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Differences in Responses to Neoadjuvant Anti-HER2 Therapy between HER2 2+/ISH+ and HER2 3+ in HER2-Positive Breast
Lingjun Ma1, Ran Zheng1, Lingyun Xu2
1Department of Breast Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Purpose:
Dual anti-human epidermal growth factor receptor 2 (HER2) drugs have become the standard regimen for neoadjuvant systemic treatment (NST) to HER2-positive breast cancer patients. However, the efficacy varies greatly among patients with different HER2 protein expression levels.
Materials And Methods:
A total of 575 HER2-positive breast cancer patients from multiple centers throughout China from 2013 to 2022 were retrospectively analyzed. We compared clinicopathological features in different HER2 immunohistochemistry classes (HER2 2+/in situ hybridization [ISH] + or HER2 3+), and their difference in response to NST and survival with single or dual anti-HER2 drugs. Drug sensitivity assays were used to evaluate different efficacy of anti-HER2 drugs in vitro.
Results:
Compared to HER2 3+ subgroup, the HER2 2+/ISH+ group had a higher proportion of hormone receptor-positive status (48.7% vs. 76.1%, p < 0.001), more HER2 protein loss after NST, lower pathological complete response (pCR) rate (46.07% vs. 16.24%, p < 0.001), and tended to have worse disease-free survival (DFS). In HER2 2+/ISH+ patients, treated with pertuzumab and trastuzumab in combination had no significant improvement in pCR (19.12% vs. 12.24%, p=0.287) and DFS (p=0.908) than using alone. Drug sensitivity assay showed poor efficacy with dual anti-HER2 drugs in HER2 2+/ISH+ cell lines; however, fam-trastuzumab deruxtecan drugs had a satisfactory effect.
Conclusion:
Owing to the differences in clinicopathological features and treatment efficacy, we considered the HER2 2+/ISH+ group to be a distinct subtype and defined it as the HER2-moderate-positive subgroup. In this subgroup, dual anti-HER2 drugs did not exert significant improvement in pCR and DFS. Therefore, treatment optimization is warranted, with antibody-drug conjugate drugs as potential options.
Insights
Dual anti-HER2 therapies show varied efficacy in HER2-positive breast cancer. Patients with HER2-moderate-positive (HER2 2+ISH+) disease benefit less, suggesting a need for optimized treatments like antibody-drug conjugates.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Dual anti-HER2 therapy is standard for HER2-positive breast cancer.
- Treatment efficacy varies based on HER2 protein expression levels.
Purpose of the Study:
- To compare clinicopathological features and treatment response in HER2 2+ISH+ versus HER2 3+ breast cancer patients.
- To evaluate the efficacy of single vs. dual anti-HER2 drugs in HER2-moderate-positive breast cancer.
- To explore novel therapeutic options for HER2-moderate-positive breast cancer.
Main Methods:
- Retrospective analysis of 575 HER2-positive breast cancer patients.
- Comparison of clinicopathological features and response to neoadjuvant systemic treatment (NST).
- In vitro drug sensitivity assays for anti-HER2 drugs.
Main Results:
- HER2 2+ISH+ patients had higher HR+ rates, more HER2 loss post-NST, lower pathological complete response (pCR) rates, and worse disease-free survival (DFS).
- Dual anti-HER2 therapy did not significantly improve pCR or DFS in HER2 2+ISH+ patients compared to single-agent therapy.
- In vitro assays showed poor efficacy of dual anti-HER2 drugs in HER2 2+ISH+ cell lines, but T-DXd demonstrated satisfactory effects.
Conclusions:
- HER2 2+ISH+ breast cancer represents a distinct subtype (HER2-moderate-positive) with different characteristics and treatment responses.
- Dual anti-HER2 drugs offer limited benefit for HER2-moderate-positive patients.
- Antibody-drug conjugates (ADCs) are promising therapeutic options for this subgroup.
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