NTRK and ALK rearrangements in malignant pleural mesothelioma, pulmonary neuroendocrine tumours and non-small cell lung cancer

Our plain-English summary of NTRK and ALK rearrangements in malignant pleural mesothelioma, pulmonary neuroendocrine tumours and non-small cell lung cancer, by J.L. Leal, G. Peters, M. Szaumkessel, et al (Lung Cancer, 2020).

The study

• Authors: J.L. Leal, G. Peters, M. Szaumkessel, T. Leong, K. Asadi, G. Rivalland, H. Do, C. Senko, P.L. Mitchell, C.Z. Quing, A. Dobrovic, B. Thapa, T. John
• Journal: Lung Cancer
• Published: 2020;146:154-159
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Gene rearrangements involving NTRK1, NTRK2, NTRK3, ROS1 and ALK have been identified in many types of cancer, including non-small cell lung cancer (NSCLC). Data in malignant pleural mesothelioma (MPM), lung neuroendocrine tumors (NETs) and small-cell lung cancer (SCLC) are lacking. Given the activity of NTRK, ROS-1 and ALK inhibitors in tumors harboring gene fusions, we sought to explore such rearrangements in these less common tumors in addition to NSCLC.

Methods: Archival tumor tissue from patients with MPM, lung NETs, SCLC and NSCLC were used to create tissue microarrays. Immunohistochemistry (IHC) was performed using a cocktail of antibodies against TRK, ROS1 and ALK. IHC positive samples underwent RNA sequencing using the ArcherDX FusionPlex CTL diagnostic assay. Clinical data were obtained through retrospective chart review.

Results: We performed IHC on 1116 samples: 335 MPMs, 522 NSCLCs, 105 SCLCs and 154 lung NETs. There were 23 IHC positive cases (2.1%) including eight MPMs (2.4%), eight NETs (5.2%), five SCLC (4.8%) and two NSCLC (0.4%). The following fusions were detected: one MPM with an NTRK ex10-TPM3 ex8, another MPM with an ALK ex20-EML4ex13, one lung intermediate-grade NET (atypical carcinoid) with an ALK ex20-EML4 ex6/intron6, and two NSCLCs with an ALK ex20-EML4 ex6/intron6 rearrangement. None of the patients received targeted treatment.

Conclusions: To our knowledge, we report for the first time NTRK and ALK rearrangements in a small subset of MPM. An ALK rearrangement was also detected in lung intermediate-grade NET (or atypical carcinoid). Our data suggest that IHC could be a useful screening test in such patients to ensure that all therapeutic strategies including targeted therapy are utilized.

Copyright © 2020 Elsevier B.V. All rights reserved.

In plain English

This study, by Australian researchers, searched stored tumor tissue for rare gene changes (NTRK, ROS1 and ALK fusions) that some targeted drugs act on. The authors tested 1116 samples: 335 malignant pleural mesotheliomas, 522 non-small cell lung cancers, 105 small-cell lung cancers and 154 lung neuroendocrine tumors. A staining test (immunohistochemistry) was positive in 23 samples, including eight of the 335 mesotheliomas (2.4%). Only these positive samples were then checked by RNA sequencing. Fusions were found in two of the 335 mesotheliomas: one NTRK1 fusion and one ALK fusion. One lung neuroendocrine tumor (an atypical carcinoid) and two non-small cell lung cancers had ALK fusions. No fusion was found in the five small-cell cancers that stained positive. The patient with the NTRK-positive mesothelioma had biphasic mesothelioma and documented asbestos exposure. The ALK-positive mesothelioma was sarcomatoid. No patient received targeted treatment. The authors concluded that, to their knowledge, this was the first study to show these rearrangements in pleural mesothelioma, and that staining could be a screening test. They called the staining test's accuracy low and said small samples may have missed fusions.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective laboratory study of archived tumor tissue placed on tissue microarrays. Samples were screened by immunohistochemistry, and only the positive ones were checked by RNA sequencing. Clinical data came from chart review.
• Who was studied: 1116 patient tumor samples: 335 malignant pleural mesotheliomas, 522 surgical non-small cell lung cancers, 105 small-cell lung cancers and 154 surgical lung neuroendocrine tumors. The authors are from Australian institutions (Victoria and Canberra). The study period is not stated.
• Exposure: Asbestos exposure was not studied. The study looked at gene rearrangements in tumors. Documented asbestos exposure is mentioned for only one patient, the one with the NTRK-positive mesothelioma.
• Main results:
  • 23 of 1116 samples (2.1%) were positive on the staining test. These were 8 mesotheliomas (2.4% of mesothelioma samples), 8 lung neuroendocrine tumors (5.2%), 5 small-cell lung cancers (4.8%) and 2 non-small cell lung cancers (0.4%).
  • RNA sequencing was done on the eight stain-positive mesotheliomas. One had an NTRK1 exon 10 to TPM3 exon 8 fusion, and another had an ALK exon 20 to EML4 exon 13 fusion. That is two of 335 mesotheliomas (0.6%).
  • One of the eight stain-positive lung neuroendocrine tumors had an ALK exon 20 to EML4 exon 6/intron 6 rearrangement. This tumor was an atypical carcinoid.
  • Both stain-positive non-small cell lung cancers had ALK exon 20 to EML4 exon 6/intron 6 fusions. No fusion was found in the five stain-positive small-cell lung cancers. Only stain-positive samples were sequenced.
  • The NTRK-positive mesothelioma patient had biphasic histology. After surgery, chemotherapy and radiotherapy, this patient died shortly after completing treatment due to progressive disease.
  • The ALK-positive mesothelioma had sarcomatoid histology. That patient did not receive systemic treatment because of rapidly progressive disease.
  • None of the patients were treated with targeted therapies.
  • The authors described the accuracy of the staining screening method as low. Many stain-positive samples had no fusion on sequencing.
• The authors' conclusion: The authors concluded that, to their knowledge, this was the first study to show NTRK and ALK rearrangements in pleural mesothelioma. They wrote that staining-based screening is reasonable to use for all thoracic tumor types, including these rare subtypes.
• Limitations the authors state:
  • The study was not designed to determine the sensitivity of the method.
  • Tissue microarray samples were small, which may have caused false negatives.
  • Tissue microarrays had fewer tumor cells than full tissue sections.
  • Because a cocktail of antibodies was used, the authors could not tell which antibody caused a positive stain.
  • The non-small cell lung cancer cases were limited to surgically treated stages I to III. The authors suggested this cohort bias may explain the low fusion frequency in that group.
  • Finding a targetable fusion does not guarantee a response to treatment.
  • There are no standard approaches, so the screening method remains investigational.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Non-Small Cell Lung Cancer, ROS1, Lung Cancer, Immunohistochemistry, Targeted Therapy.

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