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Molecular Tumor Markers Could Reveal New Therapeutic Targets for Lung Cancer Treatment

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Key Points

  • Molecular profiling of small cell lung cancer and lung neuroendocrine tumors is not routinely performed.
  • Numerous mutations were found to be in common with non–small cell lung cancer tumors.
  • Common molecular markers could reveal new therapeutic targets for patients with similar types of lung cancer.
  • Molecular profiling of small cell lung tumors and neuroendocrine lung tumors could become standard.

 

Analysis of 607 small cell lung cancer (SCLC) tumors and neuroendocrine tumors identified common molecular markers among both groups that could reveal new therapeutic targets for patients with similar types of lung cancer, according to research presented at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology (Abstract 12). 

This study examined the clinical specimens of 607 total cases of SCLC tumors (375) and lung neuroendocrine tumors (232), which included carcinoid, atypical carcinoid, and large-cell neuroendocrine tumors. Biomarker testing was achieved through a combination of DNA sequencing (next-generation sequencing or Sanger-based), immunohistochemistry to identify which proteins are present, and in situ hybridization testing to determine if any of the markers that can cause cancer cells to grow or to become resistant to treatment are present.

Wide Spectrum of Gene Markers

Sequencing data were obtained from 201 total specimens (SCLC = 115, neuroendocrine lung tumors = 86).  The 115 SCLC tumors harbored a wide spectrum of gene markers. Sequencing revealed mutations in p53 (57%), RB1 (11%), ATM, cMET (6%), PTEN (6%), BRAF (3%), SMAD4, KRAS (3%), ABL1, APB, CTNNB1, EGFR, FBXW7, FGFR2 (2%), HNF1A, HRAS, JAK3 (2%), MLH1 and PIK3CA (1%).

Multiple genes of interest were found in the neuroendocrine tumor group of 86 tumors, including 66 pulmonary neuroendocrine carcinomas and 20 carcinoid tumors. Among the neuroendocrine tumors, mutations were seen in p53 (44%), FGFR2 (9%), ATM (9%), KRAS (6%) and PIK3CA (4%) as well as EGFR (2%) and BRAF (4%). Analysis of the carcinoid tumors revealed fewer markers, with notable mutations in p53 (11%), HRAS (11%), and BRAF (6%).

EGFR amplification was verified for 11% (5) of the 46 SCLC tumors tested. No SCLC tumors displayed amplification of cMET or HER2. The neuroendocrine tumors exhibited amplification of EGFR (13%), cMET (3%), and HER2 (4%) amplification, while the carcinoid tumors only showed amplification in EGFR (8%).

 The overexpression of cKIT (64% vs 37%), RRM1 (54% vs 28%), TOP2A (91% vs 48%), TOP01 (63% vs 43%), and TS (46% vs 25%) was found more frequently in SCLC tumors compared to lung neuroendocrine tumors, respectively (P = .0001 for all). Low expression of PTEN was more often identified in SCLC tumors compared to lung neuroendocrine tumors (56% vs 36%; P = .001). 

Molecular profiling of these lung cancer subtypes is not routinely performed, however, numerous mutations were found to be in common with non–small cell lung cancer tumors. Specifically, an EGFR mutation was noted in one small cell lung cancer specimen and one neuroendocrine specimen, an ALK rearrangement was detected in a neuroendocrine tumor, and HER2 amplification was seen in a neuroendocrine specimen.

Unique Vulnerabilities

“Even cancers that appear to be very similar can be dramatically different at the molecular level, and these differences may reflect unique vulnerabilities that could positively impact therapeutic options and decisions,” said Stephen V. Liu, MD, Senior Study Author and Assistant Professor of Medicine in the Division of Hematology/Oncology at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC.

“We are pleased that this research confirms these rarer subtypes; it calls for additional investigation on a larger scale. Once confirmed, molecular profiling of small cell tumors and [neuroendocrine tumors] could become standard, as it is currently for non–small cell lung cancers, which will be especially important as more molecularly targeted chemotherapy agents are developed,” Dr. Liu said.

The 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology is sponsored by the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), the International Association for the Study of Lung Cancer (IASLC), and The University of Chicago Medicine.

For full disclosures of the study authors, view the study abstract.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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