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Sequential small cell transformation and T790M mutation in an epidermal growth factor-mutant lung adenocarcinoma: A
Malvika Shastri1, Parikshaa Gupta1, Nalini Gupta1
1Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Background:
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) resistance may be acquired via genotypic and/or phenotypic transformations. Herein, we report an extremely uncommon case with sequential small cell transformation and EGFR T790M mutation, in an elderly female with EGFR exon 21 L858R-mutant lung adenocarcinoma, following treatment with a first-generation EGFR-TKI.
Case:
A 67-year-old female never-smoker presented with a cough and dyspnoea of 2 months' duration. Computerised tomography revealed a 39 mm lesion in the upper lobe of the right lung with pleural effusion. Pleural fluid cytology revealed metastatic lung adenocarcinoma, and EGFR testing revealed exon 21 L858R mutation. She was started on gefitinib. After a progression-free survival of 31 months, she presented with disease progression and multiple extra-thoracic metastases. Fine needle aspiration cytology of a chest wall lesion revealed metastatic small cell carcinoma. EGFR testing on this aspirate revealed persistent L858R mutation only. In view of small cell transformation, chemotherapy (etoposide and carboplatin) was administered. After 4 months, ascitic fluid cytology revealed metastatic adenocarcinoma with persistent L858R mutation and an acquired T790M mutation (both detected on liquid biopsy as well) indicating amplification of the adenocarcinoma clone and regression of the small cell carcinoma clone. She was then initiated on osimertinib.
Conclusions:
The index case highlights the significance of serial EGFR genotyping along with repeated tissue and/or blood sampling in the prompt detection of genetic and phenotypic resistance mechanisms to EGFR-TKIs. Furthermore, it lends evidence in support of the upfront treatment approaches targeting the heterogeneity of acquired EGFR-TKI resistance mechanisms.
Insights
This case study details an elderly woman with EGFR exon 21 L858R-mutant lung adenocarcinoma who developed sequential small cell transformation and an EGFR T790M mutation after first-generation EGFR-TKI treatment, highlighting resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in lung cancer can involve complex genetic and phenotypic changes.
- Understanding these resistance mechanisms is crucial for optimizing treatment strategies in non-small cell lung cancer (NSCLC).
Observation:
- A 67-year-old female with EGFR exon 21 L858R-mutant lung adenocarcinoma initially responded to gefitinib but later developed disease progression.
- The patient experienced sequential transformation to small cell carcinoma, followed by the acquisition of an EGFR T790M mutation alongside persistent L858R mutation, indicating a shift in tumorClone dynamics.
Findings:
- Serial EGFR genotyping and liquid biopsies revealed a complex resistance pattern, including small cell transformation and the emergence of the T790M mutation.
- The adenocarcinoma clone with both L858R and T790M mutations re-emerged, suggesting a heterogeneous response to treatment.
Implications:
- This case underscores the importance of serial molecular profiling (tissue and liquid biopsies) to detect evolving resistance mechanisms to EGFR-TKIs.
- It supports the need for treatment strategies that can address the heterogeneity of acquired resistance in EGFR-mutant lung cancer.
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