Potential Cost Effectiveness of FES-PET to Determine Estrogen Receptor Status in Metastatic Breast Cancer in the United States

For the nearly 155,000 women living with metastatic breast cancer (mBC) in the United States, establishing estrogen receptor (ER) status is a critical determinant of treatment course.^1,2 Typically, patients with ER-positive cancer are treated with endocrine therapy, while patients with ER-negative cancer are treated with chemotherapy or chemo-immunotherapy combination. Biopsy of suspected metastatic site remains the standard of care to confirm metastatic disease and reassess biomarkers of ER, progesterone receptor, and human epidermal receptor-2 (HER2).^2,3 Inter- and intra-tumor heterogeneity, challenging biopsy sites, and specimen processing in bone metastases reflect key limitations of biopsy and highlight the need for a non-invasive diagnostic test when biopsy is not feasible.^4,5 18F-fluoroestradiol (FES) is an estrogen analogue that can detect ER binding over the body burden of cancer and provide simultaneous assessment of multiple tumor sites.⁶ It serves as a functional assay of ER expression and correlates strongly with detection of ER-positive breast cancer.⁶ In addition, FES-positron emission tomography (FES-PET) has shown promise in identifying heterogeneity in metastatic tumor lesions and predicting response to endocrine therapy.^7-9 The US Food and Drug Administration (FDA) recently approved FES-PET, and it expected to be available in clinics by early 2021.¹⁰

Before implementation into clinical practice, a rigorous, evidence-based evaluation of novel technologies must be performed to establish value to patients and health systems. The emergence of molecular imaging, such as FES-PET, improves the ability to select appropriate therapy for patients based on functional tumor characteristics shown by imaging, but it also could contribute to the rising costs of cancer care in the United States. However, an expensive technology can be high value with the consideration of downstream benefits, such as improvements in survival and quality of life. The economic implication of FES-PET has been evaluated in Netherlands, where it is a potentially cost-effective intervention in selection of first-line treatment of breast cancer.¹¹ Due to differences in health systems between European countries and the United States, a rigorous analysis in the United States is warranted before routine use of FES-PET in clinics. Although, FES-PET’s current approval is as an adjunct to biopsy, the role for FES-PET is expanding and it may soon be an available option for patients with unobtainable or inconclusive biopsies.¹⁰

The authors developed a decision model that compares biopsy and FES-PET for diagnosis and management of mBC The model evaluates the cost-effectiveness of FES-PET from a US payor perspective. We anticipate the study will provide early evidence of the value of FES-PET, highlight key drivers of value, and reveal areas of uncertainty for future research. Our findings can define the role of FES-PET in clinical practice and inform decisions about clinical implementation and payer considerations.

We developed a decision model (Figure 1) in Microsoft Excel for Mac Version 16.39 (Microsoft Inc, Redmond, WA) to evaluate cost effectiveness of biopsy compared with FES-PET for a hypothetical cohort of patients with suspected mBC over a lifetime horizon. The estimation of estrogen sensitive disease (Truth) was obtained by adjusting the prevalence of estrogen sensitive disease in primary breast cancer to account for rates of discordant receptor status in the metastatic setting. The diagnostic test determines ER status (Test Result) as positive or negative to reflect estrogen sensitive or estrogen insensitive mBC. According to “Test Result”, patients receive one of two treatment categories: (1) endocrine therapy with ER-positive test result or (2) nonendocrine therapy with ER-negative test result. The Truth is compared with the Test Result to determine whether the treatment (Outcome) is appropriate or inappropriate. For example, a patient with a test result of ER-positive that accurately reflects the true prevalence endocrine-sensitive disease receives appropriate therapy with endocrine treatment. Direct medical expenditures related to treatment, monitoring, and adverse events were accounted for over a lifetime horizon. Overall survival was assessed by treatment regimen and derived from relevant phase 3 trials. Survival beyond the study observation periods was extrapolated using mixture-cure analysis (SAS Version 9.4, SAS Institute Inc, Cary, NC) and parametric curve fits.¹²

The primary outcome was the incremental cost-effectiveness ratio (ICER). The analysis was conducted from a US payor perspective and reports costs in 2020 US dollars. Future medical cost, life years, and quality-adjusted life-years (QALYs) are discounted at 3% per year.¹³ Model inputs and data sources are provided in Table 1, and additional inputs are described below (Table 1 Continued).

Sensitivity and Specificity of Tests

A Lancet Oncology review tabulated the findings of several studies evaluating FES-PET to determine a sensitivity of 84% and specificity of 98% for evaluating ER status in metastatic lesions.⁶ In this model, the sensitivity and specificity of core needle biopsy of bone was utilized, as this is the most common site of metastases.^14,15 The data were obtained from a review discussing diagnostic methods for bone metastases.¹⁴ Core needle biopsy of bone was performed in 105 patients with primary musculoskeletal neoplasm at a tertiary care center followed by confirmatory open biopsy and demonstrated a sensitivity of 79% and specificity of 82%.¹⁵ The probability of inconclusive bone biopsy (20%) is based on expert opinion.¹⁶

Treatment Selection

Model outcomes were assessed in several endocrine and non-endocrine treatment regimens to reflect real-world variation in treatment selection and cost. Endocrine therapies include letrozole or ribociclib (a cyclin D kinase 4/6 inhibitor, CDK4/6) + letrozole. Nonendocrine therapies include capecitabine and docetaxel. We chose therapies supported by the National Comprehensive Cancer Network (NCCN) guidelines with the most robust survival data.²

Survival

Endocrine Therapy: Letrozole and Ribociclib + Letrozole

Survival data for patients treated with letrozole and ribociclib + Letrozole were derived from the MONALEESA-7 trial.¹⁷ To estimate mean overall survival (OS) for patients treated with letrozole or ribociclib + letrozole we fit a range of curves (Weibull, LogLog, LogLogistic, Gompertz) to 42-month MONALEESA-7 OS data, selected the curve (Gompertz) that minimized the Akaike information criterion (AIC) and extrapolated the curve to 20 years of follow-up.¹⁸ We assumed only a small percentage of patients would be alive after 20 years based on several studies on mBC demonstrating median OS time of 3 years.¹⁹

Chemotherapy: Capecitabine and Docetaxel

Survival data for patients treated with capecitabine were derived from the phase 3 PELICAN trial.²⁰ Docetaxel survival data were derived from a phase 3 trial that compared docetaxel with nab-paclitaxel.²¹ To estimate mean OS for patients who were treated with capecitabine and docetaxel, we fit a range of curves (Weibull, LogLog, LogLogistic, Gompertz) to 54-month PELICAN OS data and the 80-month docetaxel vs nab-paclitaxel OS data, selected the curve (Gompertz) that minimized the AIC, and extrapolated the curve to 20 years of follow-up.¹⁸

Resource Use and Cost

Diagnostic Testing

The cost of biopsy incorporated expenditures from image-guided bone biopsy and additional costs accrued from repeat biopsy (20% due to inconclusive result) using Centers for Medicare and Medicaid (CMS) Reimbursement costs and the Healthcare Common Procedure Coding System.²² Because FES-PET is not yet available, we used a list price of $4000, an educated estimate based on costs of other hybrid scanners (fluciclovine PET-CT ~$4000) and advice from experts on FES-PET.²³

Treatment Costs

The cost of letrozole, ribociclib, capecitabine, and docetaxel was based on wholesale acquisition cost as of July 2020 (Table 1).²⁴ Additional resources in the calculated costs included: infusion, outpatient visits, and monthly monitoring costs (obtained from CMS Physician and Laboratory and Fee Schedules 2020).²³

Adverse Events Costs

Grade 3 and 4 adverse events (AEs) rates were obtained from the phase 3 trials used for survival data as well as meta-analyses.^20,21,25-27 The analysis included only serious AEs (Grade >3 according to the “Common Terminology Criteria for Adverse Events” with AEs assumed to occur in the first cycle.²⁸ Costs for treatment of AEs were obtained from corresponding ICD-10 codes in the Healthcare Cost and Utilization Project Inpatient Sample 2017 (Table 1) and inflation was accounted for using the Federal Reserve Bank of St. Louis Economic Research database.^29,30

Health State Utilities

Values for treatment-related health utility (endocrine vs chemotherapy) and adverse effects were obtained from a meta-analysis that evaluated 49 publications on health utilities in mBC.³¹ Health utility for endocrine + CDK4/6 inhibitor was calculated using health utility data for endocrine therapy alone and incorporating health disutility from adverse effects associated with CDK4/6 inhibitors. A second source of interview-based data provided additional adverse effect disutility (Table 1).³²

Outcomes

We used the model framework to estimate expected life years, QALY, and total costs for biopsy and FES-PET strategies. The ICER was calculated as the ratio of the difference in costs and the difference in effects (eg, QALYs) between strategies.

Scenario Analysis

Given the variation in treatment selection in the real world, we also conducted scenario analysis in which patients received different endocrine and chemotherapy options, based on common regimens recommended by NCCN guidelines.² In this model, the allocation of endocrine or chemotherapy as first-line therapy is determined by the results of the diagnostic testing (biopsy or FES-PET). In scenario 1, patients received letrozole as endocrine option or docetaxel as chemotherapy option. In scenario 2, patients received endocrine therapy with ribociclib + letrozole (with goserelin) or chemotherapy with capecitabine. Finally, in scenario 3, patients received endocrine therapy with ribociclib + letrozole (with goserelin) or chemotherapy with docetaxel. Goserelin, a luteinizing hormone releasing hormone agonist, is given to premenopausal patients with hormone-sensitive breast cancer to decrease estrogen production. The chosen therapies range from intravenous chemotherapy to oral targeted agents over a wide array of costs and represent the key categories in first-line treatment for mBC.²

Threshold Analysis

Because FES-PET is not yet commercially available, the true cost is unknown. Our estimate relies on the cost being similar to other molecular PET-based imaging. Due to uncertainty in cost of FES-PET, we conducted threshold analyses to determine the testing cost where the incremental cost per QALY gained would exceed $150,000 per QALY gained—commonly cited willingness-to-pay threshold for cancer therapies in the United States.³³

Uncertainty Analysis

We evaluated the impact of uncertainty in all model inputs on model outcomes with probabilistic sensitivity analyses using Monte Carlo simulation with 5000 runs. Table 1 displays the distributions used for inputs. distributions of log-normal, beta, and normal for hazard ratios, probabilities, and utilities. Given that the probability of inconclusive biopsy was based on expert opinion, we modeled a wide uncertainty range (10%-30%).

In our model, treatment selection was defined as appropriate or inappropriate based on ER status and reflected the accuracy of the diagnostic test. In the base case, appropriate therapy was provided for 93.1% of patients who received FES-PET and 80.1% of patients who received biopsy. FES-PET resulted in appropriate endocrine therapy selection for 63.7% vs 51.5% of patients with the biopsy strategy in our model. Over a lifetime horizon, the differences between FES-PET or biopsy driven treatment selection translated into 4.45 and 4.04 life years, 3.17 and 2.94 QALYs, and lifetime costs of $21,242.51 and $22,443.06, respectively (Table 2). In the base case, FES-PET was expected to be the dominant strategy—increasing QALY by 0.23 and reducing cost by $1200.55 per patient.

Scenario Analysis

FES-PET resulted in more QALYs when compared with the biopsy strategy (range: +0.23-+0.27 QALY) in all alternative scenarios and higher costs in scenarios that applied CDK4/6 therapies (range: +$40,183-+$40,549). Table 3 demonstrates outcomes for alternative scenarios. In scenario one, where letrozole was compared with docetaxel, ICER was calculated to be $3630 per QALY gained. In scenarios where CDK4/6 inhibitors were used as endocrine therapy of choice, FES-PET was more costly than biopsy. We attribute this finding to differences in each test’s sensitivity to identify hormone-sensitive disease. FES-PET was more likely than biopsy to accurately identify endocrine-sensitive disease (63.7% vs 51.5%). Therefore, we would expect that costs of FES-PET to be higher when the endocrine therapy included a CDK4/6 inhibitor. The incremental QALYs for scenario 2 (ribociclib + letrozole vs capecitabine) and scenario 3 (ribociclib + letrozole vs docetaxel) were 0.27. The corresponding ICERs for FES-PET in scenario 2 and scenario 3 were calculated to be $148,825 and $150,181.

Threshold Analyses

In a threshold analysis that examined the base case scenario, the FES-PET strategy was <$150,000 per QALY gained vs biopsy if imaging cost was <$39,500. In scenarios with ribociclib, FES-PET strategy could be cost-effective (US threshold of <150,000 per QALY gained) if imaging costs remained <$3850.

Sensitivity Analysis Results

In the base case, the probabilistic analyses of FES vs biopsy demonstrated that FES-PET increased QALY in 92% of simulations; decreased cost in 67% of simulations; and was cost-effective in 91%, 92%, and 92% at willingness to pay thresholds of $50,000, $100,000, and $150,000 per QALY gained. In scenarios with ribociclib, most simulations resulted in increased QALY (range: 92.9%-93.4% of simulations) and higher costs (range: 98.1%- 98.2% of simulations) for FES-PET strategy.

Outcomes for patients with mBC improve with accurate determination of ER status and selection of first-line therapy, but current methods of confirming ER status have limitations. The novel molecular imaging technique, FES-PET, shows promise as a functional and predictive diagnostic test.^8,9 Its role in breast cancer is being evaluated in clinical trials for its value as predictive assay in patients with newly diagnosed mBC receiving endocrine therapy (EAI 142 Trial).³⁴ The data are encouraging and have led to a recent expedited approval by the FDA.¹⁰

Although investigations show the benefit of FES-PET in treatment selection, the economic implications of this diagnostic tool have not been evaluated in the United States. However, FES-PET is available in Europe, and a recent study in the Netherlands demonstrated that FES-PET is a potentially cost-effective intervention in selecting of first-line treatment for mBC.¹¹ Due to the differences in health care costs between Europe and the United States, these cost-effectiveness results do not necessarily generalize to the US setting. A robust, cost-effectiveness analysis from the perspective of US health care system is needed to inform clinical, payer, and policymaker stakeholders about the expected value of implementing FES-PET in routine clinical care in the United States.

Our study approach focused on a FES-PET vs biopsy strategy to evaluate a suspected recurrence of breast cancer. In this modeling study, we found that FES-PET is a potentially cost-effective imaging modality when compared with biopsy (<$150,000 per QALY gained) in the United States. Because FES-PET is not yet commercially available, it would be beneficial to reexamine this analysis when direct costs of the test are known. In our scenario analysis, we demonstrate the model outcomes for various treatment options currently recommended as options for first line selection per NCCN guidelines.² We felt that this captured the breadth of treatments that patients may receive for a diagnosis of mBC. Our results demonstrated that FES-PET strategy was near or marginally over upper limit of acceptable value in the United States (<$150,000/QALY) for scenarios with CDK4/6 inhibitors, however, remained a dominant strategy when endocrine monotherapy was chosen.

The variations in drug costs drove differences in value. Most dramatic were scenarios that involved treatment with CDK4/6 inhibitors. The high cost of CDK4/6 treatment combined with the finding that FES-PET was more likely than biopsy to accurately identify hormone-sensitive disease led to more total costs. We note that efficacy inputs were based on OS data from the cohort in the MONALEESA-7 study.¹⁷ It is possible that our model underestimates input for efficacy (median follow-up 42 months). Survival data from three larger studies (PALOMA-2, MONALEESA-2, and MONARCH-3) show remarkable improvements in progression-free survival with OS data still maturing.^27,35,36 Final analysis may demonstrate additional survival benefit and offset or even overcome the costs associated with CDK4/6 inhibitors.

Assumptions are made that may not reflect real world are inherent to the nature of modeling studies. In our model, the diagnostic test accuracy in ER status assessment was the sole determinate for “appropriate” or “inappropriate” treatment classifications. It does not capture the nuances of clinical decision-making. For example, patients with endocrine-sensitive disease may appropriately receive nonendocrine therapy for visceral crisis. Even so, these scenarios are uncommon, and our findings are applicable to most patients with mBC. We gathered data from various randomized controlled trials (RCT) to obtain the most robust information for the varying treatments. As a result, scenarios may include data for endocrine therapy from one RCT and nonendocrine therapy from anther RCT. Prospective data from a single RCT for each scenario would be ideal, though due to selection of various treatments, this was unavailable.

Ideally, we would include palbociclib and letrozole, two widely used medications in first-line treatment of mBC. The maturing OS from PALOMA-2 is highly anticipated for future analyses. Still, the incorporation of a wide range of treatment with robust survival data strengthens the utility of our results. We realize that extrapolation of survival beyond the time horizon of the trials may impact cost-effectiveness, but we do not consider this to be driving the outcome. While observational studies may provide longer survival data, we chose to use prospective studies with contemporary treatments to adequately capture the survival estimates in the modern era.

Due to lack of overall survival data for post-menopausal women treated with CDK4/6 inhibitors, our model used data available for premenopausal or perimenopausal women (MONALEESA-7).¹⁷ When OS trial data from PALOMA2, MONALEESA-2, and MONARCH-3 are available, additional analysis can be performed to ascertain the value of FES-PET in the post-menopausal population.^27,35,36 While this may limit generalizability, our data serve as a glimpse into the potential cost-effectiveness of FES-PET. One feature of our model that limits the interpretation of our results is the estimation of sensitivity and specificity of biopsy. Since biopsy accuracy of mBC lesions are not published in the literature, this input is based on a single institution analysis from bone biopsy of a primary musculoskeletal neoplasm. However, Koleva-Kolarova and colleagues tested similar values for biopsy sensitivity (77% vs 80%) and specificity (76% vs 80%) over various mBC sites (bone, lung, brain and liver), which reaffirms the estimate used in our model.¹¹ Finally, we do not consider detriments to quality of life from additional biopsies in our model. Prospective trials with real-world data can overcome this limitation and potentially show an even greater quality of life improvement with FES-PET strategy compared to biopsy.

Currently, the clinical utility of FES-PET centers around identification of endocrine sensitive metastatic disease and initiation of appropriate treatment. FES-PET may have broad range of applications with personalized medicine and staging in early breast cancer. Preliminary data at our institution highlights its value as a prognostication tool to aid in selection of therapy and detection of lobular breast cancer.^37,38 Although FES-PET does not capture HER2 receptor expression, there is lower likelihood of discordance with HER2 when compared with ER status. While FES-PET alone may not obviate the need for a pathological evaluation, it could serve as an alternative diagnostic method for hormone status assessment when biopsy is inconclusive or not feasible, a common clinical scenario. Based on recent FDA approval of FES tracer, we anticipate accessibility to this test within the next year.¹⁰ Our findings are timely and informs clinicians and payors of the potential value of FES-PET as researchers continue to define its role in mBC.

We found that FES-PET is a potentially cost-effective strategy to identify patients who are likely to benefit from endocrine-based therapies compared to biopsy. Prospective trials studying novel imaging modalities should include cost effectiveness analyses to confirm the value of new technologies prior to adoption in routine clinical practice.

Authors: Poorni M. Manohar, MD¹; Hannah M. Linden, MD¹; Josh A. Roth, PhD, MHA^2,3

Affiliations: ¹University of Washington/Seattle Cancer Care Alliance, Seattle, WA
²Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Institute, Seattle, WA
³Comparative Health Outcomes, Policy and Economics Institute, School of Pharmacy, University of Washington, Seattle, WA

Disclosures: Drs Manohoar and Linden have no disclosures to report. Dr Roth has revived research grants from BMS, Bayer, and Seattle Genetics. He is currently employed by Genentech but was not at the time this study was conducted.

Address correspondence to:
Poorni M. Manohar, MD
(400) 478-6330
manoharp@uw.edu