A population-based comparison of treatment patterns, resource utilization, and costs by cancer stage for Ontario patients with hormone receptor-positive/HER2-negative breast cancer

Purpose To update and expand on data related to treatment, resource utilization, and costs by cancer stage in Canadian patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer (BC). Methods We analyzed data for adult women diagnosed with invasive HR+/HER2− BC between 2012 and 2016 utilizing the publicly funded health care system in Ontario. Baseline characteristics, treatment received, and health care use were descriptively compared by cancer stage (I–III vs. IV). Resource use was multiplied by unit costs for publicly funded health care services to calculate costs. Results Our study included 21,360 patients with stage I–III plus 813 with stage IV HR+/HER2− BC. Surgery was performed on 20,510 patients with stage I–III disease (96.0%), with the majority having a lumpectomy, and radiation was received by 15,934 (74.6%). Few (n = 1601, 7.8%) received neoadjuvant and most (n = 15,655, 76.3%) received adjuvant systemic treatment. Seven hundred and fifty eight patients with metastatic disease (93.2%) received systemic therapy; 542 (66.7%) received endocrine therapy. Annual per patient health care costs were three times higher in the stage IV vs. stage I–III cohort with inpatient hospital services representing nearly 40% of total costs. Conclusion The costs associated with metastatic HR+/HER2− BC reflect a significant disease burden. Low endocrine treatment rates captured by the publicly funded system suggest guideline non-adherence or that a fair portion of Ontarian patients may be incurring out-of-pocket drug costs. Electronic supplementary material The online version of this article (10.1007/s10549-020-05960-4) contains supplementary material, which is available to authorized users.


Introduction
Breast cancer (BC) is a heterogenous disease that can be defined by morphologic or molecular features that predict a patient's prognosis. One of the most clinically driven classification schemes relies on immunohistochemical measures of receptor expression to guide systemic therapy [1]. Tumors testing positive for hormone receptors (HR+) and negative for human epidermal growth factor receptor 2 (HER2−) represent the most common BC subtype; approximately 70% of cases [2]. Patients with HR+/HER2− BC have higher 5-year survival rates compared to those with triple negative or HER2 + BC. The median overall survival among patients with stage IV HR+/HER2− disease ranges from four to five years [2,3].

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Treatment of HR+/HER2− BC has primarily focused on endocrine therapy to downregulate HR signaling [2]. For stage I-III HR+ BC, this entails at least 5 years of tamoxifen or aromatase inhibition (AI; with anastrozole, exemestane, or letrozole in post-menopausal or ovarian suppressed women), with extended adjuvant therapy recommended for women at high risk of recurrence [4]. The decision to add adjuvant chemotherapy is informed by a combination of clinical and genomic risk assessment, as well as patient preference [5]. Standard surgical approaches include mastectomy or lumpectomy with lymph node sampling, typically followed by radiation [2].
Historically, the treatment of patients with metastatic HR+ BC has involved serial endocrine treatment as the preferred approach, except in the setting of visceral crisis or life threatening disease, when chemotherapy is preferred as first line therapy [2, 6,7]. Recent evidence supports additional inhibition of cyclin-dependent kinase (CDK) 4/6, which has become standard of care in the first line setting, as well as inhibition of the PI3K/AKT/mTOR pathway, often in later lines of therapy [8,9].
To date, population-based studies in BC have most commonly reported disease characteristics of a broad population or risk/outcome within a specific breast subtype. One realworld assessment of Ontario BC patients reported on direct healthcare costs by cancer stage [10], but there are no similar studies specific to the HR+/HER2− subtype. We sought to assess the occurrence, management, resource utilization, and costs according to stage I-III versus metastatic disease in Ontario women diagnosed with HR+/HER2− BC.

Study design
We conducted a retrospective, observational, populationbased study to assess the treatment resource utilization and health care costs for a cohort of Ontario women diagnosed with stage I-III versus stage IV HR+/HER2− BC. The study was approved by the Ontario Cancer Research Ethics Board in 2017 and conducted in 2019 by ICES using all relevant databases under their purview (Table S1).
ICES is an independent non-profit organization that houses de-identified population-based health and social data on publicly funded services provided in Ontario. Cases are linked across databases by their unique Ontario Health Insurance Plan (OHIP) number. In Ontario, all Canadian citizens and permanent residents are eligible to receive publicly funded hospital care, most physician services, outpatient and emergency services, and, for those 65 years of age or older or on social assistance, prescription drug coverage.
Supplemental drug funding is also provided by the government through special programs within the Ontario Drug Benefit (ODB) program or the New Drug Funding Program (NDFP).
Incident cases of invasive BC [11] in adult women (18-105 years old) diagnosed between Apr 1, 2012 and Mar 31, 2016 were extracted from the Ontario Cancer Registry (OCR). This timeframe was selected based on feasibility data from ICES and took into consideration availability of laboratory test results for HER2 and HR status as well as the target population of 40,000 women with breast cancer. Those diagnosed with a secondary non-BC malignancy were excluded from the analysis, as well as any incomplete/invalid records (i.e., missing age/gender). The final cohort for this sub study only included patients with a known and negative HER2 status, a known and positive HR status, and a documented cancer stage (Fig. S1). Molecular subtype was determined from synoptic pathology reports housed in the OCR. Receptor status was defined according to Cancer Care Ontario (CCO) and ASCO/CAP guidelines, with HR+ status defined as ER and/or PR expression of ≥ 1% by immunohistochemistry [12][13][14]. Patients were assigned to the stage I-III or stage IV cohort based on their stage at initial diagnosis; therefore, all patients in the stage IV cohort had de novo metastatic disease. Patients were followed until the earliest of the following: date of last contact with the health care system, end of OHIP eligibility, death, or end of study, which was Mar 31, 2017.

Measures and data sources
Variables of interest for data collection included age, rurality [15], comorbidity index [16], income status [17], and various tumor characteristics. American Joint Committee on Cancer disease stage at diagnosis was reported according to the Collaborative Staging Methodology (v.1.0, 2004) which incorporates TNM information [18]. Tumor characteristics of interest were derived from the OCR and included histologic grade (reported according to the Nottingham combined scoring system) [19], laterality, pathologic tumor size, and lymph node status.
Treatment-related variables of interest included treatments received (surgery, radiation, or systemic therapy), time between diagnosis and the start of each treatment modality, and use of targeted and endocrine therapies according to stage. The authors reviewed database treatment codes and ensured queries related to systemic therapy were specific to anti-cancer therapies (including chemotherapies, endocrine and targeted therapies). Surgery dates and types were derived from the Canadian Institute for Health Information (CIHI) Discharge Abstract and Same Day Surgery databases. Rates of radiation therapy (RT) were calculated using radiation exposure data captured in OHIP, National Ambulatory Care Reporting System (NACRS), and/or the Cancer Activity Level Reporting (ALR) databases between diagnosis and study end. Rates of systemic therapy were calculated using drug exposure data from the OHIP, NACRS, ALR, NDFP, and/or ODB databases.
For patients with stage I-III disease, systemic therapy was categorized as neoadjuvant (NAT, occurring before surgery) or adjuvant (AT, occurring within 24 weeks after surgery-a broad window intended to ensure the capture of systemic therapy in case of delay following locoregional therapy). Since the majority of systemic anti-cancer therapies are reimbursed (by ODB or NDFP), dispensed, and administered by the cancer clinics, CCO's ALR database was considered the most comprehensive provincial record of cancer regimens received.
Health resource utilization measures included number of events/uses as well as length of stay where applicable and were queried in the databases outlined in Table S1. Costs were determined by multiplying the health resource utilized by the unit cost. Unit costs for emergency room visits, day hospitalizations/surgeries, and inpatient/rehabilitation stays were sourced from CIHI and the Ontario Case Costing Initiative. Costs for biopsies, imaging, physician visits, and laboratory tests were sourced from the Ontario Ministry of Health and Long-Term Care (MOHLTC). Health service cost components were summed to calculate the total direct cost for the full period of care. To estimate annual direct health care costs per patient, total costs over the study period were divided by the period of care and the number of patients. All reported costs were inflated to 2017 Canadian dollars using the Consumer Price Index calculator [20].
Hospital outpatient cost data were derived from the MOHLTC and defined as billings involving day surgery, medical day care, or clinic care related to clinic attendance, rehabilitation services, or diagnostic tests. These costs were then linked to OHIP records using a validated algorithm [21].

Statistical methods
Considering the descriptive nature of our study and that there were approximately 9614 new cases of BC each year among an Ontario population of approximately 13 million [22], our sample size was fixed as the number of cases identified over the four-year period of the study.
Results are reported using descriptive statistics for center (mean, median) and dispersion (SD and interquartile range [IQR]) for all continuous variables. Categorical variables were summarized using counts and percentages. In accordance with ICES policies, cells with fewer than six patients and any interrelated cells were suppressed to prevent re-identification.

Patient characteristics
Among the 34,340 women newly diagnosed with BC and meeting the criteria for inclusion, 22,247 (64.8%) had HR+ BC. Notably, 3914 patients had an unknown histologic subtype and 74 had no reported disease stage and were, therefore, excluded from further analyses.
The mean age of women with stage I-III and stage IV HR+/HER2− BC was 62.1 (± 13.1) years and 62.8 (± 14.0), respectively. Table 1 highlights key demographic and tumor characteristics observed in the cohort of patients with stage I, II or III versus stage IV disease at diagnosis. Patients were evenly distributed among income quintiles and comorbidity data were missing for a significant proportion of patients.

Treatment
Rates of surgery and RT were lower in the stage IV cohort compared with the stage I-III cohort, although the metastatic cohort had higher systemic treatment rates (Table 2).

Resource utilization and costs
The full HR+/HER2− cohort was responsible for total measured costs of $1,271,092,661 between April 2012 and March 2017. In terms of total measured costs by resource type, ambulatory cancer clinic visits and OHIP professional fees combined accounted for over half of the costs incurred (32.5% and 20.3%, respectively) (Fig. 1).
For patients with stage I-III HR+/HER2− BC, the average annual per patient total cost was $22,662, compared with $77,112 for patients with stage IV disease (Table 3 and S4). Costs were higher for patients with stage IV disease for all resource use categories except same day surgery, which was higher for patients with stage I-III disease. Ambulatory cancer clinic visits, hospital inpatient services, and OHIP professional fees were the primary contributors to annual costs in both subgroups.
OHIP professional, hospital outpatient services, ambulatory cancer, and ODB were highly utilized and by a similar proportion of patients regardless of disease stage (Fig. 2, Table S4). Emergency, home care, and inpatient services as well as the NDFP were, in contrast, utilized by a higher proportion of patients with stage IV BC.
Of the 22,173 patients with HR+/HER2− BC, 10,176 (46%) had at least one inpatient hospital stay. Among them, patients with metastatic disease had an average number of inpatient visits three times that of patients with stage I-III disease and a substantially longer average length of stay (32.7 versus 4.6 days, respectively) ( Table S4).
Patients with stage IV HR+/HER2− BC also had roughly three times the number of OHIP professional encounters and twice as many hospital outpatient visits than patients with stage I-III disease. Costs related to the   (Table S4).

Patient characteristics
The incidence of HR+/HER2− BC among all BC subtypes in our study was 64.8%, with 3.7% diagnosed as stage IV. These incidences are in line with those observed in a European registry analysis [23] and a US populationbased case-control study [24]. Interestingly, the proportion of patients with ER positive tumors was higher in our cohort than others (99% versus 86%) [23,24]. The majority of patients with stage I-III HR+/HER2− BC in our study had favorable prognostic features such as tumor size < 2 cm (53%), lymph node negative status (62%), and well to moderately differentiated tumor pathology (75%).

Treatment
Patients with stage I-III HR+/HER2− BC underwent lumpectomy or mastectomy at rates of 71% and 25%, respectively, which demonstrates support for breast-conserving surgery comparable to [25] or greater than [26][27][28][29] that reported in other cohorts. Unfortunately, because systemic therapies can be entered into the ALR database as single agents and/or combination regimens and may be entered differently with each administration, it was prohibitively difficult to discern which regimens were given and for what duration. Thus, although collected, in-depth data on systemic chemotherapy was of little value for reporting.
Considering that endocrine therapy is recommended for all patients with HR+ disease, regardless of disease characteristics, the endocrine treatment rate (68.9%) for women with early stage disease was lower than expected [30][31][32]. Other real-world reports have noted similar or higher rates of adjuvant endocrine therapy usage (70-86%), with some highlighting challenges related to adherence and duration of treatment [27,[33][34][35][36][37][38][39][40][41]. Unfortunately, an analysis of factors influencing treatment was beyond the scope of our research, but is warranted in order to optimize outcomes [42] in patients with this subtype of BC.
Systemic treatment in the de novo metastatic setting was high (93.2%); however, only 66.7% overall received endocrine therapy; a rate lower than that reported in comparable cohorts [23,43]. Since public funding for endocrine therapy does not cover all patients for whom it is recommended (i.e., those < 65 years of age) we were not able to wholly assess exposure rates using administrative claims data alone. Further research on guideline adherence would be valuable for this subgroup since indications for upfront chemotherapy in HR+ disease are rare [9]. It was not until the latter part of our study that mTOR and cyclin-dependent kinase (CDK) 4/6 inhibitors were introduced into clinical practice [8,9,[44][45][46]. This is reflected in the low usage rates for our metastatic cohort; 4.9% and 2.1%, respectively, the latter of which is expected to increase over time.

Resource utilization and costs
In the first Canadian study to look at health care costs specific to patients with staged HR+/HER2− BC, we have shown total annual costs to be approximately three times higher for patients with stage IV versus I-III disease ($77,112 and $22,662, respectively). Patients with stage IV disease utilized significantly more emergency, home care, and inpatient services, reflecting the known intensified care requirements in this setting. In addition, use of the NDFP was higher for patients with stage IV BC; likely a reflection of bisphosphonate and targeted therapy usage. Our data serve as a timely baseline for assessing the economic impact of new therapeutic approaches in both adjuvant (i.e., extended therapy [4]) and palliative care.
There are, of course, significant challenges associated with comparing costs between studies, due to methodological differences as well as variability in health care systems internationally and even inter-provincially [47]. However, it is important to note that while some studies confirm a similar trend of increased expense in later cancer stages [48][49][50], this is not always the case [51,52], and the contributors (i.e., hospitalization, medication, etc.) can differ significantly between tumor sites [48].

Limitations
Limitations of our study include those inherent to administrative and claims database analyses, such as missing clinical variables of interest (e.g., ethnicity, menopausal status, genetic test results, ovarian suppression rates, and recurrence or progression). Notably, lack of recurrence data restricted our ability to delineate distant recurrences from the stage I-III cohort and apply them to the stage IV cohort. Therefore, costs reported for the stage I-III cohort may be inflated. Given our province-wide, population-based sampling, biases were limited, but involved the exclusion of patients without histologic subtype (n = 3914) or tumor staging (n = 74) information and the lack of prescription drug cost data for patients under 65 years of age.
Because only publicly funded services were captured in the databases utilized, the total cost of care to society cannot be calculated (i.e., out-of-pocket patient expenses, loss of productivity). In addition, cost data in a matched control group without BC were not assessed; thus, the total costs reported for these patients represents all publicly funded health care costs and not solely HR+/HER2− BC-attributable costs.
Finally, assessing clinical outcomes or the statistical significance of differences between groups by stage at diagnosis was beyond the scope of this study, but could have provided additional context and/or highlighted implications of various treatment patterns.

Conclusion
In our subset of patients with HR+/HER2− BC, rates of endocrine therapy appear to be lower than other similar real-world cohorts. We postulate that some patients may be incurring out-of-pocket treatment expenses not captured in the databases surveyed. Endocrine treatment is the cornerstone of therapy for patients with HR+/HER2− BC and is a critical to minimizing recurrence and prolonging survival. Hence, we must ensure optimal exposure to endocrine treatments in addition to the pursuit of new therapeutic approaches. Finally, despite more favorable survival for patients with metastatic HR+/HER-BC compared with other molecular subtypes [53], our resource utilization data indicate high inpatient treatment rates and reflect the wellknown burden of illness borne by these patients.
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