PI3K mutations detected in liquid biopsy are associated to reduced sensitivity to CDK4/6 inhibitors in metastatic breast cancer patients
PI3K mutations detected in liquid biopsy are associated to reduced sensitivity to CDK4/6 inhibitors in metastatic breast cancer patients
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DOI：
10.1016/j.phrs.2020.105241
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发表时间：
2021-01-17
影响因子：
9.3
通讯作者：
Cucchiara, Federico
中科院分区：
文献类型：
--
作者：
Del Re, Marzia;Crucitta, Stefania;Cucchiara, Federico
背景资料：由于PIK 3CA突变导致的PI 3 K通路过度活化导致内分泌抵抗，PIK 3CA是乳腺癌（BC）中最常见的突变基因之一，约40%的HR+、HER 2-晚期BC（ABC）发生。细胞周期蛋白依赖性激酶4和6抑制剂（CDK 4/6 i）改变了HR+、HER 2- ABC的治疗前景。已经确定了对CDK 4/6 i的抗性的假定机制，但关于PI 3 K失调的数据有限。本研究评估了PIK 3CA突变对CDK 4/6 i加激素治疗的影响，并评估了可能提示ABC患者PI 3 K筛查的潜在特征。方法：ABC患者入组，在CDK 4/6 i加激素治疗前基线时收集12 mL血液置于EDTA管中。分离血浆并提取循环游离DNA（cfDNA）。在ddPCR上进行PIK 3CA突变分析。选择并分析的突变包括：p.C420R、p.E542 K、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，以调查这种突变的预测能力和任何与临床factors.Results：30例患者入组。在接受CDK 4/6 i加激素治疗的受试者中，基线时的PIK 3CA突变状态与较短的中位PFS（7.44 vs 12.9个月，p = 0.01）独立相关。发现PIK 3CA突变与原发性病变中的Ki 67表达相关（p = 0.006）。此外，考虑到先前治疗线中的治疗管理，发现PI 3 K突变的概率也有所提高（McFadden R-2 = 0.415，p = 0.004; ROC曲线的AUC = 0.914）。这项初步研究的结果表明，液体活检中PI 3 K突变的存在与接受CDK 4/6 i治疗的ABC患者的PFS较差相关，并且液体活检是一种有用的工具，可以建议更好的定制药物干预。
Background: 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.Methods: 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.Results: 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-2 = 0.415, p = 0.004; AUC of the ROC curve = 0.914).Conclusion: 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.