Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer
Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer
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DOI：
10.1093/annonc/mdx784
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发表时间：
2018-03-01
影响因子：
50.5
通讯作者：
Bardia, A.
中科院分区：
文献类型：
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作者：
Condorelli, R.;Spring, L.;Bardia, A.
虽然细胞周期蛋白D1-CDK 4/6-视网膜母细胞瘤途径的失调在激素受体阳性（HR+）乳腺癌中是常见的，但Rb在HR+乳腺癌中通常是完整的，并且作用于Rb上游的靶向CDK 4/6抑制剂常规用于临床实践。然而，可能导致对CDK 4/6抑制剂临床耐药的因素尚不清楚。我们确定了接受CDK 4/6抑制剂后组织和外周血样本中具有基因分型前和后的患者。在开始使用CDK 4/6抑制剂之前和使用CDK 4/6抑制剂后疾病进展后收集的肿瘤组织或血液中进行基因分型，覆盖RB 1编码区的90%以上。我们在循环肿瘤DNA（ctDNA）中发现了可检测的获得性RB 1突变暴露于CDK 4/6抑制剂后在3例患者中，分别给予（palbociclib、palbociclib、ribociclib）5、8和13个月。RB 1突变包括患者#1的RB 1基因外显子8供体剪接位点置换;患者#2的RB 1基因外显子22供体剪接位点置换、外显子19缺失、外显子3插入;患者#3的RB 1外显子16 H483 Y突变。这些RB 1突变在CDK 4/6前样本中均不存在，突出表明这些导致Rb 1功能丧失的分子改变可能是在CDK 4/6抑制剂的选择性压力下出现的，可能导致治疗耐药。这是第一份描述转移性乳腺癌患者暴露于palbociclib或ribociclib后出现体细胞RB 1突变的临床报告。需要进一步的研究来验证这些发现，确定这些突变是如何在CDK 4/6抑制剂的选择性压力下暂时出现的，并制定合理的治疗策略。
While deregulation of the cyclin D1-CDK4/6-retinoblastoma pathway is common in hormone receptor positive (HR+) breast cancer, Rb is usually intact in HR+ breast cancer, and targeted CDK 4/6 inhibitors that act upstream of Rb, are routinely being utilized in clinical practice. However, factors that can lead to clinical resistance to CDK 4/6 inhibitors are not known.We identified patients who had pre- and post-genotyping in tissue and peripheral blood samples after receiving CDK 4/6 inhibitors. Genotyping was carried out in tumor tissue or blood collected before start of CDK 4/6 inhibitor and after disease progression on CDK 4/6 inhibitor, covering more than 90% of the coding region in RB1.We identified detectable acquired RB1 mutations in circulating tumor DNA (ctDNA) after exposure to CDK4/6 inhibitor (palbociclib, palbociclib, ribociclib) for 5, 8, and 13 months, respectively, in three patients. The RB1 mutations included substitution in donor splicing site of exon 8 of the RB1 gene in patient #1; substitution in donor splicing site of exon 22 of RB1 gene, exon 19 deletion, exon 3 insertion in patient #2; and RB1 exon 16 H483Y mutation in patient #3. None of these RB1 mutations were present in the pre-CDK 4/6 specimen highlighting these molecular alterations, which lead to functional loss of Rb1, likely emerged under selective pressure from the CDK4/6 inhibitor potentially confering therapeutic resistance.This is the first clinical report to describe the emergence of somatic RB1 mutations after exposure to palbociclib or ribociclib, in patients with metastatic breast cancer. Further research is needed to validate these findings, identify how these mutations temporally emerge under selective pressure of CDK 4/6 inhibitor, and develop rational therapeutic strategies.