The frequency and impact of ROS1 rearrangement on clinical outcomes in never smokers with lung adenocarcinoma

H. R. Kim; S. M. Lim; H. J. Kim; S. K. Hwang; J. K. Park; E. Shin; M. K. Bae; S.-H. I. Ou; J. Wang; S. S. Jewell; D. R. Kang; R. A. Soo; H. Haack; J. H. Kim; H. S. Shim; B. C. Cho

doi:10.1093/annonc/mdt220

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The frequency and impact of ROS1 rearrangement on clinical outcomes in never smokers with lung adenocarcinoma

Authors: H. R. Kim ; S. M. Lim ; H. J. Kim ; S. K. Hwang ; J. K. Park ; E. Shin ; M. K. Bae ; S.-H. I. Ou ; J. Wang ; S. S. Jewell ; D. R. Kang ; R. A. Soo ; H. Haack ; J. H. Kim ; H. S. Shim ; B. C. Cho

Citation: ANNALS OF ONCOLOGY, Vol.24(9) : 2364-2370, 2013

Journal Title: ANNALS OF ONCOLOGY

ISSN: 0923-7534

Issue Date: 2013

MeSH: Adenocarcinoma/drug therapy ; Adenocarcinoma/genetics* ; Adult ; Aged ; Antigens, Differentiation, B-Lymphocyte/genetics ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics* ; Cell Line, Tumor ; Cell Survival/drug effects ; Disease-Free Survival ; Female ; Gene Frequency/genetics ; Gene Rearrangement/genetics ; Glutamates/pharmacology ; Glutamates/therapeutic use ; Guanine/analogs & derivatives ; Guanine/pharmacology ; Guanine/therapeutic use ; Histocompatibility Antigens Class II/genetics ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics* ; Male ; Middle Aged ; Mutation/genetics ; Pemetrexed ; Protein-Tyrosine Kinases/genetics* ; Protein-Tyrosine Kinases/metabolism ; Proto-Oncogene Proteins/genetics* ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins p21(ras) ; Pyrazoles/pharmacology ; Pyridines/pharmacology ; Pyrimidines/pharmacology ; Quinazolines/pharmacology ; Receptor Protein-Tyrosine Kinases/genetics ; Receptor Protein-Tyrosine Kinases/metabolism ; Receptor, Epidermal Growth Factor/genetics ; Recombinant Fusion Proteins/genetics* ; Recombinant Fusion Proteins/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Smoking ; Treatment Outcome ; ras Proteins/genetics

Keywords: ROS1 ; lung adenocarcinoma ; never smoker ; outcome

Abstract: BACKGROUND: To determine the frequency and predictive impact of ROS1 rearrangements on treatment outcomes in never-smoking patients with lung adenocarcinoma.

PATIENTS AND METHODS: We concurrently analyzed ROS1 and ALK rearrangements and mutations in the epidermal growth factor receptor (EGFR), and KRAS in 208 never smokers with lung adenocarcinoma. ROS1 and ALK rearrangements were identified by fluorescent in situ hybridization.

RESULTS: Of 208 tumors screened, 7 (3.4%) were ROS1 rearranged, and 15 (7.2%) were ALK-rearranged. CD74-ROS1 fusions were identified in two patients using reverse transcriptase-polymerase chain reaction. The frequency of ROS1 rearrangement was 5.7% (6 of 105) among EGFR/KRAS/ALK-negative patients. Patients with ROS1 rearrangement had a higher objective response rate (ORR; 60.0% versus 8.5%; P = 0.01) and a longer median progression-free survival (PFS; not reached versus 3.3 months; P = 0.008) to pemetrexed than those without ROS1/ALK rearrangement. The PFS to EGFR-tyrosine kinase inhibitors in patients harboring ROS1 rearrangement was shorter than those without ROS1/ALK rearrangement (2.5 versus 7.8 months; P = 0.01).

CONCLUSIONS: The frequency of ROS1 rearrangements in clinically selected patients is higher than that reported for unselected patients, suggesting that ROS1 rearrangement is a druggable target in East-Asian never smokers with lung adenocarcinoma. Given the different treatment outcomes to conventional therapies and availability of ROS1 inhibitors, identification of ROS1 rearrangement can lead to successful treatment in ROS1-rearranged lung adenocarcinomas.