Synthesis: Trastuzumab deruxtecan in HER2-low (DESTINY-Breast04)

Evidence grades (GRADE-adapted): A high — multiple well-conducted RCTs or systematic reviews converge. B moderate — single pivotal RCT or consistent observational evidence. C limited — single observational study, mechanistic, or expert consensus. D preclinical / hypothesis-generating.

Trastuzumab deruxtecan as a drug

Trastuzumab deruxtecan (T-DXd, formerly DS-8201a; trade name Enhertu) is an antibody-drug conjugate consisting of the anti-HER2 antibody trastuzumab linked via a tetrapeptide-based cleavable linker to a topoisomerase-I-inhibitor payload (DXd, a derivative of exatecan). The construct achieves a drug-to-antibody ratio of approximately 8:1, several-fold higher than the older trastuzumab emtansine (T-DM1) ratio of ~3.5:1, and the linker design enables release of payload extracellularly in the tumor microenvironment in addition to internalized release — producing a "bystander effect" that allows payload delivery to tumor cells with low or absent HER2 expression that happen to be in proximity to HER2-expressing cells^[1]A.

This bystander-effect biology motivated the hypothesis that T-DXd might benefit not only HER2-amplified breast cancer (its original indication, established by DESTINY-Breast03 vs T-DM1 in second-line HER2+ metastatic disease) but also breast cancers expressing HER2 at sub-amplification levels — the "HER2-low" category. DESTINY-Breast04 was the pivotal trial testing this hypothesis.

The HER2-low concept

Prior to 2022, HER2-low and HER2-zero tumors were treated as a single category: HER2-negative. Both were ineligible for HER2-directed therapy; HER2-targeted treatment was reserved for IHC 3+ or IHC 2+/ISH-amplified disease. The HER2-low concept reframes this division based on IHC staining intensity:

• HER2-positive (HER2-amplified): IHC 3+, or IHC 2+ with ISH-positive (HER2:CEP17 ≥ 2.0 or HER2 copy number ≥ 6.0). Eligible for full HER2-targeted therapy.
• HER2-low: IHC 1+ or IHC 2+/ISH-negative. Below the threshold for HER2-targeted therapy historically, but actionable for T-DXd post-DESTINY-Breast04.
• HER2-zero (HER2-null): IHC 0. No HER2 expression detectable by current standard IHC. Not currently eligible for T-DXd (under investigation in DESTINY-Breast06).

In historically-TNBC tumors (ER−/PR−/HER2−), approximately 45–55% fall into the HER2-low category under modern reading practices^[2]B. This is a substantial fraction; the implication is that nearly half of TNBC patients have an additional HER2-directed treatment line available that wasn't available before 2022. The remaining HER2-zero TNBC patients do not have access to T-DXd under the current label.

See the IHC for ER/PR/HER2 synthesis for the analytical-scoring details and the substantial inter-observer-agreement issues at the IHC 0 vs 1+ boundary that now determines T-DXd eligibility.

DESTINY-Breast04 — trial design and results

Modi and colleagues randomized 557 patients with previously treated HER2-low metastatic breast cancer to trastuzumab deruxtecan vs physician's choice of chemotherapy (eribulin, capecitabine, gemcitabine, nab-paclitaxel, or paclitaxel)^[3]A. Eligibility included both HR+ and HR− (the latter being the relevant subset for the TNBC population). Patients were required to have at least one prior chemotherapy in the metastatic setting and to have HER2-low status (IHC 1+ or IHC 2+/ISH−) confirmed centrally on a recent biopsy.

The primary endpoint was PFS in the HR+ subgroup (n=494, ~88% of total enrollment). Secondary endpoints included PFS in the full population and PFS in the HR− subgroup.

HR-negative subgroup — the TNBC-relevant analysis

The HR− subgroup (n=63) was small — reflecting that historically-TNBC tumors enriched for the broader trial population represent a minority of HER2-low breast cancers overall. Even so, the HR− subgroup analysis showed striking benefit:

• Median PFS: 8.5 vs 2.9 months (HR 0.46; 95% CI 0.24–0.89)
• Median OS: 18.2 vs 8.3 months (HR 0.48; 95% CI 0.24–0.95)
• Objective response rate: 50% vs 17%

The full-population (HR+ and HR− combined) primary endpoint was also positive: PFS 9.9 vs 5.1 months (HR 0.50); OS 23.4 vs 16.8 months (HR 0.64).

Regulatory consequence: the FDA approved T-DXd for HER2-low metastatic breast cancer (both HR+ and HR−) in August 2022. EMA followed in 2023. The approval covers patients who have received prior chemotherapy for metastatic disease, or who recurred within 6 months of completing adjuvant chemotherapy.

Interstitial lung disease — the defining toxicity

The most consequential T-DXd toxicity is interstitial lung disease (ILD) / pneumonitis, observed in approximately 10–15% of patients treated for any indication and in approximately 12% of patients in DESTINY-Breast04. Most cases are low-grade (grade 1 or 2) but a small minority are grade 3 or higher; grade 5 (fatal) ILD has occurred in approximately 0.5–1% of patients across the T-DXd program^[4]A.

Management is guided by a published algorithm:

• Grade 1 (asymptomatic radiographic findings): withhold T-DXd, monitor with serial imaging, consider corticosteroids per pulmonologist input. Restart cautiously if resolution to baseline.
• Grade 2 (symptomatic but not requiring oxygen): withhold T-DXd permanently; treat with corticosteroids (1 mg/kg prednisone or equivalent).
• Grade 3+ (oxygen-requiring or ICU): permanent discontinuation; high-dose corticosteroids; consider IVIG and second-line immunosuppression.

Risk factors for ILD include prior lung radiation, prior pulmonary disease, low body weight, renal impairment, and elevated baseline LDH. Monitoring includes baseline chest CT, periodic imaging during treatment, and prompt evaluation of any new respiratory symptoms. Pulmonology consultation is standard for any suspected ILD case.

Other notable T-DXd toxicities include nausea (~70%, often requiring scheduled triple antiemetic therapy), fatigue, alopecia, low blood counts, and cardiac toxicity (decreased left ventricular ejection fraction; less common than with older HER2-targeted therapies but warranting baseline and serial echocardiography).

DESTINY-Breast06 — HER2-ultralow expansion

DESTINY-Breast06 tested T-DXd in patients with HR+ metastatic breast cancer including a HER2-ultralow subgroup (defined as IHC 0 with faint, incomplete membrane staining in > 10% of tumor cells — an interpretation between HER2-zero and HER2-low). The trial was positive in 2024, with the HER2-ultralow subgroup showing PFS benefit comparable to the HER2-low subgroup^[5]A. This led to expansion of the T-DXd label in 2024/2025 to include HER2-ultralow HR+ breast cancer.

A parallel investigation in HER2-ultralow HR− (TNBC) disease has not yet had a definitive positive randomized readout as of mid-2026. The biology hypothesis is the same: bystander-effect-mediated payload delivery should not require high HER2 expression. Whether this hypothesis holds for the HR− subset and whether it extends to truly HER2-zero (IHC 0 without faint staining) disease are open questions, with ongoing trials.

Practical sequencing implications for metastatic TNBC

With both sacituzumab govitecan and T-DXd available for the HER2-low TNBC subset, current practice patterns:

• First-line metastatic: dictated by PD-L1 CPS and germline BRCA status (see first-line synthesis). T-DXd is not first-line for TNBC.
• Second-line metastatic, HER2-low: sacituzumab govitecan or T-DXd; sequence informed by toxicity considerations (avoid T-DXd in patients with significant pulmonary baseline; avoid sacituzumab in patients with neutropenia history or severe diarrhea) and by patient-specific factors.
• Third-line metastatic, HER2-low: whichever ADC was not used in second-line.
• HER2-zero TNBC: sacituzumab is the only ADC option until DESTINY-Breast15 or equivalent reads out positively for HER2-ultralow / HER2-zero TNBC.

A persistent operational issue: HER2-low status is determined from the most recent biopsy. Patients with archival primary-tumor HER2 IHC alone may need a fresh biopsy at metastatic recurrence to confirm HER2-low eligibility, particularly if the primary was scored a decade ago using pre-2018 criteria. Discordance between primary tumor and metastasis HER2 scoring is documented at 15–25% — meaning a patient initially called HER2-zero on archival tissue may have HER2-low metastatic disease, or vice versa^[6]B.

Evidence table

Open questions and active investigation

• HER2-ultralow and HER2-zero TNBC. The HER2-ultralow HR+ subgroup was positive in DESTINY-Breast06; whether the HR− equivalent shows the same benefit is the most consequential next data point. If positive, T-DXd becomes an option for nearly all metastatic TNBC patients regardless of HER2 status.
• HER2 IHC harmonization for the 0 vs 1+ boundary. Inter-pathologist agreement at the boundary that now determines T-DXd eligibility is poor (kappa ~0.26 in some studies). Digital-pathology AI assist is the most plausible remediation; FDA-cleared devices are likely within 2–3 years.
• Earlier-line T-DXd in TNBC. Several trials are testing T-DXd in first-line metastatic TNBC, particularly in HR− HER2-low (DESTINY-Breast15 and others). If positive, T-DXd may compete with sacituzumab in earlier lines.
• Sequencing with sacituzumab. Limited prospective data on optimal sequence; retrospective series show some cross-resistance with diminishing magnitude of benefit on the second ADC. Direct randomized comparison (e.g., TROPION-Breast03-style) would substantially inform practice.
• Adjuvant T-DXd in HER2-low residual disease. The DESTINY-Breast05 trial in HER2-positive residual disease is reading out; HER2-low equivalent trials are early-stage. If positive, T-DXd may compete with sacituzumab in the adjuvant residual-disease space.
• Long-term ILD risk and survivorship. The cumulative ILD risk with extended treatment duration in long-responding patients is not well characterized; trials with mature follow-up are needed.

For the sacituzumab companion (alternative ADC in the same setting), see Sacituzumab govitecan (ASCENT). For the HER2-low IHC analytical questions, see IHC for ER/PR/HER2 and the TNBC definition. For the first-line decision tree, see First-line metastatic synthesis. For the patient-layer companion, see Treatment options.

References

Each citation links to the original publication via DOI. The same records are searchable in the evidence library by title or DOI.

1. Ogitani Y, Aida T, Hagihara K, et al. DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1. Clin Cancer Res. 2016;22(20):5097–5108. doi:10.1158/1078-0432.CCR-15-2822. ↩
2. Tarantino P, Hamilton E, Tolaney SM, et al. HER2-Low Breast Cancer: Pathological and Clinical Landscape. J Clin Oncol. 2020;38(17):1951–1962. doi:10.1200/JCO.19.02488. ↩
3. Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer (DESTINY-Breast04). N Engl J Med. 2022;387(1):9–20. doi:10.1056/NEJMoa2203690. ↩
4. Powell CA, Modi S, Iwata H, et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open. 2022;7(4):100554. doi:10.1016/j.esmoop.2022.100554. ↩
5. Bardia A, Hu X, Dent R, et al. Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer (DESTINY-Breast06). N Engl J Med. 2024;391(22):2110–2122. doi:10.1056/NEJMoa2407932. ↩
6. Tarantino P, Gandini S, Nicolò E, et al. Evolution of low HER2 expression between early and advanced-stage breast cancer. Eur J Cancer. 2022;163:35–43. doi:10.1016/j.ejca.2021.12.022. ↩

Last reviewed: 2026-06-04. Researcher-layer synthesis page. Evidence grades follow the GRADE-adapted rubric defined at the top of this page.