PDF(Pubmed)
Abstract：
OBJECTIVE: HER3, a member of the EGFR receptor family, plays a central role in driving oncogenic cell proliferation in breast cancer. Novel HER3 therapeutics are showing promising results while recently developed HER3 PET imaging modalities aid in predicting and assessing early treatment response. However, baseline HER3 expression, as well as changes in expression while on neoadjuvant therapy, have not been well-characterized. We conducted a prospective clinical study, pre- and post-neoadjuvant/systemic therapy, in patients with newly diagnosed breast cancer to determine HER3 expression, and to identify possible resistance mechanisms maintained through the HER3 receptor.
METHODS: The study was conducted between May 25, 2018 and October 12, 2019. Thirty-four patients with newly diagnosed breast cancer of any subtype (ER ± , PR ± , HER2 ±) were enrolled in the study. Two core biopsy specimens were obtained from each patient at the time of diagnosis. Four patients underwent a second research biopsy following initiation of neoadjuvant/systemic therapy or systemic therapy which we define as neoadjuvant therapy. Molecular characterization of HER3 and downstream signaling nodes of the PI3K/AKT and MAPK pathways pre- and post-initiation of therapy was performed. Transcriptional validation of finings was performed in an external dataset (GSE122630).
RESULTS: Variable baseline HER3 expression was found in newly diagnosed breast cancer and correlated positively with pAKT across subtypes (r = 0.45). In patients receiving neoadjuvant/systemic therapy, changes in HER3 expression were variable. In a hormone receptor-positive (ER +/PR +/HER2-) patient, there was a statistically significant increase in HER3 expression post neoadjuvant therapy, while there was no significant change in HER3 expression in a ER +/PR +/HER2+ patient. However, both of these patients showed increased downstream signaling in the PI3K/AKT pathway. One subject with ER +/PR -/HER2- breast cancer and another subject with ER +/PR +/HER2 + breast cancer showed decreased HER3 expression. Transcriptomic findings, revealed an immune suppressive environment in patients with decreased HER3 expression post therapy.
CONCLUSIONS: This study demonstrates variable HER3 expression across breast cancer subtypes. HER3 expression can be assessed early, post-neoadjuvant therapy, providing valuable insight into cancer biology and potentially serving as a prognostic biomarker. Clinical translation of neoadjuvant therapy assessment can be achieved using HER3 PET imaging, offering real-time information on tumor biology and guiding personalized treatment for breast cancer patients.
METHODS: The study was conducted between May 25, 2018 and October 12, 2019. Thirty-four patients with newly diagnosed breast cancer of any subtype (ER ± , PR ± , HER2 ±) were enrolled in the study. Two core biopsy specimens were obtained from each patient at the time of diagnosis. Four patients underwent a second research biopsy following initiation of neoadjuvant/systemic therapy or systemic therapy which we define as neoadjuvant therapy. Molecular characterization of HER3 and downstream signaling nodes of the PI3K/AKT and MAPK pathways pre- and post-initiation of therapy was performed. Transcriptional validation of finings was performed in an external dataset (GSE122630).
RESULTS: Variable baseline HER3 expression was found in newly diagnosed breast cancer and correlated positively with pAKT across subtypes (r = 0.45). In patients receiving neoadjuvant/systemic therapy, changes in HER3 expression were variable. In a hormone receptor-positive (ER +/PR +/HER2-) patient, there was a statistically significant increase in HER3 expression post neoadjuvant therapy, while there was no significant change in HER3 expression in a ER +/PR +/HER2+ patient. However, both of these patients showed increased downstream signaling in the PI3K/AKT pathway. One subject with ER +/PR -/HER2- breast cancer and another subject with ER +/PR +/HER2 + breast cancer showed decreased HER3 expression. Transcriptomic findings, revealed an immune suppressive environment in patients with decreased HER3 expression post therapy.
CONCLUSIONS: This study demonstrates variable HER3 expression across breast cancer subtypes. HER3 expression can be assessed early, post-neoadjuvant therapy, providing valuable insight into cancer biology and potentially serving as a prognostic biomarker. Clinical translation of neoadjuvant therapy assessment can be achieved using HER3 PET imaging, offering real-time information on tumor biology and guiding personalized treatment for breast cancer patients.
摘要：
目的：HER3，EGFR受体家族成员，在驱动乳腺癌的致癌细胞增殖中起着核心作用。新型HER3疗法显示出有希望的结果，而最近开发的HER3PET成像方式有助于预测和评估早期治疗反应。然而,基线HER3表达，以及新辅助治疗时表达的变化，没有得到很好的表征。我们进行了一项前瞻性临床研究，新辅助/全身治疗前后，在新诊断的乳腺癌患者中确定HER3表达，并确定通过HER3受体维持的可能的抗性机制。
方法：该研究于2018年5月25日至2019年10月12日进行。34例新诊断的任何亚型乳腺癌患者（ER±，PR±,HER2±)纳入研究。在诊断时从每个患者获得两个核心活检标本。四名患者在开始新辅助/全身治疗或全身治疗后接受了第二次研究活检，我们将其定义为新辅助治疗。在治疗开始之前和之后进行HER3和PI3K/AKT和MAPK途径的下游信号传导节点的分子表征。在外部数据集(GSE122630)中进行筛选的转录验证。
结果：在新诊断的乳腺癌中发现了不同的基线HER3表达，并且与pAKT呈正相关（r=0.45）。在接受新辅助/全身治疗的患者中，HER3表达的变化是可变的。在激素受体阳性（ER/PR/HER2-）患者中，新辅助治疗后HER3表达有统计学意义的增加,而ER+/PR+/HER2+患者的HER3表达无显著变化。然而,这两名患者均显示PI3K/AKT通路下游信号传导增加.一名患有ER+/PR-/HER2-乳腺癌的受试者和另一名患有ER+/PR+/HER2+乳腺癌的受试者显示出降低的HER3表达。转录组发现,显示治疗后HER3表达降低的患者存在免疫抑制环境。
结论：本研究证实了不同乳腺癌亚型的HER3表达。HER3表达可以早期评估，新辅助治疗后，为癌症生物学提供有价值的见解，并可能作为预后生物标志物。新辅助治疗评估的临床转化可以使用HER3PET成像来实现，提供有关肿瘤生物学的实时信息，并指导乳腺癌患者的个性化治疗。
方法：该研究于2018年5月25日至2019年10月12日进行。34例新诊断的任何亚型乳腺癌患者（ER±，PR±,HER2±)纳入研究。在诊断时从每个患者获得两个核心活检标本。四名患者在开始新辅助/全身治疗或全身治疗后接受了第二次研究活检，我们将其定义为新辅助治疗。在治疗开始之前和之后进行HER3和PI3K/AKT和MAPK途径的下游信号传导节点的分子表征。在外部数据集(GSE122630)中进行筛选的转录验证。
结果：在新诊断的乳腺癌中发现了不同的基线HER3表达，并且与pAKT呈正相关（r=0.45）。在接受新辅助/全身治疗的患者中，HER3表达的变化是可变的。在激素受体阳性（ER/PR/HER2-）患者中，新辅助治疗后HER3表达有统计学意义的增加,而ER+/PR+/HER2+患者的HER3表达无显著变化。然而,这两名患者均显示PI3K/AKT通路下游信号传导增加.一名患有ER+/PR-/HER2-乳腺癌的受试者和另一名患有ER+/PR+/HER2+乳腺癌的受试者显示出降低的HER3表达。转录组发现,显示治疗后HER3表达降低的患者存在免疫抑制环境。
结论：本研究证实了不同乳腺癌亚型的HER3表达。HER3表达可以早期评估，新辅助治疗后，为癌症生物学提供有价值的见解，并可能作为预后生物标志物。新辅助治疗评估的临床转化可以使用HER3PET成像来实现，提供有关肿瘤生物学的实时信息，并指导乳腺癌患者的个性化治疗。
