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HER2阳性乳腺癌包括HER2高表达型、管腔A型、管腔B型、基底细胞样型、正常细胞样型，大约分别占67%、15%、11%、6%、2%。不过，大约20%～60%的HER2阳性或HER2高表达型乳腺癌抗HER2治疗后未获完全缓解。 2020年1月20日，英国《自然》旗下《自然通讯》在线发表西班牙乳腺癌研究协作组、巴塞罗那大学、帕多瓦大学、巴伦西亚大学、莱里达大学、马德里大学、加泰罗尼亚理工大学、圣地亚哥大学、巴利阿里群岛大学、卡斯特利翁大学的研究报告，分析了乳腺癌细胞株和PAMELA研究HER2阳性或HER2高表达乳腺癌术前拉帕替尼＋曲妥珠单抗新辅助治疗之前、期间、之后的基因表达数据。 该研究发现，无论患者肿瘤还是体外模型，HER2双药阻断都可能诱发HER2高表达型乳腺癌变为增殖指数较低的管腔A型乳腺癌。激素受体阳性乳腺癌与激素受体阴性乳腺癌相比，这些生物学变化尤其显著。有趣的是，抗HER2治疗诱发的管腔A型乳腺癌，对CDK4/6抑制剂的敏感性反而提高。此外，体外HER2靶向治疗中止或抗HER2治疗获得性耐药，可能引起原来HER2高表达表现型恢复。 因此，该研究结果证实持续抗HER2治疗的作用，以及CDK4/6抑制剂对亚型变化的治疗作用。 相关链接 Nat Commun. 2020 Jan 20. [Epub ahead of print] Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade. Fara Brasó-Maristany, Gaia Griguolo, Tomás Pascual, Laia Paré, Paolo Nuciforo, Antonio Llombart-Cussac, Begona Bermejo, Mafalda Oliveira, Serafín Morales, Noelia Martínez, Maria Vidal, Barbara Adamo, Olga Martínez, Sonia Pernas, Rafael López, Montserrat Munoz, Núria Chic, Patricia Galván, Isabel Garau, Luis Manso, Jesús Alarcón, Eduardo Martínez, Sara Gregorio, Roger R. Gomis, Patricia Villagrasa, Javier Cortés, Eva Ciruelos, Aleix Prat. Hospital Clínic de Barcelona, Barcelona, Spain; August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain; University of Padova, Padova, Italy; Istituto Oncologico Veneto, Padova, Italy; SOLTI Breast Cancer Research Group, Barcelona, Spain; Vall d'Hebrón University Hospital, Barcelona, Spain; Vall d'Hebron Institute of Oncology, Barcelona, Spain; Hospital Universitario Arnau de Vilanova, Valencia, Spain; Hospital Clínico Universitario de Valencia, Valencia, Spain; Hospital Universitario Arnau de Vilanova, Lleida, Spain; Hospital Universitario Ramón y Cajal, Madrid, Spain; Institut Catala d'Oncologia, Avinguda de la Gran Via de l'Hospitalet, Hospitalet de Llobregat, Spain; Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain; Hospital Son Llàtzer, Palma de Mallorca, Spain; Hospital Universitario 12 de Octubre, Madrid, Spain; Hospital Universitario Son Espases, Palma de Mallorca, Spain; Consorcio Hospitalario Provincial de Castellón, Castellón de la Plana, Spain; Institute for Research in Biomedicine, Barcelona, Spain; Institute of Oncology, Quiron Group, Barcelona, Spain. The HER2-enriched (HER2-E) subtype within HER2-positive (HER2+) breast cancer is highly addicted to the HER2 pathway. However, ~20-60% of HER2+/HER2-E tumors do not achieve a complete response following anti-HER2 therapies. Here we evaluate gene expression data before, during and after neoadjuvant treatment with lapatinib and trastuzumab in HER2+/HER2-E tumors of the PAMELA trial and breast cancer cell lines. Our results reveal that dual HER2 blockade in HER2-E disease induces a low-proliferative Luminal A phenotype both in patient's tumors and in vitro models. These biological changes are more evident in hormone receptor-positive (HR+) disease compared to HR-negative disease. Interestingly, increasing the luminal phenotype with anti-HER2 therapy increased sensitivity to CDK4/6 inhibition. Finally, discontinuation of HER2-targeted therapy in vitro, or acquired resistance to anti-HER2 therapy, leads to restoration of the original HER2-E phenotype. Our findings support the use of maintenance anti-HER2 therapy and the therapeutic exploitation of subtype switching with CDK4/6 inhibition. SUBJECTS: Breast cancer; Gene expression; Oncology DOI: 10.1038/s41467-019-14111-3
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