Santarpia Libero, Bottai Giulia, Kelly Catherine M, Győrffy Balázs, Székely Borbala, Pusztai Lajos
Oncology Experimental Therapeutics, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Clinical and Research Institute, Milan, Italy
Oncology Experimental Therapeutics, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Clinical and Research Institute, Milan, Italy.
Oncologist. 2016 Sep;21(9):1063-78. doi: 10.1634/theoncologist.2015-0369. Epub 2016 Jul 6.
: Advances in DNA and RNA sequencing revealed substantially greater genomic complexity in breast cancer than simple models of a few driver mutations would suggest. Only very few, recurrent mutations or copy-number variations in cancer-causing genes have been identified. The two most common alterations in breast cancer are TP53 (affecting the majority of triple-negative breast cancers) and PIK3CA (affecting almost half of estrogen receptor-positive cancers) mutations, followed by a long tail of individually rare mutations affecting <1%-20% of cases. Each cancer harbors from a few dozen to a few hundred potentially high-functional impact somatic variants, along with a much larger number of potentially high-functional impact germline variants. It is likely that it is the combined effect of all genomic variations that drives the clinical behavior of a given cancer. Furthermore, entirely new classes of oncogenic events are being discovered in the noncoding areas of the genome and in noncoding RNA species driven by errors in RNA editing. In light of this complexity, it is not unexpected that, with the exception of HER2 amplification, no robust molecular predictors of benefit from targeted therapies have been identified. In this review, we summarize the current genomic portrait of breast cancer, focusing on genetic aberrations that are actively being targeted with investigational drugs.
Next-generation sequencing is now widely available in the clinic, but interpretation of the results is challenging, and its impact on treatment selection is often limited. This work provides an overview of frequently encountered molecular abnormalities in breast cancer and discusses their potential therapeutic implications. This review emphasizes the importance of administering investigational targeted therapies, or off-label use of approved targeted drugs, in the context of a formal clinical trial or registry programs to facilitate learning about the clinical utility of tumor target profiling.
DNA和RNA测序技术的进步揭示了乳腺癌的基因组复杂性远高于少数驱动突变的简单模型所表明的情况。在致癌基因中，仅发现了极少数的复发性突变或拷贝数变异。乳腺癌中两种最常见的改变是TP53突变（影响大多数三阴性乳腺癌）和PIK3CA突变（影响近一半的雌激素受体阳性癌症），其次是一长串个别罕见的突变，影响不到1%-20%的病例。每个癌症都含有几十到几百个潜在具有高功能影响的体细胞变异，以及数量更多的潜在具有高功能影响的种系变异。很可能是所有基因组变异的综合作用驱动了特定癌症的临床行为。此外，在基因组的非编码区域和由RNA编辑错误驱动的非编码RNA物种中，正在发现全新类型的致癌事件。鉴于这种复杂性，除了HER2扩增外，尚未发现从靶向治疗中获益的可靠分子预测指标，这并不意外。在本综述中，我们总结了乳腺癌目前的基因组概况，重点关注正在被研究药物积极靶向的基因畸变。
下一代测序目前在临床上已广泛可用，但结果的解读具有挑战性，其对治疗选择的影响往往有限。这项工作概述了乳腺癌中常见的分子异常，并讨论了它们潜在的治疗意义。本综述强调了在正式的临床试验或注册项目背景下给予研究性靶向治疗或批准的靶向药物的非标签使用的重要性，以促进了解肿瘤靶点分析的临床效用。
