Lien Huang-Chun, Lo Chiao, Lee Yi-Hsuang, Lin Po-Hang, Wang Ming-Yang, Kuo Wen-Hung, Tsai Li-Wei, Lu Yen-Shen, Hu Hsiang-Wei, Li Yu-Chia, Huang Chiun-Sheng
Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan.
Breast Cancer Res. 2024 Jun 12;26(1):100. doi: 10.1186/s13058-024-01852-3.
Immunohistochemistry (IHC) and in situ hybridization (ISH) remain standard biomarkers for therapeutic decisions in human epidermal growth factor 2 (HER2)-positive breast cancers (BCs); however, they are insufficient to explain the heterogeneous anti-HER2 response.
We aimed to investigate the correlation of in situ HER2 RNA expression (isHRE), using RNAscope, with HER2 biomarkers and the impact of isHRE on the pathological complete response (pCR) rates of 278 patients with HER2 IHC/fluorescence ISH (FISH)-positive BC receiving neoadjuvant chemotherapy and anti-HER2 targeted treatment (NCTT).
We validated HER2 RNAscope scoring as a semiquantitative method to determine isHRE and showed a positive correlation between RNAscope scores and pCR rates, with particularly different rates between patients with a score of 5 versus 1-4 BCs (66.7% vs. 15.9%, p < 0.0001). There were higher RNAscope scores and pCR rates in patients with HER2 IHC 3 + versus IHC 2+/FISH + BCs and HER2 RNAscope scores and pCR rates showed similar non-linear positive correlations with HER2 copy numbers and HER2/centromere 17 ratios. Moreover, in each HER2-positive IHC/FISH category, higher pCR rates were observed in patients with RNAscope scores of 5 versus 1-4 BC. Patients achieving pCR had BCs with notably higher HER2 RNAscope scores. Multivariate analysis identified HER2 RNAscope 5 as a strong pCR predictor [odds ratio = 10.865, p < 0.001]. The combined impact of multivariate analysis-defined pCR predictors demonstrated that a higher pCR rate was observed in patients with a score of 5 versus a score of 1-4 BCs regardless of the status of hormone receptor and mono-or dual anti-HER2 blockade.
Our results demonstrated that high isHRE (RNAscope score 5) is a strong pCR predictor in patients with HER2-positive BCs receiving NCTT, highlighting the complementary role of isHRE in stratifying HER2 status in tissue. Such stratification is relevant to anti-HER2 therapeutic efficacy, particularly using the cutoff of score 1-4 versus 5.
免疫组织化学（IHC）和原位杂交（ISH）仍然是人类表皮生长因子2（HER2）阳性乳腺癌（BC）治疗决策的标准生物标志物；然而，它们不足以解释抗HER2反应的异质性。
我们旨在研究使用RNAscope检测的原位HER2 RNA表达（isHRE）与HER2生物标志物之间的相关性，以及isHRE对278例接受新辅助化疗和抗HER2靶向治疗（NCTT）的HER2 IHC/荧光ISH（FISH）阳性BC患者病理完全缓解（pCR）率的影响。
我们验证了HER2 RNAscope评分作为确定isHRE的半定量方法，并显示RNAscope评分与pCR率之间呈正相关，评分5分的患者与1-4分的BC患者的pCR率差异尤为明显（66.7%对15.9%，p<0.0001）。HER2 IHC 3+与IHC 2+/FISH+的BC患者中，RNAscope评分和pCR率更高，且HER2 RNAscope评分和pCR率与HER2拷贝数和HER2/着丝粒17比值呈相似的非线性正相关。此外，在每个HER2阳性IHC/FISH类别中，RNAscope评分为5分的患者与1-4分的BC患者相比，pCR率更高。实现pCR的患者的BC具有明显更高的HER2 RNAscope评分。多因素分析确定HER2 RNAscope 5为强pCR预测因子[比值比=10.865，p<0.001]。多因素分析定义的pCR预测因子的综合影响表明，无论激素受体状态和单药或双药抗HER2阻断情况如何，评分为5分的患者与1-4分的BC患者相比，pCR率更高。
我们的结果表明，高isHRE（RNAscope评分5）是接受NCTT的HER2阳性BC患者的强pCR预测因子，突出了isHRE在组织中分层HER2状态的补充作用。这种分层与抗HER2治疗疗效相关，特别是使用评分1-4与5的临界值时。
