Histologic Transformation of ALK-Rearranged Lung Adenocarcinomas to High-Grade LCNEC: Clinical and Molecular Description of Three Cases

IF 3.3 3区医学 Q2 ONCOLOGY Clinical lung cancer Pub Date : 2025-01-01 DOI:10.1016/j.cllc.2024.11.012

Paolo Ambrosini , Daniela Miliziano , Giorgia Di Liberti , Daniele Lorenzini , Silvia Marchesi , Anna Bassetti , Elena Tamborini , Rita Leporati , Teresa Beninato , Laura Mazzeo , Marta Brambilla , Monica Ganzinelli , Arsela Prelaj , Claudia Proto , Filippo Guglielmo De Braud , Giuseppe Lo Russo , Mario Occhipinti

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Abstract

•
Anaplastic lymphoma kinase (ALK) rearrangements occur in 3-5% of non-small cell lung cancer (NSCLC) cases, with high sensitivity to ALK-tyrosine kinase inhibitors (TKIs) like alectinib, brigatinib, lorlatinib, and ensartinib. Resistance to tehse treatments is common and nearly inevitable, driven by genetic alterations and histologic transformations, notably to small cell lung carcinoma (SCLC).
•
In the present series, we describe a rare resistance mechanism in three cases of ALK-rearranged NSCLC transforming into high-grade large cell neuroendocrine carcinoma (LCNEC) after ALK-TKI treatment. These patients exhibited both histologic transformation and on-target ALK mutations, such as L1196M, D1203N, and L1198F, emphasizing the dual resistance mechanisms.
•
The identification of LCNEC transformation as a resistance mechanism emphasizes the importance of individualizing treatment strategies. The clinical outcomes of LCNEC-transformed cases varied, with some patients responding poorly to chemotherapy, underscoring the aggressive nature of this transformation. Regular tissue re-biopsies at disease progression can guide therapy choices by identifying resistance mechanisms. Liquid biopsies can serve as an alternative for monitoring molecular resistance in situations where tissue biopsies are not attainable. These findings advocate for an adaptive treatment approach, integrating molecular and histologic evaluations to optimize outcomes for patients with ALK-rearranged NSCLC.

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来源期刊

Clinical lung cancer 医学-肿瘤学

CiteScore

7.00

自引率

2.80%

发文量

159

审稿时长

24 days

期刊介绍： Clinical Lung Cancer is a peer-reviewed bimonthly journal that publishes original articles describing various aspects of clinical and translational research of lung cancer. Clinical Lung Cancer is devoted to articles on detection, diagnosis, prevention, and treatment of lung cancer. The main emphasis is on recent scientific developments in all areas related to lung cancer. Specific areas of interest include clinical research and mechanistic approaches; drug sensitivity and resistance; gene and antisense therapy; pathology, markers, and prognostic indicators; chemoprevention strategies; multimodality therapy; and integration of various approaches.