Lorlatinib and compound mutations in ALK+ large-cell neuroendocrine lung carcinoma: a case report.

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2022-10-01 DOI:10.1101/mcs.a006234
Christiane Wiedemann, Daniel Kazdal, Jelena Cvetkovic, Julia Kunz, David Fisch, Martina Kirchner, Mark Kriegsmann, Holger Sültmann, Claus-Peter Heussel, Helge Bischoff, Michael Thomas, Albrecht Stenzinger, Petros Christopoulos
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引用次数: 4

Abstract

Large-cell neuroendocrine lung carcinoma (LCNEC) is a high-grade neoplasm with median survival of 1 year and limited therapeutic options. Here, we report the unusual case of a 47-yr-old female smoker with stage IV LCNEC featuring EML4-ALK variant 2 (E20:A20), wild-type TP53/RB1, and low tumor mutational burden of 3.91 mut/Mb. Despite early progression within 3 mo under crizotinib, a durable response was achieved with alectinib. Oligoprogression in the left breast 10 mo later was treated by surgery, followed by a switch to ceritinib upon multifocal progression and detection of ALK:p.V1180L in the mastectomy specimen, but without success. Another rebiopsy revealed ALK:p.L1196M, but the tumor did not respond to brigatinib or carboplatin/pemetrexed, before stabilization under lorlatinib. Diffuse progression 8 mo later with detection of ALK :p.L1196M/p.G1202R and p.L1196M/ p.D1203N evolving from the previous p.L1196M did not respond to chemoimmunotherapy, and the patient succumbed with an overall survival (OS) of 37 mo. This case illustrates the importance of molecular profiling for LCNEC regardless of smoking status, and the superiority of next-generation ALK inhibitors compared to crizotinib for ALK+ cases. Lorlatinib retained efficacy in the heavily pretreated setting, whereas its upfront use could possibly have prevented the stepwise emergence of compound ALK mutations. Furthermore, the disease course was more aggressive and OS shorter compared to the V2/TP53wt ALK+ lung adenocarcinoma, whereas crizotinib, ceritinib, and brigatinib did not confer the benefit expected according to next-generation sequencing results, which also underline the need for more potent drugs against ALK in the high-risk setting of neuroendocrine histology.

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Lorlatinib和复合突变在ALK+大细胞神经内分泌肺癌中:1例报告。
大细胞神经内分泌肺癌(LCNEC)是一种高级别肿瘤,中位生存期为1年,治疗选择有限。在这里,我们报告了一个不寻常的病例,47岁女性吸烟者患有IV期LCNEC,其特征是EML4-ALK变体2 (E20:A20),野生型TP53/RB1,肿瘤突变负荷低,为3.91 mut/Mb。尽管使用克唑替尼后3个月内出现早期进展,但使用阿勒替尼可获得持久的缓解。10个月后左乳少进展通过手术治疗,随后在多灶进展和ALK检测后切换到ceritinib:p。V1180L在乳腺切除标本中,但没有成功。另一次复查显示ALK:p。L1196M,但肿瘤对布加替尼或卡铂/培美曲塞没有反应,在氯拉替尼稳定之前。8个月后弥漫性进展伴ALK检测:p.L1196M/p。G1202R和p.L1196M/ p.D1203N从先前的p.L1196M进化而来,对化学免疫治疗没有反应,患者的总生存期(OS)为37个月。该病例说明了分子分析对LCNEC的重要性,无论吸烟状况如何,以及与克唑替尼相比,下一代ALK抑制剂对ALK+病例的优越性。Lorlatinib在大量预处理的环境中保持疗效,而其前期使用可能已经阻止了化合物ALK突变的逐步出现。此外,与V2/TP53wt ALK+肺腺癌相比,疾病病程更具侵袭性,OS更短,而根据下一代测序结果,克里唑替尼、塞瑞替尼和布加替尼并没有带来预期的益处,这也强调了在神经内分泌组织学的高风险环境中需要更有效的抗ALK药物。
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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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