Title: Pulmonary adenocarcinoma: Questioning six years follow up of resistance mutations with anti- ALK therapy – case report
Abstract:
ALK rearrangements are detected in 2–5% of NSCLCs (85% correspond to EML4-ALK) sensitive to ALK TKIs; resistance mutations schedule is unknown. A case demonstrates NGS as the actual methodology for recognition of rearrangements, amplifications, and point mutations.
Methods :
Bronchial biopsies - 62-years old woman pulmonary adenocarcinoma (CK7/TTF1):
2016 – FISH [ZytoLight SPEC ALK/EML4 TriCheck Probe (2p23)] - 100 cells were validated.
2022 – NGS in Genexus (Thermo Fisher Platform). Microdissection performed before DNA/RNA extraction and nucleic acids obtained with MagMAX FFPE DNA/RNA Ultra Kit. Oncomine Precision Assay Panel: DNA Hotspots (SNVs/Indels), CNVs (polysomy/amplification), inter- genetic and intra-genetic fusions.
Results :
2016 – June - ALK positive (80% of cells with fusion). Patient started therapy-Crizotinib.
2018 – Sepetember - clinical and imaging progression; Ceritinib was prescribed and maintained without side effects, for 16 months.
2019 – December - Lorlatinib – introduced due to brain metastisation on EC CT, maintained without side effects.
2022 – May - Clinical progression – two missenses mutations were detected in ALK gene: [c.3607G>A;p.(Asp1203Asn) ; c.3586C>A;p.(Leu1196Met)] with 8,3% and 8,2% allelic frequency respectively. ALK Fusion (EML4-ALK.E20A20) and one ALK imbalance were detected. ALK fusions therapeutic response for TKIs, run without information about ALK imbalance; the
referred missense mutations have been considered secondary resistance/acquired mechanism after Crizotinib treatment. The patient died in November 2022.
Conclusion :
The introduction of next-generation sequencing for research of therapeutic targets has been detecting ALK gene imbalances beyond resistance point mutations, together with the predominant ALK fusions genes targeted by TKIs. This 62-years woman tumour kept EML4-ALK fusion gene responding to Crizotinib for two years and the resistance missense mutations were determined four years later. Crizotinib induced heterogeneity might be questioned together with imbalances, beyond the original/primary mutations status of ALK gene, when FISH has now lost is role.
Audience Take Away Notes :
- Discussion of molecular targets in Lung cancer
- Diferent molecular target detection methods
- Case report of a specific genetic mutation and therapy
