Research advances and new challenges in overcoming triple-negative breast cancer.
Research advances and new challenges in overcoming triple-negative breast cancer.
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DOI：
10.20517/cdr.2021.04
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Pegram M
中科院分区：
文献类型：
--
作者：
Zong Y;Pegram M
三阴性乳腺癌（TNBC）是一个病理学术语，用于识别缺乏雌激素和孕激素受体表达且不存在HER 2受体病理性过表达或ERBB 2基因扩增的浸润性乳腺癌。TNBC包括基于基因组、转录组和表型表征的多种不同疾病实体的集合。尽管随着新疗法的开发，临床结果有所改善，但TNBC仍然是所有乳腺癌临床亚型中预后最差的。我们将系统地回顾TNBC基因组进化的证据，以及疾病进展和治疗耐药性的潜在机制，部分由下一代DNA测序技术（包括单细胞测序）的进展定义，提供治疗策略的新视角，并有望揭示新的潜在治疗靶点。此外，我们还综述了针对同源重组缺陷、PI 3激酶/AKT/PTEN通路激活、雄激素受体阻断、免疫检查点抑制以及结合新型细胞表面靶点的抗体-药物缀合物的新疗法，包括临床前和临床研究的最新进展，这些研究进一步验证了靶向疗法在TNBC中的作用。尽管在TNBC治疗方面取得了重大进展，包括FDA批准2种PARP抑制剂用于转移性TNBC，在生殖系BRCA突变的高风险HER 2阴性早期乳腺癌早期患者中进行的3期安慰剂对照研究中，奥拉帕尼辅助治疗的优效性边界被跨越，FDA批准2种PD-（L）1检查点抗体用于转移性TNBC，以及FDA批准用于TNBC的第一抗体药物缀合物，仍然存在重大挑战。例如，尽管在转移性TNBC中免疫疗法的曙光，但持久的应答仅限于一小部分患者，缺乏用于患者选择的确定性生物标志物，并且FDA的肿瘤学药物咨询委员会最近投票反对批准抗PD-1检查点抗体高风险早期TNBC用于新辅助治疗。此外，尽管转移性TNBC中AKT抑制的早期阳性随机2期研究，但最近的3期注册试验未能验证早期2期数据。最后，我们注意到雄激素受体阻断剂在TNBC中的临床疗效的一级证据仍然缺乏。为了应对这些和其他挑战，我们将对基础，转化和临床研究的兴趣持续指数增长进行分类，以开发TNBC的新治疗模式。
Triple-negative breast cancer (TNBC) is a pathological term used to identify invasive breast cancers that lack expression of estrogen and progesterone receptors and do not have pathologic overexpression of the HER2 receptor or harbor ERBB2 gene amplification. TNBC includes a collection of multiple distinct disease entities based upon genomic, transcriptomic and phenotypic characterization. Despite improved clinical outcomes with the development of novel therapeutics, TNBC still yields the worst prognosis among all clinical subtypes of breast cancer. We will systematically review evidence of the genomic evolution of TNBC, as well as potential mechanisms of disease progression and treatment resistance, defined in part by advances in next-generation DNA sequencing technology (including single cell sequencing), providing a new perspective on treatment strategies, and promise to reveal new potential therapeutic targets. Moreover, we review novel therapies aimed at homologous recombination deficiency, PI3 kinase/AKT/PTEN pathway activation, androgen receptor blockade, immune checkpoint inhibition, as well as antibody-drug conjugates engaging novel cell surface targets, including recent progress in pre-clinical and clinical studies which further validate the role of targeted therapies in TNBC. Despite major advances in treatment for TNBC, including FDA approval of 2 PARP inhibitors for metastatic TNBC, the crossing of the superiority boundary in a phase 3, placebo-controlled study of adjuvant olaparib in early-stage patients with germline BRCA-mutated high-risk HER2-negative early breast cancer, the FDA approval of 2 PD-(L)1 checkpoint antibodies for metastatic TNBC, and the FDA approval of the first antibody drug conjugate for TNBC, significant challenges remain. For example, despite the dawn of immunotherapy in metastatic TNBC, durable responses are limited to a small subset of patients, definitive biomarkers for patient selection are lacking, and the Oncology Drug Advisory Committee to the FDA has recently voted against approval of an anti-PD-1 checkpoint antibody high risk early-stage TNBC in the neoadjuvant setting. Also, despite early positive randomized phase 2 studies of AKT inhibition in metastatic TNBC, a recent phase 3 registration trial failed to validate earlier phase 2 data. Finally, we note that level one evidence for clinical efficacy of androgen receptor blockade in TNBC is still lacking. To meet these and other challenges, we will catalogue the ongoing exponential increase in interest in basic, translational, and clinical research to develop new treatment paradigms for TNBC.
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影响因子：
3.1
作者：
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