General
ROMA

Blood-based Biomarkers as Tools for More Precise Pre-operative Referral for Ovarian Cancer

17/07/2024
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The American Cancer Society estimates that in the US, in 2024, 19,680 women will receive a diagnosis of Ovarian Cancer (OC), and 12,740 women will die from the disease. Ovarian Cancer is the fifth leading cause of cancer-related death among women.1

Ovarian cancer is often referred to as the “silent killer” since it is characterized by little to no clinical presentation until it reaches a large size or has metastasized. Common symptoms associated with ovarian cancer include pelvic pain, abdominal bloating, increased abdominal size, back pain, and difficulty eating, symptoms that can easily be confused with other benign pathologies.2 Because of this, most ovarian carcinomas are diagnosed at an advanced stage, with 60% of women having a metastatic disease (Stage IV) at the time of diagnosis.3

The staging of ovarian cancer is based on two similar systems: the FIGO (International Federation of Gynecology and Obstetrics) system and the AJCC (American Joint Committee on Cancer) TNM staging system. Both systems use surgical results to determine the extent of the primary tumor (T), whether the cancer is present in the lymph nodes (N), or whether it has metastasized (M) to other parts of the body (such as the liver, bones, or brain).4,5

Based on this classification, OC is characterized by four different stages depending on the extent of cancer spread, ranging from localized disease (Stage I) to widespread metastasis to distant organs (Stage IV).

The stage of ovarian cancer is one of the most influential prognostic factors for ovarian cancer survival. The 5-year overall survival rate for patients diagnosed with stage I ovarian cancer is more than 89%,6 while stage II is approximately 60%.7 However, in advanced-stage disease (stage III and IV), the 5-year survival rate significantly declines to approximately 30 - 41%,6,7 thus highlighting the importance of early detection in OC.

According to the National Comprehensive Cancer Network, the current primary treatment of advanced ovarian cancer is optimal primary debulking surgery (also called cytoreductive surgery) followed by adjuvant platinum-based combination chemotherapy.8 The goal of this initial surgical intervention is to stage the patient and properly assess the extent of the disease. It also aims to resect all macroscopic signs of the disease and potentially provide symptomatic relief caused by tumors compressing or involving adjacent organs. Additionally, optimal cytoreduction in advanced stages has repeatedly been associated with improved endpoints, including chemosensitivity, progression-free survival, and overall survival.9

Because of the high disease burden, the heterogeneous nature of the malignancy, and the importance of optimal cytoreduction, receiving careful triage and high-quality care is imperative.10

Over the years, studies have indicated that in case of malignancy, the correct referral of women with OC to gynecologic oncologists significantly impacts the success of cytoreductive surgery, enhancing disease-free intervals,11,12 and improving the overall survival rate in patients with advanced OC,11,13 compared to those treated by gynecologists or general surgeons.14–16

Therefore, appropriate pre-operative referrals are crucial for patient outcome improvement, especially for those with advanced-stage disease, but sadly, they are also very challenging.

Current Pre-Operative Referral Process for Ovarian Cancer

Over the years, extensive efforts have been made to identify the best and most accurate approach to assess women with an adnexal mass and improve triage.

The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) have established guidelines for appropriately referring women with a malignant pelvic mass to a gynecologic oncologist.17,18 These guidelines recommend including the patient's medical history, physical examination, imaging, serum biomarker measurements, and the use of formal risk stratification algorithms such as the Risk of Ovarian Malignancy Algorithm (ROMA).18

According to these guidelines, patients that present at least one of the following indicators should be considered for referral to a gynecologic oncologist: an adnexal mass, unexplained ascites, elevated CA125 level (>200 U/mL in premenopausal and > 35 U/mL in post-menopausal patients), positive imaging results suggestive of malignancy, evidence of abdominal or distant metastasis, or an elevated score on a formal risk assessment test.18

Although the ACOG/SGO Joint Opinion Guidelines provide valuable recommendations for patient referral, these recommendations are not fully incorporated into the current standard of care.19

Despite the clear benefits associated with gynecologic oncologist care, only 30% to 40% of women with OC are correctly referred to and treated by these specialists.20 Although the reasons for the low referral rates to gynecologic oncologists are not fully understood, studies have hypothesized that the low referral rates could be due to the discovery of cancer during non-cancer related surgeries, as well as the women’s and general practitioners' failure to recognize the presenting symptoms of ovarian cancer or disagreement about standards of care.21–23

In the US, the standard practice for ovarian cancer assessment does not include the use of a formal risk stratification algorithm but only combines physical examination, imaging evaluation, and biomarker measurements (such as serum CA125 levels).24 This approach has significant limitations. Physical examination, for example, is an unreliable method to detect ovarian masses. An ovarian tumor (especially in early stages) is usually not palpable during a pelvic exam unless it has grown significantly. A study by Ueland et al. showed that the accuracy of pelvic examination in ovarian detection was related to patient age, patient weight, and uterine weight. Subtle changes in the ovarian anatomy are often challenging to detect, especially in women over 55 years of age or who weigh more than 200 pounds.25 As for imaging evaluation, the inability of transvaginal sonography to reliably distinguish between benign and malignant ovarian tumors (due to the possible overlap in their sonographic features) represents another significant limitation. Additionally, some tumors can metastasize before reaching a detectable size by transvaginal ultrasound.26 Several studies involving women at high risk have, in fact, shown minimal to no sonographic abnormalities in patients with high-grade serous ovarian cancer, even though many of these patients were in an advanced stage of the disease.27,28

To overcome these limitations, the inclusion of serum biomarkers testing has become significantly important for monitoring disease progression or recurrence in a noninvasive and cost-effective way.29

CA 125 (MUC16) is the most widely used tumor marker in ovarian cancer and is often considered the “gold standard.”30 It has been used clinically to monitor women diagnosed with ovarian cancer for prognosis, surveillance, and optimization of care, but its intended use does not include preoperative assessment.31 Although this biomarker is still the most extensively used biomarker for early detection of ovarian carcinoma, high levels of serum CA 125 can also be associated with other malignancies, including breast and lung cancer,32 as well as benign and physiological conditions, including pregnancy, endometriosis, and menstruation, resulting in a reduction of specificity.31,33 Furthermore, CA 125 levels appear to be elevated in only 50%- 60% of stage I epithelial ovarian cancers, indicating low sensitivity in the early stages of the disease.34 These limitations were further confirmed in a prospective study that included CA 125 level measurements, imaging results, and physical exams to detect early-stage OC. The study revealed that utilizing CA 125 (using cutoff values of more than 200 units/ml in premenopausal women) to detect early ovarian cancer stages (I and II) resulted in a sensitivity of only 55.6%.35

Therefore, there is an urgent need to include risk assessment tools in the initial clinical assessment. These tools would allow patient stratification into low—and high-risk groups for ovarian malignancy, thus improving the triage of women with an adnexal mass and optimizing the referral process.

Risk Stratification Algorithms in the Triage of Pelvic Mass

Due to this clinical need, pre-surgical algorithms were developed to assess the probability of malignancy in patients upon surgery. These algorithms primarily include serum biomarker measurements, clinical information, which may include age and menopausal status, and imaging results into a single index to help assess the risk that an adnexal mass will be found to be cancerous or benign upon surgery.

OVA1

In 2009, the multivariate index assay OVA1® became available in the US market as a new algorithm to aid in determining if an adnexal mass is malignant prior to surgery. The test combines five serum biomarkers (CA 125, Transthyretin, Apolipoprotein A1, Beta-2 Microglobulin, and Transferrin), imaging, and menopausal status. This algorithm provides a risk assessment score between 0 and 10.36 In the premenopausal group, women are considered at high risk if the score is ≥ 5.0, while in the postmenopausal group, the threshold is ≥4.4.37

In 2016, OVERA®, the second generation of OVA1®, received FDA authorization. This test incorporates three of the original biomarkers used in OVA1® (CA 125, Apolipoprotein A1, and Transferrin) with the addition of HE4 and follicle-stimulation hormone (FSH). Because FSH is part of the panel, there is no need to determine menopausal status. Similarly to OVA1®, the OVERA® score ranges from 0.0 to 10.0, where values below 5.0 indicate a low risk of finding malignancies upon surgery, whereas values higher than 5.0 indicate a high risk.38 When comparing to OVA1®, OVERA® shows similar sensitivity (OVERA®: 91%; OVA1®: 94%) but an improved specificity and PPV (OVERA®: Spec. = 69%, PPV = 40%; OVA1®: Spec. = 54%, PPV = 31%).38 However, this specificity is still low compared to other biomarker-based algorithms.39

The low specificity of both OVA1 and OVERA could result in more disease-free women being erroneously referred to gynecologic oncologists for unnecessary surgical evaluations.

A societal perspective cost-minimization model analysis also indicated that the use of the OVA1 could potentially increase the number of referrals to gynecologic oncologists for patients with benign masses and may also significantly increase costs linked to the management of women with pelvic masses.40

Risk of Ovarian Malignancy Algorithm (ROMA)

In 2009, Moore et al. developed a new algorithm called the Risk of Ovarian Malignancy Algorithm (ROMA®), based on the encouraging results of HE4 in epithelial ovarian cancer (EOC) diagnosis, especially when combined with CA 125.41 This approach involves linking serum HE4 and CA 125 levels with the patient's menopausal status, which is defined by the absence of menstruation or clinical signs of menopause for 6 months.

The ROMA® score corresponds to the Predicted Probability (PP) and is expressed as a percentage rate.42 It uses the cutoff values, > 13.1% in pre-menopausal women and > 27.7% for post-menopausal women, to identify and differentiate women considered at high risk of ovarian cancer from the low-risk group.43 The ROMA® test provides the individual HE4 and CA 125 concentration values in addition to the score.

The algorithm creators reported a sensitivity of 93.8% (88.9% for pre-menopausal and 94.6% for post-menopausal women) and a specificity of 75% for diagnosing EOC.41

The ROMA® assay became available on the US market in 2011 as a qualitative serum test for assessing the likelihood of finding malignancies upon surgery in women with an adnexal mass.

Compared to other algorithms, such as the Risk of Malignancy Index (RMI), the ROMA® score showed superior performance in diagnosing OC, with higher sensitivity (94.3% vs. 84.6% at 75% specificity). This performance difference was even more pronounced when diagnosing early stages (stage I and II) of ovarian cancer.43,44

Primary care physicians can use the ROMA® score to effectively evaluate whether to refer a patient to a gynecologist or a gynecologic oncologist for initial surgery, thereby reducing the risk of complications and improving the patient’s survival rate.

A better referral is linked not only to improved survival rates but also to important economic considerations. A recent study by Underkofler et al. delved into the improvements the ROMA® algorithm brought to the correct triage of women with adnexal masses scheduled for surgery, comparing the algorithm to the initial clinical risk assessment,45 which includes physical examination, serum CA 125 levels, and imaging studies.24 This study used a health-economic decision model to evaluate the potential impact algorithms such as ROMA® may have on healthcare costs. They demonstrated that implementing ROMA® in the clinical pathway could significantly improve referral and, consequently, reduce unnecessary procedures (such as repeated surgeries) and related costs.

When comparing women with benign disease vs. women diagnosed with EOC and with borderline/low malignant potential tumors, the study predicted that ROMA® could lead to a 17% decrease in surgeries performed by gynecologists in women at higher risk of malignancy, coupled with a 64% increase in initial surgeries conducted by gynecologic oncologists, compared to the initial clinical risk assessment. This referral shift could be linked to the observed increase in the true positive (TP) rate and the decreased false negative (FN) rate observed using the ROMA® score. Furthermore, this shift towards more accurate risk assessment facilitated by ROMA® also led to a 63% decrease in the number of repeated surgeries performed by gynecologic oncologists on women at higher risk of malignancy. These results suggest that using the ROMA® score correctly classified more subjects at high risk of malignancy during the initial assessment and thus facilitates the correct referral to a gynecologic oncologist for surgery.

When combined with the initial clinical risk assessment, ROMA® continued to exhibit favorable outcomes, predicting a 26% reduction in the total number of surgeries performed by gynecologists, a 100% increase in initial surgeries performed by gynecologic oncologists, and a 68% decrease in repeat surgeries by gynecologic oncologists.

Lastly, this study also assessed the projected impact of the ROMA® algorithm on total healthcare cost for patients triaged for a pelvic mass and compared it to the initial clinical risk assessment by using a health-economic decision model. Based on these projections, using the ROMA® algorithm reduced by 3.3% the total healthcare costs linked to assessing women with benign disease versus EOC and borderline/low malignant potential tumors compared to initial clinical risk assessment. Using ROMA® resulted in a 4% reduction in laparoscopy-related costs and a 3.1% decrease in laparotomy-related costs compared to the initial clinical risk assessment, amounting to a substantial cost difference of $87,904. Additionally, in the same group of subjects, adding ROMA® to the initial clinical risk assessment led to a 4.6% decrease in total laparoscopies, a 3.6% reduction in laparotomies, and a 4.4% decrease in total surgeries, resulting in a total cost reduction of $103,197. Together, these predictions showcase ROMA’s potential for optimizing overall healthcare costs.

Conclusions

While ovarian tumors are relatively common, only a fraction of them are malignant.46 Furthermore, the symptoms of ovarian cancer can be vague and thus can be easily confused with physiological processes or benign diseases.2 The ability to distinguish malignant tumors before surgery and thus optimize patient triage may significantly improve patients’ outcomes. Women with ovarian cancer operated on by gynecologic oncologists have better outcomes than those operated on by general surgeons,11 yet only a small percentage are referred to a gynecologic oncologist for primary surgery.20 This highlights the urgent medical need for appropriate preoperative referral of women with an adnexal mass to ensure they receive the best possible care and outcomes.

Current guidelines for the referral of women with suspected ovarian cancer include medical history, physical examination, imaging studies, serum biomarker levels, and risk stratification algorithms.47 Sadly, these guidelines are not consistently followed, leading to missed opportunities for appropriate triage and thus negatively impacting patients' outcomes. Furthermore, relying solely on CA 125 measurements can result in a high rate of false positives due to its low specificity and thus lead to unnecessary referrals of women with benign conditions to gynecologic oncologists.45 This inefficiency in the referral process can cause delays in diagnosis and treatment, impacting patient outcomes and healthcare costs.

By incorporating serum concentrations of HE4 and CA125 and menopausal status, the ROMA algorithm provides a more accurate assessment of the likelihood of malignancy in women with adnexal masses upon surgery and thus allows for better triage of women with OC. Studies have demonstrated that implementing ROMA can significantly reduce unnecessary surgeries and healthcare costs while improving the accuracy of referrals of women with OC to gynecologic oncologists.45 This approach not only optimizes patient care but also contributes to more cost-effective healthcare delivery for women at risk of ovarian cancer.

References

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