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ORIGINAL ARTICLE
Year : 2019  |  Volume : 56  |  Issue : 3  |  Page : 216-221
 

Role of serum HE4 as a prognostic marker in carcinoma of the ovary


Department of Surgical Oncology, King George's Medical University, Lucknow, Uttar Pradesh, India

Date of Web Publication19-Jul-2019

Correspondence Address:
Vijay Kumar
Department of Surgical Oncology, King George's Medical University, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_305_18

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 » Abstract 


BACKGROUND: Epithelial ovarian cancer is the second most common gynecological cancer. Human Epididymis Protein 4 is a novel biomarker for ovarian cancer. This study aims to explore the role of HE4 in monitoring recurrence and prognostication of ovarian cancer by predicting overall survival (OS) and progression-free survival (PFS).
MATERIALS AND METHODS: In total, 149 patients with ovarian carcinoma were enrolled in the study. Baseline and post-treatment 3 monthly biomarker levels were recorded. For analysis, patients were divided into primary debulking surgery (PDS) and interval debulking surgery (IDS) groups. Statistical analysis was done using SPSS 24.
RESULTS: Median age of patients at diagnosis was 45 (19–75) years. Recurrence was seen in 68.5% (n = 102) patients. The sensitivity of serum HE4 in detecting recurrence was 85.3% (95%CI: 76.95%–91.5%) and specificity was 91.5% (95%CI: 89.5%–98.2%). A >80% decline in HE4 levels during treatment indicated a better PFS, which was statistically significant in both groups (P = 0.04 in PDS and P = <0.001 in IDS group). Multivariate analysis suggested that OS was influenced by optimal cytoreduction in both groups of patients and stage in the IDS group. On the contrary, PFS was influenced by stage and response in HE4 levels in both groups.
CONCLUSION: HE4 levels have similar sensitivity but more specificity when compared with CA125 in diagnosing recurrent ovarian cancer. A >80% decline in HE4 levels during treatment predicts better PFS and can help in prognostication.


Keywords: Human epididymis protein 4, ovarian cancer, prognosticating cancer, recurrence


How to cite this article:
Lakshmanan M, Kumar V, Chaturvedi A, Misra S, Gupta S, Akhtar N, Rajan S, Jain K, Garg S. Role of serum HE4 as a prognostic marker in carcinoma of the ovary. Indian J Cancer 2019;56:216-21

How to cite this URL:
Lakshmanan M, Kumar V, Chaturvedi A, Misra S, Gupta S, Akhtar N, Rajan S, Jain K, Garg S. Role of serum HE4 as a prognostic marker in carcinoma of the ovary. Indian J Cancer [serial online] 2019 [cited 2019 Oct 14];56:216-21. Available from: http://www.indianjcancer.com/text.asp?2019/56/3/216/263030





 » Introduction Top


Epithelial ovarian cancer (EOC) is the seventh most common malignancy in women representing 4% of all cancers in women worldwide.[1] In India, EOC is the eighth leading cause of death among women.[2] As a result of its biological characteristics and lack of screening tools, EOC is usually diagnosed at an advanced stage (FIGO stage III–IV). In these patients, median survival ranges from 18 to 24 months with an 80% probability of recurrence of the disease within 5 years.[3] Despite the high recurrence rate of OC, surveillance strategies are not standardized yet. This has led to a variety of follow-up strategies. At present, periodical evaluation of CA-125, if elevated previously, combined with physical examination and/or imaging is the recommended follow-up strategy for ovarian cancer. Follow-up is done typically every 2–4 months in the first 2 years after primary treatment and then every 3–6 months until the fifth year and annually thereafter.[4]

However, the use of CA125 is compromised by its low specificity, particularly in premenopausal women.[5] HE4, also known as whey acidic four disulphide core 2 protein (WFDC2) is a novel ovarian cancer biomarker, which was initially identified in the epithelium of the epididymis and originally predicted to be a proteinase inhibitor involved in sperm maturation.[6],[7] It belongs to a family of WFDC proteins, but its biological function remains unknown.[7] It is overexpressed in ovarian cancer and has demonstrated higher specificity compared with serum CA 125 in detecting ovarian cancer.[8] Serum HE4 was approved by the USFDA in 2010 to monitor recurrence and disease progression in EOC in conjunction with CA125. The role of serum HE4 in predicting survival has been studied in only one recent study by Vallius et al., where the investigators demonstrated that the change in serum HE4 levels during neoadjuvant chemotherapy helps to predict overall survival (OS).[9] Our study was initiated to explore the role of serum HE4 in detecting recurrence and prognosticating ovarian cancer by predicting OS and progression-free survival (PFS).


 » Materials and Methods Top


This was a single-center prospective study wherein all patients with a diagnosis of EOC treated in the Department of Surgical Oncology, King George's Medical University, Lucknow, India, between January 2015 and January 2017 were enrolled.

Inclusion criteria was proven case of EOC in patients over 18 years. Exclusion criteria were patients not willing to give informed consent, patients with history of other cancer within 5 years and patients with comorbidities such as renal, liver, and cardiac illness, which could affect the outcomes.

As per institutional protocol, all patients with early stage ovarian cancer (FIGO stage I, II, IIIa) were treated with primary debulking surgery (PDS) followed by adjuvant chemotherapy and patients with advanced EOC (FIGO stage IIIb, IIIc, IV) received neoadjuvant chemotherapy (NACT) followed by interval cytoreduction and adjuvant chemotherapy. Paclitaxel and Carboplatin was the regimen of choice for both neoadjuvant and adjuvant chemotherapy. Paclitaxel was given as a dose of 175 mg/m 2 intravenous infusion over 3 hs on day 1 and Carboplatin was given at a dose of AUC 5-7 intravenous infusion on day 2. The dose was repeated every three weeks. Chemotherapy response was assessed with contrast enhanced computerized tomography (CECT) scan of abdomen and pelvis and graded using RECIST 1.1 criteria after four cycles. Baseline value of serum Carbohydrate Antigen 125 (CA 125) and serum HE4 was measured prior to starting treatment and repeated after four cycles (before surgery) and 1 month after completing treatment. Patients were subsequently followed up every 3 months with a physical examination and serum CA125 and serum HE4.

Optimal cytoreduction was defined as macroscopic disease <1 cm following surgery. The standard procedure was done as total abdominal hysterectomy with bilateral salphingoophrectomy and total omentectomy. Ascitic fluid, if any, was taken for cytology and, if absent, peritoneal washings were taken. Formal nodal dissection was not performed, but enlarged nodes were sampled.

For the blood tests, venous samples were drawn. After centrifugation, all serum samples were frozen at −80°C till further use. Serum levels of both of these markers were measured by fully automated Abbott/ARCHITECT system utilizing Chemiluminescent Microparticle Immunoassay technology with flexible assay protocols, referred to as Chemiflex ®. For serum CA 125, value >35 U/mL was considered abnormal. For serum HE4, value >70 pmo1/L was considered abnormal for premenopausal females, and value >140 pmo1/L was considered abnormal for postmenopausal females.

For the purpose of analysis, we divided patients into two groups, those who had PDS and those who had neoadjuvant chemotherapy followed by surgery. Based on Vallius et al.'s paper, we further divided our patients into groups based on response of biomarker to therapy

  1. PDS patients


    1. Serum CA125 response more than or less than 80% after treatment completion (difference between baseline CA125 and post-treatment CA125)
    2. Serum HE4 response more than or less than 80% after treatment completion (difference between baseline HE4 and post-treatment HE4).


  2. Interval debulking surgery (IDS) patients


    1. Serum CA125 response more than or less than 80% after neoadjuvant chemotherapy (difference between baseline CA125 and presurgery CA125)
    2. Serum CA125 response more than or less than 80% after treatment completion (difference between baseline CA125 and post-treatment CA125)
    3. Serum HE4 response more than or less than 80% after neoadjuvant chemotherapy (difference between baseline HE4 and presurgery HE4)
    4. Serum HE4 response more than or less than 80% after treatment completion (difference between baseline CA125 and post-treatment CA125).


The data was analyzed using SPSS version 24. Categorical variables were compared using Chi-square test. Survival data were plotted using Kaplan–Meir survival curve and they were compared using log rank test. Multivariate analysis was done using Cox Proportional Hazard Regression. The study protocol was approved by the Institutional ethics committee of King George's Medical University, Lucknow, India.s


 » Results Top


In total, 149 patients were enrolled in our study. The median age of patients in this study group was 45 years with a range of 19–75 years. Majority of the patients were premenopausal (54.4%, n = 81) and multiparous (85.9%, n = 128). The stage distribution of patients in this study group is as follows, 47.7% (n = 71) patients were Stage III followed by 20.8% (n = 31) Stage IV, 18.8% (n = 28) Stage II, and 12.8% (n = 19) Stage I patients. The most common histology noted was papillary serous adenocarcinoma (79.2%, n = 118) followed by mucinous adenocarcinoma (16.8%, n = 25) and miscellaneous entities, such as clear cell and endometroid (4%, n = 6). The overall median CA125 at the time of diagnosis was 1475. 8 U/mL (interquartile range [IQR] = 1,000–2,338.7 U/mL). The overall median serum HE4 levels at time of diagnosis was 1016.5 pmol/L (IQR = 523–1,949.3 pmol/L).

Of the 149 patients, 97 (65.1%) received chemotherapy. The response to chemotherapy was assessed using RECIST 1.1 criteria in CECT imaging of abdomen and pelvis. Complete response was noted in 7.4% (n = 11), partial response was seen in 53.7% (n = 80), stable disease in 24.8% (n = 37), and disease progression in 14.1% (n = 21).

Optimal debulking was possible in 84.6% of patients undergoing PDS and 51.8% of patients undergoing IDS.

After completion of treatment, patients were followed up with blood tests for biomarkers every 3 months. Recurrence if suspected was documented with imaging. The sensitivity of serum HE4 in detecting recurrence was 85.3% (95%CI: 76.9%–91.5%) and specificity was 91.5% (95%CI: 79.6%–97.6%). The positive predictive value for serum HE4 was 95.6% (95%CI: 89.5%–98.2%) and negative predictive value was 74.1% (95%CI: 80.8%–92.1%).

The mean lead time of serum HE4 over serum CA125 in detecting recurrence was found to be 2.76 months and median lead time was 3 months.

Results of log rank analysis of OS and PFS in patients represented in [Table 1] and [Figure 1], [Figure 2], [Figure 3].
Table 1: Survival analysis of patient-based response of biomarker to treatment

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Figure 1: Overall survival and progression-free survival curves in the primary debulking surgery group based on biomarker response to treatment

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Figure 2: Overall survival and progression-free survival curves in the interval debulking surgery group based on biomarker response to neoadjuvant chemotherapy

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Figure 3: Overall survival and progression-free survival curves in the interval debulking surgery group based on biomarker response to treatment

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Univariate analysis was done using all 149 patients together. It was noted that OS was statistically significant and influenced by stage (P- value = 0.001), optimal cytoreduction (P-value <0.001) and platinum sensitivity (P-value <0.001). PFS was influenced by stage (P value ≤0.001), optimal cytoreduction (P-value ≤0.001) and platinum sensitivity (P-value ≤0.001). [Table 2] lists the various variables tested in multivariate analysis in both PDS and IDS patients.
Table 2: Multivariate analysis

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 » Discussion Top


Biomarkers are currently an integral part of follow-up of patients with ovarian cancer. At present CA125 is the most common tumor marker used for monitoring of disease recurrence after completion of treatment, but it is nonspecific. Result of the EORTC 55955 trial showed no evidence of survival benefit with early treatment of relapse on the basis of a raised CA 125 concentration alone, and therefore, the value of routine measurement of CA 125 in the follow-up of patients with ovarian cancer who attain a complete response after first-line treatment is not proven.[10] Serum HE4 is a promising marker that has been shown to perform better than CA125 in various studies.[11],[12] We did this study to evaluate the role of serum HE4 in detecting recurrence of ovarian cancer and predicting survival in these patients. Our study is one of the largest in terms of number of patients enrolled for evaluation of serum HE4 as a marker of recurrence.

The Gynaecologic Oncology Group defines optimal cytoreduction as largest residual nodule <1 cm in size.[13] Using this definition, in this study we were able to achieve optimal cytoreduction rate of 84.6% in patients undergoing PDS and only 51.8% in patients undergoing IDS. Reported optimal cytoreduction rates in PDS in literature ranges from 15% to 85%.[14],[15] In the NACT followed by IDS setting, the rate of cytoreduction varies approximately from 50.4% to 89.6% in recent studies.[16] In the EORTC/NCIC randomized trial, Vergote et al. included only advanced EOC patients and reported an optimal cytoreduction rate of 41.6% in patients who underwent PDS compared with 80.6% in patients who received neoadjuvant chemotherapy followed by IDS.[17] Our optimal cytoreduction rate in the neoadjuvant group is on the lower side, but it is still within the range reported in literature. This is due to suboptimal response to chemotherapy. Financial concerns and adverse events related to chemotherapy influence strict adherence to chemotherapy schedule. Patients fear the cost of treatment and loss of income while undergoing treatment. A lot of patients are undernourished women who have a high incidence of adverse events related to chemotherapy, such as vomiting and neutropenia, which makes them reluctant to receive chemotherapy at prescribed intervals. Failure to adhere to the chemotherapy schedule results in inconsistent response to chemotherapy, which, in turn, leads to reduced percentage of optimal cytoreduction. Optimal cytoreduction was found to significantly influence OS and PFS.

Serum HE4 has been evaluated as a marker of recurrence in a few studies and has been found to perform better than serum CA125 in this regard. Anastasi et al. evaluated eight patients and reported that serum HE4 has a sensitivity of 96.9% versus 85.7% for serum CA125 in detecting recurrence and serum HE4 rises 5–8 months before CA125 in recurrent ovarian cancer.[3] Manganaro et al. followed up 21 patients with serum HE4 and serum CA125. They found that serum HE4 rises ~3 months before serum CA125.[11] Nassir et al. evaluated serum HE4 in a subset of 92 patients enrolled in the OVCAD study and reported that serum HE4 in combination with serum CA125 was better than serum HE4 alone in predicting recurrence.[12] Our study is one of the largest in terms of number of patients enrolled for evaluation of serum HE4 as a marker of recurrence. We followed up 149 women with ovarian cancer, out of whom 102 developed recurrence and found that serum HE4 had equivalent sensitivity (85.3% vs 84.3%) and higher specificity (91.4% vs 70.2%) than serum CA125 in detecting recurrence and a lead time of ~3 months over CA125.

CA125 response during NACT and its relation to survival has been evaluated in various studies. Tate et al.[18] followed up 50 patients and reported that CA125 response of >50%, 4 weeks after second cycle chemotherapy is an independent prognostic factor for survival. Vasudev et al. studied 63 patients and reported that CA-125 regression rate during preoperative neoadjuvant chemotherapy is of independent prognostic value.[19] We found only one study by Vallius et al., which evaluated serum HE4 response during NACT and found it to have a significant relationship with OS. In their study, among patients with serum HE4 changes of >80% and <80%, the median OS was 3.38 and 1.6 years, respectively (P = 0.01), and median PFS was 1.3 and 0.81 years, respectively (P = 0.06).[9] In this study, patients who underwent PDS and those undergoing IDS were analyzed separately. We evaluated serum CA125 and serum HE4 response after treatment completion in both the groups and after neoadjuvant chemotherapy in the IDS group. We found that a >80% fall in serum HE4 levels after treatment completion indicated a significantly better PFS than those with <80% depreciation in both groups (15.5 vs 8.6 months, P = <0.001 in IDS group and 20.4 vs 15.4 months, P = 0.043 in PDS group). Similarly, serum HE4 fall of >80% after NACT also indicated a better PFS than <80% decrease in serum HE4 levels (15.3 vs 10.7 months, P = 0.001). However, OS was not significantly influenced by serum HE4 response. This finding was confirmed by both univariate and multivariate analysis in both the groups. On the contrary, a similar analysis of serum CA125 response showed that CA125 response of more than or less than 80% did not significantly influence OS and PFS.


 » Conclusion Top


We conclude that >80% response in serum HE4 levels to treatment is a valuable marker to predict better PFS and can play an important role in prognosticating ovarian cancer patients. We also noted that serum HE4 levels have similar sensitivity but more specificity when compared with serum CA125 levels in diagnosing recurrent ovarian cancer. Serum HE4 has a lead time of 3 months over CA125 in diagnosing recurrence.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Stewart BW, Wild CP, editors. World Cancer Report 2014. Lyon, France: International Agency for Research on Cancer; 2014.  Back to cited text no. 1
    
2.
Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, et al. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. Cancer Today; 2018. Available from: http://gco.iarc.fr/today. [Last accessed on 2018 Nov 10].  Back to cited text no. 2
    
3.
Anastasi E, Marchei GG, Viggiani V, Gennarini G, Frati L, Reale MG. HE4: A new potential early biomarker for the recurrence of ovarian cancer. Tumor Biol 2010;31:113-9.  Back to cited text no. 3
    
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National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®). Ovarian Cancer including Fallopian Tube Cancer/Primary Peritoneal Cancer (Version 4.2017). https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. [Last accessed on 2017 Nov 20].  Back to cited text no. 4
    
5.
Buamah P. Benign condition associated with raised serum CA-125 concentration. J Surg Oncol 2000;75:264-5.  Back to cited text no. 5
    
6.
Kirchhoff C, Habben I, Ivell R, Krull N. A major human epididymis-specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors. Biol Reprod 1991;45:350-7.  Back to cited text no. 6
    
7.
Bouchard D, Morisset D, Bourbonnais Y, Tremblay GM. Proteins with whey-acidic-protein motifs and cancer. Lancet Oncol 2006;7;167-74.  Back to cited text no. 7
    
8.
Hamed EO, Ahmed H, Sedeek OB, Mohammed AM, Abd-Alla AA, Abdel Ghaffar HM. Significance of HE 4 estimation in comparison with CA 125 in diagnosis of ovarian cancer and assessment of treatment response. Diagn Pathol 2013;8:11.  Back to cited text no. 8
    
9.
Vallius T, Hynninen J, Auranen A, Carpén O, Matomäki J, Oksa S, et al. Serum HE4 and CA125 as predictors of response and outcome during neoadjuvant chemotherapy of advanced high-grade serous ovarian cancer. Tumor Biol 2014;35:12389-95.  Back to cited text no. 9
    
10.
Rustin GJ, van der Burg ME, Griffin CL, Guthrie D, Lamont A, Jayson GC, et al. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): A randomized trial. Lancet 2010;376:1155-63.  Back to cited text no. 10
    
11.
Manganaro L, Michienzi S, Vinci V, Falzarno R, Saldari M, Granato T, et al. Serum HE4 levels combined with CECT imaging improve the management of monitoring women affected by epithelial ovarian cancer. Oncol Rep 2013;30:2481-7.  Back to cited text no. 11
    
12.
Nassir M, Guan J, Luketina H, Siepmann T, Rohr I, Richter R, et al. The role of HE4 for prediction of recurrence in epithelial ovarian cancer patients-results from the OVCAD study. Tumor Biol 2016;37:3009-16.  Back to cited text no. 12
    
13.
Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A Gynaecologic Oncology Group study. J Clin Oncol 2003;21:3194-200.  Back to cited text no. 13
    
14.
Bristow RE, Tomacruz RS, Armstrong DK, 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;20:1248-59.  Back to cited text no. 14
    
15.
Dauplat J, Le Bouëdec G, Pomel C, Scherer C. Cytoreductive surgery for advanced stages of ovarian cancer. Semin Surg Oncol 2000;19:42-8.  Back to cited text no. 15
    
16.
Kang S, Nam BH. Does neoadjuvant chemotherapy increase optimal cytoreduction rate in advanced ovarian cancer? Meta-analysis of 21 studies. Ann Surg Oncol 2009;16:2315-20.  Back to cited text no. 16
    
17.
Vergote I, Tropé CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al. Neoadjuvant chemotherapy or primary in stage IIIC or IV ovarian Cancer. N Eng1 J Med 2010;363:943-53.  Back to cited text no. 17
    
18.
Tate S, Hirai Y, Takeshima N, Hasumi K. CA125 regression during neoadjuvant chemotherapy as an independent prognostic factor for survival in patients with advanced ovarian serous adenocarcinoma. Gynecol Oncol 2005;96:143-9.  Back to cited text no. 18
    
19.
Vasudev NS, Trigonis I, Cairns DA, Hall GD, Jackson DP, Broadhead T, et al. The prognostic and predictive value of CA 125 regression during neoadjuvant chemotherapy for advanced ovarian or primary peritoneal carcinoma. Arch Gynecol Obstet 2011;284:221-7.  Back to cited text no. 19
    


    Figures

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    Tables

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