BACKGROUND Metaplastic breast cancer (MBC) is a rare form of breast cancer characterized by an aggressive clinical presentation, with a poor response to standard chemotherapy. MBCs are typically triple-negative breast cancers (TNBCs), frequently with alterations to genes of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways. The objective of this study was to determine the response to PI3K and MAPK pathway inhibitors in patient-derived xenografts (PDXs) of MBCs with targetable alterations. METHODS We compared survival between triple-negative MBCs and other histological subtypes, in a clinical cohort of 323 TNBC patients. PDX models were established from primary breast tumors classified as MBC. PI3K-AKT-mTOR and RTK-MAPK pathway alterations were detected by targeted next-generation sequencing (NGS) and analyses of copy number alterations. Activation of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways was analyzed with reverse-phase protein arrays (RPPA). PDXs carrying an activating mutation of PIK3CA and genomic changes to the RTK-MAPK signaling pathways were treated with a combination consisting of a PI3K inhibitor and a MEK inhibitor. RESULTS In our clinical cohort, the patients with MBC had a worse prognosis than those with other histological subtypes. We established nine metaplastic TNBC PDXs. Three had a pathogenic mutation of PIK3CA and additional alterations to genes associated with RTK-MAPK signaling. The MBC PDXs expressed typical EMT and stem cell genes and were of the mesenchymal or mesenchymal stem-like TNBC subtypes. On histological analysis, MBC PDXs presented squamous or chondroid differentiation. RPPA analysis showed activation of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways. In vivo, the combination of PI3K and MAPK inhibitors displayed marked antitumor activity in PDXs carrying genomic alterations of PIK3CA, AKT1, BRAF, and FGFR4. CONCLUSION The treatment of metaplastic breast cancer PDXs by activation of the PI3K-AKT-mTOR and RTK-MAPK pathways at the genomic and protein levels with a combination of PI3K and MEK inhibitors resulted in tumor regression in mutated models and may therefore be of interest for therapeutic purposes.

中文翻译：

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PI3K和MEK抑制剂的组合在PIK3CA突变的化生性乳腺癌的PDX模型中产生持久的缓解。

背景技术化生性乳腺癌（MBC）是一种罕见的乳腺癌，其特征是侵袭性的临床表现，对标准化学疗法的反应较差。MBC通常是三阴性乳腺癌（TNBC），通常伴随着PI3K-AKT-mTOR和RTK-MAPK信号通路基因的改变。这项研究的目的是确定具有目标性改变的患者MBC异种移植物（PDXs）对PI3K和MAPK途径抑制剂的反应。方法我们比较了323例TNBC患者的临床队列中三阴性MBC与其他组织学亚型之间的生存率。从分类为MBC的原发性乳腺肿瘤建立PDX模型。PI3K-AKT-mTOR和RTK-MAPK途径的改变是通过靶向下一代测序（NGS）和拷贝数改变的分析来检测的。PI3K-AKT-mTOR和RTK-MAPK信号通路的激活用反相蛋白阵列（RPPA）分析。携带PIK3CA活化突变和RTK-MAPK信号通路基因组变化的PDX用PI3K抑制剂和MEK抑制剂组合处理。结果在我们的临床队列中，MBC患者的预后比其他组织学亚型的患者差。我们建立了九个化生的TNBC PDX。其中三个发生了PIK3CA的致病性突变，并且与RTK-MAPK信号传导相关的基因发生了其他改变。MBC PDXs表达典型的EMT和干细胞基因，属于间充质或间充质干样TNBC亚型。根据组织学分析，MBC PDXs呈现鳞状或软骨样分化。RPPA分析显示PI3K-AKT-mTOR和RTK-MAPK信号通路被激活。在体内，PI3K和MAPK抑制剂的组合在带有PIK3CA，AKT1，BRAF和FGFR4基因组改变的PDX中显示出显着的抗肿瘤活性。结论通过在基因组和蛋白质水平上激活PI3K-AKT-mTOR和RTK-MAPK途径与PI3K和MEK抑制剂的组合来治疗化生性乳腺癌PDX，可导致突变模型中的肿瘤消退，因此可能是引起人们兴趣的治疗目的。