非小egfr获得性耐药的肿瘤时空异质性研究

Spatiotemporal T790M Heterogeneity in Individual Patients with EGFR-mutant Non-small Cell Lung Cancer after Acquired Resistance to EGFR-TKI.
Abstract
INTRODUCTION:
Epidermal growth factor receptor (EGFR) mutation T790M accounts for approximately half of acquired resistances to EGFR-tyrosine kinase inhibitor (TKI). Since T790M is mediated by TKI exposure, its penetration and "on-off" may affect T790M status.
METHODS:
We retrospectively reviewed T790M status and clinical course of patients who had undergone multiple rebiopsies after acquired resistance to EGFR-TKI.
RESULTS:
Of 145 patients with EGFR-mutant NSCLC receiving rebiopsy after acquired resistance, 30 underwent multiple site rebiopsies, and 24 received repeated rebiopsies at the same lesion. In 22 patients who underwent rebiopsies from both central nervous system (CNS) (20 cerebrospinal fluids [CSF] and 2 brain tumoral tissues) and thoracic lesions (7 lung tissues, 14 pleural effusions, and 1 lymph node), 12 were thoracic-T790M-positive. Of these 12 patients, 10 were CNS-T790M-negative, despite exhibiting thoracic-T790M-positive. All 10 thoracic-T790M-negatives were CNS-T790M-negative. Three patients revealed a spatial heterogeneous T790M status among their thoracic lesions. In 24 patients receiving repeated rebiopsies at the same lesion (12 lung tissues, 6 CSFs, and 6 pleural effusions), T790M status of lung lesions varied in 5 patients after TKI-free interval. In all 5 patients whose T790M status changed from positive to negative, EGFR-TKI rechallenge was effective. In 3 of these 5 patients, after further TKI exposure, T790M status changed from negative to positive again. There was also a patient whose CSF T790M status changed from negative to positive after high-dose erlotinib therapy.
145个非小细胞肺癌egfr突变的病人在获得性耐药后接受活检，30个多部位，24个同部位重复活检。22个患者中枢神经系统活检（20个脑脊液，2个脑肿瘤组织），至于胸部7个肺组织、14个胸腔积液、1个淋巴结。12个胸组织患者t790m阳性，其中10个中枢神经t790m阴性。所有10个胸组织t790m阴性中枢神经t790m也阴性。3个患者在他们的肺组织显示空间的异质性。24个接受重复活检的患者（12个肺组织，6个脑脊液，6个胸腔积液）中，其中5个患者在tki空窗后肺组织的t790m发生变化，这5个患者其t790m从阳性变为阴性，5个中3个egfr tki重新有效。又过一段时间，服药的3人t790m又从阴性到阳性。也有1个患者经过高剂量的厄洛替尼治疗后其中枢神经t790m从阴性到阳性。
CONCLUSIONS:
T790M status in an individual patient can be spatiotemporally heterogeneous due to selective pressure from EGFR-TKI.
PMID:
26309190
[PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/26309190

结论：
个体患者的T790突变状态因EFGR-TKI治疗的选择压力而可能造成时空多样性

就是说根据取病理的部位不同，T790突变结果也有不同？

12个胸组织患者t790m阳性，其中10个中枢神经t790m阴性。
1个患者经过高剂量的厄洛替尼治疗后其中枢神经t790m从阴性到阳性。

看来耐药后脑部大多数情况下仍然还没有T790的概率是比较大的，厄洛替尼高剂量脉冲可能会导致T790突变。停用TKI后T790可能逆转。

谢，已学习