Patterns of resource utilization and cost for postmenopausal women with hormone-receptor–positive, human epidermal growth factor receptor-2–negative advanced breast cancer in Europe

Breast cancer is one of the most commonly diagnosed cancers in women, with an estimated 463 819 new cases diagnosed in Europe in 2012 [1]. The economic burden of this disease is also high; across the European Union, breast cancer generated the highest estimated healthcare costs (6 billion Euros/year) and accounted for 13 % of the total healthcare costs for cancer [2, 3]. However, healthcare resource utilization in breast cancer varies by disease stage and treatment choice [4]. In advanced breast cancer (ABC), hormone therapy and chemotherapy are treatment options that have (to some extent) guideline-specific recommendations regarding initiation of use [5–10].

Hormone therapy is recommended as adjuvant therapy and is viewed as standard of care for hormone-receptor–positive (HR⁺) ABC [6–9]. The value of adjuvant chemotherapy in this setting is unclear [11], and most guidelines recommend sequential endocrine therapies except in patients with proof of hormone resistance or symptomatic visceral disease [8, 9, 12]. However, guidelines for the sequence and preferred number of hormone therapy lines that can be used before switching to chemotherapy in ABC—outside of medical necessity—are not always clear [8, 9, 12]. This lack of clarity can result in varied interpretation of guidelines and can lead to heterogeneous treatment management and costs.

Use of chemotherapy in HR⁺ ABC is associated with extensive healthcare costs in the United States (US) [13–16]; evaluations of chemotherapy costs for HR⁺ ABC in Europe have not been reported. For example, a US study of 1266 women with HR⁺ ABC reported that treatment costs for the year following initiation of chemotherapy were $32 083 higher than the 1-year treatment costs before chemotherapy [14]. Furthermore, a recent evaluation of total direct costs in the US for treating ABC reported that the monthly per-patient direct cost was lowest with systemic hormone therapy ($5303) compared with chemotherapy ($13 261) [13]. The cost of chemotherapy in the US can be primarily attributed to costs other than the drug itself (25 % drug cost and 75 % nondrug costs such as infusion administration and hospitalizations or emergency room visits related to drug) [16]. Because European treatment patterns may vary from those in the US, similar evaluation of chemotherapy use and costs versus hormone therapy across Europe is needed.

This chart review evaluates the resource utilization and direct cost implications of chemotherapy versus hormone therapy based on actual physician-reported treatments from adjuvant therapy to completion of 3 or more lines of therapy in the advanced setting in postmenopausal women diagnosed with HR⁺, human epidermal growth factor receptor-2–negative (HER2⁻) ABC from 2008 through 2012 in France, Germany, The Netherlands, Belgium, and Sweden.

Several treatment options are provided by international guidelines for European patients with ABC at each point in disease progression. However, physicians in individual countries may have limited treatment choices that are guided by country-specific restrictions, separate guidelines, or required procedures. Furthermore, specific guidance may be influenced by a country’s healthcare resources and/or benefit-to-cost ratios. The present study used recent patient records to examine uses of healthcare resources and their associated costs across 5 European countries in the ABC setting. The results demonstrated that total direct costs over the first 3 lines of therapy for HR⁺, HER2⁻ ABC in postmenopausal women were €10 000 to €14 000 lower if a hormone therapy-based regimen was used for 1 additional line of therapy versus switching to chemotherapy. The increase in direct costs for chemotherapy versus hormone therapy was also found in first-line and second-line treatments individually. Moreover, chemotherapy costs were increased despite longer duration of therapy in the cohort receiving hormone therapy.

The results of this study are supported by a study that found increased treatment costs associated with chemotherapy compared with hormone therapy in the ABC setting. A recent evaluation of total direct costs in the US for treating ABC reported that the monthly per-patient direct cost was lowest with systemic hormone therapy ($5303; n = 3187) compared with HER2-targeted therapy ($10 083; n = 711) or chemotherapy ($13 261; n = 2278) and was highest with no systemic therapy at all ($13 926; n = 1522) [13]. Until the present study, similar studies in Europe had not been performed.

Potential cost improvements may have been lost for patients who were eligible for and could have received benefit from hormone therapy in second line but who instead received chemotherapy. Accordingly, this study further examined the possible reasons for the increased cost associated with chemotherapy-based regimens. There were increased healthcare resource utilization costs for monitoring events, complementary therapies to manage side effects, and physician visits with chemotherapy-based regimens compared with hormone therapy. These findings are supported by a US study of 1444 women receiving chemotherapy for ABC, wherein healthcare resources other than the cost of chemotherapy comprised >50 % of the total costs: outpatient services accounted for 29 % of the total cost and medications other than chemotherapy accounted for 26 % [19]. In addition, patients receiving chemotherapy also had greater targeted therapy use compared with patients receiving hormone therapy in our study. Globally, the general use of targeted therapies will most likely increase as more of these agents are shown to provide clinical benefit and are approved. In the future, targeted therapies may also be used increasingly in combination with hormone therapy. Consequently, the total costs for hormone therapy-based therapy will increase. However, combinations with targeted agents may allow the extended use of lower-cost hormone therapy in patients who may derive clinical benefit, allowing a delay in switching to cytotoxic chemotherapy. In this study, the group of patients receiving targeted therapy in combination with hormone therapy was too small to be evaluated. We anticipate that a more in-depth review of these costs will become feasible in the future.

Another increased cost associated with chemotherapy-based versus hormone therapy-based regimens was indirect cost from lower work productivity, with a 3-fold lower proportion of patients working during second-line chemotherapy compared with hormone therapy. Overall, indirect costs associated with work status vary according to age. For example, a Swedish study stratified the total cost of all breast cancer cases in 2002 and reported higher indirect costs in breast cancer from sick leave, early retirement, and premature mortality (70 % of total) compared with direct costs [20]. However, the primary reason indirect costs dominated the total cost was because most of these breast cancer cases were in patients <65 years of age who were still in the workforce. Patients in the present study had a median age of 63 years; therefore, in theory, the working population accounted for ~50 % of the study’s total population, which would lessen the effect of indirect costs. A US study modeling the total costs specifically for ABC over 5 years (based on data from 2007) reported that lost work productivity accounted for only 21 % of the total cost for ABC [21]. The present study is the first to report a detailed assessment of work status over time stratified by treatment regimen in the ABC setting.

Limitations of this study are those primarily inherent to chart reviews. As with any chart review, there are limitations to the information available retrospectively that could have affected treatment decisions, such as accurate assessment of HER2 status. Although the inclusion criteria stated HER2⁻ disease, trastuzumab and lapatinib were used in a small percentage of patients. It is unclear whether these patients had confirmed HER2⁻ disease and HER2-targeted therapies were used because there were limited treatment options, the patients had unconfirmed HER2⁻ disease and HER2-targeted therapies were used as general practice, or the patients had participated in a past trial of HER2-targeted therapy that did not require documented HER2⁺ status at study entry. In some cases, the anti-HER2 therapy might have been used when the metastatic site was not able to be biopsied with the expectation that the tumor characteristics might have changed. Additionally, physicians may have based the treatment on results from the EGF30008 trial of lapatinib in combination with endocrine therapy [22].

In addition, accurate detailed information on the therapeutic regimens may be limited. These concerns were somewhat mitigated by having the treating physician complete the questionnaire using relatively recent patient charts. However, information that the treating physician may not be familiar with may be limiting, such as an accurate number of HCP visits for drug administration that can result in underestimation of utilization costs. In addition, HCP visits could have been underreported. In that case, HCP visit costs could be higher than the reported costs for the lines of therapy and cohorts wherein chemotherapy was used.

Another limitation to this study is the assumption that unit costs were the same within each country. Costs were calculated for each patient based on national costs in the country of the patient. However, local differences may exist that would introduce uncertainties into the difference between chemotherapy and hormone therapy costs. This study presents an average cost difference across the 5 European countries. Furthermore, standard medical practices are similar across the countries included in this study.

Finally, although the chart review covered treatments received from 2008 to 2012, only 2012 reference costs were used. However, the inflation rate in the European Union was ~8.1 % between 2008 and 2012, which is not considered to be a significant enough change to impact the resource utilization frequency/distribution [17].

In this first study to evaluate the real-world experience in treating ABC in Europe, chemotherapy-based regimens appear to be associated with increased total direct costs compared with hormone therapy-based regimens. The results of the ongoing OPTIMA study in the United Kingdom are awaited to further aid in making the decision to initiate chemotherapy in patients with breast cancer and will also include a cost analysis [23]. Current international guidelines for the treatment of ABC recommend hormone therapy as long as patients are eligible (i.e., responsive and without symptomatic visceral metastases or need for rapid treatment control) [5, 8–10, 12], and this study supports these guidelines with regard to healthcare resource utilization, healthcare costs, and work productivity.