Treatment patterns, clinical outcomes and health care costs associated with her2-positive breast cancer with central nervous system metastases: a French multicentre observational study

In 2011, an estimated 53,000 new cases of breast cancer (BC) were diagnosed and almost 11,500 women died from BC in France [1]. About 5%-15% of new cases of BC are diagnosed at the metastatic stage, when the estimated five-year survival rate is 13% [1]. The apparent incidence of central nervous system (CNS) metastases in BC is increasing [2]. This may be due in part to improved imaging and earlier detection of CNS lesions and in part to the availability of more effective systemic treatments that allow more patients to live long enough to develop CNS metastases [3, 4]. In general, survival for BC patients with CNS metastases is poor, with one-year survival of approximately 20% [2]. Compared with patients without CNS metastases, patients with CNS metastases tend to be younger and more likely to have hormone receptor-negative disease and a higher disease burden [5, 6].

Over-expression of the gene encoding human epidermal growth factor receptor 2 (HER2) plays an important role in the pathogenesis of certain types of BC [7]. Positive HER2 status is associated with poor prognosis and a higher incidence of CNS metastases in BC. HER2-positive tumours may have a biological predisposition to metastasise within the CNS and about 40% of patients with brain metastases reported in published case series have HER2-positive BC [2, 8]. However, despite these initial poor global prognostic features, patients with HER2-positive disease seem to have a better short-term prognosis at the onset of CNS metastases than HER2-negative patients. The development of anti-HER2 targeted therapies such as trastuzumab and lapatinib combined with chemotherapy has significantly improved survival in HER2-positive advanced BC patients [9–12]. Indeed, it has been shown that combination of trastuzumab with standard chemotherapy is associated with significantly improved survival following development of CNS metastases in BC patients compared to patients receiving standard chemotherapy only [5]. This has encouraged systematic screening of HER2 status in patients with BC. In the case series above [2, 8], many patients were responding to trastuzumab or had stable systemic disease when they developed brain metastases. However, like many other targeted therapies and cytotoxic chemotherapies, trastuzumab does not easily cross the intact blood–brain barrier [13]. This may lead to sanctuarisation of CNS metastases within the nervous system, allowing them to develop independently of the quality of peripheral disease control.

The management of HER2-positive BC with CNS metastases is based on diversified, non-standardised and increasingly innovative and expensive pharmacological treatments, including targeted therapies, as well as radiotherapy and surgery [8, 14]. The costs, risks and benefits of such approaches remain poorly characterised. However, healthcare cost assessment is necessary for such emerging innovative and expensive targeted therapies, particularly in the context of cost-containment initiatives implemented by health authorities in many countries. For example, in France, the recent Program of Social Security funding emphasised the need for input from economic studies to facilitate the decision process relating to reimbursement of health technologies.

Individual current cost data on HER2-positive BC with CNS metastases are limited and published series have mainly reported costs of advanced BC, regardless of their subtype [15–17]. Economic data on healthcare costs can be derived from several sources, including analysis of prescription claims databases, observational studies of patient cohorts and modelling approaches. Each approach has its own advantages and limitations, although cohort studies are thought to provide the most exhaustive information, and represent the only approach that allows costs to be matched to outcomes on an individual patient basis.

The objective of the present study was to describe treatment patterns and health care costs associated with CNS metastases in HER2-positive BC patients over a two-year follow-up period.

This retrospective observational study has described treatment patterns, survival and health care resource utilisation for 200 HER2-positive BC patients with CNS metastases treated in ten representative French cancer centres. The clinical characteristics of the observed patients are consistent with those of recently published series on HER2-positive BC with CNS metastases in terms of metastasis characteristics, overall survival from metastatic BC diagnosis, time from metastatic BC diagnosis to development of CNS metastases and treatments after diagnosis of CNS metastases [5, 24].

In our study, costs were assessed by site of relapse (CNS metastasis as first relapse or CNS metastasis as secondary site, associated with other metastases). We also considered the line of cytotoxic therapy and the use of targeted therapies specific for HER2. The most frequent treatment approach offered to patients with HER2-positive BC with CNS metastases in this population was chemotherapy, followed by radiotherapy. Chemotherapy was the most important source of cost, comparable to hospitalisation costs. The weight of chemotherapy in expenditure for BC patients underlines the importance of further clinical research to identify the most effective chemotherapeutic treatment regimens for this population of patients. Given the diversity of treatment strategies used in BC with CNS metastases, and our findings showing that chemotherapy is both costly and frequently associated with poor clinical outcome, it seems important to test and validate different treatment algorithms under real-world conditions. This would provide a better estimate of the relative cost-effectiveness of different treatment options for BC with CNS metastases.

In addition, the poor outcomes and high treatment costs observed in these BC patients with CNS metastases suggest a need to diagnose and treat these metastases as early as possible, and before neurological signs appear, in order to optimise the chances of therapeutic success. However, more proactive screening for CNS metastases and earlier treatment may paradoxically generate higher costs of care due to improved life expectancy and longer duration of therapy. Such increased costs would, however, be expected to be partially offset by a better quality of life. Specialist care structures for patients with CNS metastases would also be useful in order to teach patients to recognise and cope with neurological complications with the goal of improving quality of life for patients and their entourage and of limiting emergency department visits and hospitalisations.

We found that the mean cost in the first year following diagnosis was 35,735€ per patient [95% CI: 31,716-39,898]. This estimate appears to be in the same range as those reported in previously published studies, although comparisons should be interpreted with caution due to potential differences in the study population, the range of costs considered and the method of analysis. A small retrospective study in 47 HER2-positive metastatic BC patients in France [25] reported total per-patient direct yearly costs from diagnosis to first metastatic progression of €39,607 for those patients who received trastuzumab. Data from a single-centre, retrospective, observational study of 131 HER2-positive metastatic BC patients receiving trastuzumab in France reported overall annual direct costs per year of €47,832, costs being driven primarily by the costs of trastuzumab (44%) and hospitalisation (41%) [26]. Data from Sweden also indicate that patients with HER2-positive tumours incur higher cost than HER2-negative patients, probably due to the higher cost of targeted therapies, and also to radiotherapy [16].

Further information on the costs of metastatic BC is available from insurance claims databases. A recent French national database analysis estimated the mean annual cost of BC with brain metastases at €29,995 per patient treated with trastuzumab, and assumed to be HER2-positive [27]. In a database analysis from the USA, the direct costs of brain metastases secondary to BC, included medication, outpatient care and inpatient admissions were US$60,045 (€50,898) at six months and US$99,899 (€84,681) at 12 months (2006) [28]. The mean total cost for BC patients with brain metastases was more than twice that of patients without brain metastases at 6 and 12 months.

Although claims database analyses enable broad and exhaustive estimates of cost of illness at a national level to be made relatively rapidly and easily, they are less powerful for comparing sub-groups of populations and for matching economic data to clinical outcomes at the individual patient level. In this respect, observational cohort studies present a number of advantages. Although such studies may be time-consuming and require substantial investment of resources, they provide accurate and detailed information on health care consumption at an individual patient level in both hospital and community settings, and allow the reconstitution of the entire healthcare trajectory of individual patient to be reconstituted. Moreover, cohort analyses provide information on costs in relation to survival and other clinical endpoints. In particular, the influence of potentially different prognosis between sub-groups on health-care consumption can be assessed. Such data are important to collect in order to refine modelling studies of healthcare costs which are critical to inform decision-making with regard to healthcare resource allocation. In France, the recent commitment to including economic assessments into decision-making relating to the drug reimbursement process makes observational cohort studies particularly relevant.

The findings of this study suggest several avenues for future research into the management of BC with CNS metastases in everyday care. These include comparison of costs and outcomes associated with different treatment strategies, which may well not be the same in everyday care than in clinical trials where patients are selected and treatment adherence is optimized. Moreover, the economic and clinical implications of early detection of CNS metastases also need to be evaluated. In addition, it would be of interest to investigate patient-and disease- related determinants of cost and outcome in BC with CNS metastases.

This study has a number of limitations, notably those common to all retrospective observational studies. In particular, the method of selecting patients on the basis of ICD codes may not have allowed exhaustive recruitment due to incomplete or erroneous information in the patient records. We also limited our study to treatments received in the treating centre, which may have led to an underestimation of total costs. In particular, we noticed that surgical interventions were not often performed in the treating centre and are thus not included in the cost estimation. Finally, we used Bang and Tsiatis’ method to handle cost-censored data using the Kaplan-Meier estimator, which may introduce error due to the presence of outliers. This is because the weight attributed to patients incurring very high or low costs will increase over the follow-up period, assuming that they survive.

Our analysis is limited to direct medical costs viewed from the health insurance perspective. Information on non-medical costs such as ambulance transportation and indirect costs such as loss of productivity were not collected since they are not documented in the patient records. Moreover, information on loss of productivity related to sick leave is difficult to collect retrospectively. In many cases, patients with metastatic BC have to stop working altogether. Previous studies have estimated that direct medical costs constitute only about 40% of the total societal cost of these patients [16, 17, 29].

In conclusion, this study documents the use of a range of individualised disease management strategies in a national cohort of HER2-positive BC patients with CNS metastases. Expensive targeted therapies and cytotoxic agents appear to be the main cost drivers, together with hospitalisation costs. Identifying cost drivers may help optimise healthcare expenditure and inform the development of cost-effective therapeutic strategies.