Abstract
BACKGROUND:
The introduction of cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6is) has transformed the treatment landscape for patients with hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2−) metastatic breast cancer (MBC). To our knowledge, no studies have quantified health care resource utilization (HRU) or economic burden following CDK4/6i initiation in the Medicare population.
OBJECTIVE:
To describe HRU and quantify health care costs among Medicare-enrolled patients with HR+ HER2− MBC treated with CDK4/6is in the first-line setting.
METHODS:
We conducted a retrospective cohort study on Medicare-enrolled patients with HR+ HER2− MBC who initiated a CDK4/6i in the first-line setting between February 2, 2016, and December 31, 2022, using claims from the Merative MarketScan database. We examined all-cause HRU by summarizing the number of inpatient (IP), outpatient (OP), and emergency department (ED) visits as well as the length of stay during the 6 months following CDK4/6i initiation. Additionally, we assessed all-cause health care costs, including IP, OP, ED, and pharmacy, over the 1 year following CDK4/6i initiation using the Kaplan-Meier sample average estimator to account for censoring. We reported total health care costs as the sum of IP, OP, ED, and pharmacy costs.
RESULTS:
901 patients met the inclusion criteria with a mean age of 74 years (SD = 6.84). Nearly 24% (n = 214) had an IP admission in the 6 months following CDK4/6i initiation. Among patients with an IP admission, the mean number of admissions per patient was 1.65 (SD = 0.98) with a mean length of stay per admission of 5.98 (SD = 6.25) days. Roughly 30% (n = 271) of patients had an ED visit, with a mean of 2.1 (SD = 1.54) visits per patient among those who had a visit. Most patients (n = 868, 96.44%) had an OP service, and among those with an OP service, the mean number of days with OP services was 19.96 (SD = 12.29). Mean total health care costs over the 1-year period following CDK4/6is were $62,228 (95% CI = 52,281-73,029) per patient with the main drivers being OP services ($31,686 [95% CI = 27,168-36,925]) and pharmacy costs ($22,727 [95% CI = 19,273-25,931]).
CONCLUSIONS:
There are numerous sources of HRU and cost in patients following CDK4/6i initiation in the Medicare population. Patients with HR+ HER2− MBC incur high HRU, providing insights for health care decision-makers to optimize treatment strategies and resource allocation for this population.
Plain language summary
This study investigated health care resource utilization (HRU) and costs for Medicare-enrolled patients with hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2−) metastatic breast cancer (MBC) who received cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6is) as their first-line treatment. We found various sources of HRU and expenses, particularly in the outpatient setting, following the initiation of CDK4/6is in this population.
Implications for managed care pharmacy
Real-world evidence of HRU and economic burden provide important insights into the patient experience and impact on the health care system. To our knowledge, no studies have comprehensively assessed HRU and costs associated with Medicare-enrolled patients with HR+ and HER2− MBC treated in the first-line setting with a CDK4/6i. The findings of this study may directly help health care decision-makers understand costs in this population and could help support the development of cost-effective modeling.
Breast cancer (BC) is the most common cancer and the second leading cause of cancer-associated death in women in the United States.1 In 2020, the Centers for Disease Control and Prevention (CDC) reported a total of $29.8 billion in annual medical costs for BC care, making it a substantial economic burden in the United States.2 BC is divided into 4 subtypes based on tumor receptor status, with roughly 87.2% of new BC cases representing the hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2−) subtype.3 Metastatic BC (MBC), BC in which the cancer has spread to other regions of the body, is the most expensive to treat and is expected to increase by 54.8% between 2015 and 2030.4
The introduction of cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6is) (palbociclib, ribociclib, and abemaciclib) has transformed the treatment landscape for patients with HR+ HER2− MBC. Before the introduction of CDK4/6is, women were primarily treated with chemotherapy or endocrine therapy despite the less-than-desirable toxicity and tolerability profiles.5 Although CDK4/6is have become the standard of care in the first-line setting, patients will eventually progress because of resistance, with a median overall survival of approximately 5 years.5 After progression on a CDK4/6i, optimal second-line treatment has yet to be clearly defined.6
Real-world evidence of health care resource utilization (HRU) and economic burden provides important insights into the patient experience and impact on the health care system. Evaluation of HRU and costs via electronic claim records can help inform clinical research, value assessment, drug development, and payers, as the data give us insight into the experience patients with HR+ HER2− MBC are having and can show how best to support patients.
The HRU and economic burden of patients with HR+ HER2− MBC in the commercially insured population is well documented7-11; however, exploration of HRU and costs, specifically following the initiation of CDK4/6i, in the Medicare population is limited.12,13 The Medicare population is a unique clinical subset of patients that may have different disease progression and complications and react differently to treatment owing to older age and higher comorbidities. In this study, we aim to comprehensively assess HRU and costs associated with Medicare-enrolled patients with HR+ HER2− MBC treated in the first-line setting with a CDK4/6i.
Methods
STUDY DESIGN AND DATA SOURCE
We conducted a retrospective cohort study using health insurance claims to describe HRU and costs among Medicare-enrolled patients with HR+ HER2− MBC who initiated a CDK4/6i in the first-line setting.
Data from Merative MarketScan Medicare Databases was used to identify patients and capture HRU and costs. The MarketScan Medicare Supplemental and Coordination of Benefits Database is created for Medicare-eligible retirees with employer-sponsored Medicare Supplemental plans. The database includes both the Medicare-paid amounts and the employer-paid supplemental insurance amounts, with only plans in which both the Medicare-paid amounts and the employer-paid amounts are selected. We collected all enrollment, inpatient (IP), outpatient (OP), and drug claim records.14 The study period was from February 19, 2015 (US Food and Drug Administration approval of the first CDK4/6i) through December 31, 2022 (end of available data) (Figure 1).
FIGURE 1.
Study Design
SAMPLE SELECTION
We used the Medicare databases to identify patients with HR+ HER2− MBC who started a CDK4/6i in the first-line setting. We selected patients with primary BC for initial study inclusion by requiring them to have at least 2 primary BC OP claims, dated at least 30 days apart, or at least 1 IP claim (proxy is 174x and C50x) in any billing position during the study period. To identify patients with MBC, we looked for the presence of at least 2 claims with a diagnosis of a secondary malignancy on 2 distinct dates during the study period (proxy is 197x, 198x, 199x, C77x, C78x, C79x, and C80) with the first metastatic claim being after the primary BC diagnosis. To avoid misclassification of diagnosis codes, the presence of 2 medical claims for secondary malignancy after the diagnosis of the primary breast was required.15
We required a patient with MBC to initiate a CDK4/6i in the first-line setting. We considered a CDK4/6i first line if the agent was given within 90 days of the MBC diagnosis. The date of the first claim for a CDK4/6i defined the study index date. We identified tumor HR and HER2 status using previously published algorithms.7-11 HR+ status was confirmed by evidence of a claim for a CDK4/6i (as therapy indicates) and HER2− status by no evidence of claims for therapies targeting HER2 positivity (HER2 +). The cohort selection is depicted in Figure 2.
FIGURE 2.
Cohort Selection Process
Patients had to meet the following inclusion criteria at the index date: (1) Medicare enrollment, (2) BC as the first or only cancer diagnosis, and (3) 6 months of continuous Medicare enrollment before the study index date to ensure incident cancer and to calculate the comorbidity index score.
We excluded patients if they met any of the following criteria: (1) presence of a claim for MBC diagnosis or CDK4/6i in any billing position during the washout period to ensure incident MBC CDK4/6 initiation, (2) claims for HER2+ medications anytime during the study period, and (3) diagnosis of cancer other than BC in any billing position during the study period to ensure that BC is primary cancer and that secondary malignancies are associated with BC.
We define the index period from the index date through 1 year, the end of the patient’s continuous health plan enrollment, or the end of data availability, whichever occurred first. Diagnoses and treatment codes can be found in Supplementary Tables 1 and 2 (252.1KB, pdf) (available in online article).
STUDY MEASURES AND OUTCOMES
Baseline Patient Characteristics. We assessed baseline characteristics, including patient age, region, year of CDK4/6i initiation, type of CDK4/6i initiated, organ-level metastatic sites, and pre-index systemic therapies, on the index date. Using diagnosis codes from medical claims collected during the 6-month pre-index period, we calculated a modified Charlson Comorbidity Index score that excluded malignancies.16,17 We assessed metastatic sites only at baseline, defining them based on the presence of at least 1 claim with International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) or ICD-10-CM diagnosis codes for secondary malignant neoplasm observed at the index date. A full list of codes used to define metastatic sites is provided in Supplementary Table 1 (252.1KB, pdf) .
The proportion of patients receiving anticancer therapies including surgery, CT, ET, and other targeted therapies before the index date was assessed. We identified all anticancer treatments by using Healthcare Common Procedure Coding System codes, ICD-9-CM procedure codes, ICD-10-CM procedure codes, and National Drug Code numbers/generic drug names. We identified and adapted codes for anticancer therapies using previously published papers,11,13 which can be found in Supplementary Table 3 (252.1KB, pdf) .
HRU and Costs. Our primary outcomes of interest were HRU in the 6 months following CDK4/6 initiation and 1-year costs following first-line CDK4/6i initiation in Medicare-enrolled patients with HR+/HER2− MBC. For the best interpretability, our interest was in obtaining mean estimates of health care utilization and costs. Although 85% of our cohort was still under follow-up at 6 months after the initiation of CDK4/6i treatment, 40% of the initial cohort was lost to follow-up between 6 and 12 months after initiation. Given the large amount of censoring, mean estimates for health care utilization (eg, number of OP visits) over a 1-year follow-up window would have been biased. Therefore, we limited the window to 6 months. For the cost analysis, we were able to employ the Kaplan-Meier sample average (KMSA) method to estimate mean costs while accounting for censoring; therefore, we used a 1-year follow-up window to obtain a more complete picture of costs over the full year.
HRU components analyzed include the number of IP admissions, IP days, length of stay per IP admission, days with emergency department (ED) services, number of OP services, and days with OP services. The MarketScan variable “STDPLAC” was used to define health care settings and service types. We adapted codes to define different care settings from previously published literature.18,19 Codes are available in Supplementary Table 4 (252.1KB, pdf) .
We assessed total 1-year costs as well as costs separately by care setting/service type (IP, ED, OP, and pharmacy). Total health care costs are the sum of IP, ER, OP, and pharmacy costs. The cost estimates represent all payments directly by the Centers for Medicare & Medicaid Services according to the paid amounts included in each claim, excluding employer-paid amounts and patients’ deductibles and copayments. No discounts or rebates were considered. We adjusted costs to 2023 US dollars using the medical care component of the US Consumer Price Index.20
STATISTICAL ANALYSIS
We summarized baseline characteristics using descriptive characteristics. To characterize continuous variables, we used mean (SD), median, and interquartile range, as appropriate. For categorical variables, we summarized frequencies.
We calculated the number of patients having at least 1 admission, the mean number of IP admissions, and, among those who had IP admissions, the mean length of stay per admission. For ED services, we calculated the number of patients having at least 1 visit, and, among those who had an ED visit, we calculated the mean number of visits per patient. For OP services, we calculated the number of patients having at least 1 service, and, among those who had an OP visit, the mean number of days with OP services per patient.
The mean 1-year cumulative cost following first-line CDK4/6i initiation was estimated using the KMSA to account for differential follow-up caused by censoring. We censored patients at discontinuation of insurance coverage or the end of the study period, whichever occurred first. Mortality information is not captured in the MarketScan database; therefore, deaths could not be explicitly identified in our analysis. We estimated the cumulative mean costs during the 1-year period by calculating the sum of the monthly mean costs among patients who remained in the health plan at the start of each month weighted by the probability of remaining in the health plan at the start of each month.21 Nonparametric bootstrapping with 10,000 independent samples was used to generate the 95% CIs for the KMSA estimates. We reported costs as 1-year and monthly means. We performed cohort selection and statistical analyses using SAS version 9.4 (SAS Institute).
Results
BASELINE CHARACTERISTICS
A total of 901 Medicare-enrolled patients with HR+ HER2− MBC met the study inclusion criteria. The mean age of the cohort was 74 years (SD 6.8), with a mean Charlson Comorbidity Index score of 0.6 (SD 0.8). Patients were more likely to reside in the North Central than any other region, and the most common CDK4/6i initiated was palbociclib (n = 804, 90%). At baseline, 651 (72%) patients had evidence of bone metastasis, 316 (35%) had visceral disease, 160 (18%) had lung metastasis, 187 (16%) had liver metastasis, and 119 (13%) had lymph metastasis. Before CDK4/6i initiation, most patients received some form of systematic therapy. Nearly 68% (n = 612) of patients received endocrine monotherapy, 2.1% (n = 19) received combination endocrine and chemotherapy, 0.3% (n = 3) received monotherapy with chemotherapy, and 30% (n = 267) received no prior systematic treatments. At the end of our follow-up period, 569 patients were still taking CDK4/6is. The baseline characteristics are presented in Table 1.
TABLE 1.
Baseline Characteristics of Cohort
| Characteristic | Total study population (N = 901) |
|---|---|
| Age, mean (SD), years | 74.1 (6.9) |
| Year of CDK4/6i initiation, n (%) | |
| 2015 | 85 (9.4) |
| 2016 | 190 (21.1) |
| 2017 | 151 (16.8) |
| 2018 | 107 (11.8) |
| 2019 | 99 (11.0) |
| 2020 | 123 (13.9) |
| 2021 | 123 (13.7) |
| 2022 | 23 (2.6) |
| Type of CDK4/6i initiated first line, n (%) | |
| Palbociclib | 804 (89.2) |
| Ribociclib | 36 (4.0) |
| Abemaciclib | 61 (6.8) |
| Region, n (%) | |
| Northeast (1) | 226 (25.1) |
| North Central (2) | 376 (41.7) |
| South (3) | 219 (24.1) |
| West (4) | 80 (8.9) |
| Charlson Comorbidity Index | |
| Mean (SD) | 0.64 (0.8) |
| 0, n (%) | 457 (50.7) |
| 1, n (%) | 316 (35.1) |
| 2, n (%) | 94 (10.4) |
| ≥3, n (%) | 34 (3.8) |
| Site of metastasis,a n (%) | |
| Bone | 651 (72.6) |
| Brain | 53 (5.8) |
| Liver | 137 (15.8) |
| Lung | 160 (18.1) |
| Lymph | 119 (13.2) |
| Kidney | 3 (0.4) |
| Other | 237 (25.8) |
| Ovary | 3 (0.2) |
| Visceral | 316 (35.4) |
| Pre-index cancer treatments, n (%) | |
| Endocrine therapy only | 612 (68.0) |
| Chemotherapy only | 3 (0.3) |
| Endocrine therapy and chemotherapy | 19 (2.1) |
| No endocrine therapy or chemotherapy | 267 (30) |
| Surgery | 7 (0.8) |
a Categories are not mutually exclusive.
CDK4/6i = cyclin-dependent kinases 4 and 6 inhibitor.
PRIMARY OUTCOME
HRU. During the 6 months following the index date, 214 (23.8%) patients had at least 1 IP admission. Among those with an IP admission, the mean number of admissions per patient was 1.7 (SD 0.98), and the mean length of stay was 5.9 days (SD 6.3). A total of 271 (30%) patients had an ED visit, and, among those with a visit, the mean number of visits per patient was 2.1 (SD 1.5).
Nearly 97% of patients had at least 1 OP service, with the mean number of days with OP services among those patients per patient being 19.9 (SD 12.3) (Table 2).
TABLE 2.
Health Care Resource Utilization
| Characteristic | Total study population (N = 901) |
|---|---|
| Inpatient admissions | |
| Had ≥1 admission, n (%) | 214 (23.8) |
| Number of admissions among patients with ≥1 admission, mean (SD)a | 1.7 (1.0) |
| Median (IQR) | 1 (1-3) |
| Min | 1 |
| Max | 5 |
| Length of stay per admission among patients with ≥1 admission, mean (SD),a days | 5.9 (6.3) |
| Median (IQR) | 4 (3-7) |
| Min | 1 |
| Max | 44 |
| Emergency department visits | |
| Had ≥1 visit, n (%) | 271 (30) |
| Number of visits per patient among patients with ≥1 visit, mean (SD)a | 2.1 (1.5) |
| Median (IQR) | 2 (1-2) |
| Min | 1 |
| Max | 10 |
| Outpatient services | |
| Had ≥1 service, n (%) | 868 (96.4) |
| Days with outpatient services, among patients with ≥1 service, mean (SD)a | 19.96 (12.3) |
| Median (IQR) | 18 (11-26) |
| Min | 1 |
| Max | 110 |
Health care resource utilization was calculated during the 6 months following the index date.
a The denominator includes only those with at least 1 service.
IQR = interquartile range.
Health Care Costs. The mean total 1-year health care costs per patient following CDK4/6i initiation were $62,229 (95% CI = $52,281-$73,029), which was a sum of IP, OP, ED, and pharmacy costs. The main driver of costs was OP services, with a mean of $31,686 (95% CI = $27,168-$36,925) per patient, which represented approximately 50% of the mean total 1-year health care costs. Following OP services, pharmacy costs were the next driver of costs with a mean of $22,727 (95% CI = $19,273-$25,931) per patient. All-cause IP services and ED visits were $6,878 (95% CI = $5,132-$8,979) and $937.58 (95% CI = $708-$1,193), respectively. (Table 3)
TABLE 3.
Health Care Costs
| Setting | Month | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | |
| IP services | ||||||||||||
| Mean monthly costs | $1,584 | $755 | $341 | $916 | $419 | $4,345 | $479 | $407 | $662 | $465 | $227 | $189 |
| Total IP costs, mean (95% CI)a | $6,878 ($5,132-$8,979) | |||||||||||
| ED visits | ||||||||||||
| Mean monthly costs | $170 | $101 | $159 | $86 | $74 | $24 | $64 | $71 | $40 | $49 | $39 | $60 |
| Total ED costs, mean (95% CI)a | $938 ($708-$1,194) | |||||||||||
| OP services | ||||||||||||
| Mean monthly costs | $4,272 | $2,507 | $2,855 | $3,013 | $2,806 | $2,659 | $2,636 | $2,278 | $2,072 | $2,663 | $1,970 | $1,955 |
| Total OP costs, mean (95% CI)a | $31,686 ($27,168-$36,925) | |||||||||||
| Pharmacy costs | ||||||||||||
| Mean monthly costs | $4,396 | $1,924 | $2,313 | $2,119 | $1,941 | $1,799 | $1,696 | $1,412 | $1,399 | $1,261 | $1,249 | $1,218 |
| Total pharmacy costs, mean (95% CI)a | $22,727 ($19,273-$25,932) | |||||||||||
| Mean total costs | ||||||||||||
| Mean total monthly costs | $10,423 | $5,287 | $5,668 | $6,134 | $5,241 | $4,917 | $4,874 | $4,167 | $4,174 | $4,439 | $3,485 | $3,422 |
| Total annual health care costs, mean (95% CI) | $62,229 ($52,281-$73,030) | |||||||||||
a Mean 1-year total costs following cyclin-dependent kinases 4 and 6 inhibitor initiation, calculated using the Kaplan-Meier sample average.
ED = emergency department; IP = inpatient; OP = outpatient.
Discussion
We conducted a retrospective cohort study using MarketScan claims data to describe HRU and costs of Medicare-enrolled patients with HR+ HER2− MBC who initiated a CDK4/6i in the first-line setting. We found a mean Medicare per patient 1-year all-cause expenditure of $62,229 (95% CI = $52,281-$73,030) following CDK4/6i initiation. Nearly 50% of the overall expenditure was caused by OP services with a mean total cost of $31,686 per patient (95% CI = $27,168-$36,925), which can be attributed to 96.4% of the cohort having at least 1 OP service in the first 6 months following therapy start. After further investigation, the high OP costs may be attributable to infusion therapies. Previous studies have suggested that the high OP costs may be attributable to infusion therapies; however, this needs to be confirmed in future work.22,23 The next cost driver was pharmacy costs, followed by IP services and ED visits. Lower costs associated with IP services and ED care in the total health care expenditure may be attributed to only 23.8% (n = 214) of patients having an IP admission and 30% (n = 271) having a visit to the ED.
To our knowledge, this is the first study offering a comprehensive assessment of real-world economic outcomes of Medicare-enrolled patients with HR+/HER2− MBC who started a CDK4/6i in the first-line setting. A previous study by Burne et al (N = 4,320) assessed the mean 6-month HRU and mean monthly economic impact during CDK4/6i therapy in a privately insured population7 and found similar results. They assessed HRU and costs during treatment for the 3 CDK4/6is (abemaciclib, palbociclib, and ribociclib) and found, like our study, OP services followed by pharmacy to be the main drivers of costs in all 3 cohorts. In the abemaciclib, palbociclib, and ribociclib cohorts, they found that patients had an average of 0.7, 0.4, and 0.5 IP admissions, respectively. They found the abemaciclib, palbociclib, and ribociclib cohorts to have a mean number of ED service days of 0.9, 0.6, and 1.1, respectively, and a mean number of OP service days of 26.9, 23.7, and 24.4, respectively. They reported no difference in HRU between the 3 agents but lower overall per patient mean monthly costs in the ribociclib cohort (abemaciclib, $12,378; palbociclib, $7,928; and ribociclib, $7,136).
Overall, patients with HR+ HER2− MBC represent a subset of patients who use a substantial amount of HRU. This highlighted economic burden can help health care decision-makers recognize the high costs associated with this patient population and plan for optimal treatment strategies.
LIMITATIONS
There are several limitations to our study. First, verification of patients with HR+ HER2− MBC who initiated a CDK4/6i in the first-line setting is not directly identifiable in Marketscan because of the unavailability of biomarkers. The patient’s HR+ and HER2− status was identified following a previously published algorithm in which evidence of treatment with endocrine therapy and an absence of evidence of treatment with an HER2-targeted therapy were needed. Owing to the lack of biomarkers in the database, it is possible that misclassification occurred. Metastatic status was identified using secondary malignant codes, which are subject to misclassification. The line of therapy is additionally difficult to determine using claims data. To ensure incident CDK4/6i use in the first-line setting, we required patients to receive the index agent within 90 days of MBC diagnosis. There may be a portion of patients that we missed who initiated a CDK4/6i in the first-line setting more than 90 days after their MBC diagnosis. By implementing this restriction, we may select patients who are healthier and more motivated to receive care or have better access to care. Additionally, the duration of follow-up differed among the patients. To account for differential follow-up, outcomes were analyzed using the KMSA estimator. We assumed all censoring was noninformative and that patients whose costs were observed were representative of patients whose costs were not observed, and this assumption may be violated. Furthermore, we assumed that most costs incurred are attributed to MBC itself; however, because we analyzed all-cause costs, it is possible that costs not related to MBC itself were captured. It is also important to note that these results may not apply to younger populations with MBC, and they may only represent individuals who receive commercial insurance in addition to Medicare. We acknowledge that oral oncology drug costs are typically high and that these costs may not be reflected in our analysis because supplemental commercial insurance often covers these costs and not Medicare. Lastly, this study was susceptible to other inherent issues with retrospective cohort studies using claims data, such as coding errors or differences in billing practices.
Conclusions
This retrospective real-world study described and assessed HRU and costs in Medicare-enrolled patients with HR+ HER2− MBC who initiated a CDK4/6i in the first-line setting. There are numerous sources of HRU and cost in patients following CDK4/6i initiation in the Medicare population, especially in the OP setting. Patients with HR+ HER2− MBC incur high HRU, providing insights for health care decision-makers to optimize treatment strategies and resource allocation for this population. Additionally, this analysis may directly help stakeholders understand the costs in this population and help inform cost-effective modeling.
DATA AVAILABILITY
Merative MarketScan databases were used to support the findings of this study. Availability of these data sets is under licensed contract with the University of Washington for the completion of this study.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Merative MarketScan databases were used to support the findings of this study. Availability of these data sets is under licensed contract with the University of Washington for the completion of this study.