Highlights
– Trastuzumab deruxtecan (T-DXd) significantly prolongs progression‑free survival (PFS) and overall survival (OS) compared with physician’s choice chemotherapy in patients with HER2‑low metastatic breast cancer (mBC).
– Extended follow‑up (median ~32 months) confirms an OS benefit across the overall and hormone receptor (HR)‑positive populations (HR ~0.69).
– Patient‑reported outcomes (PROs) show global health status/quality of life (GHS/QoL) preserved with T‑DXd and delayed definitive deterioration across symptom and functioning domains, despite longer treatment exposure.
– Safety profile includes higher, adjudicated rates of interstitial lung disease (ILD)/pneumonitis (12.1% drug‑related; ~0.8% fatal in the primary report); careful monitoring and early management are required.
Background and clinical context
Historically, HER2‑targeted therapies have been reserved for cancers with HER2 overexpression or amplification (IHC 3+ or IHC 2+/ISH positive). Up to 50% of breast cancers express lower HER2 levels (IHC 1+ or IHC 2+/ISH‑negative), a population previously categorized as HER2‑negative for therapeutic decision making. This “HER2‑low” subgroup represents a substantial unmet need because conventional anti‑HER2 agents showed minimal activity in these tumors. Antibody‑drug conjugates (ADCs) with potent payloads and bystander killing capability have the potential to exploit even low antigen expression to deliver cytotoxic therapy selectively to tumor cells and adjacent microenvironment.
Study design and methods (overview of the three reports)
The DESTINY‑Breast04 program comprises a randomized, open‑label, phase 3 trial (NCT03734029) and subsequent prespecified and post hoc analyses covering primary efficacy, long‑term survival, and patient‑reported outcomes.
Population and definitions
Eligible patients had metastatic breast cancer with HER2‑low expression, defined as IHC 1+ or IHC 2+/ISH‑negative, and had received one or two prior lines of chemotherapy in the metastatic setting. Both hormone receptor (HR)‑positive and HR‑negative tumors were included; the trial stratified analyses by HR status with the primary endpoint assessed in the HR‑positive cohort.
Interventions and comparators
Participants were randomized 2:1 to receive trastuzumab deruxtecan (T‑DXd) versus physician’s choice (TPC) chemotherapy. Physician’s choice included approved single‑agent chemotherapies appropriate for the patient. Endpoints included PFS (primary in HR‑positive cohort), PFS among all patients, OS in HR‑positive cohort and overall, safety, and PRO measures using validated instruments.
Key findings — efficacy and survival
Primary randomized results (NEJM primary report)
The primary analysis included 557 randomized patients. In the HR‑positive cohort (n=494), T‑DXd yielded a median PFS of 10.1 months versus 5.4 months with physician’s choice (hazard ratio [HR] for progression or death 0.51; P<0.001). Median OS in the HR‑positive cohort was 23.9 months with T‑DXd vs 17.5 months with physician’s choice (HR for death 0.64; P=0.003). In the overall intent‑to‑treat population, median PFS was 9.9 vs 5.1 months (HR 0.50; P<0.001) and median OS 23.4 vs 16.8 months (HR 0.64; P=0.001). These effect sizes indicate a clinically meaningful benefit across both PFS and OS endpoints.
Long‑term survival analysis (Nat Med extended follow‑up)
With extended median follow‑up of 32.0 months, updated analyses confirmed an OS advantage for T‑DXd. In the overall cohort, median OS was 22.9 months for T‑DXd vs 16.8 months for TPC (HR 0.69; 95% CI 0.55–0.86). In the HR‑positive cohort, median OS was 23.9 vs 17.6 months (HR 0.69; 95% CI 0.55–0.87). Exploratory subgroup analyses also favored T‑DXd in HR‑negative and different ER strata, although numbers in some subgroups were small and exploratory by design. The extended analysis supports durability of the survival benefit observed in the primary report.
Patient‑reported outcomes
The PRO analysis (Oncologist report) enrolled patients who completed baseline questionnaires (T‑DXd n=331; physician’s choice n=163). Baseline global health status/quality of life (GHS/QoL) scores were similar between arms and showed no clinically meaningful decline during treatment in either group despite a substantially longer median treatment duration with T‑DXd (median 8.2 months) compared with physician’s choice (3.5 months).
Time to definitive deterioration (TDD) of GHS/QoL was delayed with T‑DXd vs physician’s choice (median 11.4 vs 7.5 months; HR 0.69; 95% CI 0.52–0.92). T‑DXd also delayed TDD for all prespecified symptom and functioning PROs, including pain. One signal that favored chemotherapy was a shorter TDD for nausea and vomiting with T‑DXd (i.e., more or earlier deterioration), highlighting the need for effective antiemetic prophylaxis.
Overall, T‑DXd preserved patient‑reported global QoL and delayed deterioration across domains despite longer exposure and improved clinical outcomes, an important consideration for treatment selection in palliative settings.
Safety and tolerability
Adverse events (AEs) of grade ≥3 occurred in 52.6% of patients receiving T‑DXd versus 67.4% for physician’s choice chemotherapy in the primary analysis, suggesting an acceptable overall toxicity burden when compared to standard chemotherapy options. Common toxicities with T‑DXd included gastrointestinal symptoms, hematologic events (e.g., neutropenia), and fatigue—consistent with prior ADC experience.
A notable and clinically important toxicity is interstitial lung disease (ILD)/pneumonitis. In the primary report, adjudicated drug‑related ILD/pneumonitis occurred in 12.1% of patients treated with T‑DXd; approximately 0.8% experienced grade 5 events. The extended follow‑up reported an overall acceptable and manageable safety profile but maintained the ILD signal, necessitating vigilance.
Clinical implications: early detection, prompt interruption of T‑DXd, and corticosteroid therapy where indicated are essential. Baseline pulmonary assessment and education of patients to report new respiratory symptoms urgently are recommended. Anti‑emetic prophylaxis can mitigate nausea/vomiting signals and help preserve QoL.
Mechanistic rationale and translational insight
T‑DXd is an ADC composed of a monoclonal antibody targeting HER2 linked to a topoisomerase I inhibitor payload (deruxtecan) via a cleavable linker, with a high drug‑to‑antibody ratio (DAR). The cleavable linker and membrane‑permeable payload facilitate a bystander effect, enabling cytotoxic delivery to neighboring tumor cells with low or heterogeneous HER2 expression. This mechanism provides biological plausibility for efficacy in HER2‑low tumors where classic anti‑HER2 agents are ineffective.
Expert commentary, guidelines, and clinical applicability
DESTINY‑Breast04 establishes T‑DXd as a practice‑changing therapy for patients with HER2‑low mBC who have received prior chemotherapy, supporting its adoption as a standard of care in this setting. The survival benefit, maintained QoL, and broad magnitude of effect across HR subgroups make it an important addition to the metastatic breast cancer therapeutic landscape.
Key clinical considerations for implementation include accurate HER2 testing and reporting (IHC 1+ vs 2+/ISH‑negative), multidisciplinary discussion for patients with borderline or discordant testing, and robust ILD monitoring protocols. The HER2‑low concept is assay‑dependent and requires careful pathology review; reproducibility and interobserver variability of IHC scoring remain practical challenges.
Limitations and open questions
– HER2 testing variability: HER2‑low classification depends on IHC scoring, which can vary by assay and observer. Standardization and training are needed to ensure eligible patients are identified consistently.
– HR‑negative subgroup size: The HR‑negative cohort was relatively small; exploratory signals favoring T‑DXd warrant confirmation in larger or pooled analyses.
– Sequencing and combination therapy: Optimal sequencing relative to endocrine therapy, CDK4/6 inhibitors, and other agents remains to be defined, especially in earlier lines and in adjuvant settings. Ongoing trials will address combinations and earlier use.
– Long‑term safety: While extended follow‑up supports durable benefit, continued pharmacovigilance for ILD and other late toxicities is essential.
Conclusion
DESTINY‑Breast04 demonstrates that trastuzumab deruxtecan delivers meaningful PFS and OS benefits in HER2‑low metastatic breast cancer, preserves patient‑reported quality of life, and establishes a new therapeutic standard after prior chemotherapy. Clinicians should balance the demonstrated survival advantage with the known ILD risk by applying careful patient selection, education, baseline pulmonary assessment, and early management strategies. Further work is needed to refine HER2‑low testing, optimize sequencing, and evaluate combinations to extend benefits to broader patient populations.
Funding and clinicaltrials.gov
Funding: See the primary publications for detailed disclosures of trial sponsorship and funding sources.
ClinicalTrials.gov identifier: NCT03734029.
References
Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil‑Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY‑Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2‑Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690. Epub 2022 Jun 5. PMID: 35665782; PMCID: PMC10561652.
Modi S, Jacot W, Iwata H, Park YH, Vidal Losada M, Li W, Tsurutani J, Ueno NT, Zaman K, Prat A, Papazisis K, Rugo HS, Yamashita T, Harbeck N, Im SA, De Laurentiis M, Pierga JY, Wang X, Gombos A, Tokunaga E, Orbegoso Aguilar C, Yung L, Xiao F, Cheng Y, Cameron D. Trastuzumab deruxtecan in HER2‑low metastatic breast cancer: long‑term survival analysis of the randomized, phase 3 DESTINY‑Breast04 trial. Nat Med. 2025 Oct 8. doi: 10.1038/s41591-025-03981-4. Epub ahead of print. PMID: 41062831.
Ueno NT, Cottone F, Dunton K, Jacot W, Yamashita T, Sohn J, Tokunaga E, Prat A, Tsurutani J, Park YH, Rugo HS, Xu B, Cardoso F, Mitri Z, Mahtani R, Aguilar CO, Xiao F, Harbeck N, Cameron DA, Modi S. Patient‑reported outcomes from DESTINY‑Breast04: trastuzumab deruxtecan versus physician’s choice of chemotherapy in patients with HER2‑low mBC. Oncologist. 2025 May 8;30(5):oyaf048. doi: 10.1093/oncolo/oyaf048. PMID: 40349139; PMCID: PMC12065936.
