Economic Evaluation of Treatment With Trastuzumab Deruxtecan for HER2-Low Advanced or Metastatic Breast Cancer in Previously Treated Patients

Abstract

Objectives

This study evaluates the efficiency and budgetary impact of trastuzumab deruxtecan (T-DXd) compared with standard therapy in previously treated HER2-low advanced or metastatic breast cancer, from the perspective of the Spanish National Health System.

Methods

A partitioned survival model was developed using data from the DESTINY-BREAST04 trial. Health outcomes were measured in quality-adjusted life years (QALYs) for both the overall population and the hormone receptor-positive (RH+) subgroup. The analysis was conducted from the perspective of the Spanish National Health System over a 75-month time horizon. A univariate sensitivity analysis was performed to explore parameter uncertainty. Costs were derived from Spanish healthcare databases and expert input.

Results

At 75 months, for the overall patient population, the total healthcare cost for patients treated with T-DXd was €201,328.27, compared with €64,654.80 with standard therapy. T-DXd provided 1.24 QALYs (2.24 life years), while standard therapy provided 1.03 QALYs (1.86 life years). The incremental cost–utility ratio (ICUR) for T-DXd compared with standard of care (SOC) was €648,710.32/QALY. For the hormone receptor-positive (RH+) subgroup, the total healthcare cost for patients treated with T-DXd was €204,262.69, compared with €71,596.21 with standard therapy. T-DXd provided 1.33 QALYs (2.46 life years), while standard therapy provided 1.08 QALYs (1.99 life years). The ICUR for T-DXd compared with SOC was €541,758.59/QALY. The estimated 5-year budget impact ranged from €72 million to €140 million for the overall population and €64 million to €124 million for the RH+ subgroup.

Conclusions

Trastuzumab deruxtecan in HER2-low advanced or metastatic breast cancer shows limited cost effectiveness and represents a significant budgetary challenge for the Spanish National Health System, particularly in RH+ patients.

Supplementary Information

The online version contains supplementary material available at 10.1007/s41669-025-00592-0.

Key Points for Decision Makers

In previously treated patients with HER2-low advanced or metastatic breast cancer, trastuzumab deruxtecan (T-DXd) shows a high incremental cost-effectiveness ratio compared with standard therapies, exceeding commonly accepted willingness-to-pay thresholds in the Spanish healthcare system.

The budget impact analysis for the Spanish National Health System reveals significant financial pressure due to T-DXd, raising concerns about its affordability and sustainability for widespread adoption in this patient population.

Introduction

Breast cancer is the most common malignancy in women across Europe, with approximately 500,000 new cases diagnosed annually, accounting for nearly 25% of all cancer diagnoses in women [1]. Despite advances in treatment, breast cancer remains the leading cause of cancer-related mortality among women in Europe, with over 130,000 deaths reported each year [2]. In Spain, breast cancer is the most frequently diagnosed malignancy in women, representing 30% of all female cancer cases. According to the Spanish Society of Oncological Medicine (SEOM), an estimated 36,395 new cases of breast cancer would be diagnosed in Spain in 2024. This makes it the most common neoplasm in Spain, ahead of colorectal, lung, endometrial, thyroid and pancreatic cancer. These figures highlight the public health burden of breast cancer both in Europe and in Spain [1].

Among the subtypes of breast cancer, tumours with low HER2 expression, defined as those with lower concentrations of the HER2 protein on their cell surface, represent approximately 45–55% of all breast cancers [2]. These tumours are characterized by limited treatment options. Historically, patients with HER2-low tumours have been treated with chemotherapy regimens such as capecitabine, eribulin, and paclitaxel, which are associated with significant toxicity and suboptimal outcomes [3–5].

The recent approval of trastuzumab deruxtecan (T-DXd) offers a novel therapeutic option for patients with HER2-low metastatic breast cancer. T-DXd, administered intravenously, specifically targets HER2, leading to internalization and cleavage of the intracellular linkage via lysosomal enzymes. Once released, deruxtecan (DXd), a topoisomerase I inhibitor, crosses the cell membrane, damages DNA and induces cell death by apoptosis [6].

The efficacy of T-DXd treatment was demonstrated in the DESTINY BREAST04 clinical trial [3]. This trial involved patients with unresectable and/or metastatic low-HER2 breast cancer, with positive or negative hormone receptors (HR), who had previously undergone one or two rounds of chemotherapy. A total of 557 patients were included. The patients were randomly assigned in a 2:1 ratio to receive either trastuzumab deruxtecan (5.4 mg/kg) or the doctor's choice of chemotherapy support (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). Follow-up was conducted for 34 months [3]. The trial showed that treatment with T-DXd resulted in a statistically significant improvement in progression-free survival (HR 0.50; 95% CI 0.40–0.63) and overall survival (HR 0.64; 95% CI 0.49–0.84) compared with standard treatment.

T-DXd is approved in Spain and the European Union for treatment of unresectable or metastatic breast cancer with low HER2 expression (HER2-low) after prior chemotherapy. This treatment was initially approved for patients with unresectable or metastatic HER2-positive breast cancer who have previously received one or more guideline therapies targeting HER2 or who have experienced a recurrence of disease within 6 months of completing adjuvant or neoadjuvant chemotherapy [6, 7]. It has also been approved for use in gastric or gastroesophageal junction adenocarcinoma [7].

This report aims to assess the incremental cost-effectiveness ratio and budgetary impact of T-DXd treatment compared with standard of care in women with advanced or metastatic HER2-low breast cancer who have previously received one or two rounds of chemotherapy. The analysis is conducted from the perspective of the Spanish National Health System.

Materials and Methods

A cost-utility analysis was conducted using a partitioned survival model with three mutually exclusive health states: progression-free (initial state), progression, and death (end state) (Fig. 1). The model was developed using data from the DESTINY-BREAST04 clinical trial [3] and cost and resource use data were adapted to reflect the perspective of the Spanish National Health System (NHS). Cost data were sourced from official Ministry of Health databases and published literature. The analysis was conducted over a 75-month time horizon, incorporating monthly cycles. This period was selected to extend the evaluation beyond the 34-month follow-up period of the DESTINY-BREAST04 clinical trial, with the objective of more accurately capturing long-term variations in costs and outcomes between treatments. This report was created using the CHEERS 2022 checklist adapted into Spanish [8] (Table S1 in the electronic supplementary material [ESM]). The alternative therapies analysed were T-DXd versus standard of care (capecitabine, gemcitabine, eribulin, paclitaxel, nab-paclitaxel, sacituzumab govitecan, or vinorelbine). These two options were compared in two groups—the total sample enrolled in the DESTINY-BREAST04 clinical trial and a subgroup of hormone receptor-positive (RH+) patients. This trial was chosen because it provides robust and high-quality evidence on the efficacy of T-DXd in HER2-low metastatic breast cancer, making it the most relevant source for this analysis.

Fig. 1.

Diagram of the partitioned survival model used in the cost-effectiveness analysis, including three mutually exclusive health states: progression-free, post-progression, and death

Health outcomes were measured as quality-adjusted life years (QALY), which is the length of survival weighted for quality of life (utility). Additionally, overall survival (OS) and progression-free survival (PFS), as reported in the clinical trial, were used to validate the model's outcomes and ensure consistency with the source data. Adverse events were included in the model if they occurred in at least 20% of patients and were grade ≥ 3. The only exception was nausea and vomiting, which, as T-DXd is considered a moderately emetogenic agent [9], was classified as a single adverse event type with all grades included due to the high number of patients experiencing this type of event.

OS and PFS curves were modelled to determine the average time spent by patients with these two health states. Data points obtained by digitizing survival curves and aggregated data from the DESTINY-BREAST04 publication were used to trace Kaplan-Meier curves, according to the algorithm described by Guyot et al. (2012) [10]. Cox regression hazard ratios (HRs) were calculated to compare the obtained data with the original data. Multiple parametric distributions (e.g., gamma, lognormal, Weibull, Gompertz) were analysed. The final curve selection was based on (1) Akaike information criterion (AIC) values, which reward the goodness of fit of the model to the data and penalize overfitting; (2) visual comparison of the modelled curves with the test curve; and (3) clinical validation conducted by health professionals [11] (Tables S2, S3, Fig. S1, see ESM). Based on these criteria, the Weibull distribution was selected for both OS and PFS curves, as it provided the best balance of goodness-of-fit, interpretability, and clinical relevance. The AIC values supporting this choice are detailed in Tables S2 and S3 of the ESM. The Kaplan-Meier curves and the selected parametric survival curves for both OS and PFS are shown in Figures 2a and 2b, respectively. All the above analyses were performed using the Flexsurv package of the statistical program ‘R’ v3.3.2.

Fig. 2.

Projected health state distribution over 75 months for patients receiving trastuzumab deruxtecan

Utility values were obtained from the systematic review performed by Paracha et al. (2016) [12]. This review aimed to identify utility values related to health states in breast cancer. Data were preferably collected using direct methods developed for health technology assessment agencies. Utility values related to the presence of adverse events were neither applied nor estimated.

The study estimated the total healthcare costs within the Spanish National Health System (NHS) for different approaches. Given the complexity and difficulty of collecting data on all potential subsequent treatment rounds after disease progression, the most likely treatment options were agreed based on recommendations from the EMA, the Therapeutic Position Statements of the Spanish Agency for Medicine and Healthcare Products [4, 5], the Austrian Institute for Healthcare Technology Assessment (AIHTA) [13], and the Guide to the Integrated Breast Cancer Care Process of the Public Health System of Andalusia [14]. A panel of three experts, including one oncologist and two hospital pharmacists, reached consensus through structured discussions and iterative feedback sessions to estimate the frequency of use of each type of drug (capecitabine, gemcitabine, eribulin, paclitaxel, nab-paclitaxel, sacituzumab govitecan, and vinorelbine). These estimates also considered the frequencies described in the hallmark trials for each scenario. Table S4 shows the treatments used after relapse and the proportions used (see ESM). Bot-Plus was used to obtain the laboratory sales price of drugs in the primary care setting [15], while the official Ministry of Health database, Nomenclator [16] (March 2020), was used for the hospital setting, after deducting possible legal discounts. A standard weight of 70 kg and a body surface area of 1.65 m² were considered for patients.

Defined activities, established standards, and identified resources were used to estimate the costs of adverse events. Cost data for diagnostic tests, clinic visits, and procedures were extracted from the 2005 Official Bulletin of the Council of Andalusia [17, 18] and subsequent updates. Medical costs post-progression were assumed to remain stable due to a lack of specific data on variations in resource use during this phase. This assumption has been tested through sensitivity analysis to explore its potential impact on the results. The costs of T-DXd and premedication (ondansetron and dexamethasone) were also included [6, 9]. Table 1 provides a comprehensive overview of the considerations used to estimate the direct healthcare costs, including the monthly costs of adverse events, follow-up care, pharmaceutical treatments, and medical appointments. These considerations represent the most relevant factors based on the availability and reliability of the data. Costs were updated to 2023 using the Consumer Price Index [19] as more recent data were not available at the time of analysis. A total of five healthcare professionals, including two hospital pharmacists, two pharmacoeconomists, and one medical oncologist, validated the data to ensure that the assumptions were consistent with clinical practice in the NHS. Consensus was reached through structured discussions and iterative feedback sessions.

Table 1.

Direct healthcare costs used to estimate the monthly costs of adverse events, follow-up care, medications, and related visits in patients with HER2-low metastatic breast cancer

Types of adverse events			Monthly cost (€)
Anaemiaa			12,745.65
Epoetin alfa		x4	1531.28
Follow-up consultations (specialized)			78.05
Transfusions		x2	11,128.75
Haemogram			7.58
Neutropeniab			219.46
Ratiograstim (biosimilar filgrastim)		x4	35.47
Haemogram			7.58
Follow-up consultations (specialized)			78.05
Diarrhoea			615.46
Loperamide			6.10
Medical oncologyc			531.31
Follow-up consultations (specialized)			78.05
Nausea and vomiting (grade ≤2)			84.49
Follow-up consultations (specialized)			78.05
Ondansetron 8 mg intravenous route			6.44
Nausea and vomiting (grade ≥ 3)			531.31
Medical oncology			531.31
Constipation			81.16
Follow-up consultations (specialized)			78.05
Duphalac 10g, 10 sticks 15 mL			3.11
Thrombopenia			85.63
Haemogram			7.58
Follow-up consultations (specialized)			78.05
Aminotransferase elevated			85.63
Haemogram			7.58
Follow-up consultations (specialized)			78.05
Follow-up examinations			120.23
Axial computed tomography (every 5 months)			34.60
Haemogram			7.58
Follow-up consultations (specialized)			78.05
Medications
Capecitabine (1250 mg/m2 oral) twice/day.  Days 1–14 every 21 days	€0.001/mg		82.50
Eribulin (1.23 mg/m2 IV). Days 1 and 8 every 21 days	€363.64/mg		1372.68
Gemcitabine (1000 mg/m2 IV). Days 1, 8 and 15 every 28 days	€0.044/mg		231.77
Paclitaxel (175 mg/m2 IV) every 21 days	€1,309/mg		539.92
Nab-paclitaxel (260 mg/m2 IV) every 21 days	€2.40/mg		1470.86
Trastuzumab deruxtecan (5.4 mg/kg IV) every 21 daysd	€17.65/mg		9531.16
Ondansetron (8 mg IV) prior to each T-DXd cycle	€2.17/mg		6.19
Ondansetron (16 mg orally) before each cycle of T-DXd	€2.36/mg		6.76
Dexamethasone (12 mg intravenously) before each cycle of T-DXd	€0.82/mg		1.94
Dexamethasone (8 mg oral) before each cycle of T-DXd	€0.41/mg		0.59
Sacituzumab-govitecan (10 mg/kg IV) days 1 and 8 every 21 days	€5155/mg		5155.00
Vinorelbine (60–80 mg orally) once per week	€1356/mg		749.18
Drug administration costs
Capecitabine (1250 mg/m2 oral) twice/day.  Days 1–14 every 21 days	€ 0		0
Eribulin (1.23 mg/m2 IV). Days 1 and 8 every 21 days	€443.50		1268.41
Gemcitabine (1000 mg/m2 IV). Days 1, 8 and 15 every 21 days	€443.50		1902.61
Paclitaxel (175 mg/m2 IV). Every 21 days	€443.50		634.21
Nab-paclitaxel (260 mg/m2 IV) every 21 days	€443.50		634.21
Vinorelbine (60–80 mg orally) once per week	€0		0
Trastuzumab deruxtecan (5.4 mg/kg IV) every 21 days	€443.50		769.52
Sacituzumab govitecan (10 mg/kg IV) days 1 and 8 every 21 days	€443.50		1518.04

Costs are calculated based on the dosage per administration and the frequency described (e.g., per cycle, weekly), multiplied to reflect a monthly total. Subtotals reflect average costs derived from multiple sources, and minor discrepancies may occur due to rounding or adjustments in the aggregation process. When a multiplier is indicated (e.g., × 4, × 2), the cost reflects the total for the specified number of units administered

All health care costs were collected from the Official Bulletin of the Council of Andalusia (BOJA) 2005 and its updates [17, 18]

All drug costs were obtained from the BOTPLUS database and the Official Gazette [15, 16]

All costs have been updated to the year 2023

IV intravenous, T-DXd trastuzumab deruxtecan

^aTwo blood transfusions and four doses of epoetin alfa were considered

^bGrowth factors were considered to be filgrastim once a week and a visit to a specialist

^cThe cost of medical oncology was considered as the cost of hospitalization

^dThe cost of premedication (ondansetron and dexamethasone) was included in the cost of T-DXd

Table 2 summarizes the main cost and utility inputs used in the base-case analysis. These include pharmaceutical acquisition costs, management costs of adverse events, follow-up costs, and health state utilities. All values were derived from published literature, official Spanish healthcare databases, or expert consensus, and reflect the perspective of the Spanish National Health System. These inputs served as the basis for both the cost-effectiveness and budget impact analyses.

Table 2.

Cost and utility values employed in the budget impact evaluation and cost-effectiveness analysis of trastuzumab deruxtecan (T-DXd) versus standard treatment

Model parametersa
Concept	Mean value
Monthly pharmaceuticals cost (euros)
Trastuzumab deruxtecanb	€10,300.68
Capecitabine	€82.50
Eribulin	€3626.61
Gemcitabine	€1963.26
Sacituzumab govitecan	€6673.04
Paclitaxel	€1309.44
Nab-paclitaxel	€2240.38
Vinorelbine	€749.18
Monthly cost of adverse events (euros)
Anaemia	€12,745.65
Neutropenia	€235.51
Diarrhoea	€615.46
Nausea and sickness (Grade ≤ 2)	€84.49
Nausea and sickness (Grade ≥ 3)	€531.31
Constipation	€81.16
Thrombopenia	€85.63
Elevated aminotransferase	€85.63
Monthly follow-up costs (euros)
Follow-up	€120.23
Utility values
Paracha et al. [12]
Free	0.66
Following progression	0.45
Death	0
Lang et al. [20]
Free	0.85
Following progression	0.52
Death	0

^aPharmaceuticals cost includes administrative costs and the cost of adverse events including specialist appointments

^bThe cost of trastuzumab deruxtecan also includes the cost of antiemesis

In order to ensure the accuracy of the cost estimates, it was necessary to make several assumptions regarding pharmaceutical treatments, adverse events, and follow-up care. The following considerations were critical to defining the costs included in the model and ensuring alignment with clinical practice and available data sources:

• Pharmaceutical cost considerations: Follow-up costs incorporated the performance of computed axial tomography every 5 months and a blood count analysis every 30 days. With regards to specialist appointments, it was assumed that all patients receiving oral treatment had a monthly specialist appointment, whilst those treated intravenously had a specialist appointment for each administration. Finally, it was assumed that all patients who were going to die ceased treatment 1 month prior.

• Considerations for the cost of adverse events: For each adverse event, in addition to pharmacological treatment, one specialist appointment was also counted. In the case of adverse events that led to treatment disruption, disruption was standardized in a cycle.

• Considerations for appointments: Appointment costs extracted from the 2016 Official Bulletin of the Council of Andalusia (BOJA) was updated in 2023 using the Consumer Price Index (CPI).

Analyses were performed in Microsoft Excel 2016. The base-case analysis applied a 3% discount rate to all costs and health outcomes, in line with common practice in health economic evaluations. Cost parameters were informed by real-world pricing obtained from a panel of experts, including one oncologist and two hospital pharmacists, who shared insights based on structured discussions and clinical experience. These expert-informed estimates were incorporated into the base-case model, and the corresponding outcomes are presented in Table 3 and Table S5 (in the ESM).

Table 3.

Incremental cost-effectiveness analysis of trastuzumab deruxtecan (T-DXd) compared with standard treatment, considering a 75-month time horizon, for all patients and the hormone receptor-positive subgroup

Alternative	Cost in euros (€)	Incremental cost (€)	Effectiveness (QALY)	Incremental effectiveness (QALY)	ICURa
All patients. Utility values reported by Paracha et al. [12]
T-DXd	201,328.27		1.24
Standard	64,654.80	136,673.47	1.03	0.21	648,710.32
All patients. Utility values reported by Lang et al. [20]
T-DXd	201,328.27		1.62
Standard	64,654.80	136,673.47	1.26	0.36	379,822.38
RH+. Utility values reported by Paracha et al. [12]
T-DXd	204,262.69		1.33
Standard	71,596.21	132,666.48	1.08	0.2	541,758.59
RH+. Utility values reported by Lang et al. [20]
T-DXd	204,262.69		1.72
Standard	71,596.21	132,666.48	1.34	0.38	350,319.29

All patients: Analysis performed with the whole sample included in the clinical trial; RH+: Analysis performed with the subgroup of patients with positive hormone receptors

ICUR incremental cost utility ratio, QALY quality-adjusted life years, T-DXd trastuzumab deruxtecan

^aCost per QALY when changing from current standard treatment to trastuzumab deruxtecan

To facilitate interpretation of results in relation to acceptable cost-effectiveness thresholds, we also applied four willingness-to-pay thresholds (€21,000, €24,000, €25,000, and €60,000/QALY) derived from the Spanish context [21, 22], and calculated the price at which T-DXd would become cost effective in both the full and RH+ populations.

A univariate sensitivity analysis was conducted to explore parameter uncertainty. Where standard deviations or confidence intervals were unavailable, plausible variations were applied to key model inputs. These analyses were based on the inputs presented in Table 2.

We also explored the impact of alternative assumptions in scenario analyses:

• Utility values from a US-based economic evaluation by Lang et al. (2023) [20] were applied to test the robustness of base-case results.

• A 5% discount rate was used in place of the base-case 3% to evaluate the impact of higher discounting on cost-effectiveness outcomes.

With regards to budgetary impact, an estimated 35,001 new cases of breast cancer were diagnosed in Spain in 2023 [1], with approximately 50% characterized by low levels of the HER2 protein and 10% in a metastatic state [2]. Between 70% and 90% of patients could be considered for first-line treatment [23], and 10–15% of invasive cases lack hormone receptors and have low levels of HER2 [24]. Among the total cases, 1750 were identified as metastatic low HER2 breast cancer, including 1532 hormone receptor positive (RH+) cases and 175 hormone receptor negative (RH-) cases. Within this group, 1400 patients could be eligible for treatment, including 1225 RH+ patients.

The budget impact analysis was conducted using a decision-analytic model to estimate the financial consequences of adopting T-DXd in clinical practice from the perspective of the Spanish National Health System. The analysis was structured in two stages: a preliminary static analysis, estimating costs over a 5-year period assuming a fixed patient population, and a dynamic analysis, incorporating annual incidence rates to account for new eligible patients each year. This approach allowed us to assess both the immediate and cumulative financial impact of T-DXd treatment over time.

The cost projections for the 5-year period were based on treatment duration, drug acquisition costs, and healthcare resource utilization, with consideration given to disease progression and treatment discontinuation rates. Furthermore, sensitivity analyses were conducted to evaluate the impact of key parameters on budget estimates. One-way sensitivity analyses assessed variations in market penetration rates, drug costs (including potential discounts), and incidence rates, while a scenario analysis explored the effect of alternative time horizons.

In order to reflect potential adoption patterns, it was assumed that T-DXd would achieve a gradual increase in market penetration, reaching 100% among eligible patients by the end of the 5-year period. This scenario considers an initial lower market share, consistent with real-world adoption dynamics, followed by a progressive increase as clinical experience accumulates and prescribing practices evolve. While this assumption represents an upper-bound estimate, it allows for a more complete evaluation of the potential financial impact of T-DXd introduction.

Results

Figure 2 shows 75-month models for both treatment options in the overall sample and the RH+ subgroup. In the overall sample, patients receiving T-DXd gained an average 1.24 QALYs (2.24 life years) compared with 1.03 QALYs (1.86 life years) in the standard arm, a difference of 0.21 QALYs (0.38 life years). In RH+ patients, an average of 1.33 QALYs (2.46 life years) was observed with T-DXd, relative to 1.08 QALYs (1.99 life years) in the standard group, revealing a difference of 0.24 QALYs (0.47 life years) (Table 3).

The average cost of treating all women with T-DXd at 75 months was €201,328.27, with pharmaceutical treatment constituting 97.80% (€196,901.07) of the total cost. In the standard group, the average cost was €64,654.80, with pharmaceutical treatment accounting for 94.52% of the total cost (€61,109.92). Within the group of RH+ patients, the average cost for T-DXd treatment at 75 months was €204,262.69, compared with €71,596.21 for the standard treatment group. These results are detailed in Table S5 in the ESM and are also utilized in the cost-effectiveness calculations shown in Table 3.

Incremental cost-effectiveness ratios (ICURs) were then calculated for both groups. For all patients receiving T-DXd, the ICUR was €648,710.32/QALY, representing the additional cost of gaining one QALY compared with standard treatment. Further, in the RH+ group, the ICUR for T-DXd was €541,758.59/QALY. Sensitivity analyses using utility values from Lang et al. (2023) [20] showed ICURs of €379,822.38/QALY in the overall patient group and €350,319.29/QALY in the RH+ patient group (Table 3).

The highest prices of T-DXd treatment according to different willingness-to-pay thresholds, when considering an ICUR threshold of €21,000/QALY, were €288.21 and €280.08 for the overall patient sample and the RH+ patient subgroup, respectively. Correspondingly, at an ICUR threshold of €60,000/QALY, these prices were €379.97 and €391.29 for the total patient sample and the RH+ patient subgroup, respectively. Results for these and the intermediate thresholds (€24,000 and €25,000/QALY) are presented in Supplementary Table S6 (see ESM).

The preliminary budget impact analysis estimated the 5-year cost difference between T-DXd and standard of care to range from €72 million to €140 million for the overall patient sample. For the RH+ subgroup, the cost difference ranged from €64 million to €124 million, depending on the pricing scenario. These findings are summarized in Table S7 (see ESM).

A dynamic cohort budget impact analysis was conducted, projecting a 5-year cost difference of €113 million to €217 million for the overall patient group and €113 million to €209 million for the RH+ subgroup. This approach accounts for the annual addition of new patient cohorts, capturing the cumulative financial impact over time (details in Table S8, see ESM).

Discussion

T-DXd treatment of HER2-low breast cancer had not been previously evaluated in Spain. As far as we are aware, the present study is the first economic evaluation of T-DXd in metastatic HER2-low breast cancer in Spain. According to our findings, trastuzumab deruxtecan was not cost effective from the perspective of the Spanish healthcare system, with an ICUR of approximately €649,000/QALY for all patients and €542,000/QALY for the RH+ subgroup. With regards to budgetary impact, the preliminary analysis estimated a 5-year cost difference ranging from €72 million to €140 million for all patients and from €64 million to €124 million for the RH+ subgroup.

Turning to the existing scientific literature, three economic evaluations based on data published by Modi et al. (2022) [3] have examined the cost effectiveness of T-DXd in the US context. Two studies concluded that this treatment is not cost effective. Specifically, Lang et al. (2023) [20] obtained an ICUR of US$346,571.80/QALY for the overall patient sample and US$337,789.40/QALY for the RH+ subgroup. Meanwhile, Yang et al. (2023) [25] performed analyses for three patient groups (all patients, RH+ and RH-) and reported ICURs of US$317,494/QALY, US$353,903/QALY, and US$259,825/QALY, respectively. In contrast, the third of the mentioned studies in the US context, Shi et al. (2023) [26], reported ICURs ranging from US$82,808/QALY to US$93,358/QALY, indicating cost effectiveness.

Several potential reasons may underlie the differences in outcomes. Firstly, the costs associated with treatments and adverse events were significantly higher in the studies by Lang et al. [20] and Yang et al. [25] than in our study. It is important to note that a higher incidence of adverse events in the intervention group contributes to increased cost differences between the two treatment alternatives. Shi et al. [26], however, reported incremental costs ranging between US$66,583 and US$68,877, which were lower than those reported by Lang et al. [20] and Yang et al. [25].

Another crucial consideration is the significant impact that choices regarding the modelling function applied to survival curves can have on outcomes. These functions are critical for estimating the time that patients spend in different health states, which affects costs and health outcomes. Shi et al. [26] used log-logistic and log-normal functions, producing higher incremental effectiveness (QALY) results (0.794, 0.817, and 0.737 for the three patient groups) than those reported in the aforementioned publications [20, 25] and our study. These higher estimates of efficacy tend to overestimate the efficacy of T-DXd treatment, resulting in more favourable outcomes. Sensitivity analysis in our study confirmed that ICURs decreased when using the functions selected by Shi et al. [26].

Aside from the functions used, another factor influencing differences in findings is the application of utility values for progression-free and relapse health states. In particular, Shi et al. [26] used values (0.83 for progression-free and 0.44 for disease relapse) significantly deviating from other studies. On the other hand, sensitivity analyses with utility values from Lang et al. [20] and Yang et al. [25] produced ICURs (€380,173.92/QALY and €351,166.41/QALY) that were more in line with their reported values, highlighting the impact of utility value variations on ICURs.

Partitioned survival analysis was chosen because the number of patients in each health state is derived directly from the configured survival curves, offering advantages over the Markov model. It eliminates the need to estimate transition probabilities and avoids additional assumptions, such as whether death is allowed in all health states. Nonetheless, this model also limits the potential for conducting sensitivity analyses [27].

It is important to note some limitations of the present study when interpreting outcomes. Firstly, the DESTINY-BREAST04 trial did not provide individual utility values, relying instead on literature for extraction. The utility values used were primarily derived from international studies, which may not fully capture the preferences or experiences of Spanish patients. This potential limitation could affect the generalizability of the results to the Spanish population. In addition, no reduction in utility (or lack of utility) was applied to patients with adverse events, which is a limitation as certain complications, such as fatigue, can significantly impact the quality of life of patients treated with T-DXd.

The efficacy of sacituzumab govitecan [5] in women with relapsed disease, together with Spanish clinical practice and expert consensus, has led to its consideration as a potential treatment option. However, it has not been evaluated in patients previously treated with T-DXd, and doubts remain about its efficacy in this context due to the shared mechanism of action with topoisomerase inhibitors, as both agents bind to cytotoxic agents and antibodies.

The model in this study, which took a health system perspective, did not include indirect costs such as lost working days for treatment administration. A societal perspective could potentially increase the total costs by including informal treatment, health centre visits, etc. Given the higher frequency of adverse events in the T-DXd arm, these unaccounted-for indirect costs could increase the cost differences between treatment alternatives, thereby increasing the incremental cost of T-DXd. Whilst this approach provides a more extensive perspective, it is acknowledged that a lifetime horizon could offer a more comprehensive assessment, capturing potential long-term differences in costs and benefits between treatments. For instance, extending the time horizon might better account for clinical benefits that manifest beyond the trial period, particularly in treatments like T-DXd that may have durable effects. Conducting future analyses incorporating a lifetime horizon would facilitate a more precise evaluation of the cost effectiveness and budgetary implications of T-DXd within the Spanish National Health System.

A major challenge in the present analysis was allocating resources and costs to complications due to the lack of up-to-date databases. To overcome this, an up-to-date database detailing costs would be beneficial.

Conclusion

This study provides a cost-effectiveness and budget impact assessment of T-DXd for patients with HER2-low advanced or metastatic breast cancer in Spain. The findings indicate that while T-DXd demonstrates clinical benefits in comparison with standard chemotherapy, its high incremental cost-effectiveness ratio surpasses the commonly accepted willingness-to-pay thresholds. The budget impact analysis highlights the financial implications of widespread adoption within the Spanish National Health System. The findings emphasize the necessity for further evaluation of cost-containment strategies and potential price negotiations to ensure the accessibility and sustainability of T-DXd in clinical practice.

Supplementary Information

Below is the link to the electronic supplementary material.

Declarations

Competing Interests

All authors state that they have no relevant conflict of interests which could have an impact on study design, analysis or the presentation of findings.

Funding

The present research work was conducted without funding.

Author Contributions

All authors made a meaningful contribution to the conception, design, analysis and interpretation of data, elaboration and critical review of the manuscript, approved the final manuscript and agreed to assume responsibility for all aspects of the work.

Declaration of Transparency

The corresponding author, on behalf of all other co-signatories, guarantees the accuracy, transparency and veracity of the data and information contained in the present manuscript. They also guarantee that no relevant information has been omitted and that all disagreements between authors have been appropriately resolved and discussed.

Ethics Approval

Not applicable.

Consent to Participate

Not applicable as no human participants were involved in this study.

Consent for Publication

Not applicable, as no patient data or individual participant information is included in this study.

Availability of Data and Materials

The data inputs used in the analyses—including clinical efficacy, utility values, and cost parameters—are described in detail in the manuscript and supplementary materials and were obtained from published literature and official Spanish healthcare databases. Any additional datasets generated during the current study are available from the corresponding author upon reasonable request.

Code Availability

The economic evaluation and budget impact analysis were conducted using Microsoft Excel 2016, employing a partitioned survival model to estimate costs and health outcomes. The Excel model(s) used for these analyses are available from the corresponding author upon reasonable request.