World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access
Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc
Journal website https://wjon.elmerpub.com

Review

Volume 17, Number 2, April 2026, pages 129-142

Advances in Targeted Therapy for Human Epidermal Growth Factor Receptor 2-Low Tumors: From Trastuzumab to Antibody-Drug Conjugates

Figures

↓  Figure 1. Major signaling pathways of human epidermal growth factor receptor (HER) family. There are four HER family members, HER1 to HER4. The dimerization and phosphorylation of HER activate several signaling pathways and then regulate cell activities.
Figure 1.
↓  Figure 2. The mechanisms of trastuzumab’s antitumor effect. Trastuzumab binds to human epidermal growth factor receptor 2 (HER2) to form the trastuzumab-HER2 complex, then inhibits the activity of several downstream signaling pathways. VEGF: vascular endothelial growth factor; MMPs: matrix metalloproteinases.
Figure 2.

Tables

↓  Table 1. The Definition and Testing Criteria of Four Types of HER2 Status
 
Type Definition Testing standards
IHC FISH
HER2: human epidermal growth factor receptor 2; CEP17: chromosome enumeration probe; FISH: fluorescence in situ hybridization; ISH: in situ hybridization; IHC: immunohistochemistry.
HER2-positive Overexpression or gene amplification of HER2 protein on the surface of tumor cells. 3+: strong and intact cell membrane staining (> 10% tumor cells) HER2/CEP17 ratio ≥ 2.0, or HER2 gene copy number ≥ 6.0/cell
HER2-negative Tumor cells do not have HER2 overexpression or gene amplification. 0: no staining or weak/incomplete staining (≤ 10% tumor cells) HER2/CEP17 ratio < 2.0, and the HER2 gene copy number was < 4.0/cell
Low HER2 expression HER2 protein expression and gene amplification on the surface of tumor cells are between positive and negative. 2+: > 10% of cells, membrane staining is weak to moderate and completely stained and ISH-negative. 1+: > in 10% of cells, membrane staining was weak to moderate and completely stained and ISH-negative 2+ but ISH-negative: moderate intact or incomplete membrane staining without HER2 gene amplification (HER2/CEP17 ratio < 2.0 and HER2 gene copy number < 4.0/cell)
Ultra-low HER2 expression HER2 protein expression and gene amplification on the surface of tumor cells ranged from low expression to negative. 0: no cell membrane staining or only weak, incomplete membrane staining Negative: HER2/CEP17 ratio < 2.0, and HER2 gene copy number < less than 4.0/cell

 

↓  Table 2. The action Characteristics of Trastuzumab and Trastuzumab-Drug Conjugate (T-DC)
 
Mechanism Trastuzumab T-DC
HER2: human epidermal growth factor receptor 2; IHC: immunohistochemistry; ISH: in situ hybridization; ADCC: antibody-dependent cell-mediated cytotoxicity.
Primary target HER2-high expression (IHC 3+ or ISH+) Low HER2 expression (IHC 1+/2+ or ultra-low expression)
Central Blocking of signaling pathways, ADCC effects Targeted delivery of cytotoxins, bystander effects
Dependence Relies on HER2-high expression and immune microenvironment Depends on HER2 internalization efficiency and linker stability
Applicable tumor type Breast cancer, gastric cancer (HER2-positive) Pan-solid tumors such as breast cancer, gastric cancer, and colorectal cancer
Mechanisms of resistance HER2 downstream signaling pathway activation and ADCC escape HER2 expression was lost and the drug efflux pump was upregulated

 

↓  Table 3. Characteristics, Mechanism of Action and Clinical Application of the Two Types of Trastuzumab-Drug Conjugate (T-DC)
 
Characteristic Trastuzumab emtansine (T-DM1) Trastuzumab deruxtecan (T-DXd)
HER2: human epidermal growth factor receptor 2.
Connector Non-cleavable Cleavable
Load Microtubule inhibitor Topoisomerase I inhibitor
Drug-antibody ratio 3.5 8
Bystander effect Limited Significant
Indications HER2-positive breast cancer HER2-positive/-low breast cancer, gastric cancer
Efficacy of brain metastases Limited Significant
Major toxicity Thrombocytopenia, hepatotoxicity Interstitial lung disease, gastrointestinal toxicity

 

↓  Table 4. Details of Several T-DXd trials
 
Trial name Stage Crowd Interventions Key efficacy endpoints References
mBC: metastatic breast cancer; TPC: treatment of the physician’s choice; OS: overall survival; CI: confidence interval; CR: complete response; DCR: disease control rate; DoR: duration of response; ORR: objective response rate; PFS: progression-free survival; PR: partial response; CR: complete response; TTR: time to response; CBR: clinical benefit rate; HER2: human epidermal growth factor receptor 2; T-DXd: trastuzumab deruxtecan; ITT: intent-to-treat; IHC: immunohistochemistry.
DESTINY-PanTumor02 II Patients with previously treated, locally advanced or metastatic HER2-expressing (IHC 3+/2+) solid tumors (including endometrium, cervix, ovary, bladder, biliary tract, pancreas and other cancers) T-DXd For all patients: confirmed ORR: 37.1% (95% CI, 31.3–43.2); median PFS: 6.9 months (95% CI, 5.6–8.0); median OS: 13.4 months (95% CI, 11.9–15.5) [54]
For centrally confirmed IHC 3+ patients: confirmed ORR: 61.3% (95% CI, 49.4–72.4); median PFS: 11.9 months (95% CI, 8.2–13.0); median OS: 21.1 months (95% CI, 15.3–29.6)
DESTINY-Breast04 III Patients with prior chemotherapy, unresectable or metastatic HER2-low expression (IHC 1+ or IHC 2+/ISH–) breast cancer T-DXd vs. chemotherapy of doctor’s choice (TPC) Median PFS: 10.1 vs. 5.4 months (T-DXd vs. TPC); median OS 23.9 vs. 17.5 months (T-DXd vs. TPC) [55]
DESTINY-Breast06 III Patients with HR-positive, HER2-low, or very low-expressing mBC who have progressed after at least first-line endocrine therapy and have not received metastatic chemotherapy T-DXd vs. chemotherapy of doctor’s choice (TPC: capecitabine/albumin paclitaxel/paclitaxel) For HER2-low expression population: median PFS: 13.2 vs. 8.1 months (T-DXd vs. TPC). [56]
For ITT population, including very low HER2 expression): median PFS: 13.2 vs. 8.1 months.
DESTINY-Gastric02 II Patients with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen T-DXd Confirmed ORR: 41·8% (95% CI, 30·8–53·4); median PFS: 5.6 months (95% CI, 4.2–8.3); median OS: 12.1 months (95% CI, 9.4–15.4); median DoR: 8.1 months (95% CI, 5.9–NE); DCR: 81.0% (64/79; 95% CI, 70.6–89.0); median TTR: 1.4 months (95% CI, 1.4–2.7); CR: 5.1%; PR: 36.7%. [57]
DAISY II Patients with mBC stratified by HER2 expression level into three cohorts: HER2-overexpressing, HER2-low, and HER2-non-expressing T-DXd Primary endpoint (confirmed ORR): cohort 1, 70.6% (95%, CI 58.3–81); cohort 2, 37.5% (95% CI, 26.4–49.7); cohort 3, 29.7% (95% CI, 15.9–47). [58]
Secondary endpoints (median PFS): cohort 1, 11.1 months (95% CI, 8.5–14.4); cohort 2, 6.7 months (95% CI, 4.4–8.3); cohort 3, 4.2 months (95% CI, 2.0–5.7)
Median OS (not fully mature at data cutoff): cohort 1 and cohort 2, not reached; cohort 3, 11.6 months.
CBR: cohort 1, 85.3%; cohort 2, 56.9%; cohort 3, 35.1%.
DoR: cohort 1, 9.7 months; cohort 2, 7.6 months; cohort 3, 6.8 months.