Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Italy.
Unit of Medical Oncology, Department of Translational Research and New Technologies in Medicine, University of Pisa, Italy.
Pharmacol Res. 2021 Jan;163:105241. doi: 10.1016/j.phrs.2020.105241. Epub 2020 Oct 10.
PI3K pathway hyperactivation due to PIK3CA mutations contributes to endocrine resistance, and PIK3CA is one of the most frequently mutated genes in breast cancer (BC), occurring approximately 40 % of HR+, HER2- advanced BC (ABC). Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have changed the treatment landscape of HR+, HER2- ABC. Putative mechanisms of resistance to CDK4/6i have been identified, but limited data are available on PI3K deregulation. The present study evaluates the impact of PIK3CA mutations on CDK4/6i plus hormone therapy and evaluates potential characteristics that may suggest for a PI3K screening in patients with ABC.
ABC patients were enrolled, and 12 mL of blood were collected in EDTA tubes at baseline prior to CDK4/6i plus hormone therapy. Plasma was separated and circulating free DNA (cfDNA) was extracted. PIK3CA mutation analysis was performed on a ddPCR. Selected and analyzed mutations included: p.C420R, p.E542 K, p.E545A, p.E545D, p.E545G, p.E545K, p.Q546E, p.Q546R, p.H1047L, p.H1047R, p.H1047Y. Statistical analysis were performed to investigate the predictive power of such mutations and any association with clinical factors.
Thirty patients were enrolled. PIK3CA mutation status at baseline was independently associated with shorter median PFS (7.44 vs 12.9 months, p = 0.01) in subject receiving CDK4/6i plus hormone therapy. PIK3CA mutations were found to be associated to Ki67 expression in primary lesions (p = 0.006). Moreover, the probability to find a PI3K mutation improved considering also the therapeutic management in previous lines of treatment (McFadden's R = 0.415, p = 0.004; AUC of the ROC curve = 0.914).
The findings of this pilot study suggest that the presence of a PI3K mutation in liquid biopsy correlates with a worse PFS in patients with ABC receiving CDK4/6i, and that liquid biopsy is a useful tool to suggests a better tailored pharmacological intervention.
PI3K 通路的过度激活归因于 PIK3CA 突变，导致内分泌耐药，PIK3CA 是乳腺癌（BC）中突变频率最高的基因之一，约占 HR+、HER2-晚期 BC（ABC）的 40%。细胞周期蛋白依赖性激酶 4 和 6 抑制剂（CDK4/6i）改变了 HR+、HER2-ABC 的治疗格局。已经确定了对 CDK4/6i 产生耐药的潜在机制，但关于 PI3K 失调的数据有限。本研究评估了 PIK3CA 突变对 CDK4/6i 联合激素治疗的影响，并评估了 ABC 患者中可能提示进行 PI3K 筛查的潜在特征。
ABC 患者入组，在接受 CDK4/6i 联合激素治疗前，于 EDTA 管中采集 12mL 血液。分离血浆并提取循环游离 DNA（cfDNA）。在 ddPCR 上进行 PIK3CA 突变分析。选择并分析的突变包括：p.C420R、p.E542K、p.E545A、p.E545D、p.E545G、p.E545K、p.Q546E、p.Q546R、p.H1047L、p.H1047R、p.H1047Y。进行统计学分析以研究这些突变的预测能力及其与临床因素的任何关联。
共纳入 30 例患者。在接受 CDK4/6i 联合激素治疗的患者中，基线时 PIK3CA 突变状态与较短的中位 PFS 独立相关（7.44 与 12.9 个月，p=0.01）。PI3K 突变与原发性病变中的 Ki67 表达相关（p=0.006）。此外，考虑到前几线治疗中的治疗管理，发现 PI3K 突变的概率提高（McFadden's R=0.415，p=0.004；ROC 曲线的 AUC=0.914）。
这项初步研究的结果表明，在接受 CDK4/6i 的 ABC 患者中，液体活检中存在 PI3K 突变与较差的 PFS 相关，液体活检是一种有用的工具，可以提示更好的个体化药物干预。
