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TP53突变在三阴性和HER2阳性乳腺癌蒽环类/紫杉类新辅助化疗中的作用

2016-09-12 肿瘤标靶 SIBCS


  编者按:以下数据来自德国研究结果,无法完全代表中国患者实际情况和临床医生具体意见。以下原文为在线预先发表版,并非最终正式发表版。以下文字由谷歌翻译提供支持,欢迎留言提出修改建议,谢谢!


  TP53突变常见于乳腺癌,然而其对化疗效果的临床意义存在争议。


  2016年9月7日,美国《肿瘤标靶》在线发表柏林大学夏里特医学院附属医院、德国癌症联盟、海德堡大学医院、美国麻省总医院(马萨诸塞州综合医院)、慕尼黑血液肿瘤医院、基尔石勒苏益格-荷斯坦大学附属医院、柏林女性肿瘤医院乳腺中心、慕尼黑技术大学、法兰克福贝桑尼血液肿瘤中心、埃森米特医院、奥芬巴赫萨纳医院、罗斯托克城南医院、澳大利亚彼得·麦卡勒姆癌症中心、柏林布赫赫利俄斯医院、德国乳腺组织的研究报告,探讨了TP53突变在三阴性和HER2阳性乳腺癌蒽环类/紫杉类新辅助化疗中的作用。


  该研究将450例在Ⅱ期新辅助研究(GeparSixto)中接受过治疗、经福尔马林固定、空芯针穿刺活检石蜡包埋的HER2阳性和三阴性乳腺癌(TNBC)标本作为对象,对TP53基因外显子5~8进行桑格测序(双脱氧链终止法)。TP53水平与新辅助蒽环类/紫杉类化疗±卡铂+曲妥珠单抗/拉帕替尼用于HER2阳性乳腺癌和贝伐珠单抗用于TNBC的效果进行关联。通过免疫组织化学评估TNBC亚组的p53蛋白表达。


  结果发现,在450例乳腺癌样本中,297例(66.0%)为TP53突变。TNBC与HER2阳性乳腺癌相比,突变率显著较高(74.8%比55.4%,P<0.0001)。无论整个研究组还是各个分子亚型,无论突变还是不同突变类型和效应均与病理学完全缓解(pCR)无相关性(各个P>0.05)。错义突变与其他所有突变类型相比,在TNBC(P=0.093)和HER2阳性乳腺癌(P=0.071)中与较好的生存有相关性(但不显著)。在TNBC中,错义突变还与肿瘤浸润淋巴细胞(TIL)数量较高有显著相关性(P=0.028)。p53蛋白质过度表达还与生存改善有显著相关性(P=0.019)。


  因此,虽然该研究证实TNBC和HER2阳性乳腺癌的TP53突变率高,但是突变无法预测这两个乳腺癌分子亚型对密集新辅助化疗的效果。


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Oncotarget. 2016 Sep 7. [Epub ahead of print]


Role of TP53 mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy.


Darb-Esfahani S, Denkert C, Stenzinger A, Salat C, Sinn B, Schem C, Endris V, Klare P, Schmitt W, Blohmer JU, Weichert W, Mobs M, Tesch H, Kümmel S, Sinn P, Jackisch C, Dietel M, Reimer T, Loi S, Untch M, von Minckwitz G, Nekljudova V, Loibl S.


Charité Universitatsmedizin Berlin, Berlin, Germany; German Cancer Consortium, Berlin, Germany; University Hospital Heidelberg, Heidelberg, Germany; Massachusetts General Hospital, Boston, MA, USA; Hamatoonkologische Schwerpunktpraxis, Munich, Germany; University Hospital Schleswig-Hostein, Kiel, Germany; Praxisklinik Krebsheilkunde für Frauen/Brustzentrum, Berlin, Germany; Technical University Munich, Munich, Germany; Center for Hematology and Oncology Bethanien, Frankfurt/Main, Germany; Breast Unit, Kliniken Essen Mitte, Essen, Germany; Sana Klinikum Offenbach, Offenbach, Germany; Klinikum Südstadt Rostock, Rostock, Germany; Peter MacCallum Cancer Centre, St Andrews Place East Melbourne, Victoria Australia, Australia; Helios Klinikum Berlin-Buch, Berlin, Germany; German Breast Group c/o (GBG Forschungs GmbH), Neu-Isenburg, Germany.


BACKGROUND: TP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial.


METHODS: 450 pre-therapeutic, formalin-fixed, paraffin-embedded core biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC. p53 protein expression was evaluated by immunohistochemistry in the TNBC subgroup.


RESULTS: Of 450 breast cancer samples 297 (66.0%) were TP53 mutant. Mutations were significantly more frequent in TNBC (74.8%) compared to HER2-positive cancers (55.4%, P < 0.0001). Neither mutations nor different mutation types and effects were associated with pCR neither in the whole study group nor in molecular subtypes (P > 0.05 each). Missense mutations tended to be associated with a better survival compared to all other types of mutations in TNBC (P = 0.093) and in HER2-positive cancers (P = 0.071). In TNBC, missense mutations were also linked to higher numbers of tumor-infiltrating lymphocytes (TILs, P = 0.028). p53 protein overexpression was also linked with improved survival (P = 0.019).


CONCLUSIONS: Our study confirms high TP53 mutation rates in TNBC and HER2-positive breast cancer. Mutations did not predict the response to an intense neoadjuvant chemotherapy in these two molecular breast cancer subtypes.


KEYWORDS: HER2; TP53; mutation; pathological complete response; triple negative breast cancer


PMID: 27611952


DOI: 10.18632/oncotarget.11891














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