Institute Gustave Roussy, Paris, France.
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
Ann Oncol. 2018 Mar 1;29(3):640-645. doi: 10.1093/annonc/mdx784.
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.
尽管细胞周期蛋白 D1-CDK4/6-视网膜母细胞瘤通路的失调控在激素受体阳性（HR+）乳腺癌中很常见，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 CDK4/6 抑制剂在临床实践中经常被使用。然而，导致对 CDK4/6 抑制剂产生临床耐药的因素尚不清楚。
我们确定了在接受 CDK4/6 抑制剂后在组织和外周血样本中进行了基因分型的患者。基因分型在肿瘤组织或在开始使用 CDK4/6 抑制剂之前和在 CDK4/6 抑制剂进展后采集的血液中进行，覆盖了 RB1 编码区的 90%以上。
我们在三名患者中分别在暴露于 CDK4/6 抑制剂（帕博西尼、哌柏西利、瑞博西尼）后 5、8 和 13 个月的循环肿瘤 DNA（ctDNA）中检测到可检测到的获得性 RB1 突变。RB1 突变包括患者 #1 的 RB1 基因外显子 8 的供体位点替代；患者 #2 的 RB1 基因外显子 22 的供体位点替代、外显子 19 缺失、外显子 3 插入；以及患者 #3 的 RB1 外显子 16 H483Y 突变。这些 RB1 突变均不存在于 CDK4/6 前标本中，突出了这些导致 Rb1 功能丧失的分子改变，这些改变可能是在 CDK4/6 抑制剂的选择性压力下出现的，可能赋予了治疗耐药性。
这是第一项描述在接受转移性乳腺癌患者的帕博西尼或瑞博西尼治疗后出现体细胞 RB1 突变的临床报告。需要进一步研究来验证这些发现，确定这些突变如何在 CDK4/6 抑制剂的选择性压力下随时间出现，并制定合理的治疗策略。
