ROS1 is a therapeutic target in NSCLC, with gene fusions occurring in 1–2% of patients1,2

Patients with ROS1+ NSCLC require an effective treatment with both systemic and central nervous system (CNS) activity3–6

up to

40%

of patients with ROS1+ NSCLC have CNS metastases at diagnosis3,4

in

47%

patients CNS is the first and only site of progression3

The most common sites of metastasis for patients with all types of stage IV lung cancer7

  •  CNS 12.4%
     (36% for ROS1 +    NSCLC)3 

  •  Lung 18.5%7 

  •  Bone 16.4%7 

Despite advances in therapy for ROS1+ NSCLC, additional treatment options are needed to improve clinical outcomes3

High quality molecular testing, such as FISH and NGS, is needed to confirm patients with actionable ROS1 gene fusions8

Testing for ROS1 rearrangement should be systematically carried out in advanced non-squamous NSCLC9

  • ROS1 testing involves the detection of ROS1 gene rearrangements or overexpression of ROS1-fusion proteins10
  • FISH, IHC and RT-PCR are currently used in routine clinical practice:

FISH has been the standard approach to detecting ROS1 rearrangements9

IHC may be used to identify candidate tumours but due to low specificity, other testing is required to confirm the diagnosis9

RT-PCR has good sensitivity and specificity; however, its use may be limited by the presence of numerous ROS1 fusion partners, both identified and still unknown, and difficulties in obtaining good quality RNA11

  • NGS is emerging as a technology with the sensitivity and accuracy necessary to identify all ROS1 fusions with a single test8,12–18

ROS1 fusion proteins drive cancer through aberrant signalling19–21

Genetic rearrangements leading to constitutive expression of ROS1 have been identified in a number of tumour types, including NSCLC19–21

In ROS1+ NSCLC, the ROS1 gene undergoes a chromosomal rearrangement, resulting in the fusion of the tyrosine kinase domain of ROS1 with one of several partner proteins21

The resulting ROS1-fusion kinases are constitutively activated to trigger growth and survival signalling pathways that drive cellular proliferation21

Chromosomal Rearrangement

Image adapted from Gainor and Shaw, 2013

Footnotes:

CNS, central nervous system; FISH, fluorescence in situ hybridisation; IHC, immunohistochemistry; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; RT-PCR, reverse transcription polymerase chain reaction.

1

Bergethon K, et al. J Clin Oncol 2012;30:863–870.

2

Dugay F, et al. Oncotarget 2017;8:53336–53351.

3

Patil T, et al. J Thorac Oncol 2018;13:1717–1726. 

4

Gainor JF, et al. J Clin Oncol Precis Oncol 2017.

5

Mazières J, et al. J Clin Oncol 2015;33:992–999.

6

Wu YL, et al. J Clin Oncol 2018;36:1405–1411.

7

Oikawa A, et al. Oncol Lett 2012;3:629–634.

8

Bubendorf L, et al. Virchows Arch 2016;469:489–503.

9

Planchard D. Anns Oncol 2018;29:iv192–iv237.

10

International Association for the Study of Lung Cancer. IASLC Atlas of ALK and ROS1 testing in lung cancer.

Available at: https://www.iaslc.org/sites/default/files/wysiwyg-assets/alk-ros1_atlas_low-res.pdf (Accessed April 2019).

11

Rossi G, et al. Lung Cancer (Auckl) 2017:8:45–55.

12

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Non-Small Cell Lung Cancer. V.5.2018, 2018.

Available at: www.nccn.org/professionals/physician_gls/recently_updated.aspx (Accessed April 2019).

13

Diaz L, Bardelli A. J Clin Oncol 2014;32:579–586.

14

Shan L, et al. PLoS One 2015;10:e0120422.

15

Cao B, et al. Onco Targets Ther 2016;31:131–138.

16

Zheng Z, et al. Nat Med 2014;20:1479–1484.

17

Drilon A, et al. Clin Cancer Res 2015;21:3631–3639.

18

Grada A, Weinbrecht K. J Invest Dermatol 2013;133:e11.

19

Birchmeier C, Sharma S, Wigler M. Proc Natl Acad Sci USA 1987;84: 9270–9274.

20

Rikova K, et al. Cell 2007;131:1190–1203.

21

Gainor J, Shaw A. Oncologist 2013;18:865–875.