Breast cancer remains a leading cause of cancer-related mortality worldwide (Bray et al., 2024). In China, approximately 15%–20% of cases are human epidermal growth factor receptor 2 (HER2)-positive, an aggressive subtype requiring targeted therapy (Lin et al., 2017). Trastuzumab serves as the cornerstone of treatment, significantly improving survival outcomes in both early and advanced stages (Gradishar et al., 2024; Ba et al., 2012).

Traditionally, trastuzumab is administered via intravenous (IV) infusion. While effective, IV administration imposes significant time burdens on patients and resource demands on healthcare systems. To address these limitations, a subcutaneous (SC) formulation was developed, offering a fixed dose that allows for rapid administration without the need for venous access (Gao et al., 2021). While widely adopted globally, SC trastuzumab was only approved in China in 2022, meaning clinical integration is still in the early stages.

Beyond clinical efficacy and safety, economic considerations are pivotal. Although international studies suggest SC administration reduces healthcare costs (Lopez-Vivanco et al., 2017; O'Brien et al., 2019; Rojas et al., 2020; Lee and Cheng, 2023), the unique characteristics of the Chinese healthcare system—including specific insurance policies and price variability between imported and domestic IV products—warrant a dedicated evaluation. Therefore, this study aimed to perform a systematic review and meta-analysis to comprehensively compare subcutaneous and intravenous trastuzumab in HER2-positive breast cancer regarding efficacy, safety, and patient preference. Furthermore, based on the synthesized clinical evidence, we conducted a comparative cost analysis from the perspective of the Chinese healthcare system to provide comprehensive evidence for clinical and policy decision-making.

This meta-analysis included nine studies evaluating the efficacy, safety, and patient preference of SC versus IV trastuzumab in patients with HER2-positive breast cancer. The pooled results showed no statistically significant differences in pCR or EFS between the two administration routes, supporting their clinical equivalence. These findings are consistent with results from pivotal trials such as HannaH (Pivot et al., 2013), reinforcing the therapeutic interchangeability of SC and IV trastuzumab.

Regarding safety, SC administration was associated with a higher incidence of adverse events, predominantly mild-to-moderate local injection site reactions such as pain, erythema, or induration. These are characteristic of subcutaneous delivery and are typically manageable without affecting long-term treatment adherence. Importantly, no significant difference was observed in serious adverse events, confirming that the SC formulation maintains a comparable safety profile to IV administration.

Patient preference strongly favored SC administration of trastuzumab over IV administration, with a pooled odds ratio of 63.02. Considerable heterogeneity was observed among studies (I² = 74%), likely reflecting differences in healthcare settings (e.g., home-based versus hospital-only administration), prior treatment experience, and cultural attitudes toward injections across study populations. To assess the robustness of this finding, a leave-one-out sensitivity analysis was conducted. Across all iterations, the pooled ORs ranged from 49.32 to 76.70, indicating that the observed heterogeneity did not materially affect the direction or statistical significance of the result.

The pronounced preference for SC administration appears largely attributable to its practical advantages, including markedly reduced treatment time, fewer venous punctures, and greater convenience—factors consistently valued by patients in real-world settings. These results are in line with the pivotal PrefHer study (Pivot et al., 2017a) and underscore the clinical importance of incorporating patient-centered considerations, such as comfort, treatment burden, and convenience, into therapeutic decision-making for HER2-positive breast cancer.

Importantly, most studies included in this review focused on short-to medium-term outcomes. Data on long-term OS and late-onset toxicities remain limited. A key reason for the scarcity of OS data lies in the methodological and logistical challenges of OS assessment. Detecting meaningful differences in OS typically requires very large sample sizes and extended follow-up durations often several years to capture sufficient survival events. Furthermore, when clinical efficacy is presumed equivalent, as is the case for SC and IV trastuzumab, substantial divergence in OS is neither expected nor commonly observed. As such, OS is rarely selected as a primary endpoint in comparative trials of administration routes for the same biologic agent. Among the limited evidence available, one study (Jackisch et al., 2019) reported identical OS rates of 84% in both groups, with a HR of 0.94 (95% CI: 0.61–1.45), indicating no statistically significant difference in long-term survival. These findings reinforce the therapeutic interchangeability of the two formulations and support the rationale for assessing non-survival endpoints such as patient preference, quality of life, and healthcare resource utilization. This evidence gap also underscores a major contribution of the present meta-analysis: the identification of unmet research needs that can inform future randomized controlled trial (RCT) design. Longitudinal real-world data, especially those derived from national cancer registries or electronic health records, are warranted to assess the durability and late safety profiles of SC versus IV trastuzumab. Such efforts are essential to ensure evidence-based decision-making over the full treatment trajectory.

Beyond clinical considerations, economic impact has become increasingly relevant in determining optimal treatment strategies. Previous reports suggest that SC trastuzumab may reduce healthcare resource utilization, including infusion time, chair time, and staffing needs (Pivot et al., 2013; Pivot et al., 2017a; Pivot et al., 2017b). For instance, the PrefHer substudy reported a reduction in chair time from approximately 90 min (IV) to 5–10 min (SC), accompanied by a 50%–60% reduction in active healthcare provider time per cycle (De Cock et al., 2016). A Spanish time-and-motion study reported active nursing time reduced from 27.2 to 13.2 min, yielding a cost saving of ∼€979 per patient over 18 cycles (Lopez-Vivanco et al., 2017). In Greece, cost-minimization analyses demonstrate lower total therapy costs with SC (e.g., €21,870 vs. €23,118) attributed mainly to reduced drug preparation and administration costs (Mylonas et al., 2017). Such consistent findings underscore the resource-efficiency of SC trastuzumab across diverse healthcare systems.

In China, both IV and SC formulations of trastuzumab are included in the NRDL. However, practical and logistical differences persist. IV formulations continue to dominate due to earlier market availability, centralized procurement practices, and formulary constraints in some tertiary hospitals. Conversely, SC administration may offer indirect cost savings by lowering outpatient infusion volumes, reducing nursing workload, and shortening patient waiting times—benefits that are particularly valuable in high-volume oncology centers. To address this evidence gap, we performed a CMA. This methodological approach is justified by the clinical equivalence between SC and IV formulations demonstrated in our meta-analysis, satisfying the fundamental CMA prerequisite of therapeutic equivalence. While comprehensive cost-effectiveness (CEA) or cost-utility analyses (CUA) would be necessary to capture indirect benefits—such as patient convenience, quality-of-life improvements, and adherence—CMA provides a rigorous, preliminary assessment of direct medical costs under the current Chinese reimbursement framework. Our findings indicate that under the current Chinese reimbursement and pricing framework, the total cost of the SC trastuzumab regimen was significantly lower than that of various IV formulations. One-way sensitivity analyses indicated that the cost ranking remained consistent across a ±20% variation in drug prices and patient body weight, suggesting the robustness of the model outcomes. Drug price and body weight were identified as the primary drivers of cost differences, highlighting the crucial influence of unit-dose cost and weight-based dosing on economic outcomes, whereas the effects of consumables and drug management fees were relatively limited. These findings underscore that further price reductions for the SC formulation or optimization of weight-based pricing mechanisms could amplify its economic advantage, thereby improving affordability and resource efficiency within the healthcare system. Against the backdrop of China’s current reimbursement policy, the wider implementation of SC trastuzumab carries substantial practical and policy significance. Its markedly reduced administration time can indirectly lower labor costs in infusion units and increase patient throughput, thereby enhancing hospital operational efficiency and optimizing resource allocation. From the payer perspective, selecting a lower-cost administration route without compromising clinical efficacy is consistent with the principles of value-based reimbursement. From the patient standpoint, SC administration minimizes discomfort associated with intravenous access, reduces waiting time, and improves treatment experience and adherence, which may in turn positively influence therapeutic outcomes. Collectively, these clinical, economic, and patient-centered advantages position SC trastuzumab as a highly competitive strategy within value-based oncology care. It should be acknowledged that the CMA framework inherently focuses on direct costs and does not quantify broader benefits of SC administration, including patient time savings, convenience, and potential improvements in adherence and quality of life. These dimensions are critical for future, more comprehensive pharmacoeconomic evaluations. Future studies should integrate real-world cost data, long-term clinical outcomes, and patient-reported quality-of-life metrics, ideally via CEA or CUA frameworks, to comprehensively assess the holistic value of SC trastuzumab and inform evidence-based reimbursement and resource allocation decisions in China.

These findings carry particular significance for regions where SC trastuzumab has only recently been introduced into clinical practice. For example, while SC trastuzumab has been approved in Europe since 2013 and in the United States since 2019, it was only approved in China in 2022 (Waller et al., 2021). In such settings, clinicians are still navigating the adoption process, and high-quality comparative evidence can support informed treatment decisions and policy development. The results of this study offer timely guidance for countries and regions seeking to transition toward more patient-centered and resource-efficient treatment models.

Nonetheless, several limitations should be acknowledged. First, heterogeneity was present in study designs, patient populations, and follow-up durations, which may influence the pooled outcomes. Second, the primary endpoints of this meta-analysis were pCR and EFS, as these were the outcomes most consistently reported across the included trials. Long-term survival data were notably limited: only one study reported OS; therefore, formal meta-analysis of OS was not feasible, and the precision of the pooled EFS estimate may be constrained by the small number of contributing studies. Furthermore, heterogeneity and publication bias for survival endpoints could not be reliably assessed due to insufficient study numbers. These limitations indicate that while current evidence supports comparable short-to medium-term efficacy between SC and IV trastuzumab, conclusions regarding long-term survival equivalence remain preliminary and should be interpreted with caution. Third, patient preference for administration route was derived from subjective surveys and may be influenced by cultural context, healthcare system, and prior treatment experience. Considerable heterogeneity among studies and the absence of subgroup or sensitivity analyses may limit the certainty and generalizability of the evidence. Fourth, a cost-minimization analysis was conducted based on presumed clinical equivalence between SC and IV formulations. CMA focuses on direct medical costs and may not capture broader aspects such as patient time, convenience, adherence, quality of life, or indirect costs. These factors could provide additional advantages of SC administration. Future cost-effectiveness or cost-utility studies would help more comprehensively assess the value of SC trastuzumab in China. Finally, formal assessment of publication bias (e.g., funnel plots) was not feasible due to the limited number of included studies (<10). Notably, several included trials were industry-sponsored, introducing the potential for sponsorship bias. Although our risk of bias assessment identified no overt methodological issues, the possibility of unpublished negative findings cannot be entirely excluded. Despite our broad search strategy to mitigate these risks, findings should be interpreted with this context in mind.

Future studies should aim to: (1) conduct randomized controlled trials with standardized methodology across diverse regions; (2) include long-term follow-up to assess durable outcomes; (3) performing comprehensive cost-effectiveness or cost-utility analyses, integrating real-world clinical outcomes and patient-reported quality-of-life measures to fully quantify treatment value; (4) explore the comparative value of SC trastuzumab in specific subgroups, such as elderly patients, those with limited venous access, or populations with low treatment adherence.

SC trastuzumab shows comparable efficacy and safety to IV administration in HER2-positive breast cancer, with no significant differences in pathological complete response or event-free survival. Injection site reactions are more frequent but mild and transient. Given clinical equivalence, patient preference driven by reduced administration time and convenience is a key factor. Subcutaneous delivery may improve resource utilization, especially in high-volume or resource-constrained settings. Cost-minimization analysis based on the meta-analysis results indicates that SC administration has a potential cost advantage under the current reimbursement and drug pricing system. Taken together, the clinical, patient-centered, and economic benefits suggest that SC trastuzumab has strong potential for broader adoption, providing valuable guidance for future clinical practice and health policy decision-making.