Methylation-based liquid biopsy facilitates early detection of small cell transformation in ALK-rearranged non-small cell lung cancer - Key case report and monitoring

Sep 23, 2026

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Histologic transformation from non–small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) represents a rare resistance mechanism in anaplastic lymphoma kinase (ALK)–rearranged disease. Traditional confirmation depends on tissue biopsy, which may be constrained by inaccessible lesions and limited tumor burden. A case of ALK-rearranged lung adenocarcinoma shows methylation-based circulating cell-free DNA (cfDNA) detecting an SCLC signature 5 months before tissue confirmation. Serial liquid biopsies tracked dynamic tumor fraction and histologic composition, aligning with treatment response and ongoing ALK-directed therapy, supporting longitudinal monitoring potential.

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CategoryHealthcare

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Abstract

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Introduction

The Oncologist, 2026, 31, oyag271 [https://doi.org/10.1093/oncolo/oyag271](https://doi.org/10.1093/oncolo/oyag271) [Published: July 14](Published: July 14), 2026 Precision Medicine Clinic: Molecular Tumor Board Methylation–based liquid biopsy facilitates early detection of small cell transformation inALK-rearranged non–small cell lung cancer Jinesh S. Gheeya1,*, , Raj Singh2,\#, Mingjia Li1, Saman Ahmadian3, Konstantin Shilo3, Triparna Sen1, Christian Rolfo1, , David P. Carbone1, , Dwight H. Owen1, David R. Gandara4 1 Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA 2 Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA 3 Department of Pathology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA 4 Division of Hematology & Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, California 95817, USA \# Present address: Department of Radiation Oncology, Baptist Health Lynn Cancer Institute, Boca Raton, Florida 33486, USA. *Corresponding author: Jinesh Gheeya, MD, PhD, Division of Medical Oncology, The Ohio State University, Columbus, Ohio 43210, USA ([jinesh.gheeya@osumc.edu](jinesh.gheeya@osumc.edu)) . Abstract Histologic transformation from non–small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a rare mechanism of resistance in anaplastic lymphoma kinase (ALK)–rearranged disease. Diagnosis is traditionally dependent on tissue biopsy, which may be limited by lesion accessibility and low disease burden. We report a case ofALK-rearranged lung adenocarcinoma that underwent small cell transformation, in which methylation-based circulating cell-free DNA (cfDNA) analysis detected a small cell lung cancer signature 5 months prior to tissue confirmation. Serial liquid biopsies demonstrated dynamic changes in tumor fraction and histologic composition that correlated with response to chemoradiation and continuation of ALK-directed therapy. This case highlights the potential utility of methylation-based liquid biopsy for early detection and longitudinal monitoring of histologic transformation in oncogene-driven NSCLC. Key words: ALK-rearranged non–small cell lung cancer; liquid biopsy; methylation-based cell-free DNA; small cell transformation Key Points · The presented case is a rare instance of small cell lung cancer (SCLC) transformation in ALK-positive non–small cell lung cancer (NSCLC) . · Methylation-based liquid biopsy identified the transformed SCLC 5 months prior to tissue biopsy confirmation. · Methylation-based cfDNA analysis was successfully used to monitor the transformed SCLC over time. Introduction Histologic transformation from non–small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a novel mechanism of acquired resistance to targeted therapy. In epidermal growth factor receptor (EGFR)-altered NSCLC, SCLC transformation occurs in 3%-15% of cases.1,2 In anaplastic lymphoma kinase (ALK)-rearranged NSCLC, SCLC transformation is exceedingly rare, with only a few published cases since the seminal report by Fujita et al.3–5 A systematic review of 140 patients with lung adenocarcinoma (LUAD) who developed tSCLC found that 85% had EGFR mutations and 13% had ALK alterations, with a median time to transformation of 20 months and median overall survival after transformation of 11 months.6 Historically, the diagnosis of tSCLC has relied on tissue rebiopsy and immunohistochemistry (IHC) examination, which can be challenging when metastatic lesions are small, inaccessible, or when patients are unable to undergo invasive biopsy. Liquid biopsy using circulating cell-free DNA (cfDNA) by nextgeneration sequencing (NGS) has emerged as a powerful, noninvasive tool for comprehensive genomic profiling, identifying driver mutations and resistance mechanisms, and monitoring treatment response.7 Rece

FAQs

Why is diagnosing NSCLC-to-SCLC transformation challenging in ALK-rearranged disease?

Diagnosis traditionally relies on tissue rebiopsy and immunohistochemistry, which can be difficult when metastatic lesions are small or inaccessible, and when patients cannot undergo invasive biopsy.

How did methylation-based cfDNA contribute to earlier detection in the reported case?

Methylation-based circulating cell-free DNA analysis identified an SCLC signature 5 months before tissue biopsy confirmed the transformed histology.

What did serial liquid biopsies show over time?

Serial liquid biopsies demonstrated dynamic changes in tumor fraction and histologic composition, which correlated with response to chemoradiation and continuation of ALK-directed therapy.

Sep 23, 2026

Uploaded by awa