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. 2022 Jun 7:12:911294.
doi: 10.3389/fonc.2022.911294. eCollection 2022.

Targeting ALK in Neuroendocrine Tumors of the Lung

Dilara Akhoundova  1   2   3 , Martina Haberecker  4 , Ralph Fritsch  1 , Sylvia Höller  5 , Michael K Kiessling  1   6 , Markus Rechsteiner  4 , Jan H Rüschoff  4 , Alessandra Curioni-Fontecedro  1
Affiliations

Targeting ALK in Neuroendocrine Tumors of the Lung

Dilara Akhoundova et al. Front Oncol. .

Abstract

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.

Keywords: ALK inhibitors; ALK rearrangements; large cell neuroendocrine carcinoma; neuroendocrine tumors of the lung; targeted treatment.

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Conflict of interest statement

SH reports consulting and advisory fees from Bayer outside the submitted work. RF reports grants and consulting and advisory fees from Pierre Fabre, Bayer, Merck, MSD, Astra Zeneca, Novartis, and BMS outside the submitted work. MK reports ownership relationship with Novavax, Biontech, and Mol. Partners outside the submitted work. AC-F reports patent relationship with Astra Zeneca, Bristol Meyer Squibb, Boehringer Ingelheim, Pfizer, Roche, Takeda, MSD, and Janssen-Cilag outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
ALK IHC staining patterns. Examples of negative and positive (1+, 2+, and 3+) staining patterns are illustrated. Scale bar 200 µm. neg, negative.
Figure 2
Figure 2
HE, ALK IHC, ALK FISH, and NGS sequencing data of the five ALK FISH-positive cases. Panels (A, D, E, F) were diagnosed as LCNEC, whereas (B, C) were evaluated as (AC). IHC was scored as 2+ (A), 1+ (B), and 3+ (C–F). ALK FISH break-apart probes revealed aberrant staining patterns (A, D) one fused and one split red and green signal; (B, D, E) one fused and one single red signal) consistent with ALK rearrangements. In three cases (C–F), the material was sufficient to perform NGS, confirming two times an EML4-ALK translocation (D) Variant 3a/b; (E, F) Variant 1) and one time an STRN-ALK translocation (C). HE, hematoxylin–eosin; ALK, anaplastic lymphoma kinase; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; NGS, next-generation sequencing. Scale bar 200 µm.
Figure 3
Figure 3
First-line treatment with alectinib in a 37-year-old patient with a metastatic ALK-rearranged LCNEC. (A) FDG-PET scan, whole-body overview, before (left) and 12 weeks after (right) initiation of first-line treatment with alectinib. (B) Complete response of the multiple brain metastases 10 weeks after the start of alectinib. Whole-brain radiation could be avoided. Red arrow shows excellent tumor response under treatment with alectinib.
Figure 4
Figure 4
Complete metabolic and subtotal morphologic response to molecularly targeted treatment with alectinib in a 32-year-old patient diagnosed with a metastatic ALK-rearranged LCNEC. (A) FDG-PET scan, whole-body overview, before initiation of first-line treatment with alectinib. No metabolic or morphological response had been observed after one cycle of platin-based chemotherapy administered before obtaining the results of tumor molecular profiling showing ALK rearrangement. (B) FDG-PET scan performed 8 weeks after treatment start with alectinib showing complete metabolic and subtotal morphological response of the primary tumor and the lymph node metastases (blue arrows).
See this image and copyright information in PMC

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