Women's Health Integrated Research Center, Women's Service Line, Inova Health System, Annandale, VA, USA.
Gynecologic Cancer Center of Excellence, Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD, USA.
Oncologist. 2023 Aug 3;28(8):730-736. doi: 10.1093/oncolo/oyad129.
Inflammatory myofibroblastic tumors (IMTs) are intermediate-grade mesenchymal neoplasms commonly characterized by chromosomal rearrangements causing constitutive activation of anaplastic lymphoma kinase (ALK) and/or ALK mutations causing reduced sensitivity to ALK tyrosine kinase inhibitors (TKI). We present a patient with an IMT who initially responded to first-line alectinib, but who later suffered disease relapse and presently survives with moderate residual disease after receiving second-line lorlatinib. Biopsy specimens were analyzed using next generation sequencing (DNA-seq and RNA-seq) and reverse phase protein microarray (RPPA) as part of an institutional Molecular Tumor Board (MTB) study. An EML4-ALK rearrangement and EGFR activation (pEGFRY1068) were present in both the primary and recurrent tumors, while a secondary ALK I1171N mutation was exclusive to the latter. EGFR signaling in the background of a secondary ALK mutation is correlated with reduced ALK TKI sensitivity in vitro, implicating an important mechanism of drug resistance development in this patient. The RPPA results also critically demonstrate that ALK signaling (ALKY1604) was not activated in the recurrent tumor, thereby indicating that standard-of-care use of third- or fourth-line ALK TKI would not likely be efficacious or durable. These results underscore the importance of real-time clinical integration of functional protein drug target activation data with NGS in the MTB setting for improving selection of patient-tailored therapy.
炎性肌纤维母细胞瘤（IMTs）是一种中等分级的间叶性肿瘤，通常具有染色体重排特征，导致间变性淋巴瘤激酶（ALK）的组成性激活，和/或导致 ALK 酪氨酸激酶抑制剂（TKI）敏感性降低的 ALK 突变。我们介绍了一位 IMT 患者，他最初对一线阿来替尼有反应，但后来疾病复发，目前在接受二线洛拉替尼治疗后仍有中度残留疾病存活。活检标本通过下一代测序（DNA-seq 和 RNA-seq）和反向蛋白质微阵列（RPPA）进行分析，作为机构分子肿瘤委员会（MTB）研究的一部分。原发性和复发性肿瘤中均存在 EML4-ALK 重排和 EGFR 激活（pEGFRY1068），而后者仅存在继发性 ALK I1171N 突变。在继发性 ALK 突变的背景下，EGFR 信号与体外 ALK TKI 敏感性降低相关，这表明该患者的耐药性发展存在重要机制。RPPA 结果还明确表明，复发性肿瘤中未激活 ALK 信号（ALKY1604），从而表明标准护理使用三线或四线 ALK TKI 不太可能有效或持久。这些结果强调了在 MTB 环境中实时整合功能蛋白药物靶点激活数据与 NGS 的重要性，以改善针对患者量身定制的治疗选择。
