2.1 Patient Cohort and Study Design

This study utilized retrospective observational data from both the Medical Data Vision Co., Ltd. (MDV) database and World Health Organization’s (WHO’s) VigiBase. The MDV database is a de-identified database comprising discharge summaries and medical insurance billing data obtained from inpatient and outpatient visits at Japanese hospitals using the Diagnosis Procedure Combination system [25]. The Diagnosis Procedure Combination system includes hospitals providing acute care and other services, incorporating many of Japan’s major medical and cancer centers. As of January 2021, the MDV database includes patient data for approximately 34.84 million individuals [26].

In addition, adverse event reports for the trastuzumab originator and its biosimilars were obtained from WHO’s VigiBase, the global adverse event reporting database maintained by the Uppsala Monitoring Center in Uppsala, Sweden. VigiBase is the world’s largest database of adverse event reports, with more than 33 million reports collected worldwide as of December 2023. The datasets collected up to December 2023 were used in this study. Duplicate reports, as determined by the Uppsala Monitoring Center using statistical algorithms, were excluded from the analysis.

The data were processed using the SQLite database 3.33.0 for both the MDV database and WHO’s VigiBase. The study was conducted in accordance with the Declaration of Helsinki and Good Pharmacoepidemiology Practices. According to Japan’s Ethical Guidelines for Medical and Health Research Involving Human Subjects [27], this study, being a non-interventional retrospective study using anonymized patient data, did not require informed consent. The study was conducted with approval from the Ethics Committee of Okayama University Hospital after a thorough review (approval number 2401-045).

2.2 Exclusion and Inclusion Criteria

This study utilized data from the MDV database, which included 31,661 patients with breast cancer treated with at least one antineoplastic agent (classified under the WHO ATC code L01) from April 2008 to December 2022. These patients received their first administration of anti-HER2 drugs during this period. The focus was on patients with HER2-positive breast cancer eligible for surgery. The overall study cohort consisted of patients treated with either the trastuzumab originator or its biosimilars, defined based on the following criteria: individuals with a confirmed diagnostic code for breast cancer (excluding breast sarcoma), individuals using anti-HER2 therapy, individuals with no concurrent use of trastuzumab originator and its biosimilars, individuals without a gastric cancer diagnosis, individuals who have undergone breast cancer surgery, individuals with no recurrence of breast cancer prior to surgery, individuals using anti-HER2 therapy within the specified treatment window (less than 240 days prior to surgery and up to less than 180 days post-surgery), and individuals continuing anti-HER2 therapy after preoperative chemotherapy and surgery. Patients were assigned to either the “trastuzumab originator group” or the “biosimilars group.” For cases after September 2018, observation durations and recurrence rates were specifically analyzed for post-approval cases.

2.3 Data Collection and Outcome Measures from the MDV Database

Patient characteristics were collected from medical procedure data based on the first use date of anti-HER2 drugs. Additionally, blood test results for aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and B-type natriuretic peptide (BNP) were utilized. Patients were categorized into two groups based on the timing of their initial anti-HER2 therapy: those who received their first anti-HER2 treatment preoperatively, designated as the neoadjuvant chemotherapy (NAC) group, and those who received their first treatment postoperatively, designated as the postoperative group.

The cytotoxic agents used included epirubicin, carboplatin, docetaxel, paclitaxel, doxorubicin, cyclophosphamide, methotrexate, and fluorouracil. Treatment regimens were defined as combinations of breast cancer drugs and classified into anthracycline-taxane, taxane, anti-HER2 monotherapy, and other categories. Furthermore, the classification was refined based on the concurrent use of pertuzumab. The count of administrations was strictly limited to the perioperative period, excluding any recurrences. The follow-up period was assessed from the initial administration of the anti-HER2 drugs to the last consultation.

In the studies of the “trastuzumab originator group” and “biosimilars group,” infusion reactions, heart failure, and liver dysfunction were examined. For infusion reactions, only anti-HER2 monotherapy without concomitant use of other cytotoxic agents was considered to eliminate the influence of concomitant medications. The presence or absence of pertuzumab was not considered. Patients who received an intravenous administration of dexchlorpheniramine, hydroxyzine, hydrocortisone, ropivacaine, or acetaminophen on the day of the first administration were included. For heart failure, patients were evaluated based on hospitalization records with a diagnosis of heart failure from the day of the first administration of the trastuzumab originator or its biosimilars until 60 days after the last administration. Confirmation of heart failure diagnosis during this period or BNP levels above 100 pg/mL were also considered. Liver dysfunction was assessed by measuring total bilirubin, AST, and ALT levels, and classified according to Common Terminology Criteria for Adverse Events version 5.0 criteria, with Grade 2 or higher for total bilirubin and Grade 3 or higher for AST and ALT. The analysis focused exclusively on the use of the trastuzumab originator or its biosimilars. The frequency of administration and medical costs were studied for the perioperative period of anti-HER2 drug treatment. Only the costs associated with the trastuzumab originator or its biosimilars during this period were included. Cases with more than 30 administrations were excluded.

2.4 Data Collection and Analysis from VigiBase

To assess the global reporting frequency, the total number of adverse event reports for the trastuzumab originator and biosimilars was counted using WHO’s VigiBase, the global adverse event reporting database maintained by the Uppsala Monitoring Center in Uppsala, Sweden. VigiBase is the world’s largest database of adverse event reports, with more than 33 million reports collected worldwide as of December 2023. The datasets collected up to December 2023 were used in this study. Duplicate reports, as determined by the Uppsala Monitoring Center using statistical algorithms, were excluded from the analysis. Adverse events were evaluated for the following categories: infusion reaction, cardiac disorders, lung disorders, hepatic disorders, and central nervous system vascular disorders. The definition of adverse event names conformed to the Medical Dictionary for Regulatory Activities, and adverse event risk was evaluated by calculating the reporting odds ratios (RORs) with 95% confidence intervals (CIs). A trend analysis, conducted to account for the effect of the introduction of biosimilars, was based on the accumulation of reports after biosimilars were marketed. The odds ratio and 95% CIs were calculated to confirm the accumulation of reports with the increase in reporting frequency. Using datasets up to December 2021, the global utilization of biosimilars from VigiBase is shown. The color-coded maps represent the number of reports for each of the WHO-defined regions: African Region, Region of the Americas, Eastern Mediterranean Region, European Region, South-East Asia Region, and Western Pacific Region.

2.5 Statistical Analysis

In the MDV database, descriptive statistics are presented as counts and percentages (n [%]), means with standard deviations, and/or medians with ranges (minimum-maximum or interquartile range) where applicable. Statistical comparisons between groups were conducted using Fisher’s exact test. No adjustments were made for bias or confounding factors. Missing data were not imputed. The Kaplan–Meier method was used to estimate the median recurrence period and 95% CIs. The observation period and recurrence period were assessed from the first use of the trastuzumab originator or biosimilars until the last recorded hospital visit.

In WHO’s VigiBase, individuals were divided into the following four groups: (a) Individuals who received biosimilars and exhibited adverse events. (b) Individuals who received biosimilars but did not exhibit adverse events. (c) Individuals who received the trastuzumab originator and exhibited adverse events. (d) Individuals who received the trastuzumab originator but did not exhibit adverse events. The ROR was calculated as the ratio of the odds of reporting an event when administered biosimilars to the odds of reporting an event when administered the originator. Adverse event reports were divided into the four groups to construct a 2×2 table for analysis. The ROR with 95% CI was defined as follows:

$$} = \, \left( b} \right)/\left( d} \right).$$

A significant association was assumed if the lower limit of the 95% CI was > 1 for increased risk, or the upper limit of the 95% CI was < 1 for decreased risk. All statistical analyses were performed using R statistical software version 4.0.3 (The R Foundation, Vienna, Austria).