Serum HE4 vs CA-125 for Ovarian Cancer Diagnosis
Serum HE4 vs CA-125 for Ovarian Cancer Diagnosis
Background Human epididymis protein 4 (HE4) measurements in serum have been proposed for improving the specificity of laboratory identification of ovarian cancer (OC).
Objective To critically revise the available literature on the comparison between the diagnostic accuracy of HE4 and carbohydrate antigen 125 (CA-125) to confirm the additional clinical value of HE4.
Methods A literature search was undertaken on electronic databases and references from retrieved articles; articles were analysed according to predefined criteria. Meta-analyses for HE4 and CA-125 biomarkers with OR, diagnostic sensitivity, specificity, positive (LR+) and negative (LR–) likelihood ratios as effect sizes were performed.
Results 16 articles were originally included in meta-analyses, but two for HE4 and one for CA-125 were eliminated as outliers. Furthermore, for HE4 a publication bias was detected. ORs for both HE4 (37.2, 95% CI 19.0 to 72.7, adjusted for publication bias) and CA-125 (15.4, 95% CI 10.4 to 22.8) were significant, although in a heterogeneous set of studies (p<0.0001). By combining sensitivity and specificity, the overall LR+ and LR– were 13.0 (95% CI 8.2 to 20.7) and 0.23 (95% CI 0.19 to 0.28) for HE4 and 4.2 (95% CI 3.1 to 5.6) and 0.27 (95% CI 0.23 to 0.31) for CA-125, respectively.
Conclusions HE4 measurement seems to be superior to CA-125 in terms of diagnostic performance for identification of OC in women with suspected gynaecological disease. Due to the high prevalence of OC in post-menopausal women and the need for data focused on early tumour stages, more studies tailored on these specific subsets are needed.
Ovarian cancer (OC) is the sixth most common gynaecological malignancy characterised by an incidence rate that increases with age and in post-menopausal status. The crude incidence rate changes from 4.7 per 100 000 in women <50 years of age to 29.6 per 100 000 in the age group of 50–64 years. OC is currently the first cause of death in gynaecological malignancies; ~75% of patients are diagnosed at an advanced stage, since OC is generally asymptomatic in the early stages and no effective screening approach is available. The net discrepancy between survival rates in early and advanced stages (80–90% vs 15–20%) has reinforced the need for biomarkers with higher diagnostic accuracy to set up screening programmes and/or to early distinguish malignancy from benign pelvic mass.
Carbohydrate antigen 125 (CA-125) is the established biomarker for detecting OC recurrence and monitoring therapeutic response. In addition, recent guidelines recommend its measurement in the primary care setting in women with suggestive symptoms or at high risk for OC, in combination with pelvic ultrasound, even though some authors have discouraged this application because of the low sensitivity of the test, which is even worse in early stage tumours (~50%). It is noteworthy that CA-125 is consistently expressed in serous and endometrioid OC, whereas tumours detectable at early stages have a higher prevalence of non-serous carcinomas. Overall, CA-125 effectiveness in the identification of the malignancy is threatened by its low diagnostic specificity. In fact, this glycoprotein is widely distributed on the surface of cells of mesothelial origin in various benign and malignant conditions other than OC.
Among a wide spectrum of biomarkers recently proposed to aid in the diagnosis of women with suspected OC, human epididymis protein 4 (HE4) is undoubtedly the most promising. Its measurement was from the beginning proposed to improve the diagnostic specificity of CA-125, just maintaining a similar sensitivity. HE4 has homology with some secreted serine protease inhibitors and was reported to be amplified in some CA-125-deficient OCs, whereas its expression is lower in normal ovarian tissue, ovarian benign disease and low-malignant potential tumours. After preliminary studies confirming genomic and immunohistochemical findings on HE4, a large body of literature has been recently produced. Despite the low number of initially available studies, recent guidelines resorting to a meta-analytic approach have suggested HE4 to be used as an aid in OC diagnosis. In addition, a systematic review (SR) has been recently published reporting better diagnostic performance in terms of sensitivity, specificity and likelihood ratios (LR) for HE4 than for CA-125. However, the type of included studies, the applied selection criteria and the statistical approach used to synthesise the evidence could be criticised. Exploiting the more recent increase of studies on the comparison of HE4 and CA-125 diagnostic performances for OC, we designed an SR to critically revise available literature overcoming the above-reported threats of Yu's SR. In particular, we sought to provide a synthesis of the available evidence on the diagnostic accuracy of the tests by considering only those studies evaluating both markers on the same case series. Methodologically, a stepwise selection of the studies and a further application of proper summary receiving operating curves (SROC) analysis was used to strengthen the evidence.
Abstract and Introduction
Abstract
Background Human epididymis protein 4 (HE4) measurements in serum have been proposed for improving the specificity of laboratory identification of ovarian cancer (OC).
Objective To critically revise the available literature on the comparison between the diagnostic accuracy of HE4 and carbohydrate antigen 125 (CA-125) to confirm the additional clinical value of HE4.
Methods A literature search was undertaken on electronic databases and references from retrieved articles; articles were analysed according to predefined criteria. Meta-analyses for HE4 and CA-125 biomarkers with OR, diagnostic sensitivity, specificity, positive (LR+) and negative (LR–) likelihood ratios as effect sizes were performed.
Results 16 articles were originally included in meta-analyses, but two for HE4 and one for CA-125 were eliminated as outliers. Furthermore, for HE4 a publication bias was detected. ORs for both HE4 (37.2, 95% CI 19.0 to 72.7, adjusted for publication bias) and CA-125 (15.4, 95% CI 10.4 to 22.8) were significant, although in a heterogeneous set of studies (p<0.0001). By combining sensitivity and specificity, the overall LR+ and LR– were 13.0 (95% CI 8.2 to 20.7) and 0.23 (95% CI 0.19 to 0.28) for HE4 and 4.2 (95% CI 3.1 to 5.6) and 0.27 (95% CI 0.23 to 0.31) for CA-125, respectively.
Conclusions HE4 measurement seems to be superior to CA-125 in terms of diagnostic performance for identification of OC in women with suspected gynaecological disease. Due to the high prevalence of OC in post-menopausal women and the need for data focused on early tumour stages, more studies tailored on these specific subsets are needed.
Introduction
Ovarian cancer (OC) is the sixth most common gynaecological malignancy characterised by an incidence rate that increases with age and in post-menopausal status. The crude incidence rate changes from 4.7 per 100 000 in women <50 years of age to 29.6 per 100 000 in the age group of 50–64 years. OC is currently the first cause of death in gynaecological malignancies; ~75% of patients are diagnosed at an advanced stage, since OC is generally asymptomatic in the early stages and no effective screening approach is available. The net discrepancy between survival rates in early and advanced stages (80–90% vs 15–20%) has reinforced the need for biomarkers with higher diagnostic accuracy to set up screening programmes and/or to early distinguish malignancy from benign pelvic mass.
Carbohydrate antigen 125 (CA-125) is the established biomarker for detecting OC recurrence and monitoring therapeutic response. In addition, recent guidelines recommend its measurement in the primary care setting in women with suggestive symptoms or at high risk for OC, in combination with pelvic ultrasound, even though some authors have discouraged this application because of the low sensitivity of the test, which is even worse in early stage tumours (~50%). It is noteworthy that CA-125 is consistently expressed in serous and endometrioid OC, whereas tumours detectable at early stages have a higher prevalence of non-serous carcinomas. Overall, CA-125 effectiveness in the identification of the malignancy is threatened by its low diagnostic specificity. In fact, this glycoprotein is widely distributed on the surface of cells of mesothelial origin in various benign and malignant conditions other than OC.
Among a wide spectrum of biomarkers recently proposed to aid in the diagnosis of women with suspected OC, human epididymis protein 4 (HE4) is undoubtedly the most promising. Its measurement was from the beginning proposed to improve the diagnostic specificity of CA-125, just maintaining a similar sensitivity. HE4 has homology with some secreted serine protease inhibitors and was reported to be amplified in some CA-125-deficient OCs, whereas its expression is lower in normal ovarian tissue, ovarian benign disease and low-malignant potential tumours. After preliminary studies confirming genomic and immunohistochemical findings on HE4, a large body of literature has been recently produced. Despite the low number of initially available studies, recent guidelines resorting to a meta-analytic approach have suggested HE4 to be used as an aid in OC diagnosis. In addition, a systematic review (SR) has been recently published reporting better diagnostic performance in terms of sensitivity, specificity and likelihood ratios (LR) for HE4 than for CA-125. However, the type of included studies, the applied selection criteria and the statistical approach used to synthesise the evidence could be criticised. Exploiting the more recent increase of studies on the comparison of HE4 and CA-125 diagnostic performances for OC, we designed an SR to critically revise available literature overcoming the above-reported threats of Yu's SR. In particular, we sought to provide a synthesis of the available evidence on the diagnostic accuracy of the tests by considering only those studies evaluating both markers on the same case series. Methodologically, a stepwise selection of the studies and a further application of proper summary receiving operating curves (SROC) analysis was used to strengthen the evidence.
Source...