values less than 65 kU/L. For the studies including early-stage disease (IA, B, C), the initial CA125 values would be more closely related to histology (serous vs nonserous) rather than prognosis within the serous population.36,37 Studies by Prat et al and Xu et al38,39 based on multivariate analysis suggested that the nadir concentrations after primary treatment and follow-up may provide prognostic information in terms of overall survival (OS). However, this information needs confirmation because it is not unusual to observe transient elevations in CA125 after chemotherapy, likely reflecting tumor necrosis and release of circulating CA125. Finally, there has been no consistent effort to differentiate between patients who have primary optimal cytoreduction (which can reduce CA125 before chemotherapy) and patients selected for neoadjuvant chemotherapy with interval cytoreduction, who must rely only on chemotherapy. As such, knowledge of single-point CA125 measurements would not change ongoing primary therapy and provides only limited prognostic information. The inconsistent results from different studies may also be attributed to the unspecific use of CA125 for all epithelial ovarian cancer types.

Back to Top | Article Outline

Prognosis Based on a Change in Measurements

Markman et al40 reported that a decrease in CA125 concentrations of 50% or greater during the initial 2 cycles of platinum-based chemotherapy was a powerful independent prognostic indicator for OS. Riedinger et al41 reported that one third of CA125 decrease patterns observed among 130 stages IIc to IV patients receiving paclitaxel or platinum-based chemotherapy were biexponential with a half-life greater than 14 days, indicating persistent CA125 production and a poor response to chemotherapy and impaired survival. Van Altena et al42 found that patients who achieved complete clinical remission after standard primary treatment and also reached a CA125 nadir concentration less than 5 kU/L had a significantly longer progression-free survival and OS than patients with nadir values between 6 and 35 kU/L. Overall, all investigators reported that a prolonged half-life was indicative of persistent CA125 production and was predictive of a poor response to chemotherapy.41 The recommendations by different scientific societies are provided in Table 4.

European Group on Tumor Markers Statement

• A change in sequential measurements during primary treatment is recommended as prognostic indicator for response to treatment.

(LOE III/IV, SOR B)

Back to Top | Article Outline

Monitoring

The utilization of CA125 to monitor tumor response was initially developed for evaluation of new treatments in the setting of recurrent disease. However, the mentioned criteria may also be considered during primary therapy because CA125 is used in routine clinical practice.

Back to Top | Article Outline

Criteria to Define Decrements

Rustin et al43 have proposed a set of definitions for CA125 decrements as at least a 50% reduction or a 75% reduction of an elevated pretreatment concentration. Patients can be evaluated with CA125 if the pretreatment concentration is at least twice the upper limit of normal.44 The Gynecological Cancer Intergroup reached a consensus in 2011 where the criteria to evaluate decrements proposed by Rustin et al45 were simplified and included in The Response Evaluation Criteria in Solid Tumors for use in first-line trials in ovarian cancer. A CA125 response was defined as at least a 50% reduction in CA125 levels from a pretreatment sample. The response must be confirmed and maintained for at least 28 days.46 Another definition was suggested by Tuxen et al47 who based interpretation of decreasing concentrations, on a statistical estimation adjusted to both analytical and biological variation of the marker. A similar methodology has been proposed to interpret biomarker changes during monitoring of patients with breast and prostate cancer.48,49

Back to Top | Article Outline

Criteria to Define Increments

The criteria introduced by Rustin et al50,51 depend on the CA125 concentrations. For patients with elevated pretreatment concentrations that normalize on first-line chemotherapy, the criterion require increasing concentrations to twice the upper limit of normal (>70 kU/L). For patients with elevated pretreatment concentrations that never normalizes, the criterion was a doubling of the nadir value.51 Tuxen et al47,52 also suggested 2 criteria depending on whether the increment started below or above the cutoff. For an increment starting below the cutoff, the criterion was a significant increase to above the cutoff. For an increment starting above cutoff, the criterion was a significant increase from the baseline concentration.

Back to Top | Article Outline

Design of Tumor Marker Monitoring Trials

Rustin et al53 enrolled 1442 women in complete remission after first-line platinum-based chemotherapy and a normal CA125 concentration. The majority of patients (>90%) had advanced stage ovarian cancer. They compared the outcome after the initiation of treatment of relapsed ovarian cancer based on rising CA125 levels from below cutoff (≤35 kU/L) to twice the upper limit of normal (>70 kU/L) versus the initiation of treatment commencing at clinical relapse. The patients were registered from 59 centers across Europe, Russia, and South Africa. In the CA125 guided treatment arm, second-line chemotherapy was started at a median of 4.8 months earlier and third-line chemotherapy with a median of 4.6 months earlier as compared with the treatment arm where therapy was delayed until clinically indicated. Surprisingly, in this study, early treatment on the basis of an early rise in CA125 did not improve survival or quality of life.44,54 This may reflect the ineffective therapies at the time of the study and illustrates the difficulties in conducting clinical trials over a decade.54 Results may be invalidated because not all patients received more recent and effective treatments, potentially underestimating the benefit of earlier detection of recurrence.55,56 In addition, in this trial, CA125 measurements were made in local laboratories rather than centrally, and no information is available about the analytical quality of the measurements and no indication of whether contributing laboratories participated in external quality assessment schemes or compared their results with those of other laboratories. However, all laboratories participated in local quality assurance schemes. According to the requirements of the protocol, all samples from an individual patient were measured in the same laboratory, which is crucial for a trial looking at serial change in marker levels.55

The European Group on Tumor Markers (EGTM) has recognized the challenges associated with planning, conducting, and reporting clinical tumor marker surveillance programs and now offers advice on how to design and conduct these types of studies.57 The European Society of Gynecologic Oncologists has recently advised against universally abandoning CA125 in the routine follow-up of all patients with ovarian cancer. Accordingly, CA125 monitoring should be considered in patients who (i) after complete response on primary treatment have been or are being treated as part of a clinical trial, (ii) would be eligible for (future) clinical trials on second-line treatment, (iii) will not have routine (3 monthly) follow-up including regular imaging, and (iv) are eligible for secondary surgery at recurrence.44 The current position of the EGTM is that CA125 is recommended for monitoring of patients if surveillance is likely to have clinical consequences (Table 4).

EGTM statement

• CA125 is recommended for monitoring of primary therapy and post-therapy surveillance.

• A CA125 decrement is defined as at least a 50% reduction in CA125 levels from a pre-treatment sample. The decrement must be confirmed and maintained for at least 28 days.

• A CA125 decrement may also be defined by a 50% decrease over four measurements or a 75% decrease over three measurements.

• A CA125 increment among patients with elevated pretreatment concentrations that never normalizes is defined by a doubling of the nadir value.

• A CA125 increment among patients with elevated pretreatment concentrations that normalize is defined by increasing concentrations from below the normal cut-off (35 kU/L) to twice the upper limit of normal (>70 kU/L).

• Alternatively, a CA125 decrement and increment may be based on a statistical estimation of the change adjusted to both analytical and biological variation of CA125.

(LOE III, SOR C)

Back to Top | Article Outline

Human Epididymis Protein 4

The HE4 serum levels in healthy women have been reported to range from 60 pmol/L to 150 pmol/L. Reasons for this wide range may be due to the relationship between increasing HE4 serum levels and increasing age.58,59 Women older than 49 years have higher concentrations as compared with women younger than 40 years.58 There is a correlation between the histological type and the serum concentration of HE4 with higher concentrations in serous ovarian cancer and with concentrations lowest in patients with mucinous ovarian carcinomas.58,60 The HE4 in serum has also been identified in pulmonary, endometrial, and breast carcinomas and mesotheliomas, but less frequently in gastrointestinal, renal, and transitional cell carcinomas.58,61 The most important source of false-positive results in serum is renal failure where concentration of HE4 may be greater than 2000 pmol/l.62

Back to Top | Article Outline

HE4 in Differential Diagnosis

Wu et al63 reported a meta-analysis based on 9 studies evaluating the performance of HE4 among patients with pelvic masses. The pooled sensitivity and specificity of HE4 to diagnose ovarian cancer was 83% (95% confidence interval [95% CI], 77%–88%) and 90% (95% CI, 87%–92%), respectively, when the control group consisted of healthy women. When the control group was composed of women with nonmalignant diseases, the pooled sensitivity and specificity for HE4 was 74% (95% CI, 69%–78%) and 90% (95% CI, 87%–92%), respectively. Li et al64 reported a review including 2878 patients from 11 studies where HE4 was not superior to CA125 for differential diagnosis. Yu et al,65 in a meta-analysis including 2607 patients from 12 publications, found that HE4 was better than CA125 for the diagnosis of ovarian cancer in terms of sensitivity and specificity. Hallamaa et al66 observed no significant variation in serum HE4 concentrations during the menstrual cycle or during hormonal treatment, suggesting that serum HE4 may be measured at any phase of the menstrual cycle and during hormonal treatment with contraceptives. Overall, despite several publications comparing the diagnostic performance of HE4 and CA125 in distinguishing malignant from non-malignant diseases a clear consensus has yet to be reached.67

Back to Top | Article Outline

HE4 in Prognosis

Steffensen et al68 found that an elevated HE4 concentration is a strong and independent indicator of worse prognosis in epithelial ovarian cancer patients as compared with CA125. Elevated serum HE4 levels before therapy significantly correlated with high tumor grade, serous histology, peritoneal involvement, nodal invasion, tumor stage, operative time, and residual tumor size.69

Back to Top | Article Outline

The Risk of Ovarian Malignancy Algorithm

In 2009 Moore et al70 presented the risk of ovarian malignancy algorithm (ROMA), combining HE4 and CA125 in an attempt to predict the risk of serous epithelial ovarian cancer in women with a pelvic mass. They compared the diagnostic performance of the ROMA with the performance of the RMI as reported by Jacobs et al and by Bailey et al. The diagnostic performance of the ROMA was similar to the performance of the RMI as reported by Jacobs et al27 but was superior to the performance of the RMI as reported by Bailey et al71 Molina et al58 reported on the sensitivity and specificity of ROMA among 285 patients with nonmalignant gynecological diseases (226 premenopausal and 59 postmenopausal) and 111 patients with ovarian cancer (27 premenopausal and 84 postmenopausal). Among premenopausal women, the sensitivity and specificity of ROMA was 74.1% and 88.9%, respectively. Among postmenopausal women, the sensitivity and specificity was 95.2% and 83.1%, respectively. Van Gorp et al72 investigated 389 women with a pelvic mass in a prospective study, where 228 women had nonmalignant disease and 161 women had malignant disease. They reported that neither HE4 nor the ROMA performed better than CA125 in the differentiation of ovarian cancer from other pelvic masses. Montagnana et al73 found preoperative ROMA calculations advantageous when compared to CA125, but found no advantage when compared to HE4. Karlsen et al74 found that the ROMA and the RMI approach performed similarly in differentiating between nonmalignant and malignant pelvic masses. Further well-designed prospective studies are needed to clarify whether HE4 measurements and the ROMA calculation should be implemented into routine clinical practice.

EGTM statement

• HE4 measurements, either alone or in combinations with CA125, as in ROMA, may be considered for differential diagnosis of pelvic masses especially in premenopausal patients.

(LOE III, SOR B)

In summary

CA125 is not recommended as a routine screening test in asymptomatic women due to a low sensitivity for stage I disease as well as a low specificity especially among premenopausal women.

The RMI 1 and RMI 2 algorithms, particularly in postmenopausal women, are recommended as a way to estimate the probability of malignant potential of a pelvic mass.

The ROMA and the ADNEX algorithms, particularly in premenopausal women, may be considered for estimating the probability of malignant potential of a pelvic mass.

An important application of CA125 is in the monitoring of patients if early recognition of a changing tumor burden has clinical implications.

Reports have indicated an increased specificity of HE4 as a single marker as compared to CA125. The utility in clinical practice should be further clarified.

At present, CA125 remains the best available marker for routine use among patients with serous epithelial ovarian cancer.

Back to Top | Article Outline

REFERENCES

1. Bast RC Jr, Klug TL, St John E, et al. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med. 1983; 309: 883–887.
2. Donach M, Yu Y, Artioli G, et al. Combined use of biomarkers for detection of ovarian cancer in high-risk women. Tumour Biol. 2010; 31: 209–215.
3. Jacobs I, Bast RC Jr. The CA 125 tumour-associated antigen: a review of the literature. Hum Reprod. 1989; 4: 1–12.
4. Duffy MJ, Bonfrer JM, Kulpa J, et al. CA125 in ovarian cancer: European Group on Tumor Markers guidelines for clinical use. Int J Gynecol Cancer. 2005; 15: 679–691.
5. Liu J, Matulonis UA. Anti-angiogenic agents in ovarian cancer: dawn of a new era? Curr Oncol Rep. 2011; 13: 450–458.
6. Molina R, Auge JM, Escudero JM, et al. Mucins CA 125, CA 19.9, CA 15.3 and TAG-72.3 as tumor markers in patients with lung cancer: comparison with CYFRA 21–1, CEA, SCC and NSE. Tumour Biol. 2008; 29: 371–380.
7. Kelly PJ, Archbold P, Price JH, et al. Serum CA19.9 levels are commonly elevated in primary ovarian mucinous tumours but cannot be used to predict the histological subtype. J Clin Pathol. 2010; 63: 169–173.
8. Sturgeon CM, Duffy MJ, Stenman UH, et al. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem. 2008; 54: e11–e79.
9. Høgdall EV, Christensen L, Kjaer SK, et al. Protein expression levels of carcinoembryonic antigen (CEA) in Danish ovarian cancer patients: from the Danish ‘MALOVA’ ovarian cancer study. Pathology. 2008; 40: 487–492.
10. Hayes DF, Bast RC, Desch CE, et al. Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. J Natl Cancer Inst. 1996; 88: 1456–1466.
11. Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of recommendations. BMJ. 2004; 328: 1490.
12. Buys SS, Partridge E, Black A, et al. Effect of screening on ovarian cancer mortality: the prostate, lung, colorectal and ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011; 305: 2295–2303.
13. Kobayashi H, Yamada Y, Sado T, et al. A randomized study of screening for ovarian cancer: a multicenter study in Japan. Int J Gynecol Cancer. 2008; 18: 414–420.
14. Van Nagell JR Jr, Miller RW, Desimone CP, et al. Long-term survival of women with epithelial ovarian cancer detected by ultrasonographic screening. Obstet Gynecol. 2011; 118: 1212–1221.
15. Lu KH, Skates S, Hernandez MA, et al. A 2-stage ovarian cancer screening strategy using the Risk of Ovarian Cancer Algorithm (ROCA) identifies early-stage incident cancers and demonstrates high positive predictive value. Cancer. 2013; 119: 3454–3461.
16. Menon U, Gentry-Maharaj A, Hallett R, et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol. 2009; 10: 327–340.
17. Screening for ovarian cancer: recommendations and rationale. American College of Physicians. Ann Intern Med. 1994; 121: 141–142.
18. Vasey PA, Herrstedt J, Jelic S. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of epithelial ovarian carcinoma. Ann Oncol. 2005; 16(suppl 1): i13–i15.
19. Sturgeon C. Practice guidelines for tumor marker use in the clinic. Clin Chem. 2002; 48: 1151–1159.
21. NIH consensus conference. Ovarian cancer. Screening, treatment, and follow-up. NIH Consensus Development Panel on Ovarian Cancer. JAMA. 1995; 273: 491–497.
22. Van der Velde NM, Mourits MJ, Arts HJ, et al. Time to stop ovarian cancer screening in BRCA1/2 mutation carriers? Int J Cancer. 2009; 124: 919–923.
23. Lu KH, Daniels M. Endometrial and ovarian cancer in women with Lynch syndrome: update in screening and prevention. Fam Cancer. 2013; 12: 273–277.
24. Rosenthal AN, Fraser L, Manchanda R, et al. Results of annual screening in phase I of the United Kingdom familial ovarian cancer screening study highlight the need for strict adherence to screening schedule. J Clin Oncol. 2013; 31: 49–57.
25. Skates SJ, Mai P, Horick NK, et al. Large prospective study of ovarian cancer screening in high-risk women: CA125 cut-point defined by menopausal status. Cancer Prev Res (Phila). 2011; 4: 1401–1408.
26. ACOG Committee on Gynecologic Practice. The role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer. Int J Gynaecol Obstet. 2003; 80: 235–238.
27. Jacobs I, Oram D, Fairbanks J, et al. A risk of malignancy index incorporating CA 125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer. Br J Obstet Gynaecol. 1990; 97: 922–929.
28. Tingulstad S, Hagen B, Skjeldestad FE, et al. Evaluation of a risk of malignancy index based on serum CA125, ultrasound findings and menopausal status in the pre-operative diagnosis of pelvic masses. Br J Obstet Gynaecol. 1996; 103: 826–831.
29. Morgante G, la Marca A, Ditto A, et al. Comparison of two malignancy risk indices based on serum CA125, ultrasound score and menopausal status in the diagnosis of ovarian masses. Br J Obstet Gynaecol. 1999; 106: 524–527.
30. Aslam N, Tailor A, Lawton F, et al. Prospective evaluation of three different models for the pre-operative diagnosis of ovarian cancer. BJOG. 2000; 107: 1347–1353.
31. Timmerman D, Testa AC, Bourne T, et al. Logistic regression model to distinguish between the benign and malignant adnexal mass before surgery: a multicenter study by the International Ovarian Tumor Analysis Group. J Clin Oncol. 2005; 23: 8794–8801.
32. Sayasneh A, Wynants L, Preisler J, et al. Multicentre external validation of IOTA prediction models and RMI by operators with varied training. Br J Cancer. 2013; 108: 2448–2454.
33. Van Calster B, Van Hoorde K, Valentin L, et al. Evaluating the risk of ovarian cancer before surgery using the ADNEX model to differentiate between benign, borderline, early and advanced stage invasive, and secondary metastatic tumours: prospective multicentre diagnostic study. BMJ. 2014; 349: g5920.
34. NICE Clinical Guideline 122. The Recognition and Initial Management of Ovarian Cancer. Available at:http://guidance.nice.org.uk/CG/Wave17/22.Accessed December 20114.
35. Sturgeon CM, Duffy MJ, Walker G. The National Institute for Health and Clinical Excellence (NICE) guidelines for early detection of ovarian cancer: the pivotal role of the clinical laboratory. Ann Clin Biochem. 2011; 48(Pt 4): 295–299.
36. Meyer T, Rustin GJ. Role of tumour markers in monitoring epithelial ovarian cancer. Br J Cancer. 2000; 82: 1535–1538.
37. Gadducci A, Cosio S, Tana R, et al. Serum and tissue biomarkers as predictive and prognostic variables in epithelial ovarian cancer. Crit Rev Oncol Hematol. 2009; 69: 12–27.
38. Prat A, Parera M, Peralta S, et al. Nadir CA-125 concentration in the normal range as an independent prognostic factor for optimally treated advanced epithelial ovarian cancer. Ann Oncol. 2008; 19: 327–331.
39. Xu X, Wang Y, Wang F, et al. Nadir CA-125 level as prognosis indicator of high-grade serous ovarian cancer. J Ovarian Res. 2013; 6: 31.
40. Markman M, Federico M, Liu PY, et al. Significance of early changes in the serum CA-125 antigen level on overall survival in advanced ovarian cancer. Gynecol Oncol. 2006; 103: 195–198.
41. Riedinger JM, Eche N, Basuyau JP, et al. Prognostic value of serum CA 125 bi-exponential decrease during first line paclitaxel/platinum chemotherapy: a French multicentric study. Gynecol Oncol. 2008; 109: 194–198.
42. Van Altena AM, Kolwijck E, Spanjer MJ, et al. CA125 nadir concentration is an independent predictor of tumor recurrence in patients with ovarian cancer: a population-based study. Gynecol Oncol. 2010; 119: 265–269.
43. Rustin GJ. Use of CA-125 to assess response to new agents in ovarian cancer trials. J Clin Oncol. 2003; 21(suppl 10): 187s–193s.
44. Verheijen RH, Cibula D, Zola P, et al. Cancer antigen 125: lost to follow-up?: a European society of gynaecological oncology consensus statement. Int J Gynecol Cancer. 2012; 22: 170–174.
45. Rustin GJ, Nelstrop AE, McClean P, et al. Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. J Clin Oncol. 1996; 14: 1545–1551.
46. Rustin GJ, Vergote I, Eisenhauer E, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer. 2011; 21: 419–423.
47. Tuxen MK, Sölétormos G, Dombernowsky P. Serum tumour marker CA 125 in monitoring of ovarian cancer during first-line chemotherapy. Br J Cancer. 2001; 84: 1301–1307.
48. Sölétormos G, Nielsen D, Schiøler V, et al. Tumor markers cancer antigen 15.3, carcinoembryonic antigen, and tissue polypeptide antigen for monitoring metastatic breast cancer during first-line chemotherapy and follow-up. Clin Chem. 1996; 42: 564–575.
49. Sölétormos G, Semjonow A, Sibley PE, et al. Biological variation of total prostate-specific antigen: a survey of published estimates and consequences for clinical practice. Clin Chem. 2005; 51: 1342–1351.
50. Rustin GJ, Nelstrop AE, Tuxen MK, et al. Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study. Ann Oncol. 1996; 7: 361–364.
51. Rustin GJ, Marples M, Nelstrop AE, et al. Use of CA-125 to define progression of ovarian cancer in patients with persistently elevated levels. J Clin Oncol. 2001; 19: 4054–4057.
52. Tuxen MK, Sölétormos G, Dombernowsky P. Serum tumor marker CA 125 for monitoring ovarian cancer during follow-up. Scand J Clin Lab Invest. 2002; 62: 177–188.
53. Rustin GJ, van der Burg ME, Griffin CL, et al. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet. 2010; 376: 1155–1163.
54. Rustin GJ, Karlan BY, Markman M. CA-125: To monitor or Not to Monitor? Available at:http://www.medscape.com/viewarticle/759809. Accessed December 2014.
55. Bast RC Jr. CA 125 and the detection of recurrent ovarian cancer: a reasonably accurate biomarker for a difficult disease. Cancer. 2010; 116: 2850–2853.
56. Pignata S, Cannella L, Leopardo D, et al. Follow-up with CA125 after primary therapy of advanced ovarian cancer: in favor of continuing to prescribe CA125 during follow-up. Ann Oncol. 2011; 22(suppl 8): viii40–viii44.
57. Sölétormos G, Duffy MJ, Hayes DF, et al. Design of tumor biomarker-monitoring trials: a proposal by the European Group on Tumor Markers. Clin Chem. 2013; 59: 52–59.
58. Molina R, Escudero JM, Augé JM, et al. HE4 a novel tumour marker for ovarian cancer: comparison with CA 125 and ROMA algorithm in patients with gynaecological diseases. Tumour Biol. 2011; 32: 1087–1095.
59. Zheng H, Gao Y. Serum HE4 as a useful biomarker in discriminating ovarian cancer from benign pelvic disease. Int J Gynecol Cancer. 2012; 22: 1000–1005.
60. Escudero JM, Auge JM, Filella X, et al. Comparison of serum human epididymis protein 4 with cancer antigen 125 as a tumor marker in patients with malignant and nonmalignant diseases. Clin Chem. 2011; 57: 1534–1544.
61. Simmons AR, Baggerly K, Bast RC Jr, et al. The emerging role of HE4 in the evaluation of epithelial ovarian and endometrial carcinomas. Oncology (Williston Park). 2013; 27: 548–556.
62. Nagy B Jr, Krasznai ZT, Balla H, et al. Elevated human epididymis protein 4 concentrations in chronic kidney disease. Ann Clin Biochem. 2012; 49 (Pt 4): 377–380.
63. Wu L, Dai ZY, Qian YH, et al. Diagnostic value of serum human epididymis protein 4 (HE4) in ovarian carcinoma: a systematic review and meta-analysis. Int J Gynecol Cancer. 2012; 22: 1106–1112.
64. Li F, Tie R, Chang K, et al. Does risk for ovarian malignancy algorithm excel human epididymis protein 4 and CA125 in predicting epithelial ovarian cancer: a meta-analysis. BMC Cancer. 2012; 12: 258.
65. Yu S, Yang HJ, Xie SQ, et al. Diagnostic value of HE4 for ovarian cancer: a meta-analysis. Clin Chem Lab Med. 2012; 50: 1439–1446.
66. Hallamaa M, Suvitie P, Huhtinen K, et al. Serum HE4 concentration is not dependent on menstrual cycle or hormonal treatment among endometriosis patients and healthy premenopausal women. Gynecol Oncol. 2012; 125: 667–672.
67. Macuks R, Baidekalna I, Donina S. An ovarian cancer malignancy risk index composed of HE4, CA125, ultrasonographic score, and menopausal status: use in differentiation of ovarian cancers and benign lesions. Tumour Biol. 2012; 33: 1811–1817.
68. Steffensen KD, Waldstrøm M, Brandslund I, et al. Prognostic impact of prechemotherapy serum levels of HER2, CA125, and HE4 in ovarian cancer patients. Int J Gynecol Cancer. 2011; 21: 1040–1047.
69. Midulla C, Manganaro L, Longo F, et al. HE4 combined with MDCT imaging is a good marker in the evaluation of disease extension in advanced epithelial ovarian carcinoma. Tumour Biol. 2012; 33: 1291–1298.
70. Moore RG, McMeekin DS, Brown AK, et al. A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol Oncol. 2009; 112: 40–46.
71. Bailey J, Tailor A, Naik R, et al. Risk of malignancy index for referral of ovarian cancer cases to a tertiary center: does it identify the correct cases? Int J Gynecol Cancer. 2006; 16(suppl 1): 30–34.
72. Van Gorp T, Cadron I, Despierre E, et al. HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm. Br J Cancer. 2011; 104: 863–870.
73. Montagnana M, Danese E, Ruzzenente O, et al. The ROMA (Risk of Ovarian Malignancy Algorithm) for estimating the risk of epithelial ovarian cancer in women presenting with pelvic mass: is it really useful? Clin Chem Lab Med. 2011; 49: 521–525.
74. Karlsen MA, Sandhu N, Høgdall C, et al. 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. 2012; 127: 379–383.
Keywords:

Ovarian cancer; CA125; HE4; Screening; Differential diagnosis; Monitoring

© 2016 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.