PIK3CA Mutational Status Is Associated with High Glycolytic Activity in ER+/HER2− Early Invasive Breast Cancer: a Molecular Imaging Study Using [18F]FDG PET/CT

Abstract

Purpose: 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. Procedures: This institutional review board-approved retrospective study included a dataset of 67 ER+/HER2− early breast cancer patients. All patients underwent 2-deoxy-2-[ 18 F]fluoro-Dglucose positron emission tomography/X-ray computed tomography ([ 18 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 [ 18 F]FDG PET/CT using maximum standardized uptake values (SUV max). SUV max 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 pretreatment contrast-enhanced magnetic resonance imaging. Results: PIK3CA mutations were present in 45 % of all tumors. Mutations were associated with a small tumor diameter (p G 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. Heinrich Magometschnigg and Katja Pinker as well as Peter Dubsky and Martin Filipits contributed equally to this work.

The role of metabolic ecosystem in cancer progression — metabolic plasticity and mTOR hyperactivity in tumor tissues

“…It has been suggested that other relatively frequent mutations like EGFR and PI3KCA activations correlate with the in situ proliferation and metabolic alterations (e.g., in non-small cell lung cancer — NSCLCs and breast carcinomas). A positive correlation was found among PET-CT SUVmax, EGFR , glycolytic activity, and PI3KCA mutation status in NSCLCs and breast carcinomas [ 31 , 32 ]. These results support the conclusion that not only TP53 and KRAS but also receptor tyrosine kinase pathway mutations are responsible for the metabolic switch to increased glycolysis and reduced OXPHOS [ 32 – 34 ].…”

“…A positive correlation was found among PET-CT SUVmax, EGFR , glycolytic activity, and PI3KCA mutation status in NSCLCs and breast carcinomas [ 31 , 32 ]. These results support the conclusion that not only TP53 and KRAS but also receptor tyrosine kinase pathway mutations are responsible for the metabolic switch to increased glycolysis and reduced OXPHOS [ 32 – 34 ]. Additionally, epigenetic alterations (e.g., hypermethylation) and PTEN suppression result in PDK1/MYC -dependent Akt/mTOR activation.…”

Assessment of the Spatial Heterogeneity of Breast Cancers: Associations Between Computed Tomography and Immunohistochemistry

“…Another specific tool under investigation has been the use of non-invasive imaging techniques such as PET using radiolabeled antibodies and in particular HER-2 PET/CT to help predict patient benefit from HER-2-directed therapies. 24–30…”

“…Another specific tool under investigation has been the use of non-invasive imaging techniques such as PET using radiolabeled antibodies and in particular HER-2 PET/CT to help predict patient benefit from HER-2-directed therapies. [24][25][26][27][28][29][30] Angiogenesis plays a driving role in cancer development and progression 31,32 and has been defined as one of the hallmarks of cancer. 33 Data from breast cancer show that angiogenesis in the primary cancer can predict for disease-free and overall survival.…”

The frequency and spectrum of PIK3CA mutations in patients with estrogen receptor-positive HER2-negative advanced breast cancer residing in various regions of Russia

“…Нарушения онкогенного сигнального каскада PI3K/Akt/mTOR встречаются практически при всех злокачественных новообразованиях человека, а соматические мутации PIK3CA выявляются примерно в 1/3 опухолей молочной железы [7][8][9]. Повреждения PIK3CA приводят к разнообразным функциональным последствиям, например, влияют на пролиферацию и выживаемость клеток, метаболические особенности, иммуногенность, предпочтительные зоны метастазирования и даже специфические паттерны роста опухоли, которые можно определить радиологически [10][11][12][13][14]. Мутации PIK3CA являются наиболее частым генетическим дефектом при ER+/HER2-РМЖ (28-47%); при этом они реже встречаются при HER2-позитивных (22-40%) и трижды негативных опухолях (8-18%) [5,7,[15][16][17].…”