目的:目前尚无批准的脊索瘤靶向治疗方法。尽管一些临床前研究暗示了CDK4/6抑制剂对这种罕见肿瘤的潜在适用性,目前尚无临床证据.目的阐明CDK4/6抑制剂治疗脊索瘤的疗效。
方法:下一代测序(对于全外显子组测序,在治疗前对患有晚期病变的患者的脊索瘤组织进行WES测定)和免疫组织化学(IHC)染色。然后,患者接受Palbociclib治疗4个月,直至第5个月出现进展.实施手术切除,并在术后获得肿瘤组织以评估分子改变。
结果:药物治疗前肿瘤的分子特征提示CDK4/6抑制剂的适用性,患者在接受Palbociclib治疗4个月后根据Choi标准显示部分缓解(PR),直至进展发生。然后,以E2F急剧扩增为代表的肿瘤的急剧分子改变,已知在治疗后诱导CDK4/6独立的细胞周期进入和进展,被检测到。该患者的发现证明了在药物压力下肿瘤的演变。
结论:本研究结果表明,Palbociclib用于脊索瘤的临床治疗的可行性,并暗示由于肿瘤对Palbociclib治疗的快速抵抗,因此需要联合治疗而不是单一药物给药。
OBJECTIVE: There is no approved targeted therapy for chordoma at present. Although several preclinical studies have implied the potential applicability of CDK4/6 inhibitor for this rare tumor, no clinical evidence has been documented so far. The purpose of this
study was to elucidate the therapeutic efficacy of CDK4/6 inhibitor for chordoma.
METHODS: The next generation sequencing (as for whole-exome sequencing, WES assay) and immunohistochemical (IHC) staining of the chordoma tissue from a patient with an advanced lesion were performed before treatment. Then, the patient was treated with Palbociclib for 4 months until progression occurred in the 5th month. Surgical resection was implemented and the tumor tissue was obtained postoperatively for assessment of molecular alterations.
RESULTS: Molecular features of the tumor before medical treatment suggested applicability of CDK4/6 inhibitor and the patient showed partial response (PR) according to Choi Criteria after 4 months treating with Palbociclib until progression occurred. Then, a drastic molecular alteration of the tumor as represented by emergence of dramatic E2F amplification, which is known to induce CDK4/6 independent cell-cycle entry and progression after treatment, was detected. The findings in this patient demonstrated tumor evolution under drug pressure.
CONCLUSIONS: The findings of the present
study suggest the feasibility of Palbociclib for the clinical treatment of chordoma, and imply the necessity of combination therapies rather single drug administration due to the quick resistance of the tumor to Palbociclib treatment.