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

Objective

Diagnostic factors are needed to improve the currently used serum CA125 and risk of malignancy index (RMI) in differentiating ovarian cancer (OC) from other pelvic masses, thereby achieving precise and fast referral to a tertiary center and correct selection for further diagnostics. The aim was to evaluate serum Human Epididymis protein 4 (HE4) and the risk of ovarian malignancy algorithm (ROMA) for these purposes.

Methods

Serum from 1218 patients in the prospective ongoing pelvic mass study was collected prior to diagnosis. The HE4 and CA125 data were registered and evaluated separately and combined in ROMA and compared to RMI.

Results

809 benign tumors, 79 borderline ovarian tumors, 252 OC (64 early and 188 late stage), 9 non-epithelial ovarian tumors and 69 non-ovarian cancers were evaluated. Differentiating between OC and benign disease the specificity was 62.2 (CA125), 63.2 (HE4), 76.5 (ROMA) and 81.5 (RMI) at a set sensitivity of 94.4 which corresponds to RMI = 200. The areas under the curve (AUC) were 0.854 (CA125), 0.864 (HE4), 0,897 (ROMA) and 0.905 (RMI) for benign vs. early stage OC. For premenopausal benign vs. OC AUC were 0.925 (CA125), 0.905 (HE4), 0.909 (ROMA) and 0.945 (RMI).

Conclusion

HE4 and ROMA helps differentiating OC from other pelvic masses, even in early stage OC. ROMA performs equally well as the ultrasound depending RMI and might be valuable as a first line biomarker for selecting high risk patients for referral to a tertiary center and further diagnostics. Further improvements of HE4 and ROMA in differentiating pelvic masses are still needed, especially regarding premenopausal women.     

A predictive model combining human epididymal protein 4 and radiologic features for the diagnosis of ovarian cancer

Objective

Ovarian cancer is the leading cause of death in women with gynecologic cancer. CA125 is the commonly used biomarker in the diagnosis of ovarian cancer, but has limitations in both sensitivity and specificity. Human Epididymal secretory protein (HE4) is a promising biomarker and is included in the Risk of Ovarian Malignancy Algorithm (ROMA) score, which is suggested to further increase the diagnostic accuracy than either marker alone. However, information from ultrasound and CT-scan is not included in this algorithm. This study evaluated the diagnostic accuracy of HE4 in the pre-operative diagnosis of ovarian cancer and the predictive values of biomarkers, ultrasound and CT-scan and combinations hereof.

Methods

HE4 and CA125 were measured in 361 subjects (34 benign, 147 ovarian cancer and 180 controls). Sensitivity, specificity and area under the curve (AUC) for CA125, HE4, ROMA and RMI scores were calculated using the receiver operating characteristic (ROC) methodology. The additional predictive value of ultrasound or CT-scan to the individual markers was analyzed using logistic regression.

Results

The sensitivity in predicting ovarian cancer of CA125 was 91% and of HE4 90%. The specificity was 65% and 97% respectively. HE4 demonstrated the highest discrimination (ROC-AUC = 0.96), compared to ROMA, RMI and CA125 (AUC = 0.95, 0.89 and 0.90 respectively). ROMA did not improve when it was combined with different ultrasound factors. The presence of intra-abdominal metastasis on CT-scan improved the discriminative potential of HE4 (p = 0.0004).

Conclusion

HE4 in combination with CT-scan may be incorporated in the diagnostic work-up in women with a pelvic mass.     

IOTA SR与CA125、HE4、ROMA、RMI1、GI-RADS对卵巢良恶性肿瘤的诊断价值比较

目的探讨糖链多肽抗原125(CA125)、人附睾蛋白4(HE 4)、恶性肿瘤风险算法(ROMA)、恶性风险指数1(RMI1)、国际卵巢肿瘤分析简单规则(IOTA SR)、妇科影像报告与数据系统(GI-RADS)在卵巢良恶性肿瘤鉴别诊断中的价值。方法选取2019年7月至2020年7月于锦州医科大学附属第一医院83例行附件手术并经术后病理检查确诊的卵巢肿瘤患者,术前行常规检查、血清CA 125、血清HE 4及妇科超声检查,计算ROMA值、RMI1值,根据超声结果进行IOTA SR评分及GI-RADS评分。使用推荐的临界值计算每种方法的敏感度、特异度、阳性预测值、阴性预测值和约登指数,计量资料构建受试者工作特征(ROC)曲线及计算曲线下面积(AUC)。结果卵巢恶性肿瘤组与卵巢良性肿瘤组相比,血清CA125、血清HE4、ROMA、RMI1水平显著升高,且均具有统计学意义(P<0.05)。对于卵巢良恶性肿瘤诊断,敏感度:CA125>ROMA>IOTA SR>RMI1>HE4=GI-RADS,特异度:HE4>IOTA SR>ROMA>GI-RADS>RMI1>CA125,约登指数:IOTA SR>ROMA>HE4>RMI1=GI-RADS>CA125,AUC:ROMA>RMI1>HE4>CA125,CA125约登指数明显低于其余各组,且差异有统计学意义(P<0.05),IOTA SR、ROMA、HE4、RMI1、GI-RADS各组间约登指数有差异,但差异无统计学意义(P>0.05)。结论IOTA SR在卵巢良恶性肿瘤的鉴别诊断中有较高的敏感度与特异度,诊断效能较高。     

Progranulin is a potential prognostic biomarker in advanced epithelial ovarian cancers

Objective

There are few validated relapse prediction biomarkers for epithelial ovarian cancer (EOC). We have shown progranulin (PGRN) and secretory leukocyte protease inhibitor (SLPI) are up regulated, overexpressed survival factors in EOC. We hypothesized they would predict presence of occult EOC.

Method

PGRN, SLPI, and the known biomarker HE4 were measured in EOC patient plasma samples, prospectively collected every 3 months from initial remission until relapse. Clinical data and CA125 results were incorporated into statistical analyses. Exploratory Kaplan-Meier estimates, dividing markers at median values, evaluated association with progression-free survival (PFS) and overall survival (OS). Area-under-the-curve (AUC) statistics were computed from receiver operating characteristic (ROC) curves to evaluate discrimination ability. A Cox proportional hazards model assessed the association between PFS, OS, and biomarkers, adjusting for clinical prognostic factors.

Results

Samples from 23 advanced stage EOC patients were evaluated. PGRN at 3 months was the only biomarker independently associated with PFS (P < 0.0001) and OS (P < 0.003). When used to predict progression by 18 months, sensitivity and specificity were 93% and 100%, respectively, with AUC = 0.944. The Cox model hazard ratio for PFS, divided at 59 ng/ml by ROC analysis and adjusted for clinical factors, was 23.5 (95% CI: 2.49-220). Combinations with SLPI, HE4, and/or CA125 did not improve the model.

Conclusions

We report pilot data indicating a potential independent association of PGRN on EOC patient PFS and OS. A validation study will be required to confirm this finding and to inform whether PGRN warrants evaluation as a potential screening biomarker.     

HE4 is an independent prognostic marker in endometrial cancer patients

Objective

To evaluate the prognostic value of pretherapeutic serum HE4 in endometrial cancer in comparison to CA125.

Methods

HE4 and CA125 serum levels were analyzed by means of chemiluminescent microparticle immunoassays in 183 patients with endometrial cancer treated at the Department of Obstetrics and Gynecology, Innsbruck Medical University, between 1999 and 2009. The Kaplan-Meier method and Cox's proportional hazards analysis were performed to determine the prognostic significance of HE4, CA125 and the combination of both markers.

Results

In univariate analysis both markers, HE4 and CA125, were of prognostic value for overall survival (p < 0.001 and p = 0.028) and disease-free survival (p = 0.015 and p = 0.045). In multivariate analysis HE4 was seen to have independent prognostic value in overall survival (HR 2.407, p = 0.017) in contrast to CA125. The combination of both markers showed a higher hazard ratio (HR 4.04, p = 0.023) for overall survival in comparison to HE4 alone. In the subgroup endometrioid histological type (n = 132) only HE4 was of prognostic value for overall survival in univariate (p = 0.001) and multivariate analysis (p = 0.023).

Conclusions

Pretherapeutic serum HE4 levels alone and in combination with CA125 are an independent prognostic marker in endometrial cancer patients.     

Prognostic value of elevated preoperative serum CA125 in ovarian tumors of low malignant potential: a multinational collaborative study (ANZGOG0801)

Objective

Previous studies on prognostic factors in ovarian tumors of low malignant potential (LMP) were too small for robust conclusions. We examined the prognostic impact of preoperative serum CA125 ≥ 50 U/ml levels in patients diagnosed with ovarian LMP tumors in a large multinational cohort.

Methods

This retrospective study included 940 patients with ovarian LMP tumors diagnosed between 1985 and 2008 at six gynecologic cancer centers. Patients either had radical treatment (bilateral salpingo-oophorectomy with or without hysterectomy) or conservative, fertility-sparing treatment. Multivariate Cox proportional hazard models were used to determine independent prognostic factors for disease-free (DFS) and overall survival (OS). Based on receiver operating characteristic curve (ROC), a preoperative serum CA125 level ≥ 50 U/ml was considered “elevated”.

Results

CA125 was more often elevated in serous than in mucinous tumors and in advanced FIGO stages (2 to 4) compared to stage1. DFS at 5 years was 89% and 95% in patients with elevated and normal CA125 levels (p < 0.05). Similarly, the 5-year OS was 90% among patients with elevated CA125 compared to 95% among patients with normal levels (p < 0.05). For both DFS and OS elevated CA125 levels and advanced stages of the disease were independent prognostic factors. Analysis of subgroups revealed that CA125 was only prognostic in serous LMP tumors.

Conclusions

In the context of serous ovarian LMP tumors, elevated preoperative serum CA125 represents a biomarker independently associated with impaired disease-free and overall survival. CA125 is available in most centers and could inform surgeons about the risk of treatment failure.     

CA125 surveillance increases optimal resectability at secondary cytoreductive surgery for recurrent epithelial ovarian cancer

Objective

Recent data suggest that serial CA125 surveillance following remission in asymptomatic patients with epithelial ovarian cancer (EOC) does not impact overall survival. However, earlier detection of recurrence may influence resectability at secondary cytoreductive surgery (SCS). We hypothesized that a shorter time interval between CA125 elevation and SCS correlates with a higher likelihood of optimal resection among eligible patients.

Methods

We identified patients with recurrent epithelial ovarian cancer who underwent SCS from 1995 to 2009 at our institution. All patients initially underwent primary cytoreductive surgery followed by platinum-based chemotherapy. CA125 elevation was considered the first value two-times the patient's nadir level. Our “study interval” was the time between CA125 elevation and SCS. Optimal SCS was defined as microscopic residual disease (≤ 0.5 cm). Our analysis compared patients who underwent optimal vs. suboptimal SCS.

Results

Seventy-four patients who underwent SCS for recurrent EOC met inclusion criteria. Median disease-free interval prior to SCS was 19 vs. 12 months for the optimal and suboptimal SCS groups. More patients undergoing suboptimal SCS had ascites (21% vs. 2%, p = 0.01) and carcinomatosis (42% vs. 5%, p < 0.0001). Patients who underwent optimal SCS went to the operating room 5.3 vs. 16.4 weeks (HR 1.03, 95% CI 1.01-1.06, p = 0.04) from the time of their CA125 elevation. Optimal SCS was associated with a longer overall survival (47 vs. 23 months, p < 0.0001).

Conclusions

Each week delay after first CA125 elevation correlated with a 3% increased chance of suboptimal resection at SCS. Serial CA125 surveillance for early detection of recurrence may increase rates of optimal SCS and potentially influence overall survival.     

Evaluation of ovarian cancer remission markers HE4, MMP7 and Mesothelin by comparison to the established marker CA125

Objective

Evaluate and compare the effectiveness of CA125, HE4, Mesothelin and MMP7 marker levels to monitor ovarian cancer patients after surgery and chemotherapy. Evaluate the lead time of a rise of marker levels before recurrence.

Methods

The study consists of 23 patients with advanced stage ovarian/fallopian tube cancer. Blood was drawn after front line surgery and chemotherapy treatment and at 3 month intervals thereafter. One patient had chemoresistant disease, two patients remained in remission and 20 patients had recurring disease and were used for marker evaluation.

Results

In five patients HE4 was the only marker to elevate before recurrence with a lead time of up to 4½ months including one patient who did not have a CA125 response at all. In a further two patients, HE4 increased before CA125 did. In four of these seven patients, HE4 levels were consistently at or above threshold during remission when both CA125 and imaging results were negative. MMP7 elevated before recurrence in one patient who was negative for the other markers. Mesothelin elevated in two patients who were also positive for CA125 and HE4.

Conclusions

HE4 can predict ovarian cancer recurrence earlier than CA125 and it can be elevated in patients that do not express CA125 at sufficient levels to make a clinical decision. MMP7 and Mesothelin have lower potential as markers for ovarian cancer recurrence to complement CA125. A failure of HE4 levels to normalize at completion of standard therapy may indicate a poor prognosis.     

CA 125 normalization with chemotherapy is independently predictive of survival in advanced endometrial cancer

Objective

Changes in CA 125 with chemotherapy predict outcome for epithelial ovarian cancer. There is no such data for advanced endometrial cancer.

Method

Retrospective review of all women receiving carboplatin and paclitaxel for advanced endometrial cancer at any of the institutions of the British Columbia Cancer Agency between September 1995 and September 2006.

Results

185 newly diagnosed women were treated. Univariable analysis for progression-free survival identified as adverse predictors: grade 3, positive residual, age > 60, deep myometrial invasion, increasing stage/substage, papillary serous subtype, presence of cervical involvement, ECOG 1 or greater, CA 125 above 35 either preoperatively or at start of cycle 1 and CA 125 greater than 24 at the start of cycle 3. Upon multivariate analysis, CA 125 above 24 at cycle 3, grade 3 and positive residual remained as independent predictors. The single most important factor identified by decision tree analysis was CA 125 level at cycle 3.

Conclusion

As with epithelial ovarian cancer, changes in CA 125 are highly predictive of outcome for advanced, chemotherapy treated endometrial cancer.     

Prognosis of ovarian clear cell carcinoma compared to other histological subtypes: a meta-analysis

Objective

To compare the survival outcome between clear cell carcinoma (CCC) and other histological subtypes in epithelial ovarian carcinoma (EOC).

Methods

From January 1974 to February 2011, we identified a total of 31,800 (CCC; 2152, non-CCC; 29648) patients from 12 studies meeting the inclusion criteria.

Results

Heterogeneity tests demonstrated significant between-study variation (I² = 92.1%) with no significant difference in hazard ratio (HR) for death between CCC and non-CCC (HR; 1.16, 95% CI; 0.85-1.57, random-effects model). Comparing the HR based on stage I + II, and stage III + IV, between CCC and non-CCC, showed that CCC patients had a higher hazard rate for death than those with non-CCC of the ovary (stage I + II; HR; 1.17, 95% CI; 1.01-1.36, stage III + IV; HR; 1.65, 95% CI; 1.52-1.79). In a comparison of CCC and serous EOC, advanced stage (III and IV) CCC only showed a poorer hazard rate for death than serous EOC (HR; 1.71, 95% CI; 1.57-1.86).

Conclusion

This analysis suggests that ovarian CCC patients had poorer prognosis than those with other histological subtypes of EOC, especially in advanced EOC stages. Different treatment strategies may be needed for patients with ovarian CCC.     

Comparison of candidate serologic markers for type I and type II ovarian cancer

Objective

To examine the value of individual and combinations of ovarian cancer associated blood biomarkers for the discrimination between plasma of patients with type I or II ovarian cancer and disease-free volunteers.

Methods

Levels of 14 currently promising ovarian cancer-related biomarkers, including CA125, macrophage inhibitory factor-1 (MIF-1), leptin, prolactin, osteopontin (OPN), insulin-like growth factor-II (IGF-II), autoantibodies (AAbs) to eight proteins: p53, NY-ESO-1, p16, ALPP, CTSD, B23, GRP78, and SSX, were measured in the plasma of 151 ovarian cancer patients, 23 with borderline ovarian tumors, 55 with benign tumors and 75 healthy controls.

Results

When examined individually, seven candidate biomarkers (MIF, Prolactin, CA-125, OPN, Leptin, IGF-II and p53 AAbs) had significantly different plasma levels between type II ovarian cancer patients and healthy controls. Based on the receiver operating characteristic (ROC) curves constructed and area under the curve (AUC) calculated, CA125 exhibited the greatest power to discriminate the plasma samples of type II cancer patients from normal volunteers (AUC 0.9310), followed by IGF-II (AUC 0.8514), OPN (AUC 0.7888), leptin (AUC 0.7571), prolactin (AUC 0.7247), p53 AAbs (AUC 0.7033), and MIF (AUC 0.6992). p53 AAbs levels exhibited the lowest correlation with CA125 levels among the six markers, suggesting the potential of p53 AAbs as a biomarker independent of CA125. Indeed, p53 AAbs increased the AUC of ROC curve to the greatest extent when combining CA125 with one of the other markers. At a fixed specificity of 100%, the addition of p53 AAbs to CA125 increased sensitivity from 73.8% to 85.7% to discriminate type II cancer patients from normal controls. Notably, seropositivity of p53 AAbs is comparable in type II ovarian cancer patients with negative and positive CA125, but has no value for type I ovarian cancer patients.

Conclusions

p53 AAbs might be a useful blood-based biomarker for the detection of type II ovarian cancer, especially when combined with CA125 levels.     

Correlation of serum HE4 with tumor size and myometrial invasion in endometrial cancer

Objective

To evaluate the utility of serum (HE4) as a marker for high risk disease in patients with endometrial cancer (EC).

Methods

Preoperative serum HE4 levels were measured from a cohort of 75 patients surgically treated for EC. Cases were compared to matched controls without a history of cancer. HE4 levels were analyzed as a function of primary tumor diameter, grade, stage and histological subtype. Wilcoxon rank-sum test, ROC curve, Spearman rank correlation coefficient and contingency tables were used for statistical analyses.

Results

Stage distribution was as follows: 49 stage I, 2 stage II, 20 stage III, 4 stage IV. Type I EC was present in 54 patients, type II in 21. Median HE4 was significantly elevated in both types I and II EC compared to controls (P < 0.001 and P = 0.019, respectively). There was significant correlation between type I EC, median HE4, deep myometrial invasion (MI) (> 50%, P < 0.001) and primary tumor diameter (PTD) (> 2 cm, P = 0.002). Low risk patients (type I, MI ≤ 50% and PTD ≤ 2 cm) had significantly lower median HE4 compared to all other type I EC patients (P < 0.01). In comparison to prior investigations, HE4 (cutoff of 8 mfi) was more sensitive than CA125 in detecting advanced stage disease.

Conclusion

Our data suggest that HE4 is elevated in a high proportion of EC patients, is correlated with PTD and MI, and is more sensitive than CA125 in EC. These observations suggest potential utility of HE4 in the preoperative prediction of high risk disease and the necessity for definitive surgical staging.     

Expression of 67-kDa laminin receptor was associated with tumor progression and poor prognosis in epithelial ovarian cancer

Objective

67-kDa laminin receptor (67LR) has been identified as a prognostic biomarker for a variety of human cancers. We investigated the clinical significance of 67LR expression and its functional role in epithelial ovarian cancer (EOC).

Methods

67LR expression was evaluated by immunohistochemistry in 62 patients with EOC. We assessed the correlation of 67LR expression with clinical characteristics. In vitro experiment was performed for 67LR with inhibition using siRNA to evaluate its role in cell survival, apoptosis, and invasion in EOC cells.

Results

67LR was predominantly expressed on the cell membrane in the majority of EOC samples (45/62, 73%). 67LR expression was significantly correlated with advanced stage (P = 0.001). Patients with 67LR expression had shorter progression-free survival among all the patients (P = 0.010) and in particular among patients with advanced stages (P = 0.046). When 67LR expression was inhibited by siRNA in EOC cells (HeyA8 and A2780), there was a significant decrease of cell proliferation and invasion as well as increase of apoptosis.

Conclusion

These findings suggest that 67LR expression may play an important role in tumor progression into advanced stage with poor prognosis in EOC and down-regulation of 67LR on tumor cells may be a therapeutic target in those patients.     

FDG PET/CT in staging of advanced epithelial ovarian cancer: frequency of supradiaphragmatic lymph node metastasis challenges the traditional pattern of disease spread

Objective

Epithelial ovarian cancer (EOC) spreads intra-abdominally and to the retroperitoneal lymph nodes. A greater number of distant metastases are revealed by ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) compared to conventional imaging methods. We aimed to investigate the presence and anatomic distribution of supradiaphragmatic lymph node metastasis (LNM) detected with pretreatment FDG PET/CT.

Methods

Thirty women with advanced stage (IIC-IV) EOC were scanned with whole body contrast-enhanced FDG PET/CT prior to surgery/neoadjuvant chemotherapy. We performed PET/CT analysis qualitatively and quantitatively. Additionally, contrast-enhanced CT was analyzed blinded to PET/CT scan. Intra-abdominal dissemination was verified by surgery and histopathology. Metabolically active lymph nodes were biopsied when possible. The clinical characteristics of patients with and without supradiaphragmatic LNM were compared.

Results

In 20/30patients (67%) FDG PET/CT detected supradiaphragmatic LNM in one or more locations, whereas conventional CT found LNM in 10 patients (33%). Fourteen patients had parasternal, 14 cardiophrenic, 8 other mediastinal, 6 axillar, and 1 subclavian LNM. Microscopy of all four biopsied lymph nodes (three axillar and one subclavian) confirmed metastatic dissemination. The patients with supradiaphragmatic LNM had significantly more ascites (p < 0.01), higher CA 125 levels, and more frequent subdiaphragmal carcinomatosis (p < 0.03) compared to patients without supradiaphragmatic LNM in preoperative FDG PET/CT.

Conclusions

A significant number of patients with advanced EOC showed supradiaphragmatic LNM in pre-treatment PET/CT. Our findings suggest that the route of EOC cells from the peritoneal cavity to the lymphatic system permeates the diaphragm mainly to the cardiophrenic and continues to parasternal lymph nodes.     

Interaction between preoperative CA-125 level and survival benefit of neoadjuvant chemotherapy in advanced epithelial ovarian cancer

Objective

This study aims to determine whether neoadjuvant chemotherapy (NAC) has survival benefit in selected patients with advanced epithelial ovarian cancer (EOC) who have high risk of suboptimal cytoreduction which is represented by high serum CA-125 level.

Methods

We retrospectively reviewed records of 314 patients with EOC including 94 patients who received NAC. After stratification by preoperative CA-125 levels, the progression-free survival (PFS) was compared between the NAC group and the primary debulking surgery (PDS) group.

Results

The NAC group had more FIGO stage IV disease (P < 0.001) and higher CA-125 levels (P < 0.001). Although suboptimal resection rate was higher in the PDS group (50% vs. 18%, P < 0.001), however, NAC was not associated with increased PFS in multivariate Cox analysis (P = 0.334). Nevertheless, after stratification according to CA-125 levels, NAC showed survival benefit in the subgroup with high CA-125 levels (> 2000 U/ml; HR 0.62, P = 0.037).

Conclusion

Our preliminary data suggests the possible interaction between CA-125 levels and survival benefit of NAC. The randomized trial data about NAC should be stratified by the reproducible and relevant criteria such as preoperative serum CA-125 level to elucidate true survival benefit of NAC in ovarian cancer.     

Correlation between CA-125 serum level and response by RECIST in a phase III recurrent ovarian cancer study

Objectives

To evaluate in a large phase III recurrent ovarian cancer trial (OVA-301): 1) the concordance between CA-125 level vs. best overall response (OR) and progression-free survival (PFS) determined by radiological assessment 2) the impact of early CA-125 changes over the subsequent radiological response, and 3) the prognostic value of CA-125 response and CA-125 PFS to predict radiological response and PFS.

Methods

Assessment of response in the entire randomized population was performed by the Response Evaluation Criteria in Solid Tumors 1.0 (RECIST) and modified Rustin criteria for CA-125 determination.

Results

Most CA-125 decreases were observed in RECIST responders (82% of patients treated with the combination and 74% in the PLD alone). CA-125 progression preceded RECIST progression in 35% of patients with a median lead time of 8.4 weeks. A high concordance rate between CA-125 PFS status at 4 months (PFS4) and CA-125 response as a predictor of PFS4 (87%) and radiological response (79%) was found in the combination, with high positive predictive value for radiological PFS4 (92%) and high negative predictive value for OR (90%). An early CA-125 decrease was predictive for the ultimate response since it was found in a high rate of RECIST responders.

Conclusion

Radiological response was preceded by a favorable predictive CA-125 decrease in a high proportion of patients, suggesting that CA-125 evaluation may be an appropriate tool for tumor assessment in patients with ovarian cancer.     

Comparison of four malignancy risk indices in the preoperative evaluation of patients with pelvic masses

Objective

The aim of this study was to evaluate the ability of four malignancy risk indices (RMI 1, RMI 2, RMI 3, and RMI 4), incorporating menopausal status, serum CA125 levels, and ultrasound findings, to discriminate a benign from a malignant pelvic mass.

Study design

This is a retrospective study of 253 women admitted to the Department of Obstetrics and Gynecology of Kochi Medical School, between January 2002 and April 2005 for surgical exploration of pelvic masses. To diagnose ovarian cancer, the sensitivity, specificity, and positive predictive value of serum CA125, ultrasound findings and menopausal status were taken separately and combined into RMI 1, RMI 2, RMI 3, and RMI 4.

Results

This study confirms that, for the diagnosis of malignancy, four malignancy risk indices were more accurate than menopausal status, serum CA125 levels, and ultrasound findings separately. The accuracy of the RMI 4 was better than RMI 1 (P = 0.0013), RMI 2 (P = 0.0009) and RMI 3 (P = 0.0013). The RMI 4 at a cutoff level of 450 yielded a sensitivity of 86.8%, a specificity of 91.0%, a positive predictive value of 63.5%, a negative predictive value of 97.5%, and an accuracy of 90.4%.

Conclusion

We found that, in the discrimination between benign and malignant pelvic disease, the RMI 4 method was more reliable than RMI 1, RMI 2 and RMI 3. The RMI 4 method is a simple technique that can be used in gynecology clinics as well as less-specialized centers.     

The use of HE4 in the prediction of ovarian cancer in Asian women with a pelvic mass

ObjectiveThe purpose of this study was to evaluate the performance of human epididymis protein 4 (HE4) and the Risk of Ovarian Malignancy Algorithm (ROMA) for distinguishing between benign and malignant pelvis masses in Asian women.MethodsThis was a prospective, multicenter (n = 6) study with patients from six Asian countries. Patients had a pelvic mass on imaging and were scheduled to undergo surgery. Serum CA125 and HE4 were measured on preoperative samples. CA125, HE4, and ROMA were evaluated for sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV).ResultsA total of 414 women with an adnexal mass were evaluated, of which 65 had epithelial ovarian (EOC) cancer, 16 had borderline tumors and 11 had other malignant diseases. Compared to CA125, HE4 had lower sensitivity (56.9% vs 90.8%) and NPV (91.8% vs 97.3%), but improved specificity (96.9% vs 67.1%) and PPV (78.7% vs 35.8%) for differentiating between benign pelvic mass and EOC. ROMA had similar sensitivity (89.2% vs 90.8%) and NPV (97.6% vs 97.3%) as CA125, but showed improved specificity (87.3% vs 67.1%) and PPV (58.6% vs 35.8%). ROMA accurately predicted 87.3% of benign cases as low risk, and 82.6% of stage I/II EOC and 89.2% of all EOC as high risk.ConclusionROMA showed similar sensitivity as CA125 but improved specificity and PPV, especially in premenopausal women. Using ROMA may help predict if a pelvic mass is benign or malignant and facilitate subsequent management planning.     

A high response rate to liposomal doxorubicin is seen among women with BRCA mutations treated for recurrent epithelial ovarian cancer

Objective

Ten percent of ovarian cancer is attributed to hereditary syndromes, most commonly to mutations in the BRCA1 or BRCA2 genes. These cancers are characterized by a prolonged sensitivity to platinum agents in spite of presentation at advanced stages. We hypothesized that women with BRCA-associated ovarian cancer would also show a high response rate to pegylated liposomal doxorubicin (Doxil).

Methods

A retrospective cohort study was conducted to compare the response rate, progression-free, and overall survival among women with BRCA-associated or sporadic ovarian cancer who were treated with Doxil.

Results

A response to Doxil was seen in 13 of 23 patients with BRCA mutations (56.5%; 3 by RECIST criteria and 10 by CA125 levels) compared with only 8 of 41 women with non-hereditary cancers (19.5%; 2 by RECIST criteria and 6 by CA125 levels; p = 0.004). This was associated with an improved progression-free and overall survival as measured from the time of Doxil administration. Notably, platinum sensitivity did not directly correlate with a response to Doxil.

Conclusions

Women with BRCA-associated ovarian tumors demonstrate a greater sensitivity to cytotoxic therapy with Doxil than has previously been reported in unselected cases.     

Diagnostic performance of the biomarkers HE4 and CA125 in type I and type II epithelial ovarian cancer

Objective

To evaluate the diagnostic performance of HE4 and CA125 in patients presenting with suspicious malignant ovarian cysts. We especially wanted to investigate the levels of HE4 and CA125 with regard to the gene and histology-unifying model of type I and type II epithelial ovarian cancer (EOC).

Methods

Plasma from 373 women presenting with a suspicious malignant ovarian cyst was collected prior to surgery. Histology, grade, and stage were determined according to FIGO-classification. HE4 and CA125 were analyzed using ELISA, and the markers were evaluated for significance separately and in combination. Receiver operating curves, the area under the curve, sensitivity and specificity were estimated.

Results

The combination of HE4 and CA125 resulted in the best diagnostic power in comparing benign tumors to EOC (ROC AUC 0.93, sensitivity 94.4% at 75% specificity) for type II. Diagnostic power in type I (ROC AUC 0.79, sensitivity 61.9% at 75% specificity) was less impressive. In particular, mucinous benign vs. malignant tumors could not significantly be separated by the dual marker combination. Impressively high ROC AUC 0.99 was found for the late stage type II EOC with 100% sensitivity at 75% specificity.

Conclusions

HE4 and CA125 have a good ability to diagnose the more aggressive type II tumors but a poor diagnostic ability when patients are presenting with slow-growing type I in the early stage. Our results support the hypothesis that EOC should be looked upon as several different diseases, and that we lack biomarkers for sub-groups of EOC.