三阴性乳腺癌雄激素受体研究进展
刘晓丽，姜达，崔彦芝
河北医科大学第四医院肿瘤内科
在TNBC中有着多种信号通路靶点，单靶点药物对TNBC的疗效可能有限。基于前期临床研究证实多个信号通路之间的交互作用，而对单通路抑制的靶向治疗可能会激活代偿通路。在研究AR信号通路实验中，许多其他的信号通路及信号因子表现出对AR下游信号活动的调节作用，包括磷脂酰肌醇3-激酶（PI3K）/ATK/MAPK、PTEN、P53及细胞周期因子。因而许多学者正在探索联合靶向治疗在TNBC中的效果。在乳腺癌中，AR表达与PI3K基因突变相关。在TNBC中，AR阳性的患者PI3K基因突变率高。Lehmann等的研究显示，对比其他亚型TNBC，LAR亚型对PI3K抑制剂敏感性最高。而一项来自荷兰的报告显示，野生型PIK3CA患者接受曲妥珠单抗联合拉帕替尼治疗的整体病理学完全缓解率（pCR）达53.1%，而在PIK3CA活化突变患者中pCR降至28.6%。由此可见，PI3K高突变影响单靶点靶向治疗的疗效。
J Clin Oncol. 2015;33(12):1334-9.
PIK3CA Mutations Are Associated With Decreased Benefit to Neoadjuvant Human Epidermal Growth Factor Receptor 2-Targeted Therapies in Breast Cancer.
Majewski IJ, Nuciforo P, Mittempergher L, Bosma AJ, Eidtmann H, Holmes E, Sotiriou C, Fumagalli D, Jimenez J, Aura C, Prudkin L, Díaz-Delgado MC, de la Pena L, Loi S, Ellis C, Schultz N, de Azambuja E, Harbeck N, Piccart-Gebhart M, Bernards R, Baselga J.
The Netherlands Cancer Institute, Amsterdam, the Netherlands; Vall D'Hebron Institute of Oncology; Spanish Breast Cancer Cooperative Group SOLTI, Barcelona, Spain; University Hospital Kiel, Kiel; University of Munich, Munich, Germany; Frontier Science Scotland, Kincraig, United Kingdom; Institut Jules Bordet, Université Libre de Bruxelles; BrEAST Data Center and Institut Jules Bordet, Brussels, Belgium; Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; GlaxoSmithKline, Collegeville, PA; Memorial Sloan-Kettering Cancer Center, New York, NY.
PURPOSE: We investigated whether mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) correlates with response to neoadjuvant human epidermal growth factor receptor 2 (HER2) -targeted therapies in patients with breast cancer.
PATIENTS AND METHODS: Baseline tissue biopsies were available from patients with HER2-positive early breast cancer who were enrolled onto the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (NeoALTTO). Activating mutations in PIK3CA were identified using mass spectrometry-based genotyping.
RESULTS: PIK3CA mutations were identified in 23% of HER2-positive breast tumors, and these mutations were associated with poorer outcome in all of the treatment arms. Patients treated with a combination of trastuzumab and lapatinib who had wild-type PIK3CA obtained a total pathologic complete response (pCR) rate of 53.1%, which decreased to 28.6% in patients with tumors that carried PIK3CA activating mutations (P = .012).
CONCLUSION: Activating mutations in PIK3CA predicted poor pCR in patients with HER2-positive breast cancer treated with neoadjuvant therapies that target HER2. Consequently, the combination of anti-HER2 agents and PI3K inhibitors is being investigated.
PMID: 25559818
DOI: 10.1200/JCO.2014.55.2158