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ROS-1 Rearrangements in Circulating Tumor Cells

      To the Editor:
      ROS1 is a receptor tyrosine kinase of the insulin receptor family, and ROS1 gene fusions are uncommon oncogenic drivers of NSCLC. Liquid biopsy represents a valuable alternative for molecular analyses when a traditional biopsy of the primary tumor yields insufficient tissue.
      • Vendrell J.A.
      • Mau-Them F.T.
      • Béganton B.
      • Godreuil S.
      • Coopman P.
      • Solassol J.
      Circulating cell free tumor DNA detection as a routine tool for lung cancer patient management.
      Moreover, liquid biopsies can detect aberrations missed in tissue testing of heterogeneous tumors. Here, we report the pioneering detection of ROS1 rearrangements in circulating tumor cells (CTCs) in cases in which next-generation sequencing (NGS) of plasma failed to identify a genetic alteration. Lung adenocarcinoma in a right pleural effusion was diagnosed a 44-year-old male Hispanic nonsmoker. Molecular testing of collected fluid failed to reveal a genetic aberration. Palliative chemotherapy was initiated; it consisted of carboplatin/pemetrexed/bevacizumab for six cycles, followed by maintenance chemotherapy with pemetrexed/bevacizumab for 23 cycles. At the time of disease progression, the patient’s tumor was insufficient for further molecular tests. Blood analysis was performed using the VeriStrat test (Biodesix, Boulder, CO). The patient began second-line erlotinib therapy, which was continued for 22 months until disease progression with peritoneal carcinomatosis. NGS done on plasma failed to reveal actionable gene aberrations; a biopsy was done, and a ROS1 gene translocation was identified in tissue and concordant with the results of subsequent fluorescence in situ hybridization analysis of blood CTCs (Fig. 1) . The patient began crizotinib therapy with disease stabilization. Brain metastases were detected 21 and 34 months later, and both were treated with stereotactic brain radiation. Because of the emergence of resistance, the patient was switched to ceritinib and has been stable for 6 months.
      Figure thumbnail gr1
      Figure 1ROS 1 fluorescence in situ hybridization (FISH) break -apart.
      ROS1 rearrangements have been detected in CTCs from four patients known to harbor ROS1 translocations in tumor tissue.
      • Pailler E.
      • Auger N.
      • Lindsay C.R.
      • et al.
      High level of chromosomal instability in circulating tumor cells of ROS1-rearranged non-small-cell lung cancer.
      However, our case is the first in which ROS1 rearrangements were detected in CTC analysis of a peripheral blood sample when NGS evaluation of plasma failed to reveal genetic alterations. Thanks to confirmation of the ROS1 rearrangement, the patient has been alive for 40 months while being treated with anaplastic lymphoma kinase inhibitors (criztonib first and cetinib later). Moreover, detection of a ROS1 rearrangement in CTCs but not by NGS analysis of plasma suggests that CTC analysis may improve detection of this alteration, as we have seen with other genetic aberrations. We therefore encourage future comparisons of ROS1 detection techniques. Whether tumor tissue is truly the criterion standard for molecular analysis is currently disputed, as blood tests can reveal alterations not discovered in tumor tissue.
      • Wang Q.
      • Yang X.
      • He Y.
      • et al.
      Droplet digital PCR for absolute quantification of EML4-ALK gene rearrangement in lung adenocarcinoma.
      Our study underscores the need to define an analytical criterion standard for identifying the largest possible amount of druggable alterations. In conclusion, we report that CTC analysis can identify ROS1 rearrangements. This and other liquid biopsies can improve patient clinical outcomes (i.e., expand therapeutic options) compared with tissue testing alone.

      References

        • Vendrell J.A.
        • Mau-Them F.T.
        • Béganton B.
        • Godreuil S.
        • Coopman P.
        • Solassol J.
        Circulating cell free tumor DNA detection as a routine tool for lung cancer patient management.
        Int J Mol Sci. 2017; 18: 264
        • Pailler E.
        • Auger N.
        • Lindsay C.R.
        • et al.
        High level of chromosomal instability in circulating tumor cells of ROS1-rearranged non-small-cell lung cancer.
        Ann Oncol. 2015; 26: 1408-1415
        • Wang Q.
        • Yang X.
        • He Y.
        • et al.
        Droplet digital PCR for absolute quantification of EML4-ALK gene rearrangement in lung adenocarcinoma.
        J Mol Diagn. 2015; 17: 515-520