World J Oncol

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

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 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.

**Table 1.** The Definition and Testing Criteria of Four Types of HER2 Status
Type	Definition	Testing standards
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 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 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 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

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.

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

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

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

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.