Department of Biomedical Imaging and Image-guided Therapy, Molecular and Gender Imaging, Medical University of Vienna, Vienna, Austria.
Department of Radiology, Breast Imaging Service, Memorial Sloan Kettering Cancer Center, New York, USA.
Mol Imaging Biol. 2019 Oct;21(5):991-1002. doi: 10.1007/s11307-018-01308-z.
In PIK3CA mutant breast cancer, downstream hyperactivation of the PI3K/AKT/mTOR pathway may be associated with increased glycolysis of cancer cells. The purpose of this study was to investigate the functional association of PIK3CA mutational status and tumor glycolysis in invasive ER+/HER2- early breast cancer.
This institutional review board-approved retrospective study included a dataset of 67 ER+/HER2- early breast cancer patients. All patients underwent 2-deoxy-2-[F]fluoro-D-glucose positron emission tomography/X-ray computed tomography ([F]FDG PET/CT) and clinico-pathologic assessments as part of a prospective study. For this retrospective analysis, pyrosequencing was used to detect PIK3CA mutations of exons 4, 7, 9, and 20. Tumor glucose metabolism was assessed semi-quantitatively with [F]FDG PET/CT using maximum standardized uptake values (SUV). SUV values were corrected for the partial volume effect, and metabolic tumor volume was calculated using the volume of interest automated lesion growing function 2D tumor size, i.e., maximum tumor diameter was assessed on concurrent pre-treatment contrast-enhanced magnetic resonance imaging.
PIK3CA mutations were present in 45 % of all tumors. Mutations were associated with a small tumor diameter (p < 0.01) and with low nuclear grade (p = 0.04). Glycolytic activity was positively associated with nuclear grade (p = 0.01), proliferation (p = 0.002), regional lymph node metastasis (p = 0.015), and metabolic tumor volume (p = 0.001) but not with tumor size/T-stage. In invasive ductal carcinomas, median SUV was increased in PIK3CA-mutated compared to wild-type tumors; however, this increase did not reach statistical significance (p = 0.05). Multivariate analysis of invasive ductal carcinomas revealed [F]FDG uptake to be independently associated with PIK3CA status (p = 0.002) and nuclear tumor grade (p = 0.046). Size, volume, and regional nodal status had no influence on glycolytic activity. PIK3CA mutational status did not influence glycolytic metabolism in lobular carcinomas. Glycolytic activity and PIK3CA mutational status had no significant influence on recurrence-free survival or disease-specific survival.
In ER+/HER2- invasive ductal carcinomas of the breast, glucose uptake is independently associated with PIK3CA mutations. Initial data suggest that [F]FDG uptake reflects complex genomic alterations and may have the potential to be used as candidate biomarker for monitoring therapeutic response and resistance mechanisms in emerging therapies that target the PI3K/AKT/mTOR pathway.
在 PIK3CA 突变型乳腺癌中，PI3K/AKT/mTOR 通路的下游过度激活可能与癌细胞糖酵解增加有关。本研究旨在探讨 PIK3CA 突变状态与浸润性 ER+/HER2-早期乳腺癌肿瘤糖酵解之间的功能相关性。
这项经机构审查委员会批准的回顾性研究纳入了 67 例 ER+/HER2-早期乳腺癌患者的数据。所有患者均接受了 2-脱氧-2-[F]氟代-D-葡萄糖正电子发射断层扫描/X 射线计算机断层扫描([F]FDG PET/CT)和临床病理评估，作为一项前瞻性研究的一部分。在这项回顾性分析中，焦磷酸测序用于检测外显子 4、7、9 和 20 的 PIK3CA 突变。通过 [F]FDG PET/CT 利用最大标准化摄取值(SUV)半定量评估肿瘤葡萄糖代谢。SUV 值经过部分容积效应校正，代谢肿瘤体积通过使用兴趣区自动生长功能 2D 肿瘤大小(即同时进行的对比增强磁共振成像上评估的最大肿瘤直径)进行计算。
所有肿瘤中，PIK3CA 突变的比例为 45%。突变与肿瘤直径较小有关(p<0.01)，与核分级较低有关(p=0.04)。糖酵解活性与核分级呈正相关(p=0.01)，与增殖(p=0.002)、区域淋巴结转移(p=0.015)和代谢肿瘤体积(p=0.001)相关，但与肿瘤大小/T 分期无关。在浸润性导管癌中，与野生型肿瘤相比，PIK3CA 突变型肿瘤的 SUV 中位数增加，但未达到统计学意义(p=0.05)。浸润性导管癌的多变量分析显示，[F]FDG 摄取与 PIK3CA 状态(p=0.002)和核肿瘤分级(p=0.046)独立相关。大小、体积和区域淋巴结状态对糖酵解活性没有影响。PIK3CA 突变状态不影响乳腺小叶癌的糖酵解代谢。糖酵解活性和 PIK3CA 突变状态对无复发生存率或疾病特异性生存率没有显著影响。
在 ER+/HER2-浸润性乳腺导管癌中，葡萄糖摄取与 PIK3CA 突变独立相关。初步数据表明，[F]FDG 摄取反映了复杂的基因组改变，可能有潜力作为监测治疗反应和新兴治疗中靶向 PI3K/AKT/mTOR 通路的耐药机制的候选生物标志物。
