{"id":8259,"date":"2013-03-13T07:10:16","date_gmt":"2013-03-13T07:10:16","guid":{"rendered":"https:\/\/www.lalpathlabs.com\/blog\/?p=853"},"modified":"2023-10-12T10:40:35","modified_gmt":"2023-10-12T05:10:35","slug":"he4-and-risk-for-ovarian-malignancy-algorithm","status":"publish","type":"post","link":"https:\/\/www.lalpathlabs.com\/blog\/he4-and-risk-for-ovarian-malignancy-algorithm\/","title":{"rendered":"He4 and Risk for Ovarian Cancer Algorithm"},"content":{"rendered":"

\"vol<\/a><\/p>\n

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He4 and Risk for Ovarian Malignancy Algorithm\u00a0(ROMA) as New Diagnostic and Prognostic Tools for\u00a0Epithelial Ovarian Cancer Management<\/span><\/h3>\n

Ovarian cancer (OC) is one of the most deadly gynecological cancers<\/a><\/span>\u00a0in women. In 2011, there were over 200,000 new cases diagnosed\u00a0worldwide and 125,000 deaths [1]. The risk of developing ovarian\u00a0cancer increases with age and most ovarian cancer cases occur in\u00a0women over 50 years old. Diagnosing ovarian cancer can be difficult
\nbecause the symptoms are non-specific and include abdominal\u00a0fullness, pelvic pain, gastrointestinal distress or fatigue. Over 70% of\u00a0ovarian cancers are diagnosed at an advanced stage.<\/p>\n

Suspected ovarian neoplasm is a common problem in women of all\u00a0ages. Women have 5 to 10 percent risk of requiring surgery and those\u00a0who undergo surgery have 13 to 21 percent chance of being\u00a0diagnosed with ovarian cancer. Since 1980s, CA125 has been utilized\u00a0in the management of this cancer. Most oncology societies\u00a0recommend the use of CA125 for the differential diagnosis of a\u00a0suspected pelvic mass, monitoring efficacy of treatment, and\u00a0detection of recurrence of ovarian cancer but none of the oncology\u00a0societies recommend using CA125 for screening for ovarian cancer\u00a0because CA125 does not have the sensitivity and specificity needed\u00a0for widespread screening of women.<\/p>\n

Human Epididymis Protein 4 (HE 4), has been extensively evaluated\u00a0and is currently cleared by the Food and Drug Administration (FDA) to\u00a0be used as an aid in monitoring recurrence or disease progression in\u00a0patients with ovarian epithelial cancer. HE4 is also used with CA125 in\u00a0an algorithm called Risk for Ovarian Malignancy Algorithm (ROMA).\u00a0ROMA has been cleared by FDA as an aid in assessing whether a\u00a0premenopausal or post menopausal women who presents with an\u00a0ovarian adnexal mass is at high or low likelihood of being malignant\u00a0upon surgery. Such improvement would allow for a more accurate\u00a0presurgical assessment of a woman with a pelvic mass and would\u00a0facilitate referral of truly high risk women to surgical oncologist and\u00a0cancer centre for better outcome.<\/p>\n

Ovarian Cancer Facts<\/strong><\/span><\/p>\n

Ovarian Epithelial cancer (OEC) is the most frequent cause of death\u00a0from gynecologic cancer. In most of the population based cancer\u00a0registers in India, Ovarian cancer is the third leading site of cancer\u00a0among women, trailing behind cervix and breast cancer<\/a><\/strong>. The age\u00a0adjusted incidence rates of ovarian cancer varybetween 5.4 to 8.0 per\u00a0100,000 populations in different parts of the country [2].<\/p>\n

Ovarian cancer is a relatively manageable malignancy when\u00a0diagnosed at an early stage, but late stage detection almost always\u00a0translates into poor prognosis.Early detection of ovarian cancer\u00a0corresponds to a 92% five years survival rate where as overall 5 year\u00a0survival rate for ovarian cancer is less than 50%. This is because only
\n19% of ovarian malignancies are diagnosed prior to extra-ovarian\u00a0spread owing to the lack of obvious symptoms prior to progression [3].Ovarian cancer survival rates could be improved through screening\u00a0and early detection. Disappointingly, effective screening methods\u00a0have not been established and continue to be elusive. Equally\u00a0important recent studies have demonstrated that women who have\u00a0their initial surgery performed by gynecologic oncologist and at\u00a0centers having experience in the treatment of ovarian cancer<\/a><\/span> have\u00a0better survival rates [4]. The improved survival rate is result of proper\u00a0staging which helps identify patients with unexpected occult\u00a0metastasis who need adjuvant therapy, and of aggressive debulking\u00a0of advanced disease. Thus in women presenting with an adnexal\u00a0mass, clinicians must assess the malignant potential of the pelvic\u00a0mass in order to best determine the optimal location and clinician to\u00a0provide initial intervention.The American College of Obstetricians and\u00a0gynecologists (ACOG) in conjunction with the Society of gynecologic\u00a0Oncologists (SGO) published referral guidelines in 2007 to provide\u00a0guidance on the management ofadnexal masses (Table 1).<\/p>\n

Table 1. ACOG and SGO Referral guidelines for a Newly\u00a0diagnosed Pelvic Mass<\/strong><\/span><\/p>\n

\"table<\/a><\/p>\n

Dearking et al (15)evaluated these guidelines in a large cohort of\u00a0women and found that these guidelines exhibited a positive predictive\u00a0value (PPV) of 64.6% in postmenopausal women and 39.6% in\u00a0premenopausal women. Theguidelines generally worked well in\u00a0postmenopausal women, but performedpoorly in early-stage disease,\u00a0especially among premenopausal women.<\/p>\n

Thus an effective differentiation approach is still needed that will help\u00a0differentiate benign lesions from malignant lesions and would allow\u00a0referral of high risk women to specialized center that would improve\u00a0clinical outcomes.<\/p>\n

Evaluation of Adnexal Mass<\/strong><\/span><\/p>\n

Premenopausal Women (< 50 years old) Postmenopausal Women (> 50 years old)<\/p>\n

    \n
  1. Physical examination: <\/strong>Physical examination have limited ability to identify adnexal masses, especially in patients whose body mass index is greater than 30 kg per m2.<\/li>\n<\/ol>\n
      \n
    1. Ultrasonography: <\/strong>High frequency, grey scale transvaginal ultrasonography (USG) can produce high resolution images ofadnexal mass and is the only one recommended for routine use. Color Doppler USG measures blood flow indices; however, its use is controversial because the values of these indices overlap considerably between benign and malignant masses. CT, MRI & PET should be used in special circumstances because of high cost.<\/li>\n<\/ol>\n
        \n
      1. Serum marker screening: <\/strong>CA 125 antigen is the most extensively studied serum marker for distinguishing benign from malignant pelvic masses. CA 125 is elevated in 80 percent of patients with OEC and has been show to correlate with tumor volume and stage making it an excellent marker for monitoring response to therapy. However, it is elevated only in 50 percent patients with stage I disease. For this reason, measurement of CA 125 in not a useful screening test. CA 125 specificity is also compromised by the fact that many benign gynecologic and medical conditions as well as other malignancies can result in elevated CA 125 levels.<\/li>\n<\/ol>\n

        Several other serum tumor markers have been evaluated in combination with CA 125 to improve the sensitivity, specificity and positive predictive value of the test. Moore et. al. (6) evaluated several candidate biomarkers and found that combination of CA 125 and HE4 gave the best sensitivity and specificity of all biomarkers tested in women presenting with pelvic mass. Nolen and colleagues found that combination of CA125 & HE4 had the best discriminatory power for benign versus malignant disease than all other malignancies. Yurkovetsky and colleagues found that a combination of CA125, HE4,\u00a0Carcinoembrynic antigen and Vascular cell adhesion molecule 1 gave the best sensitivity of all the combinations tested. Currently there are many groups that are evaluating HE4 in combination with CA125, or in combination with other biomarkers.<\/p>\n

        Human Epididymis protein 4 (He4)<\/strong><\/span><\/p>\n

        He4 is a glycoprotein that is expressed in normal male and female reproductive tract and pulmonary epithelium. The gene encoding for HE4 is part of a family of protease inhibitors involved in protective immunity in ovarian malignancies as well as endometrial cancer (EC). Moore et al upon testing the efficacy of various markers of OC demonstrated that as a single maker, HE4 had the highest sensitivity of 72.9% at a set specificity of 95%. The combination of CA125 with HE4 achieved the highest sensitivity (76.4%) compared with all other single marker or dual marker combinations, and the addition of other markers to combination of HE4 & CA125 imposed only modest improvement in sensitivity of OC detection. Havrilesky and colleagues obtained similar results in an independent study of another group of OC markers. These studies demonstrate that as individual tests CA125 & HE4 have equivalent sensitivities for detecting malignancy in a woman presenting with pelvic mass, but in combination the tests could be complementary.<\/p>\n

        In contrast to CA 125, HE4 is usually not elevated in benign gynecologic conditions such as non malignant tumors, endometriosis and pelvic inflammatory disease.Huhtinen and colleagues recently analyzed serum concentration of CA125 in 225 women with OC, EC, endometriosis or healthy controls. The combination of HE4 and\u00a0<\/strong>CA125 achieved much improved sensitivity of 92.9% at 95% specificity compared with either HE4 or CA125 alone. <\/strong>HE4 levels\u00a0were elevated in both OC and EC, but not in endometriotic lesions.<\/p>\n

        HE4 has been cleared by the FDA for monitoring recurrence in\u00a0<\/strong>patients with OEC. <\/strong>Allard et al showed that HE4 demonstrated a 76.2% overall concordance with disease progression or regression, and in some cases, HE4 is elevated where CA 125 is not. CA125 is the most commonly used marker for monitoring treatment of OEC, but some 10% of patients of OC may not have elevated levels of CA125 and these patients are therefore left without a reliable marker for monitoring of disease.Recently, the novel biomarker HE4 has been shown to elevated in over half of OEC patients where CA125 was not elevated resulting in over 90% of patients having at least CA125 or HE4 as a biomarker for monitoring disease. However, most studies with HE4 have focused on its potential ability to differentiate benign from malignant lesion in women presenting with an adnexal or pelvic mass.<\/p>\n

        ROMA :<\/strong><\/span><\/p>\n

        Even in combination serum biomarkers have limited sensitivities and specificities, so efforts to improve risk stratification tools for women with pelvis masses have incorporated other factors from woman\u2019s clinical evaluation. Moore and colleagues developed an algorithm incorporating CA 125, HE4 and menopausal status, called Risk for\u00a0<\/strong>Ovarian malignancy Algorithm (ROMA) which has been cleared by FDA as an aid in assessing whether a premenopausal or postmenopausal women who presents with an ovarian adnexal mass is at high or low likelihood of finding malignancy upon surgery.<\/strong><\/p>\n

        ROMA uses the results for HE4 and CA125 to generate apredictive index (PI) for OEC calculated by thefollowing formulas:<\/p>\n

        For premenopausal women:<\/strong><\/p>\n

        PI = -12.0 +2.38 *ln(HE4) + 0.0626 *ln(CA125)<\/p>\n

        For postmenopausal women:<\/strong><\/p>\n

        PI = -8.09 +1.04 *ln(HE4) +0.732 *ln(CA125)<\/p>\n

        Then, ROMA value is calculated as follows:<\/strong><\/p>\n

        ROMAvalue (%)= exp(PI)\/[1 +exp(PI)] *100<\/p>\n

        According to the indications of the HE4 manufacturer,indexes of at least 7.4% and 25.3% indicate a highrisk for the presence of EOC in pre- or postmenopause, respectively.<\/p>\n

        Moore et al. reported that ROMA successfully classified women presenting with a pelvic mass into low and high risk groups with 93.8% of women who were found to have OEC to be correctly identified as high risk. Most recently, Moore and Colleagues compared ROMA to the Risk of Malignancy Index (RMI)that is comprised of the measurement of CA 125 levels in addition to an imaging score and assessment of menopausal status to predict OEC women presenting for surgery with a pelvic mass. At a set specificity of 75% ROMA demonstrated a sensitivity of 89% compared to 80.7% of RMI, a difference which was statistically significant (p=0.0113).<\/p>\n

        A recent metaanalysis [7] found that, first, ROMA could help distinguish OEC from benign pelvic mass with a high diagnostic accuracy (AUC: 0.93). The ROMA has high sensitivity to predict advanced stage OEC than early stage OEC and in postmenopausal women than in premenopausal women. Second, although HE4 has higher specificity than CA125 for OEC monitoring, CA125 has better diagnosis accuracy (higher AUC) than HE4 for OEC or OC prediction. This is based on the results of 4 studies that compare HE4 and CA125 within the same population. Third, based on the results of comparison of HE4, CA125 and ROMA in the same population, the overall performance (AUC) of the three tests for OEC prediction are similar. ROMA inherits the strengths and weakness of CA 125 and HE4 alone. Indeed, ROMA is more sensitive than HE4 but less sensitive that CA 125 and it is more specific than CA 125 but less specific than HE4.<\/p>\n

        Key points:<\/strong><\/span><\/p>\n