Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection.
Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection.
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DOI：
10.1371/journal.pone.0157368
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Pietenpol JA
中科院分区：
文献类型：
--
作者：
Lehmann BD;Jovanović B;Chen X;Estrada MV;Johnson KN;Shyr Y;Moses HL;Sanders ME;Pietenpol JA
三阴性乳腺癌（TNBC）是一种异质性疾病，可通过基因表达谱分为不同的分子亚型。 TNBC 被认为是一种难以治疗的癌症，一小部分患者可从新辅助化疗中显着受益，并且总体生存率要好得多。除了 BRCA1/2 突变状态之外，不存在生物标志物来识别最有可能对当前化疗产生反应的患者；迄今为止，尚无 FDA 批准的针对 TNBC 患者的靶向治疗方法。此前，我们开发了一种方法来识别 TNBC 的六种分子亚型（TNBC 型），每种亚型都表现出独特的本体论和对标准化疗的不同反应。考虑到肿瘤标本不同组织学景观的复杂性，我们使用组织病理学定量和激光捕获显微切割来确定先前描述的免疫调节（IM）和间充质干细胞样（MSL）亚型中的转录物分别来自浸润淋巴细胞和肿瘤相关基质细胞。因此，我们将 TNBC 分子亚型从六种（TNBC 型）细化为四种（TNBC 4 型）肿瘤特异性亚型（BL1、BL2、M 和 LAR），并证明了诊断年龄、分级、局部和远处疾病进展以及组织病理学方面的差异。使用五个公开的新辅助化疗乳腺癌基因表达数据集，我们回顾性评估了 300 多名 TNBC 患者的化疗反应，这些患者来自使用内在 (PAM50) 或 TNBC 类型方法进行亚型治疗的活检。 TNBC 患者的综合分析表明，TNBC 亚型对类似新辅助化疗的反应存在显着差异，BL1 患者中有 41% 达到病理完全缓解，而 BL2 患者为 18%，LAR 患者为 29%，置信区间为 95%（CI 分别为 [33, 51]、[9, 28]、[17, 41]）。总的来说，我们提供的临床前数据可以为临床试验提供信息，这些数据旨在检验这样的假设：如果现有化疗的选择和组合是根据分子 TNBC 亚型的知识来指导，则可以为 TNBC 患者实现改善的结果。
Triple-negative breast cancer (TNBC) is a heterogeneous disease that can be classified into distinct molecular subtypes by gene expression profiling. Considered a difficult-to-treat cancer, a fraction of TNBC patients benefit significantly from neoadjuvant chemotherapy and have far better overall survival. Outside of BRCA1/2 mutation status, biomarkers do not exist to identify patients most likely to respond to current chemotherapy; and, to date, no FDA-approved targeted therapies are available for TNBC patients. Previously, we developed an approach to identify six molecular subtypes TNBC (TNBCtype), with each subtype displaying unique ontologies and differential response to standard-of-care chemotherapy. Given the complexity of the varying histological landscape of tumor specimens, we used histopathological quantification and laser-capture microdissection to determine that transcripts in the previously described immunomodulatory (IM) and mesenchymal stem-like (MSL) subtypes were contributed from infiltrating lymphocytes and tumor-associated stromal cells, respectively. Therefore, we refined TNBC molecular subtypes from six (TNBCtype) into four (TNBCtype-4) tumor-specific subtypes (BL1, BL2, M and LAR) and demonstrate differences in diagnosis age, grade, local and distant disease progression and histopathology. Using five publicly available, neoadjuvant chemotherapy breast cancer gene expression datasets, we retrospectively evaluated chemotherapy response of over 300 TNBC patients from pretreatment biopsies subtyped using either the intrinsic (PAM50) or TNBCtype approaches. Combined analysis of TNBC patients demonstrated that TNBC subtypes significantly differ in response to similar neoadjuvant chemotherapy with 41% of BL1 patients achieving a pathological complete response compared to 18% for BL2 and 29% for LAR with 95% confidence intervals (CIs; [33, 51], [9, 28], [17, 41], respectively). Collectively, we provide pre-clinical data that could inform clinical trials designed to test the hypothesis that improved outcomes can be achieved for TNBC patients, if selection and combination of existing chemotherapies is directed by knowledge of molecular TNBC subtypes.