Breast Cancer Research and Treatment https://doi.org/10.1007/s10549-021-06135-5

EPIDEMIOLOGY

Cardiac assessment in Australian patients receiving (neo)adjuvant trastuzumab for HER2‑positive early breast cancer: a population‑based study

Monica Tang1 · Andrea L. Schafer1 · Belinda E. Kiely2 · Benjamin Daniels1 · Chee K. Lee2 · Robert J. Simes2 · Sallie‑Anne Pearson1

Received: 4 November 2020 / Accepted: 5 February 2021 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021

Abstract Purpose Cardiac function assessment is important for detecting and managing trastuzumab-associated cardiotoxicity. Our study estimates rates and predictors of cardiac assessment among patients receiving trastuzumab for HER2-positive early breast cancer (HER2+EBC) in Australia. Methods We conducted a retrospective cohort study of Australians initiating (neo)adjuvant trastuzumab for HER2+EBC between 1 January 2015 and 15 April 2019. We used administrative claims to determine the number of patients receiving guideline-recommended assessment, i.e. evidence of baseline cardiac assessment (between 120 days before and 30 days after trastuzumab initiation) and regular on-treatment cardiac assessments (at least every 120 days). We examined factors associated with baseline and regular on-treatment cardiac assessment. Results Our study includes 5621 patients (median age 56 years), of whom 4984 (88.7%) had a baseline cardiac function test. Among 4280 patients with at least 12 months of follow-up, 2702 (63.1%) had guideline-recommended cardiac assessment. Rates of guideline-recommended assessment increased with later year of diagnosis (60.9% in 2015 vs 68.3% in 2018, OR 1.34, 95% CI 1.06–1.69). Patients with higher baseline comorbidities and greater socioeconomic disadvantage were less likely to have guideline-recommended cardiac assessment. Cardiac assessment practices varied by State/Territory. There was no association between baseline cardiac risk or anthracycline use and the likelihood of receiving guideline-recommended cardiac assessment. Conclusion The majority of patients receiving (neo)adjuvant trastuzumab had guideline-recommended baseline and on- treatment cardiac assessment. Variations in cardiac assessment predominantly related to system-level factors, such as year of diagnosis and geography, rather than individual patient factors.

Keywords Breast neoplasms · Human epidermal growth factor 2 · Trastuzumab · Heart function tests · Observational study

Introduction HER2-targeted monoclonal antibody causes reversible myo- cyte contractility dysfunction via disruption of the Heregu- Trastuzumab is an efective targeted treatment for human lin pathway, which is involved in promoting cardiomyocyte epidermal growth factor 2 (HER2)-positive breast cancer but survival [1, 2]. In a meta-analysis of adjuvant trastuzumab it is associated with an increased risk of cardiotoxicity. This trials, 2.5% of patients developed symptomatic congestive cardiac failure and another 11.2% had asymptomatic but sig- * Monica Tang nifcant decline in left ventricular ejection fraction (LVEF) [email protected] on echocardiography [3]. However, among patients with

1 early breast cancer treated in routine practice, the rate of Centre for Big Data Research in Health, University of New clinically documented cardiac failure is up to 10% higher South Wales, Level 2, AGSM Building (G27), Sydney, NSW 2052, Australia among those receiving trastuzumab compared to those not receiving trastuzumab [4]. 2 NHMRC Clinical Trials Centre, University of Sydney, Levels 4‑6 Medical Foundation Building, 92‑94 Parramatta Rd, Patients treated in routine practice are often older and Camperdown, NSW 2050, Australia have more comorbidities than clinical trial participants, and

Vol.:(0123456789)1 3 Breast Cancer Research and Treatment therefore may be at higher risk of cardiotoxicity [5]. Regular Data sources cardiac function assessment plays an important role in the early detection of cardiac function impairment, which may We conducted a retrospective, population-based, cohort study necessitate closer monitoring, trastuzumab treatment breaks of Australians who received PBS-subsidised trastuzumab for and/or adjunctive treatments to prevent the development of the treatment of HER2+EBC in the adjuvant and neo-adjuvant symptomatic cardiac failure. Timely recognition and man- settings. The patient enrolment dataset includes sex, year of agement of trastuzumab-related cardiotoxicity is especially birth, month/year of death, remoteness of residence (Remote- important in patients with HER2-positive early breast cancer ness Area, a measure of relative access to services based on (HER2+EBC). As anti-HER2 treatment becomes increas- the road distance to the nearest urban centres) and a census- ingly efective at curing patients with HER2+EBC, there derived measure of socio-economic disadvantage based on is growing imperative to minimise the risk of cardiac dys- the patient’s residential postcode (Index of Relative Socio- function with potential long-term sequelae and functional economic Disadvantage, IRSD) [12, 13]. Given the sparsely impairment in cancer survivors. distributed population of Australia, major cities are associated Population-based studies have demonstrated that cardiac with greater socioeconomic advantage compared to regional function assessment in Australian patients receiving trastu- and remote areas [14, 15]. PBS claims comprise dispensing zumab for HER2-positive metastatic breast cancer frequently date, quantity dispensed and PBS item number, which identi- did not align with published guidelines [6–9]. The patterns fes the indication for which trastuzumab is prescribed (e.g. of cardiac monitoring among patients with HER2+EBC in early or metastatic HER2-positive breast cancer) (Supplemen- routine practice in Australia is unknown. In this study, we tary Table 1). MBS records include date of service and item used national claims data to report on cardiac monitoring number indicating the billed medical service. practices in Australian patients receiving (neo)adjuvant trastuzumab for HER2+EBC. Specifcally, we determine Study population the proportion of patients who had baseline and regular on- treatment cardiac assessment and examine factors associ- We included patients whose frst trastuzumab dispensing for ated with deviation from guideline-recommended cardiac HER2+EBC occurred between 1 January 2015 and 15 April assessment. 2019 and for whom we had linked MBS records. We identi- fed dispensings of (neo)adjuvant trastuzumab for each patient based on WHO Anatomical Therapeutic Chemical Classifca- Methods tion System (ATC) code L01XC03 and PBS item numbers for early breast cancer. We excluded 2640 patients for whom MBS Study setting records were not available (Supplementary Fig. 1). There were no signifcant diferences in baseline characteristics of patients All citizens and eligible residents in Australia are entitled with and without linked MBS records. to government-subsidised access to prescriptions medicines We identifed patients with pre-existing cardiac risk factors listed under the Pharmaceutical Benefts Scheme (PBS). or conditions based on the dispensing of medicines for the Trastuzumab has been PBS-listed for the adjuvant treatment treatment of cardiovascular disease (ATC codes C [excluding of HER2+EBC since 1 October 2006. Private health insur- topical agents for treating venous disorders] and B01AC) in ance in Australia does not reimburse publicly-subsidised the 180 days prior to trastuzumab initiation. A similar method medicines, so PBS data captures the vast majority of tras- used to classify patients with cardiac risk factors and condi- tuzumab use for HER2+EBC in Australia. One Australian tions has been previously described [16]. We used medicines validation study demonstrated that PBS data captures tras- dispensed in the 365 days prior to trastuzumab initiation to tuzumab use in > 99% of patients receiving trastuzumab for classify patients into three categories of comorbidity burden HER2+EBC [10]. Australia’s national Medicare Benefts using the Rx-Risk-V index [17], after excluding malignancy Scheme (MBS) provides all residents with subsidised access and steroid-responsive conditions, as all patients had a malig- to medical services such as physician visits, pathology tests nancy and a large proportion were prescribed steroids as part and therapeutic and diagnostic procedures, including cardiac of their chemotherapy regimen. function assessments. We have previously described this whole-of-population cohort of HER2-positive breast cancer Cardiac function tests patients who were dispensed HER2-targeted therapy [11]. Cardiac function assessment in Australia is mostly funded by the MBS in private and public outpatient settings. Cardiac tests can also be billed outside the MBS (e.g. in

1 3 Breast Cancer Research and Treatment public hospital inpatients) or when tests are fully funded by (anastrozole, letrozole or exemestane) within 120 days patients, which are not captured by our data. We identifed before or 540 days after trastuzumab initiation [20, 21]. cardiac function tests using MBS item numbers for echocar- diograms (55113, 55114, 55115, 55119, 55120, 55121) and Factors associated with cardiac assessment multiple-gated acquisition (MUGA) scans (61313) per- formed between 1 May 2014 and 15 May 2019. We used logistic regression to examine factors associated Australian guidelines recommend cardiac function assess- with guideline-recommended cardiac assessment, including ment at baseline and every 3 months during treatment with baseline characteristics and treatment factors, such as use of (neo)adjuvant trastuzumab, as does the manufacturer of anthracycline-based chemotherapy regimen. trastuzumab [18, 19]. In line with guidelines, in order to qualify for publicly-subsidised trastuzumab during the study period, PBS restrictions required patients to have cardiac Results function tests at baseline and every 3 months during treat- ment to ensure that they did not have LVEF ≤ 45% and/or Our study includes 5621 Australians initiating (neo)adju- symptomatic heart failure (Supplementary Table 2). We vant trastuzumab for HER2+EBC between 1 January 2015 defned baseline cardiac assessment as any cardiac function and 15 April 2019 who met our inclusion criteria (Table 1). test performed between 120 days before and 30 days after Median age at frst trastuzumab dispensing was 56 years a patient’s frst dispensing of (neo)adjuvant trastuzumab for (interquartile range 47–66). Most patients resided in major HER2+EBC. For patients who had more than one cardiac cities (70.7%) and there was an over-representation of function test during this period, we considered the frst test patients with the least socioeconomic disadvantage (36.7% to be the baseline assessment. in the top quintile of the IRSD). We defned on-treatment cardiac assessment as any car- One-third of patients were dispensed at least one car- diac function tests performed in the 365 days following a diovascular medicine in the 6 months prior to trastuzumab patient’s frst adjuvant trastuzumab dispensing (exclud- initiation (36.4%), and 20.5% were dispensed two or more. ing the baseline cardiac assessment, if this occurred in the The most commonly dispensed cardiovascular medicines 30 days after trastuzumab initiation). We considered patients were agents acting on the renin-angiogensin system (26.4%), to have regular on-treatment cardiac monitoring if they met lipid modifying agents (19.6%), beta-blockers (7.2%) and the following criteria: had a cardiac function test within calcium-channel blockers (6.0%). In the 12 months after 120 days of initiating trastuzumab; had less than 120 days starting trastuzumab, at least one new cardiovascular medi- interval between consecutive cardiac tests; and had less than cine was added to the regimen of 27.6% of the 2045 patients 120 days interval between their last cardiac test and their on pre-existing cardiovascular medicines and 18.8% of the fnal trastuzumab dispensing for early breast cancer. 3576 patients not already on cardiovascular medicines. We determined the proportion of patients with baseline cardiac assessment in our entire study cohort. We deter- Cardiac function tests mined the proportion of patients who had guideline-recom- mended cardiac assessments (i.e. both a baseline cardiac test Nearly all patients (n = 5324, 97.7%) had at least one MBS- and regular on-treatment cardiac monitoring) in a cohort reimbursed cardiac function test between 120 days before with at least 120 days between their frst and last trastu- and 365 days after trastuzumab initiation. Most patients zumab dispensing and at least 12 months of MBS records (n = 4984, 88.7%) had a baseline cardiac function test (i.e. initiated trastuzumab between 1 January 2015 and 15 (Table 1), the majority of which were echocardiograms May 2018). We described the types of cardiac tests (echocar- (n = 3545, 71.1%). diogram or MUGA scan) that patients received. Of 4280 patients with at least one year of follow-up and 120 or more days between their frst and last trastuzumab Concomitant chemotherapy and endocrine therapy dispensing, 4011 (93.7%) had at least one on-treatment cardiac assessment in the year after trastuzumab initiation. We examined the dispensing of chemotherapy drugs, iden- These patients received 13 750 on-treatment cardiac func- tifed by ATC codes (L01), between 120 days before and tion tests, comprising 10 460 echocardiograms (76.1%) and 60 days after trastuzumab initiation. We classifed patients 3290 MUGAs (23.9%). The median number of on-treatment as receiving an anthracycline-containing chemotherapy regi- cardiac function tests per patient was 3 (range 0–13), and men if they had ≥ 1 dispensing of doxorubicin or epirubicin most patients (n = 3401, 79.5%) had 3 or more on-treatment during this period. We used ATC codes to identify patients cardiac function tests. who were dispensed a selective oestrogen receptor modu- The majority of patients (n = 2702, 63.1%) had both lator (tamoxifen or toremifene) and/or aromatase inhibitor baseline and regular on-treatment cardiac assessments, per

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Table 1 Baseline characteristics of study population and association with having a baseline cardiac function test (n = 5621) Baseline characteristic All Patients Baseline cardiac test N = 5621 (%) Yes No Univariate analysis N = 4984 N = 637 Odds Ratio (95% CI)

Age at frst trastuzumab dispensing ≤ 40 years 618 11.0 538 80 1.00 (Ref) 41–50 years 1300 23.1 1144 156 1.09 (0.82–1.46) 51–60 years 1557 27.7 1391 166 1.25 (0.94–1.66) 61–70 years 1275 22.7 1136 139 1.22 (0.91–1.63) 71–80 years 703 12.5 627 76 1.23 (0.88–1.71) > 80 years 168 3.0 148 20 1.10 (0.65–1.86) Year of frst trastuzumab dispensing 2015 1304 23.2 1143 161 1.00 (Ref) 2016 1263 22.5 1087 176 0.87 (0.69–1.09) 2017 1328 23.6 1192 136 1.24 (0.97–1.57) 2018 1347 24.0 1127 120 1.44 (1.12–1.85) 2019 379 6.7 335 44 1.07 (0.75–1.53) Remoteness Area Major cities 3956 70.7 3499 457 1.00 (Ref) Inner regional 1174 21.0 1060 114 1.21 (0.98–1.51) Outer regional 411 7.4 360 51 0.92 (0.68–1.26) Remote and very remote 54 1.0 43 11 0.51 (0.26–1.00) State of residence New South Wales & Australian Capital Territory 2101 37.4 1910 191 1.00 (Ref) Queensland 1039 18.5 920 119 0.77 (0.61–0.99) South Australia & Northern Territory 399 7.1 387 12 3.23 (1.78–5.84) Tasmania 135 2.4 96 39 0.25 (0.17–0.37) Victoria 1445 25.7 1366 79 1.73 (1.32–2.27) Western Australia 502 8.9 197 305 0.16 (0.12–0.20) Index of Relative Socioeconomic Disadvantage quintiles 1 (most disadvantage) 395 7.0 345 50 1.00 (Ref) 2 797 14.2 716 81 1.28 (0.88–1.86) 3 881 15.7 790 91 1.26 (0.87–1.82) 4 1482 26.4 1323 159 1.21 (0.86–1.69) 5 (least disadvantage) 2064 36.7 1808 256 1.02 (0.74–1.42) Number of cardiac medications in 6 months prior to trastuzumab initiation 0 3491 62.1 3158 418 1.00 (Ref) 1 976 17.4 872 108 1.07 (0.85–1.34) 2+ 1154 20.5 954 111 1.14 (0.91–1.42) Baseline comorbidity burden (RxRisk) in year prior to trastuzumab initiation 0–1 2052 36.5 1830 222 1.00 (Ref) 2–3 2102 37.4 1866 236 0.96 (0.79–1.17) 4+ 1467 1467 1288 179 0.87 (0.71–1.08)

26 Remoteness Area missing, 2 Index of Relative Socioeconomic Disadvantage missing guideline recommendations (Table 2). Very few patients tests (n = 3794, 67.5%). Nearly all patients (95.4%) with (n = 110, 2.6%) had regular on-treatment cardiac function a baseline echocardiogram had echocardiograms only for tests without a baseline test. on-treatment monitoring. Among patients with MUGA as Two-thirds of patients with a baseline cardiac func- their baseline test, 37.8% had at least one echocardiogram tion test had one or more on-treatment cardiac function for on-treatment cardiac assessment (Table 3).

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Table 2 Baseline characteristics and association with likelihood of having guideline-recommended (baseline and regular on-treatment) cardiac assessment in patients with at least 12 months of MBS data (n = 4280) Baseline characteristic Total Patients with baseline and regular on-treatment cardiac assessment Univariate analysis Multivariable analysis

N = 4280 N = 2702 (%) Odds Ratio (95% CI) Odds Ratio (95% CI) Age at frst trastuzumab dispensing ≤ 40 years 465 273 58.7 1.00 (Ref) 1.00 (Ref) 41–50 years 1010 624 61.8 1.14 (0.91–1.42) 1.16 (0.92–1.45) 51–60 years 1245 802 64.4 1.27 (1.02–1.58) 1.33 (1.06–1.67) 61–70 years 963 621 64.5 1.28 (1.02–1.60) 1.35 (1.06–1.73) 71–80 years 485 313 64.5 1.28 (0.99–1.66) 1.39 (1.04–1.87) > 80 years 112 69 61.6 1.13 (0.74–1.72) 1.27 (0.80–2.01) Year of frst trastuzumab dispensing 2015 1272 775 60.9 1.00 (Ref) 1.00 (Ref) 2016 1228 741 60.3 0.98 (0.83–1.15) 0.97 (0.82–1.14) 2017 1303 860 66.0 1.25 (1.06–1.46) 1.25 (1.06–1.48) 2018 477 326 68.3 1.38 (1.11–1.73) 1.34 (1.06–1.69) Remoteness Area Major cities 3011 1860 61.8 1.00 (Ref) 1.00 (Ref) Inner regional 891 580 65.1 1.15 (0.99–1.35) 1.26 (1.06–1.50) Outer regional 314 219 69.8 1.43 (1.11–1.84) 1.92 (1.45–2.55) Remote and very remote 44 28 63.4 1.08 (0.58–2.01) 1.69 (0.88–3.23) State of residence New South Wales & Australian Capital Territory 1607 1083 67.4 1.00 (Ref) 1.00 (Ref) Queensland 777 445 57.3 0.65 (0.54–0.77) 0.61 (0.51–0.74) South Australia & Northern Territory 299 299 67.6 1.01 (0.77–1.31) 0.95 (0.73–1.24) Tasmania 107 63 58.9 0.69 (0.47–1.03) 0.55 (0.36–0.85) Victoria 1101 756 68.7 1.06 (0.90–1.25) 1.05 (0.89–1.25) Western Australia 389 153 39.3 0.31 (0.25–0.39) 0.29 (0.23–0.37) Index of Relative Socioeconomic Disadvantage quintiles 1 (most disadvantage) 332 203 61.1 1.00 (Ref) 1.00 (Ref) 2 636 411 64.6 1.16 (0.88–1.53) 1.23 (0.93–1.64) 3 677 435 64.3 1.14 (0.87–1.50) 1.34 (1.00–1.77) 4 1129 717 63.5 1.11 (0.86–1.42) 1.34 (1.02–1.76) 5 (least disadvantage) 1505 935 62.1 1.04 (0.82–1.33) 1.33 (1.01–1.75) Number of cardiac medications in 6 months prior to trastuzumab initiation 0 2679 1697 63.3 1.00 (Ref) 1.00 (Ref) 1 751 474 63.1 0.99 (0.84–1.17) 0.97 (0.80–1.17) 2+ 850 531 62.5 0.96 (0.82–1.13) 0.97 (0.78–1.21) Baseline comorbidity burden (RxRisk) in year prior to trastuzumab initiation 0–1 1571 1012 64.4 1.00 (Ref) 1.00 (Ref) 2–3 1617 1034 64.0 0.98 (0.85–1.13) 0.97 (0.83–1.13) 4+ 1092 656 60.1 0.83 (0.71–0.97) 0.79 (0.65–0.97)

20 Remoteness Area missing, 1 Index of Relative Socioeconomic Disadvantage missing

Concomitant chemotherapy and endocrine therapy before and 60 days after their frst trastuzumab dispensing. Less than half of patients received an anthracycline as part Nearly all patients (n = 5550, 98.7%) were dispensed at of their chemotherapy regimen (n = 2571, 45.7%). Over least one dose of cytotoxic chemotherapy between 120 days half of patients were dispensed endocrine therapy between

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Table 3 Types of cardiac Baseline cardiac func- Type(s) of cardiac function test during monitoring Total function tests performed at tion test baseline and in follow-up in patients who had a baseline Echocardiogram only MUGAs only Echocardiogram and cardiac test and at least one MUGAs on-treatment cardiac test Echocardiogram 2495 (95.4) 47 (1.8) 73 (2.8) 2615 (n = 3794) MUGA​ 230 (19.5) 733 (62.2) 216 (18.3) 1179

Row percentages in parentheses

120 days before and 540 days after trastuzumab initiation anthracycline-containing regimens versus non-anthracy- (n = 3248, 57.8%). cline-containing chemotherapy regimens (62.6% vs 63.6%, OR 0.96, 95% CI 0.85–1.09). Factors associated with cardiac assessment

The likelihood of having baseline cardiac assessment was Discussion associated with geographical factors (Table 1). Compared to patients residing in capital cities, those in remote and In this observational study of patients with HER2+EBC, very remote regions were less likely to have baseline cardiac a large majority had baseline cardiac assessment (88.7%) function assessment (OR 0.51, 95% CI 0.26–1.00). The pro- and at least one on-treatment cardiac assessment in the portion of patients with baseline cardiac assessment varied 12 months following trastuzumab initiation (93.7%). How- signifcantly by State. We found no evidence of associations ever, less than two-thirds (63.1%) had guideline-recom- between age, remoteness of residence, socioeconomic disad- mended cardiac assessments (both baseline and regular on- vantage, use of cardiovascular medicines or overall comor- treatment cardiac function tests). Age, overall comorbidity bidity burden with baseline cardiac assessment. There was burden, year of trastuzumab initiation, remoteness, socio- little diference in baseline cardiac assessment rates between economic disadvantage and State of residence impacted on patients who received an anthracycline-containing versus the likelihood of patients having guideline-recommended those who received a non-anthracycline-containing chemo- cardiac assessments. therapy regimen (OR 1.14, 95% CI 0.97–1.35). Our cardiac monitoring rates are higher than those Age, year of trastuzumab initiation, remoteness, socio- reported in US population-based studies of patients receiv- economic disadvantage and comorbidity burden were ing (neo)adjuvant trastuzumab that used similar defnitions associated with having guideline-recommended (i.e. base- of adequate cardiac assessment. In these studies, around line and regular on-treatment) cardiac assessment in our three-quarters of patients (74–79%) had a baseline car- multivariable model (Table 2). Patients aged 50–80 years diac assessment and less than half (42–46%) had regular were more likely to have guideline-recommended cardiac on-treatment assessments [22, 23]. One possible explana- assessment than those aged ≤ 40 years. The proportion of tion for these diferences is that Australia’s universal pub- patients with guideline-recommended cardiac assessments lic health system poses less fnancial barriers to testing as increased from 60.9% in 2015 to 68.3% in 2018 (OR 1.34, most patients do not incur out-of-pocket costs for these 95% CI 1.06–1.69). Patients who lived in inner and outer assessments. Furthermore, PBS restrictions linking car- regional Australia were more likely to have guideline-rec- diac assessment to drug access provide stronger impetus for ommended cardiac assessment than those in capital cities Australian clinicians and patients to adhere to guidelines. (inner regional: OR 1.26, 95% CI 1.06–1.50; outer regional: Conversely, considering that baseline and 3-monthly cardiac OR 1.92, 95% CI 1.45–2.55). After adjusting for other fac- assessments are a pre-requisite for accessing government- tors, compared to patients with the most socioeconomic subsidised trastuzumab, the proportion of patients meeting disadvantage (quintile 1), patients with less socioeconomic these prescribing criteria (63.1%) is lower than expected. disadvantage (quintiles 3, 4 and 5) were more likely to have Other studies from Europe and North America, using vari- guideline-recommended cardiac assessment. Patients in the ous defnitions of adequate cardiac monitoring, report that highest category of baseline comorbidity burden according 67–91% of patients receiving trastuzumab for HER2+EBC to RxRisk index (4+ comorbidities) were less likely to have had baseline cardiac tests and 16–79% had adequate cardiac baseline and regular on-treatment cardiac tests than those monitoring [24–29]. with 0–1 comorbidities (OR 0.79, 95% CI 0.65–0.97). The In our study, known individual baseline character- proportions of patients with guideline-recommended car- istics relating to cardiotoxicity risk did not appear to diac assessment were similar between those who received play a major role in determining whether a patient had

1 3 Breast Cancer Research and Treatment guideline-recommended cardiac assessment. We found no cardiac assessment, which ranged between 39% and 68%. evidence of an association between dispensing of cardio- Regional variations in cardiac monitoring practices have vascular medicines, which may indicate increased cardiac been previously reported in HER2+EBC patients in Canada risk, and the likelihood of having baseline and regular on- and the US [23, 26]. The Australian States and Territories treatment cardiac function tests. The rates of guideline-rec- with the highest rates of cardiac function assessment (New ommended cardiac assessment in our study were similar in South Wales, Australian Capital Territory and Victoria) are patients with and without anthracycline in their chemother- also those with the highest population density in Australia, apy regimens, in contrast to previous studies that reported suggesting that access to health care may infuence rates of associations between anthracycline use and adequate cardiac guideline-recommended cardiac testing. State-based difer- assessment [8, 22, 23]. Younger patients were less likely to ences in cardiac testing among patients with HER2+EBC receive guideline-recommended cardiac assessment, which parallel State-based diferences in MBS-funded echocardio- aligns with existing reports [8, 23]. Patients with the highest gram and MUGA tests per capita between 2015 and 2019, overall comorbidity burden (4+ baseline comorbidities) were refecting variations in general cardiac service utilisation less likely to have guideline-recommended cardiac assess- between States [38]. The reasons for these State-based ment, which is surprising as they are likely to have more variations in cardiac testing practices, both in patients with frequent contact with the health system and elicit greater HER2+EBC and the wider population, are unclear. While clinical concern regarding treatment tolerance. This could be cardiac function tests in all States and Territories are funded related to increased treatment burden and reduced functional through the national MBS, there may be potential diferences status associated with multimorbidity, which may act as bar- in healthcare delivery through public hospitals, which are riers to attending regular cardiac function tests [30, 31]. administered by individual State governments. Broader system-level factors afected cardiac assessment Due to variability in ejection fraction measurement by patterns in our study. For instance, the increase in propor- diferent cardiac assessment modalities, it is recommended tion of patients with guideline-recommended cardiac assess- that serial measurements of cardiac function should be ment suggests that clinicians were more likely to practice performed using the same modality to limit intermodality in accordance with guidelines over time. This trend is con- variation [39, 40]. Most patients with baseline echocardio- sistent with previous reports of higher rates of guideline- grams appropriately continued to have echocardiograms for recommended cardiac monitoring among patients with a on-treatment monitoring (95.4%). In contrast, a signifcant more recent year of diagnosis [22, 23]. Area-level socioeco- proportion of patients with baseline MUGAs (37.8%) had nomic disadvantage appears to hinder quality cancer care, one or more echocardiograms for ongoing monitoring. as refected by the lowest rates of guideline-recommended To our knowledge, this is the frst report of cardiac moni- cardiac assessment in patients with the most socioeconomic toring in patients with HER2+EBC receiving trastuzumab disadvantage in our study. Even in universal health systems in Australia. A strength of this study is population-wide with fewer fnancial barriers to services, other socioeco- capture of cardiac testing practices in patients receiving nomic factors, such as availability of sick leave, access to trastuzumab for HER2+EBC within a universal health sys- childcare, health literacy and transportation availability and tem. We identifed all government-subsidised cardiac func- costs, may hinder access to health care. Studies conducted tion tests, but were unable to capture tests funded outside within Canada’s universal health care system also demon- the MBS, which may lead to potential under-ascertainment strate that lower socioeconomic status is associated with of cardiac assessment. However, there is a strong fnancial underutilisation of specialist services and diagnostic imag- incentive for patients to have MBS-funded testing and the ing [32, 33]. Cardiac assessment is one of several elements large proportion of patients for whom a baseline cardiac of breast cancer care that can be afected by socioeconomic assessment was identifed (88.7%) suggests that very few status, including access to breast cancer multidisciplinary tests were performed outside the MBS. A weakness of our care and uptake of breast-conservation surgery and chemo- study, inherent in observational studies using health admin- therapy [34, 35]. istrative data, is the lack of clinical details, such as specifc Patients living in remote and very remote regions were baseline cardiac risk factors, results of cardiac function tests less likely to receive baseline cardiac assessment than capital and hence incidence of cardiotoxicity during trastuzumab city residents, consistent with previous reports of poorer can- treatment. While it is commonly accepted that baseline and cer care in non-metropolitan, rural and remote Australia [36, 3-monthly cardiac assessment is the standard of care for 37]. Surprisingly, rates of guideline-recommended cardiac patients receiving (neo)adjuvant trastuzumab, these guide- assessment were higher among patients in inner regional lines are based on management of patients in trials rather (65.1%) and outer regional Australia (69.8%) than those liv- than clinical trial evidence. It is unclear whether current car- ing in capital cities (61.8%). Furthermore, State of residence diac assessment guidelines are warranted in all patients with had the greatest impact on rates of guideline-recommended HER2+EBC, or whether frequency of monitoring could be

1 3 Breast Cancer Research and Treatment adapted according to patients’ cardiotoxicity risk [41]. In submitted work. Sallie-Anne Pearson is a member of the Drug Utilisa- fact, there is interest in de-escalating intensity of cardiac tion Sub Committee of the Pharmaceutical Benefts Advisory Com- mittee. The views expressed in this paper do not represent those of the testing for patients with early breast cancer and a randomised Committee. The Centre for Big Data Research in Health, UNSW Syd- controlled non-inferiority trial is under way comparing dif- ney has received funding from AbbVie Australia to conduct research, ferent schedules of cardiac monitoring [42]. unrelated to the present study. AbbVie did not have any knowledge of, or involvement in, the present study. All remaining authors have declared no conficts of interest relevant to the submitted work.

Conclusion Ethical approval This study was approved by the New South Wales Population and Health Services Research Ethics Committee (Approval Number: 2010/02/213). The Ethics Committee granted a waiver of the The majority of patients receiving (neo)adjuvant trastu- usual requirement for the consent of the individual to the use of their zumab for HER2+EBC had baseline and on-treatment health information in a research project, in line with the Guidelines cardiac monitoring that was in line with guidelines and approved under Sect. 95/95A of the Privacy Act 1988. The study was trastuzumab prescribing requirements in Australia. Factors performed in accordance with the Declaration of Helsinki. with the greatest association with cardiac monitoring prac- Consent for publication Not applicable. tices were mainly related to broader factors, such as year of diagnosis and geography, rather than individual patient characteristics. While it is encouraging that cardiac assess- ment improved over time, there is substantial variation in References cardiac function testing associated with socioeconomic disadvantage, remoteness and State/Territory of residence. 1. Nemeth BT, Varga ZV, Wu WJ, Pacher P (2017) Trastuzumab car- There needs to be more investigation into these system-level diotoxicity: from clinical trials to experimental studies. Br J Phar- macol 174(21):3727–3748. https​://doi.org/10.1111/bph.13643​ barriers to cardiac monitoring in order to improve the rate 2. Maurea N, Coppola C, Piscopo G, Galletta F, Riccio G, Espos- of guideline-recommended cardiac assessment in patients ito E, De Lorenzo C, De Laurentiis M, Spallarossa P, Mercuro with HER2+EBC. GJJoCM (2016) Pathophysiology of cardiotoxicity from tar- get therapy and angiogenesis inhibitors. 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J Clin Oncol 31(33):4222 for editing and reviewing the manuscript. 5. Elting LS, Cooksley C, Bekele BN, Frumovitz M, Avritscher EBC, Sun C, Bodurka DC (2006) Generalizability of cancer Funding This research is supported by the National Health and Medi- clinical trial results. Cancer 106(11):2452–2458. https​://doi. cal Research Council Centre of Research Excellence in Medicines org/10.1002/cncr.21907​ Intelligence (ID: 1196900). MT is supported by an Australian Gov- 6. Pearson S-A, Ringland CL, Ward RL (2007) Trastuzumab and ernment Research Training Program Scholarship, a National Health metastatic breast cancer: trastuzumab use in Australia—monitor- and Medical Research Council Postgraduate Research Scholarship (ID: ing the efect of an expensive medicine access program. J Clin 1151479), a National Breast Cancer Foundation Postgraduate Schol- Oncol 25(24):3688–3693 arship Top-Up (ID: DS-18–01), and a Translational Cancer Research 7. Lu CY, Srasuebkul P, Drew AK, Ward R, Pearson SA (2012) Network Clinical PhD Scholarship Top-Up award, supported by the Positive spillover efects of prescribing requirements: increased Cancer Institute NSW. AS is supported by a National Health and Medi- cardiac testing in patients treated with trastuzumab for HER2+ cal Research Council Early Career Fellowship (ID: 1158763). metastatic breast cancer. Int Med J 42(11):1229–1235 8. Lu CY, Srasuebkul P, Drew AK, Chen K, Ward RL, Pearson S-A Data availability We thank the Australian Government Services Aus- (2013) Trastuzumab therapy in Australia: which patients with tralia for providing the data. Access to the datasets analysed during HER2+ metastatic breast cancer are assessed for cardiac func- the current study is not permitted without the express permission of tion? The Breast 22(4):482–487 the approving human research ethics committees and data custodians. 9. 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42. Aseyev O, Stober C, Sulpher J, Clemons M, Johnson C, Fer- Publisher’s Note Springer Nature remains neutral with regard to gusson D, Vandermeer L, Mazzarello S, Dent S (2017) Com- jurisdictional claims in published maps and institutional afliations. parison of two care schedules for monitoring of cardiotoxicity in patients receiving trastuzumab-based therapy for early-stage breast cancer: study protocol for a randomized controlled non- inferiority trial. Clin Trials Degener Dis 2(2):40–45. https://doi.​ org/10.4103/2542-3975.20968​6

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