PDF(Pubmed)
Abstract：
This paper presents a patient with a novel Ig-like-III domain fibroblast growth factor receptor (FGFR2) alteration (W290_P307>C) along with CDKN2A/B alterations and a cadherin 1 (CDH1) alteration. Initial responsiveness to pazopanib monotherapy was encouraging, yet progression occurred after 7.5 months. Following progression, the molecular tumor board recommended a combination therapy approach comprising pazopanib, crizotinib, and palbociclib to target all of the changed pathways at the same time. Pazopanib was chosen to specifically target the FGFR2 alteration, while crizotinib was selected due to its potential synthetic lethality with the CDH1 alteration. In addition, the CDK4/6 inhibitor palbociclib was administered to address the CDKN2A/B alterations. The patient exhibited a remarkable and sustained response to this innovative combination. This case not only underscores the potential of tyrosine kinase inhibitors, exemplified by pazopanib, as a viable alternative for patients without access to pan-FGFR inhibitors, but it also emphasizes their efficacy beyond commonly detected point mutations and rearrangements. Notably, the outstanding response to combination therapy, including crizotinib, in a patient with a CDH1 alteration, further substantiates the preclinical evidence of synthetic lethality between crizotinib and CDH1 alterations. To our knowledge, this represents the first clinical evidence demonstrating the efficacy of crizotinib in a patient with a CDH1 alteration. Through careful dosage adjustments and consideration of individualized genomic information, this case exemplifies the power of personalized medicine in achieving favorable treatment outcomes.
摘要：
本文介绍了患有新型Ig样III结构域成纤维细胞生长因子受体（FGFR2）改变（W290_P307>C）以及CDKN2A/B改变和钙黏着蛋白1（CDH1）改变的患者。最初对帕唑帕尼单药治疗的反应令人鼓舞，但在7.5个月后出现进展.进展之后,分子肿瘤委员会推荐了一种包括帕唑帕尼的联合治疗方法，克唑替尼,和palbociclib同时靶向所有改变的途径。选择帕唑帕尼特异性靶向FGFR2改变，而选择克唑替尼是由于其具有CDH1改变的潜在合成致死率。此外,CDK4/6抑制剂palbociclib用于解决CDKN2A/B改变.患者对这种创新组合表现出显著和持续的反应。这个案例不仅强调了酪氨酸激酶抑制剂的潜力，以帕唑帕尼为例，作为无法获得泛FGFR抑制剂的患者的可行替代方案，但它也强调了它们的功效超出了通常检测到的点突变和重排。值得注意的是,对联合疗法的杰出反应，包括克唑替尼,在CDH1改变的患者中，进一步证实了克唑替尼和CDH1改变之间合成致死性的临床前证据.据我们所知,这是首个证明克唑替尼对CDH1改变患者有效的临床证据.通过仔细调整剂量和考虑个性化的基因组信息，这一案例体现了个性化医疗在获得良好治疗结果方面的力量.
