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Treatment Sequencing Patterns and Associated Direct Medical Costs of Metastatic Breast Cancer Care in the United States, 2011 to 2021

Key Points Question What are current treatment sequencing patterns for metastatic breast cancer and associated costs in the United States? Findings In this economic evaluation of 15 215 patients between 2011 and 2021, the mean total Medicare cost of documented anticancer therapy was found to be greatest for hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer and least for triple-negative metastatic breast cancer, with sizeable variations by subtype and year after diagnosis. Annual costs increased over time. Meaning These findings suggest that accurate metastatic breast cancer care cost estimates are critical to assess health system financial burden of therapies and to inform cost-effectiveness analyses.


Introduction
Among women in the US, breast cancer is the most diagnosed cancer and the second leading cause of cancer death, with more than 280 000 new breast cancers diagnosed each year. 1 Although modern therapies are effective in preventing metastatic disease recurrence, approximately 15% of patients will ultimately be diagnosed with distant metastatic recurrence. An estimated 150 000 patients live with metastatic breast cancer (MBC) in the US. [2][3][4] Over the past 5 decades, new therapies have substantially increased the median overall survival of patients with MBC from approximately 2 years to more than 5 years, depending on the molecular subtype of breast cancer, with greatest gains in hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (ERBB2) overexpressing breast cancers. [5][6][7] Collective strategy in the treatment of MBC is to sequence therapies until progression or unacceptable toxic effects; specific drugs depend on HR and ERBB2 status. Currently, drug selection and sequencing of therapies for MBC remains highly variable, particularly after progression on initial (ie, first line) therapy. 8 In the past 10 years, multiple new drugs were approved to treat MBC, thus changing both treatment sequencing and costs of care.
Medical expenditures for breast cancer are highest among all cancer types with an estimated overall national cost of $26 billion in 2015 and an estimated total spending of $40.6 billion for all privately insured patients in the US in 2018. 9,10 Estimates of MBC care cost may be less precise and are highly variable in the literature. 3,[11][12][13] Although existing literature has aimed to estimate costs associated with MBC, 3,11-18 these cost estimates lack subgroup specificity, fail to account for recent treatment advancements, or exclude important cost components (eg, out-of-pocket costs). 3,[11][12][13][14][15]17,18 Characterization of contemporary cancer costs are critical to evaluate the financial burden faced by payers, patients, and health systems and to inform policy. Thus, we sought to determine national treatment patterns of MBC in the US, including drug regimen frequency, sequence, and duration of use, and downstream health system and Medicare costs from 2011 to 2021.

Methods
This economic evaluation was approved by the Yale University School of Medicine institutional review board and included a waiver of informed consent because data were deidentified and this was deemed nonhuman participant research. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Data Source
We used the MBC cohort from the nationwide Flatiron Health electronic health record (EHR)-derived database. The Flatiron Health database is a longitudinal database, comprising deidentified patientlevel structured and unstructured data, curated via technology-enabled abstraction. 19 During the study period, the deidentified data originated from approximately 280 US cancer clinics (approximately 800 sites of care). 19 metastatic diagnosis, had a documented diagnosis date within 6 months of the data cutoff date, or did not have documented therapy for MBC. We further excluded patients with more than 90 days between their MBC diagnosis and first structured documented EHR activity date because of the high risk of data incompleteness. We also excluded patients who had documentation of clinical trial drug administration, concurrent or previous International Classification of Diseases, or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis codes for nonbreast invasive cancers, received antineoplastic drugs that are not used in the treatment of MBC, or missing, pending, or indeterminate ERBB2 and HR results (Figure 1). To assess the representativeness of our cohort in terms of clinical characteristics and demographic breakdown, we captured most recent insurance type, geographic region, age at MBC diagnosis, Eastern Cooperative Oncology Group performance status, sites of metastases, HR and ERBB2 status, body mass index, race, practice type, and drug names and administration dates. Race information provided by Flatiron Health Inc is collected from patients via intake forms or reported by clinicians through EHR workflow.

Statistical Analysis
All analyses were performed separately for the 4 MBC subtypes. These included HR-positive and ERBB2-negative, HR-positive and ERBB2-positive, HR-negative and ERBB2-positive, and triplenegative breast cancer (TNBC).

Treatment Patterns
To determine treatment sequencing patterns, we tabulated the most frequently used therapies for up to 5 lines of sequential therapy. In all breast cancer subtypes, less than 15% of patients received more than 5 lines of therapy (eTable 1 and eTable 2 in Supplement 1). We excluded drug regimens that were provided to less than 0.75% of patients within a subtype. We chose 0.75% as the threshold because it captured 73% of all unique first-line therapies and limited the analysis to no more than 105 unique treatment regimens per subtype and line of therapy. We also identified the most frequent drugs received by year since MBC diagnosis.

Therapy Duration and Frequency and Drug Dosage
For oral drugs, we calculated treatment duration as the time between the start and end date of treatment. For non-orally administered drugs, we calculated the total number of treatment episodes based on unique drug administration dates. To avoid calculation bias in frequency and duration, we excluded patients who were still alive but had either not moved to a subsequent therapy line or had fewer than 120 days of structured activity data since their last drug episode, per Flatiron Health guidance (eMethods in Supplement 1). To calculate annual costs (cost per year since the date of MBC diagnosis), we included all patients with data and counted all anticancer therapies that were administered during the 12-month period regardless of therapy line. When treatment spanned more than 1 year, we split the duration and costs accordingly.

Supportive Drugs
To estimate the cost of supportive care drugs, we identified all drugs related to cancer care or to the management of adverse effects of cancer therapies. We did not consider palliative care and end-of- October 2021 using the Consumer Price Index inflation calculator and applied 2021 prices to all years in the analysis. 21 Given the lack of data on drug dosage in our data set, we used standard drug doses assuming a body surface area of 1.8 m 2 and a weight of 80 kg. When it was not clear whether patients had received a generic or brand-name drug, we assumed that the cheaper drug was administered.
We first calculated total overall drug cost using patient-level data. Next, we calculated the mean and median price per patient per line for each regimen in each line of therapy by breast cancer subtype. For each drug regimen, we also calculated its contribution to the total price for that MBC  Figure 1).   whereas the letrozole and palbociclib regimen was most frequent in 2020.

JAMA Network Open | Oncology
As expected, the trends in the Medicare and AWP cost estimates are parallel (eTable 6 in Supplement 1). 22 Medicare prices are indirectly based on mean sale prices, which account for rebates and discounts but ultimately correlate with AWP and wholesale acquisition prices. 13 The       HR-negative and ERBB2-positive MBC). 6 We believe this reflects differential survival rates, with the b Note that the listed cost for all years for anticancer, supportive and total cost represent the mean cumulative cost per patient by subgroup; this cost is less than the sum of year 1 through year 10 because not all patients had 10 years of treatment data. c Given that not all patients receiving anticancer drugs in a particular subgroup and year receive supportive care drugs, the reported means reflect the ratio of the total amount spent on supportive care over the total number of patients receiving anticancer drugs in that year number and subgroup. eTable 9 in Supplement 1 shows the mean and median only for patients receiving supportive care, as well as their percentage of all patients within a subgroup by year. As such, the median supportive care cost for most years is 0, and a measure of SD would not be informative.
Decreased reliance on chemotherapies for ERBB2-positive and HR-positive subgroups can explain their decreasing supportive care cost with increasing year since diagnosis. The overall decrease in supportive care by year since diagnosis with increasing calendar year could reflect less aggressive and toxic treatments and decreased chemotherapy use with time. However, the decreasing patient count with increasing year since diagnosis limits the generalizability of these findings. Moreover, our supportive care calculations only reflect 3 main drug categories. The American Society of Clinical Oncology's Choosing Wisely campaign could also be a potential contributory factor to both of these observed trends. 34 Our findings on large treatment pattern heterogeneity are in line with prior research on sequential treatments. A previous study from the linked SEER and Medicare database found that 56% of patients received an overall treatment sequence that less than 11 other patients also received. 35 In addition to treatment guidelines, tumor types, and prior treatments, insurance coverage, patient preferences, and the integration of a physician's personal experience with current scientific literature also influence treatment choices. [35][36][37][38] Tools are in development to rank the increasing number of regimens, such as the recently developed information theoretic network metaanalysis that was used to longitudinally rank HR-positive and ERBB2-negative treatments by efficacy. 39 We found a large variety in drug regimens used at a line and yearly level by subgroup, with some regimens being particularly infrequent. Outlier regimens can be explained by receptor switch, concurrent illnesses, and other unique circumstances. 40