Author of

• 25905

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  MA16 - Novel Mechanisms for Molecular Profiling (ID 917)

  • Event: WCLC 2018
  • Type: Mini Oral Abstract Session
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD

  • 26208

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    MA16.08 - Clinical Utility of Detecting ROS1 Genetic Alterations in Plasma (ID 13522)

    14:25 - 14:30  |  Author(s): Lorin A Ferris
    • Abstract
    • Presentation
    • Slides

    Background
    

    ROS1-rearranged lung cancer harbors an oncogenic fusion protein created by the juxtaposition of the ROS1 gene to various fusion partners. Due to the lack of a conserved breakpoint and inclusion of intronic segments, ROS1 rearrangements can be challenging to identify with DNA-based sequencing approaches. The feasibility and clinical utility of detecting ROS1 fusions in circulating tumor DNA is not well established.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    The Guardant360 de-identified database was queried to identify lung cancer cases with plasma ROS1 fusions and describe the molecular features of the ROS1-rearranged cohort. In addition, we performed longitudinal analysis of plasma specimens from four patients at our institution who were treated with next-generation ROS1 inhibitors after progressing on crizotinib.

    4c3880bb027f159e801041b1021e88e8 Result
    

    From review of 24,009 plasma specimens from lung cancer patients, we identified 56 patients with ROS1 fusions. CD74 was the most common of 7 identified fusion partners [n=35 (62%) CD74, n=7 (12.5%) SDC4, n=7 (12.5%) EZR, n=3 (5%) TPM3, n=2 (4%) TFG, and n=1 (2%) each of CCDC6 and SLC34A2]. ROS1 fusions commonly co-occurred with TP53 mutations (n=36, 64%) and genes involved in cell-cycle regulation (n=11, 20%) or the WNT/ß-catenin pathway (n=16, 29%). In 4 (80%) of 5 cases where plasma genotyping occurred at crizotinib progression, we identified a putative resistance mechanism, including a ROS1 resistance mutation in 3 patients (n=2 G2032R & n=1 L2026M) and a BRAF V600E mutation in 1 patient. We analyzed longitudinal plasma specimens from 4 patients with crizotinib-resistant lung cancer who were subsequently treated with a next-generation ROS1 inhibitor (n=3 lorlatinib, n=1 entrectinib). One patient treated with lorlatinib had a pretreatment ROS1 G2032R mutation (in plasma and tissue); plasma analysis revealed stability of the G2032R allelic fraction in the setting of primary progression of pleural disease. Of the 2 patients without pretreatment ROS1 mutations who received lorlatinib, one developed a ROS1 G2032R mutation after initial response to treatment. The second patient experienced primary progression and plasma genotyping revealed low level FGFR1 copy number gain (3.3 copies); pre-crizotinib plasma was not available for comparison. One patient had a plasma PIK3CA E545K mutation at the time of crizotinib progression, and did not respond to next-line entrectinib.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Next-generation sequencing can be used to detect ROS1 fusions and resistance mutations in plasma. Longitudinal plasma analysis may provide insight into the activity of investigational drugs against ROS1 mutations that mediate resistance to crizotinib.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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