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Differences in Responses to Neoadjuvant Anti-HER2 Therapy between HER2 2+ISH+ and HER2 3+ in HER2-Positive Breast Cancer
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Lingjun Ma, Ran Zheng, Lingyun Xu, Ying Zhu, Hong Yin, Xiaoqing Zhang, Rong Deng, Jue Wang, Xiaoming Zha
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Received December 12, 2024 Accepted April 18, 2025 Published online April 21, 2025
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DOI: https://doi.org/10.4143/crt.2024.1200
[Accepted]
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 Abstract
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- Purpose
Dual anti-HER2 drugs has become the standard regimen for neoadjuvant systematic 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 IHC classes (HER2 2+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 HR+ status (48.7% vs. 76.1%; p < 0.001), more HER2 protein loss after NST, lower pCR rate (46.07% vs. 16.24%; p < 0.001), and tended to have worse 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, T-Dxd 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 (HER2-mod) subgroup. In this subgroup, dual anti-HER2 drugs did not exert significant improvement in pCR and DFS. Therefore, treatment optimization is warranted, with ADC drugs as potential options.
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