Maddox Adam L, Brehove Matthew S, Eliato Kiarash R, Saftics Andras, Romano Eugenia, Press Michael F, Mortimer Joanne, Jones Veronica, Schmolze Daniel, Seewaldt Victoria L, Jovanovic-Talisman Tijana
Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA.
Cancers (Basel). 2022 Jun 4;14(11):2795. doi: 10.3390/cancers14112795.
Trastuzumab, the prototype HER2-directed therapy, has markedly improved survival for women with HER2-positive breast cancers. However, only 40-60% of women with HER2-positive breast cancers achieve a complete pathological response to chemotherapy combined with HER2-directed therapy. The current diagnostic assays have poor positive-predictive accuracy in identifying therapy-responsive breast cancers. Here, we deployed quantitative single molecule localization microscopy to assess the molecular features of HER2 in a therapy-responsive setting. Using fluorescently labeled trastuzumab as a probe, we first compared the molecular features of HER2 in trastuzumab-sensitive (BT-474 and SK-BR-3) and trastuzumab-resistant (BT-474 and JIMT-1) cultured cell lines. Trastuzumab-sensitive cells had significantly higher detected HER2 densities and clustering. We then evaluated HER2 in pre-treatment core biopsies from women with breast cancer undergoing neoadjuvant therapy. A complete pathological response was associated with a high detected HER2 density and significant HER2 clustering. These results established the nano-organization of HER2 as a potential signature of therapy-responsive disease.
曲妥珠单抗作为HER2靶向治疗的原型药物，显著提高了HER2阳性乳腺癌女性患者的生存率。然而，只有40%-60%的HER2阳性乳腺癌女性患者对化疗联合HER2靶向治疗有完全病理反应。目前的诊断检测方法在识别对治疗有反应的乳腺癌方面阳性预测准确性较差。在此，我们采用定量单分子定位显微镜技术来评估治疗反应环境下HER2的分子特征。使用荧光标记的曲妥珠单抗作为探针，我们首先比较了曲妥珠单抗敏感（BT-474和SK-BR-3）和曲妥珠单抗耐药（BT-474和JIMT-1）培养细胞系中HER2的分子特征。曲妥珠单抗敏感细胞检测到的HER2密度和聚集程度显著更高。然后，我们评估了接受新辅助治疗的乳腺癌女性患者治疗前的核心活检组织中的HER2。完全病理反应与检测到的HER2高密度和显著的HER2聚集有关。这些结果确定了HER2的纳米组织作为治疗反应性疾病的潜在标志。
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