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Targeting ALK in Neuroendocrine Tumors of the Lung
Dilara Akhoundova1,2,3, Martina Haberecker4, Ralph Fritsch1
1Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland.
Background:
Anaplastic lymphoma kinase (ALK) rearrangements are known oncogenic drivers in non-small cell lung cancer (NSCLC). Few case reports described the occurrence of such rearrangements in large cell neuroendocrine carcinomas (LCNECs) of the lung without information on clinical responses to ALK tyrosine kinase inhibitors (TKIs) in these cases. Currently, neuroendocrine tumors of the lungs are not screened for ALK rearrangements.
Methods:
To illustrate the clinical impact of molecular characterization in LCNECs, we report the disease course in three patients with ALK-rearranged metastatic LCNEC from our clinical routine, as well as their treatment response to ALK TKIs (index cases). To gain insight into the prevalence of ALK rearrangements in neuroendocrine tumors of the lung, we analyzed a retrospective cohort of 436 tumor biopsies including LCNEC (n = 61), small cell lung cancer (SCLC) (n = 206), typical (n = 91) and atypical (n = 69) carcinoids, and mixed histology (n = 9) for the presence of ALK rearrangements using a sequential diagnostic algorithm. ALK immunohistochemistry (IHC) was evaluable in 362 cases; fluorescence in situ hybridization (FISH) was evaluable in 28 out of the 35 IHC-positive cases, followed by next-generation sequencing (NGS) that was available in 12 cases.
Results:
Within the retrospective cohort, ALK IHC was positive in 35 out of 362 (9.7%) evaluable samples. FISH was positive in 3 out of the 28 (10.7%) evaluable cases: 2 with atypical carcinoids and 1 with LCNEC. Additionally, the 3 index cases showed positive ALK IHC, which was confirmed by NGS. Within the retrospective cohort, NGS confirmed the presence of an ALK genomic rearrangement in one FISH-positive atypical carcinoid where material was sufficient for sequencing. Two out of three patients with metastatic ALK-rearranged LCNEC received up-front treatment with the ALK TKI alectinib and showed rapid tumor response at all metastatic sites, including multiple brain metastases.
Conclusions:
ALK rearrangements represent rare but targetable oncogenic driver alterations in LCNEC. Contrarily to NSCLC, the detection of ALK rearrangements in neuroendocrine tumors of the lung is challenging, since ALK IHC can lead to false-positive results and therefore needs confirmation by FISH or NGS. Up-front comprehensive molecular profiling with NGS should be performed in metastatic LCNEC in order not to miss actionable genomic alterations.
Insights
Anaplastic lymphoma kinase (ALK) rearrangements are rare but targetable drivers in large cell neuroendocrine lung cancer (LCNEC). Comprehensive molecular profiling with next-generation sequencing is crucial for identifying these actionable alterations in metastatic LCNEC.
Area of Science:
- Oncology
- Molecular Diagnostics
- Genomics
Background:
- Anaplastic lymphoma kinase (ALK) rearrangements are established oncogenic drivers in non-small cell lung cancer (NSCLC).
- Their role and clinical relevance in large cell neuroendocrine lung carcinomas (LCNECs) remain largely unexplored, with limited data on treatment responses to ALK tyrosine kinase inhibitors (TKIs).
- Current clinical practice does not typically involve screening neuroendocrine lung tumors for ALK rearrangements.
Purpose of the Study:
- To investigate the clinical impact of molecular characterization in LCNECs.
- To report the disease course and treatment response to ALK TKIs in patients with ALK-rearranged metastatic LCNEC.
- To assess the prevalence of ALK rearrangements in a cohort of neuroendocrine lung tumors.
Main Methods:
- Analysis of three index cases with ALK-rearranged metastatic LCNEC and their response to ALK TKIs.
- Retrospective analysis of 436 lung tumor biopsies (including LCNEC, SCLC, carcinoids) for ALK rearrangements.
- Utilized a sequential diagnostic algorithm involving ALK immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS).
Main Results:
- ALK rearrangements were identified in a subset of LCNEC and atypical carcinoid tumors.
- Two out of three patients with metastatic ALK-rearranged LCNEC treated with alectinib showed rapid and significant tumor response, including in brain metastases.
- ALK IHC showed a 9.7% positivity rate, but FISH and NGS confirmed rearrangements in a smaller proportion, highlighting diagnostic challenges.
Conclusions:
- ALK rearrangements are rare but actionable oncogenic drivers in LCNEC.
- Detecting ALK rearrangements in neuroendocrine lung tumors is challenging due to potential false-positive IHC results, necessitating confirmation by FISH or NGS.
- Comprehensive molecular profiling, particularly NGS, should be performed upfront in metastatic LCNEC to identify targetable genomic alterations.
