Cost of illness of HER2-positive and metastatic and recurrent HER2-positive breast cancer – a Danish register-based study from 2005 to 2016

Since 1968, all Danish citizens have been assigned a unique personal identification number, recorded in the Danish Civil Registration System (CRS) [11]. For all individuals, the CRS registers date of birth, gender, vital status, region of residence and family relationships. The CRS enables an identity-secure linkage of information among the Danish national registers. Patient-specific data were collected from the Danish National Patient Register (DNPR), which contains information on all somatic hospitalisations in Denmark since 1977. Moreover, all outpatient activities, emergency room contacts and psychiatric ward contacts, including diagnoses and performed procedures, have been included in the DNPR since 1995 [12]. Information on all tariffs and unit cost estimates for each somatic hospital contact (hospital admissions and outpatient visits) was retrieved from the DNPR, which was available from 2002 onwards. The date of diagnosis of breast cancer was retrieved from the Danish Cancer Register, which contains data on the incidence of cancer and on tumour characteristics among the Danish population, dating back to 1943 [13]. The HER2 status of study participants was obtained from the Danish National Pathology Register, which contains information on all pathology examinations conducted in Denmark since 1997 [14]. Data on primary healthcare services and unit costs were retrieved from the Danish National Health Service Register for Primary Care [15]. Prescription medicine costs were collected from the Register of Medicinal Product Statistics. Acquisition and unit cost estimates were based on the market price, including patient co-payment and public reimbursement. Information regarding home care services was retrieved from the Register of Municipal services. Information of employment was retrieved from the DREAM Database, which is owned by the Danish Ministry of Employment. The DREAM database includes information on weekly labour market public transfer payments, i.e. unemployment benefits or disability payments, for all Danish citizens since 1991. Individuals receiving such a payment are included in the database for the corresponding year, while the remaining members of the workforce are not included.

Information regarding highest obtained education was obtained from the Population’s Education Register [16] and was defined by the highest obtained education at the time of breast cancer diagnosis.

The study was conducted in Denmark. Denmark has a tax-financed universal healthcare system, where treatment is free at point of consumption. Hospitals are financed through a combination of block grant transfers and activity-based financing using a DRG-system. Primary care physicians fulfil a gatekeeper-function, where patients need a referral before receiving specialized or hospital care, unless emergency care is necessary. Private health insurance is available, but not widely used. Even if a patient is covered by private health insurance, cancer treatment is provided through the public sector. For prescription drugs, Danish citizens face an annual deductible fee of 2,0.650 Euro. After which, prescription drugs are financed 100% by the state.

All treatment facilities and pharmacies are obligated to report administrative data to the Danish Health Data Authority. The activity data is routinely used for review of hospital activity and reimbursement in accordance with the Danish DRG-system. For cancer treatments, data quality was a stated aim of the Cancer Package II (Implemented 01 January 2006).

The study population was defined as women ≥ 18 years diagnosed with incident HER2-positive breast cancer in the period between 2005 and 2016 who were treated with trastuzumab. All women with incident breast cancer were identified in the Danish Cancer Register using the ICD-10 code C50. In the Danish National Pathology Register, information on HER2 status was retrieved using SNOMED code T04 (breast) in combination with either SNOMED code F29603 (HER2 receptor overexpression) or SNOMED code FE13B5 (HER2 gene amplification). In the DNPR, treatment with trastuzumab was identified using treatment code BOHJ13. More than six treatments with trastuzumab in the year following diagnosis resulted in inclusion in the study population.

Patients who experienced recurrence or metastatic breast cancer does not qualify as early-stage breast cancer. Metastatic cancer is considered the last stage cancer, while 80% of recurrent cancer cases is identified as metastatic [17]. Hence study participants were assigned to one of two subpopulations: patients who experienced metastatic or recurrent HER2-positive breast cancer within the study period, and patients with early-stage breast cancer who did not experience metastases or recurrence within the study period.

Patients with metastatic HER2-positive breast cancer were defined as patients who were registered with TNM-M code M1 at time of diagnosis or, patients who received more than 17 treatments of trastuzumab in the 13 months after diagnosis [18, 19]. Recurrence was identified in patients who received at least six trastuzumab treatments within the first year after diagnosis, at some point afterward discontinued treatment for at least six months, and then initiated trastuzumab treatment again.

To determine the cost of illness, we compare the cost of HER2-positive patients with controls from the Danish population. One control for each patient was randomly selected from the general population via the CRS, matched on age and highest obtained education as of the year of breast cancer diagnosis. All controls were female. The DNPR was used to ensure that all controls were unexposed to breast cancer in the study period. To reduce the risk of introducing bias, we limited the matching criteria to only birth year and highest obtained education. We had in total 91,964 potential controls and the controls were matched exact on a 1:1 ratio based on age and education. If education was obtained abroad or from a not-approved Danish institution, education will be missing in The Education Register. If a patient was observed with missing in this variable, it was matched with a control who also had missing in this variable. Each control was assigned the same index date as the matched case.

Outcomes for this study included direct and indirect costs attributable to HER2-positive cancer. Direct costs consisted of costs generated from consumption primary care services, hospital care services and home care services. Indirect cost was estimated based on labour market productivity. Additionally, we included prescription medicine as a separate category.

The direct costs were estimated based on services noted in the national registers. For each contact with the healthcare system an observation in the register data is made. This observation contains date and reason for visit, services provided to the patient (including but not limited to consultation, medication/treatment provided in a hospital setting, diagnostic imaging, surgery) and the estimated cost of these services. The cost of all included services are determined by the national tariffs and fees (DRG-tariffs for the hospital sector and fees for the primary healthcare sector).

From the DREAM database yearly employment rates were estimated and subsequently labour productivity values were estimated by multiplying the yearly employment rate, with gross average yearly wages, adjusted for the number of effective weekly working hours among women. The labour productivity value estimations included only women considered to constitute the workforce, i.e. those between the ages of 18 and 65.

Due to legal restrictions regarding access to detailed data on prescription medicines, it was not possible to merge this information on a patient level with other direct costs – hence, we report this in a separate category. However, an analysis of the overall costs of prescription medicines produced an estimate of any differences in costs between cases and controls.

Prescription medication in this context include all reimbursed medications, not provided in a hospital setting. For example, anti-nausea medication is often provided in combination with chemotherapy. If that medication is provided in a hospital context, it will be registered in the DNPR. If the same prescription is re-filled at a pharmacy outside the hospital context later, that cost will be registered in this category. However, this category is not limited to cancer-related medications, but all prescription medication collected by the study participants in the study period..

All costs were set to the 2016 price level, and tariffs in both the Danish National Health Service Register for Primary Care and the DNPR were inflated using the combined price and wage index for healthcare services, according to the Danish Regions [20]. Prescription medicine prices were not inflated, as they fluctuate, making price indices difficult to interpret. In the present study, all costs are reported in euros and assume the following exchange rate: EUR 1 = DKK 7.5.

The study followed participants from one year prior to their index date, i.e. date of incident breast cancer diagnosis (1 January 2005 at the earliest), and until 10 years after index date, death, emigration, or end of follow-up (31 December 2016), whichever occurred first.

Average individual direct and indirect costs were calculated on a yearly basis according to index date for cases and controls, respectively. Due to the large number of observations in all categories, a one-sample t-test was applied to determine significance in differences between direct costs among cases and controls.

A secondary analysis estimated the direct costs of metastatic and recurrent breast cancer. Thus, date of metastases or recurrence was defined as the date of breast cancer diagnosis if the patient was diagnosed with metastatic breast cancer (de novo breast cancer), as the date of the 18^th treatment of trastuzumab if the patient was identified with more than 17 treatments of trastuzumab, or as the date of re-initiation of treatment with trastuzumab after a six-month break. Direct costs three years after recurrence were estimated. After three years, we do no longer attribute the costs to recurrence but consider it equal to the cost of HER2-positive cancer.

Finally, further analysis included an estimate of the individual average costs of prescription medicines among cases and controls.

Data management and statistical analyses were carried out using SAS statistical software (9.4; SAS Institute, Inc., Cary, NC, USA) on Statistics Denmark’s research computers via a remote server.

Table 2 presents the annual average direct costs per person among patients with HER2-positive breast cancer treated with trastuzumab compared to matched controls free of breast cancer among the total study population, the population with metastatic or recurrence of breast cancer and the population without metastatic or recurrence of breast cancer.

In the year of diagnosis, the average direct costs were 25.9 (p < 0.001) times higher among cases in the total study population compared to controls, 27.3 (p < 0.001) times higher among cases with metastases or recurrence compared to controls and 25.3 (p < 0.001) times higher among cases without metastases or recurrence compared to controls, corresponding to differences in actual costs of EUR 58,217, EUR 67,099 and EUR 54,910, respectively.

In subsequent years, the average direct costs remained statistically significantly higher among cases alive compared to controls alive in all study populations. In the 10^th year after diagnosis, the average direct costs remained significantly higher among the total study population and among patients with metastases or recurrence. Among all cases, the costs were 2.3 (p = 0.003) times higher compared to controls in year 10, whereas the costs were 10.0 (p = 0.002) times higher among cases with metastases or recurrence and 1.2 (p = 0.402) times higher among cases without metastases or recurrence compared to controls.

Figure 2 presents the average individual labour productivity among HER2-positive breast cancer patients compared to controls who were free of breast cancer from year -1 to year 10. In the year prior to index date, cases and controls in all study populations did not differ significantly regarding labour productivity: p = 0.180 among the total study population, p = 0.99 among cases with metastases or recurrence and p = 0.103 among cases without metastases or recurrence. For all three study populations, labour productivity was slightly higher among cases compared to controls.

Among the total study population, labour productivity decreased significantly in the year of diagnosis and remained statistically significantly lower during the entire follow-up period. Among the population of cases with metastases or recurrence, labour productivity was significantly lower throughout the study period; in year 10, labour productivity was 2.8 (p < 0.001) times lower among cases compared to controls, whereas cases without metastases or recurrence showed labour productivity comparable to controls from year 9 and onwards (p = 0.114).

Among patients experiencing metastases or recurrence, 201 patients (5.5% of cases) were identified with metastatic breast cancer at the time of diagnosis (i.e. de novo breast cancer), while the rest experienced a recurrence after a mean time of 1.5 years. Table 3 presents average individual direct costs three years after recurrence. In the first year after recurrence, the average individual cost increased to EUR 38,383 among cases, compared to EUR 2,129 among their matched controls. Thus, a second spike in direct costs was related to recurrence among breast cancer patients.

The average individual costs of prescription medicines are presented in Table 4. In the year prior to index date, the costs of prescription medicines did not vary significantly between cases and controls. In year 1 and year 3, cases had slightly higher costs of prescription medicines compared with controls. In the remaining years, however, we found no differences in costs of prescription medicines between cases and controls. During the entire study period, the average yearly cost of prescription medicine was EUR 343 for cases and EUR 330 for controls.