Real-world efficacy and safety of trastuzumab deruxtecan in heavily pre-treated HER2-low metastatic breast cancer across distinct immunohistochemistry statuses

Introduction

As a member of the epidermal growth factor receptor family, human epidermal growth factor receptor 2 (HER2) plays a crucial role in the invasion and metastasis of HER2-positive breast cancer (1). Based on the assessment of protein overexpression levels through immunohistochemistry (IHC), HER2 status can be classified into scores ranging from 0 to 3+ (2). HER2-low breast cancer, identified by an IHC score of 1+ or 2+ with a negative fluorescence in situ hybridization (FISH) test, accounts for approximately 45% to 55% of all breast cancers (3,4). Over the past few decades, patients with HER2-low breast cancer have been managed as HER2-negative since they did not derive any benefit from conventional anti-HER2 therapies (5). However, recent evidence suggests that HER2-low tumors may still have vulnerabilities that can be targeted with new anti-HER2 strategies (4,6).

Trastuzumab deruxtecan (T-DXd) is a novel HER2-targeted antibody-drug conjugate, well known for its remarkable anti-tumor activity in both HER2-positive and HER2-low metastatic breast cancer (MBC) (7-10). The DESTINY-Breast04 trial reported that for patients with HER2-low MBC who had previously failed chemotherapy, T-DXd achieved a median progression-free survival (PFS) of 9.9 months, markedly extending the 5.1 months observed with conventional chemotherapy (11). T-DXd provides a new treatment option and ushers in a transformative era of anti-HER2 therapy for HER2-low patients (12). In this context, both the international and Chinese guidelines recommend T-DXd as the preferred treatment option for HER2-low MBC after initial treatment failure (13,14).

According to previous trials, HER2-low MBC patients with IHC 1+ and IHC 2+ exhibit similar tumor responses to T-DXd treatment (11,15). However, the efficacy difference of T-DXd between these two categories in the real world remains unknown, as rigorously designed clinical trial data may not always reflect real-world practice and outcomes. For instance, distinguished from the DESTINY-Breast04 trial, there remains a large population of heavily pre-treated HER2-low MBC patients in the real world. It is unclear whether individuals with distinct IHC statuses would still derive the same benefit from T-DXd in this population. Additionally, for patients with IHC heterogeneity between primary and metastatic lesions, there is no clear consensus on which lesion’s IHC score is more relevant to the efficacy of T-DXd. Therefore, it is necessary to investigate the real-world efficacy of T-DXd across different IHC statuses in HER2-low MBC. This knowledge might help clinicians identify the optimal candidates for T-DXd therapy and make treatment decisions.

The objective of this study was to compare the real-world outcomes of T-DXd across distinct IHC statuses in a real-world population of patients with HER2-low MBC. Additionally, it identified independent factors influencing T-DXd efficacy in real-world treatment scenarios, with the overarching goal of optimizing treatment management for patients with HER2-low MBC. We present this article in accordance with the STROBE reporting checklist (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-8/rc).

Methods

Study design and population

This retrospective real-world study was conducted at a single center in China (Research No. CSCO BC RWS 2403). The study reviewed patients diagnosed with HER2-low MBC who were treated at The Fifth Medical Centre of Chinese PLA General Hospital between June 2022 and December 2023, focusing on those who received T-DXd. All eligible patients were included in the analysis, thus determining the study sample size. The study included patients who met the following criteria: (I) aged over 18 years old; (II) with Eastern Cooperative Oncology Group performance scores ≤2; (III) received at least one dose of T-DXd; (IV) had at least one measurable lesion at baseline; and (V) underwent at least one efficacy evaluation after baseline. The exclusion criteria were as follows: (I) patients with severe co-morbidities or other active malignancies; (II) patients who received other anti-tumor drugs concurrently with T-DXd; and (III) patients with incomplete clinicopathological information.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of The Fifth Medical Centre of Chinese PLA General Hospital (approval No. KY-2025-4-59-1). Consent forms were waived due to the retrospective nature of the study.

Pathological and IHC examination

Breast cancer was diagnosed pathologically, and metastasis was identified by imaging or pathology. HER2-low was defined as IHC 1+ or 2+ with a negative FISH test (2). All lesions with an IHC score of 2+ should undergo the FISH test. The IHC status of patients was assessed by the higher IHC score between the primary lesion and the pathologically investigated metastatic lesion. For example, if a patient had an IHC score of 1+ for the breast lesion and 2+, FISH-negative for the metastatic lesion, the patient would be classified into the IHC 2+ group. Hormone receptor (HoR) positivity was defined as ≥1% of cells with positive IHC staining for the estrogen and/or progesterone receptors.

Treatment schedule

The recommended initial dose of T-DXd was 5.4 mg/kg, given intravenously every 3 weeks (16). Clinical usage of T-DXd is available in vials containing 100 mg. Depending on the patient’s overall state, the initial dose may also be changed. Dose reductions were implemented for people who could not tolerate the adverse responses. Patients treated with T-DXd were permitted a single reduction in dose, ensuring that the minimum dose administered did not drop below 80% of the initially prescribed amount. If the patient remained intolerant, the medication was discontinued.

Efficacy and safety evaluation

The primary study endpoint was PFS, which was defined as the time from the first dose of T-DXd to the occurrence of disease progression. PFS data were collected by the medical record system and telephone follow-up. The most recent follow-up occurred in June 2024. Patients who were lost to follow-up and those who had not yet reached the primary endpoint at this time were considered right-censored. The evaluation of clinical effectiveness was performed using the Response Evaluation Criteria in Solid Tumors version 1.1 (17). Tumor responses were assessed by imaging scans conducted every two treatment cycles and categorized as complete response (CR), partial response (PR), stable disease (SD), or progressing disease (PD). The secondary endpoints were the objective response rate (ORR), clinical benefit rate (CBR), and safety. ORR was determined by calculating the percentage of patients who achieved CR or PR. On the other hand, CBR was calculated by determining the percentage of patients who achieved CR, PR, or SD persisting for ≥6 months.

Safety was evaluated through monitoring adverse events (AEs). The AEs occurring during hospitalization were monitored through medical consultations, imaging examinations, and laboratory tests. A self-monitoring form (Figure S1) was used to track AEs after discharge. The patients were instructed to have routine blood tests every 3–4 days and biochemical testing every 7 days after being discharged. The test results and the occurrence of any AEs were recorded daily. The self-monitoring form was obtained during the patient’s hospitalization, and the occurrence of AEs was recorded in the medical record system. Chest computed tomography images were done every two treatment cycles. All AEs were graded using the Common Terminology Criteria for AEs version 5.0.

Statistical analysis

Quantitative variables were summarized as median and range, or interquartile range (IQR), and were compared using the Student’s t-test or Wilcoxon rank-sum test. Categorical variables were reported as numbers and proportions and were compared using the χ² or Fisher’s exact test. The Kaplan-Meier method was used to plot PFS curves and differences between groups were determined using the log-rank test. Univariate Cox analyses were performed to identify parameters influencing PFS. To account for potential bias caused by confounding variables, factors having a P value of less than 0.05 in univariate analyses were included in a multivariate Cox model. The Schoenfeld residual test was employed to evaluate the proportional hazards assumption of each variable in the multivariate model and was visualized with Schoenfeld residual plots (18). In the multivariate model, factors with P values less than 0.05 are considered independent factors influencing PFS. All data analysis and figure presentation were done using R version 4.4.0 (19). A two-sided P<0.05 was considered statistically significant.

Results

Patient IHC status and characteristics

Between June 2022 and December 2023, 283 patients were diagnosed with HER2-low MBC, and 70 patients met the eligibility criteria. Among them, 37 were in the IHC 1+ group and 33 were in the IHC 2+ group. The flow chart of patient selection is shown in Figure S2. The median follow-up time was 7.5 months. Figure 1 shows the IHC scores of primary and metastatic lesions and the IHC conversion between paired lesions. In the IHC 1+ group, 16 patients had IHC 0 in the primary lesion, which all converted to IHC 1+ in the metastatic lesion. In the IHC 2+ group, 10 patients had IHC 0 or 1+ in the primary lesion, which all converted to IHC 2+ in the metastatic lesion.

Figure 1 Alluvial diagram illustrating the IHC scores of primary and metastatic lesions and the IHC conversion between paired lesions. IHC, immunohistochemistry.

Table 1 outlines the baseline characteristics of the study participants. The comparison of clinical characteristics between the IHC 1+ and 2+ groups showed a significant difference in the initial T-DXd doses (P=0.04), with no other differences observed. The median age of all patients was 53 years (range, 31–72 years), with one male patient (1.4%). Among them, 62 (88.6%) had positive HoR status and 64 (91.4%) had visceral metastasis. Thirty-three (47.1%) patients received ≥3 lines of chemotherapy and 21 (30%) patients received ≥3 lines of endocrine therapy before T-DXd treatment. The median number of T-DXd treatment lines was 5 (range, 1–11). The median initial dose of T-DXd was 4.6 mg/kg (IQR, 3.7–5.3 mg/kg) administered every three weeks. Regarding previous anti-cancer treatments, 59 patients (84.3%) had undergone endocrine therapy, 52 (74.3%) had received cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), and all patients had received chemotherapy.

Efficacy evaluation

At the time of the last follow-up, 50 (71.4%) patients reached the primary endpoint. In all patients, the median PFS was 5 months, with a 95% confidence interval (CI) of 3 to 7 months (Figure S3). Figure 2 shows the PFS curves of the IHC 1+ and IHC 2+ groups, with a median PFS of 3 and 5 months, respectively (P=0.01). The clinical efficacy outcomes are detailed in Table S1. In all patients, no cases of CR were observed, PR was achieved in 15 patients (21.4%), SD was seen in 38 patients (54.3%), and PD occurred in 17 patients (24.3%). The ORR was 21.4% (15 out of 70 patients), and the CBR was 30% (21 out of 70 patients). The IHC 2+ group showed numerically higher ORR (27.3% vs. 16.2%) and CBR (36.4% vs. 24.3%) compared to the IHC 1+ group, but no statistical difference was observed (both P values were 0.40).

Figure 2 PFS curves for patients with IHC 1+ and IHC 2+ in the present study. The median PFS was 3 months for the IHC 1+ group and 5 months for the IHC 2+ group (P=0.01). The shaded area represents the 95% confidence interval. Tick marks indicate data right-censored at the last follow-up. IHC, immunohistochemistry; PFS, progression-free survival.

Univariate and multivariate Cox analyses of factors affecting PFS

The univariate Cox analyses revealed that the IHC status, initial T-DXd doses, and prior lines of chemotherapy were all associated with the patients’ PFS (P values were 0.02, 0.003, and 0.01, respectively, Table S2). A multivariate Cox model was then fitted using these factors. The Schoenfeld residual test verified that all variables in the multivariate model satisfied the proportional hazard assumption. The Schoenfeld residual graphs are shown in Figure S4. The IHC status, prior chemotherapy lines, and initial T-DXd doses were independent variables influencing PFS (Table S2). Patients with IHC 2+ had a better prognosis than those with IHC 1+ [multivariate-adjusted hazard ratio (HR): 0.51, 95% CI: 0.28–0.95, P=0.03]. Furthermore, patients who had undergone three or more prior lines of chemotherapy displayed a worse prognosis compared to those who had received two or fewer lines (multivariate-adjusted HR: 1.99, 95% CI: 1.10–3.58, P=0.02). Patients who were administered a higher initial dose of T-DXd also demonstrated a better prognosis relative to those who received a lower dose (multivariate-adjusted HR: 0.64 mg/kg, 95% CI: 0.45–0.89, P=0.009).

Figure 3 displays the PFS curves categorized by HoR status, prior lines of chemotherapy, and initial doses of T-DXd. It is worth mentioning that the median PFS of T-DXd in both HoR-positive and HoR-negative patients was similar to that of the whole population (both had a median PFS of 5 months, with a P value of 0.79, Figure 3A). Patients who had received 3 or more lines of prior chemotherapy had a lower PFS compared to those who had received 2 or fewer lines (median PFS: 3 vs. 6.5 months, P=0.01, Figure 3B). Patients were divided into two groups based on their initial T-DXd doses, using a cutoff value of 4.4 mg/kg. The patients in the high-dose group had a longer PFS compared to those in the low-dose group (median PFS: 6.5 vs. 3 months, P=0.002, Figure 3C).

Figure 3 PFS curves grouped by clinical factors. (A) PFS curve according to HoR status. The median PFS for both groups was 5 months (P=0.79). (B) PFS curve according to prior lines of chemotherapy. The median PFS was 3 months for the ≥3 lines group and 6.5 months for the ≤2 lines group (P=0.01). (C) PFS curve according to initial doses of T-DXd. The median PFS was 3 months for the <4.4 mg/kg group and 6.5 months for ≥4.4 mg/kg (P=0.002). The shaded area represents the 95% confidence interval. Tick marks indicate data right-censored at the last follow-up. HoR, hormone receptor; PFS, progression-free survival; q3w, every 3 weeks; T-DXd, trastuzumab deruxtecan.

Safety evaluation

Table 2 presents the incidence of treatment-related AEs associated with T-DXd during the study period. Nausea was the most frequently reported AE, occurring in 30 patients (42.9%). The most prevalent grade 3–4 AEs included neutropenia, anaemia, and leukopenia, each observed in 7.1% of patients. Neutropenia emerged as the predominant haematological AE, documented in 24 patients (34.3%). Interstitial lung disease (ILD) represented the least common AE, affecting only 3 patients (4.3%). The toxicity profiles were basically the same between the IHC 1+ and 2+ groups. Adjustments to the treatment regimen that were unrelated to disease progression occurred in 9 patients (12.9%). Within this subgroup, intolerable AEs necessitated dose reductions in 2 patients and treatment discontinuation in 5 patients. Furthermore, treatment cessation due to financial considerations was observed in 2 patients. AEs according to different initial T-DXd doses are shown in Table S3. Patients with an initial T-DXd dose of ≥4.4 mg/kg displayed an increased incidence of all grade AEs in comparison with those with an initial dose of <4.4 mg/kg, except for constipation.

Discussion

Real-world data and evidence play an increasingly crucial role in clinical decision-making, offering insights that may better reflect actual clinical practice (20,21). On this basis, we reported the real-world efficacy and safety of T-DXd across distinct IHC statuses in HER2-low MBC. Several findings from our study are noteworthy. Firstly, compared to patients with IHC 1+, those exhibiting IHC 2+ are more likely to benefit from T-DXd treatment. Secondly, a higher IHC score between the primary and metastatic lesions is more closely associated with the T-DXd efficacy. Thirdly, intensive prior chemotherapy and insufficient initial doses may reduce the T-DXd efficacy. Additionally, the real-world efficacy of T-DXd is lower than observed in previous trials, though the safety profile remains consistent.

In the DESTINY-Breast04 trial, patients with IHC 1+ and IHC 2+ had comparable PFS. The median PFS for patients with IHC 1+ was 10 months, while for those with IHC 2+, it was 9.9 months (11). Previous studies have also shown that tumor responses to T-DXd were similar in IHC 1+ and 2+ subgroups (15,22). Nevertheless, this study demonstrated that in real-world treatment scenarios, there is a significant difference in PFS between the IHC 1+ and 2+ groups, with median PFS of 3 months and 5 months, respectively (P=0.01, Figure 2). After multivariate adjustment for initial T-DXd doses and prior lines of chemotherapy, this difference remained statistically significant (multivariate-adjusted HR: 0.51, 95% CI: 0.28–0.95, P=0.03, Table S2). It is important to note that the population in our study more accurately reflects real-world clinical practice, where HER2-low MBC patients often receive intensive prior treatments and non-standard initial T-DXd doses. Due to financial constraints and product accessibility issues, a significant proportion of patients in China are unable to receive T-DXd in the earlier lines of therapy after recurrence. After intensive prior treatments, patients commonly exhibit poorer overall conditions, resulting in decreased tolerance to standard doses. Additionally, since T-DXd is packaged in 100 mg vials, physicians typically use the entire vial to avoid wastage, which also leads to non-standard initial doses. Given the non-standard initial T-DXd doses in real-world settings, it is speculated that patients with IHC 1+ are more likely to experience reduced efficacy due to insufficient doses compared to those with IHC 2+. In other words, patients with IHC 1+ may require a standard dose more critically to maintain therapeutic effectiveness.

Previous studies have shown that about 30% of patients with HER2-zero may convert to HER2-low after metastasis, and this occurrence is more frequent among HoR-positive cases (23,24). In line with this, the current study observed that patients with IHC 0 in the primary tumor did not show a significant difference in PFS when compared to those with IHC 1+ or 2+ (P=0.32 and 0.25, respectively, Table S2). This finding indicated that the effectiveness of T-DXd is not strongly influenced by the primary tumor, instead being affected by the higher IHC score between the primary and metastatic lesions. Our research findings support the perspective of Lin et al., recommending a re-biopsy of the metastatic lesion in MBC patients with IHC 0 status in the primary tumor (23). This will aid in identifying potential candidates for T-DXd therapy.

Cox analyses were employed in the present study to investigate the characteristics that affect the real-world effectiveness of T-DXd. Some of the findings are worth emphasizing. HoR status is an important sign for patients with HER2-low MBC since HoR-negative patients cannot get endocrine treatment, leading to a worse prognosis. The findings of this research showed that the effectiveness of T-DXd is not influenced by HoR status [median PFS 5 months for each status, P=0.79, Figure 3A], which aligned with the results of the DESTINY-Breast04 trial (11). Both individuals with HoR-positive and HoR-negative breast cancer may benefit from T-DXd treatment. Intensive prior treatment is a critical issue in clinical practice. Our findings showed that patients who had received ≥3 lines of prior chemotherapy had a median PFS of 3 months, significantly shorter than the 6.5 months observed in patients who had received ≤2 lines (P=0.01, Figure 3B; multivariate-adjusted HR: 1.99, 95% CI: 1.10–3.58, Table S2). The worsening overall conditions and increased tumor burden of the patients after the failure of multiple lines of chemotherapy might be attributed to this outcome. Consequently, to ensure the effectiveness of the treatment, the optimal timing for T-DXd therapy in patients with HER2-low MBC is within two lines of prior chemotherapy failure.

The reasons for the variations in effectiveness between the present study and the DESTINY-Breast04 trial warrant a comprehensive investigation. The median PFS of the T-DXd group in the DESTINY-Breast04 trial was 9.9 months (95% CI: 9–11.3) (11), whereas the present study’s cohort had a PFS of 5 months (95% CI: 3–7). Furthermore, the DESTINY-Breast04 trial revealed ORR and CBR of 52.6% and 70.2%, respectively, while the current study had 21.4% and 30%, respectively. The observed effectiveness discrepancy might be related to the real-world situation and the study’s specific patient demographics. Specifically, in the DESTINY-Breast04 trial, the proportion of patients with brain, lung, and liver metastases was 5.4%, 29.6%, and 74.6%, respectively (11). In contrast, due to intensive prior treatment failure, the present study had higher rates of these metastases, with 22.9%, 50%, and 77.1%, respectively. The larger tumor burdens at the baseline of this study might have a negative effect on the PFS, CBR, and ORR. Moreover, our study demonstrated that the initial dose of T-DXd could independently affect PFS (multivariate-adjusted HR: 0.64 mg/kg, 95% CI: 0.45–0.89, P=0.009, Table S2). The median PFS was considerably longer in the ≥4.4 mg/kg group compared to the <4.4 mg/kg group (6.5 vs. 3 months, P=0.002, Figure 3C). Therefore, inadequate initial doses of T-DXd may also contribute to the observed reduced efficacy in this study.

This study showed that the toxicity profiles were basically the same between the IHC 1+ and 2+ groups (Table 2). However, individuals who received an initial T-DXd dose of ≥4.4 mg/kg exhibited increased AEs compared to those who received a lower dose (Table S3). The frequency of grade 3–4 AEs was similar in both dose groups, suggesting that the initial dose of ≥4.4 mg/kg did not elevate the occurrence of severe AEs. The safety outcomes of this research are mostly consistent with those of earlier trials (7,11), but show significantly lower rates of gastrointestinal problems, elevated aminotransferase levels, and ILD. The lower initial dose of T-DXd is a key factor in these outcomes. Besides, as clinicians grow more experienced in preventing common AEs caused by T-DXd, they have adopted the proactive use of hepatoprotective medicines and anti-emetics as a normal practice. ILD is a specific AE caused by T-DXd (25). A pooled analysis of 9 trials on T-DXd monotherapy found that the total incidence rate of ILD was 15.4% (26). The current analysis documented a 4.3% occurrence rate of ILD, which is lower than the 12.1% seen in the DESTINY-Breast04 trial (11). It is suggested that the lower initial dose and shorter treatment period of T-DXd in this study may have led to a decreased occurrence of ILD.

This research is limited by two primary factors. Firstly, there is an unavoidable selection bias that occurs in real-world situations. Secondly, there is a lack of evidence about the effectiveness and safety of T-DXd at the recommended initial dose of 5.4 mg/kg. Other limitations include a small sample size, the potential for an underestimation of AEs, and the use of a single-center strategy. Future prospective and multicentre investigations are required to validate the current results.

Conclusions

This study evaluates the real-world outcomes of T-DXd across distinct IHC statuses in heavily pre-treated HER2-low MBC. Patients with higher IHC scores are more likely to benefit from T-DXd treatment, regardless of whether the scores are detected from primary or metastatic lesions. Intensive prior chemotherapy and non-standard initial doses are critical issues in the real world, potentially reducing the efficacy of T-DXd in clinical practice. The study findings might help clinicians identify the optimal candidates for T-DXd therapy and make treatment decisions.

Acknowledgments

We thank all the patients for participating in the study, and we express our gratitude to the medical staff for providing the data.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-8/rc

Data Sharing Statement: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-8/dss

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-8/prf

Funding: This work was supported by the Beijing Science and Technology Project (grant No. Z181100001718215) and the Innovative Project of PLA General Hospital (grant No. CX19011).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-8/coif). Z.J. serves as the Editor-in-Chief of Translational Breast Cancer Research. J.L. serves as an unpaid Managing Editor of Translational Breast Cancer Research from November 2019 to December 2027. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of The Fifth Medical Centre of Chinese PLA General Hospital (approval No. KY-2025-4-59-1). Consent forms were waived due to the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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