Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing, China.
Pharmacogenomic Unit, Department of Genetics, Curie Institute, PSL Research University, Paris, France.
J Hematol Oncol. 2018 Oct 11;11(1):124. doi: 10.1186/s13045-018-0670-9.
Postmenopausal women with large, hormone receptor (HR)-positive/HER2-negative and low-proliferative breast cancer derived a benefit from neoadjuvant endocrine therapy (NET) in the CARMINA02 trial. This study was designed to correlate gene expression and mutation profiles with both response to NET and prognosis.
Gene expression profiling using RNA sequencing was performed in 86 pre-NET and post-NET tumor samples. Targeted next-generation sequencing of 91 candidate breast cancer-associated genes was performed on DNA samples from 89 patients. Molecular data were correlated with radiological response and relapse-free survival.
The transcriptional profile of tumors to NET in responders involved immune-associated genes enriched in activated Th1 pathway, which remained unchanged in non-responders. Immune response was confirmed by analysis of tumor-infiltrating lymphocytes (TILs). The percentage of TILs was significantly increased post-NET compared to pre-NET samples in responders (p = 0.0071), but not in non-responders (p = 0.0938). Gene expression revealed that lipid metabolism was the main molecular function related to prognosis, while PPARγ is the most important upstream regulator gene. The most frequently mutated genes were PIK3CA (48.3%), CDH1 (20.2%), PTEN (15.7%), TP53 (10.1%), LAMA2 (10.1%), BRCA2 (9.0%), MAP3K1 (7.9%), ALK (6.7%), INPP4B (6.7%), NCOR1 (6.7%), and NF1 (5.6%). Cell cycle and apoptosis pathway and PIK3CA/AKT/mTOR pathway were altered significantly more frequently in non-responders than in responders (p = 0.0017 and p = 0.0094, respectively). The average number of mutations per sample was significantly higher in endocrine-resistant tumors (2.88 vs. 1.64, p = 0.03), but no difference was observed in terms of prognosis. ESR1 hotspot mutations were detected in 3.4% of treatment-naive tumors.
The Th1-related immune system and lipid metabolism appear to play key roles in the response to endocrine therapy and prognosis in HR-positive/HER2-negative breast cancer. Deleterious somatic mutations in the cell cycle and apoptosis pathway and PIK3CA/AKT/mTOR pathway may be relevant for clinical management.
This trial is registered with ClinicalTrials.gov ( NCT00629616 ) on March 6, 2008, retrospectively registered.
在 CARMINA02 试验中，接受新辅助内分泌治疗（NET）的绝经后、激素受体（HR）阳性/HER2 阴性且增殖率低的乳腺癌患者获益。本研究旨在将基因表达和突变谱与 NET 反应和预后相关联。
对 86 例 NET 前和 NET 后肿瘤样本进行 RNA 测序的基因表达谱分析。对 89 例患者的 DNA 样本进行 91 个候选乳腺癌相关基因的靶向下一代测序。分子数据与放射学反应和无复发生存相关联。
应答者 NET 诱导的肿瘤转录谱涉及富含激活 Th1 途径的免疫相关基因，而非应答者的这些基因无变化。肿瘤浸润淋巴细胞（TILs）分析证实了免疫反应。与 NET 前样本相比，应答者的 TILs 百分比在 NET 后明显增加（p=0.0071），而非应答者则没有（p=0.0938）。基因表达显示，脂质代谢是与预后相关的主要分子功能，而 PPARγ 是最重要的上游调节基因。最常突变的基因是 PIK3CA（48.3%）、CDH1（20.2%）、PTEN（15.7%）、TP53（10.1%）、LAMA2（10.1%）、BRCA2（9.0%）、MAP3K1（7.9%）、ALK（6.7%）、INPP4B（6.7%）、NCOR1（6.7%）和 NF1（5.6%）。与应答者相比，非应答者的细胞周期和凋亡途径以及 PIK3CA/AKT/mTOR 途径的改变更为频繁（p=0.0017 和 p=0.0094）。内分泌耐药肿瘤的平均突变数明显更高（2.88 与 1.64，p=0.03），但预后无差异。在未经治疗的肿瘤中检测到 ESR1 热点突变，占 3.4%。
Th1 相关免疫系统和脂质代谢似乎在 HR 阳性/HER2 阴性乳腺癌对内分泌治疗的反应和预后中发挥关键作用。细胞周期和凋亡途径以及 PIK3CA/AKT/mTOR 途径中的有害体细胞突变可能与临床管理相关。
本试验于 2008 年 3 月 6 日在 ClinicalTrials.gov（NCT00629616）上注册，为回顾性注册。
