Clinical and prognostic implications of ALK and ROS1 rearrangements in never-smokers with surgically resected lung adenocarcinoma.
OBJECTIVE
The aim of this study is to evaluate the prevalence and prognostic significance of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangement in never-smokers with surgically resected lung adenocarcinoma.


METHODS
We retrospectively analyzed 162 consecutive never-smokers who underwent curative resection for stage IB to IIIA lung adenocarcinoma at a single institution. We concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes, and investigated ALK rearrangements by fluorescence in situ hybridization assay. ROS1 rearrangement was also determined in all triple (EGFR/KRAS/ALK)-negative tumors.


RESULTS
Of 162 never smokers with lung adenocarcinoma, 14 (8.6%) and 5 (3.1%) had ALK and ROS1 rearrangements, respectively. Nineteen of the 74 (25.7%) EGFR and KRAS mutation-negative patients were fusion-positive (ALK or ROS1 fusion). Fusion-positive patients tended to have shorter median disease-free survival (DFS) than fusion-negative patients (28.0 vs. 33.9 months; p=0.128). In multivariate analysis, fusion-positive patients had significantly poorer DFS than fusion-negative patients after adjustment for age, sex, T stage, N stage, and adjuvant chemotherapy use (p=0.022; hazard ratio, 2.11; 95% confidence interval, 1.19-4.30). The first recurrence sites were not significantly different between fusion-positive and fusion-negative patients in this study.


CONCLUSIONS
This study shows significantly poorer DFS of ALK or ROS1 fusion-positive lung adenocarcinoma in never-smokers after curative surgery.
Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Min Hwan
MH
Kim
Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Hyo Sup
HS
Shim
Biostatistics Collaboration Unit, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Dae Ryong
DR
Kang
Division of Pulmonology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Ji Ye
JY
Jung
Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Chang Young
CY
Lee
Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Dae Joon
DJ
Kim
Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Jin Gu
JG
Lee
Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Mi Kyung
MK
Bae
Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Hye Ryun
HR
Kim
Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Sun Min
SM
Lim
Division of Pulmonology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Eun Young
EY
Kim
Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Ji Soo
JS
Park
Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Kyung Young
KY
Chung
JEUK Institute for Cancer Research, JEUK Co., Ltd., Gumi-City, Kyungbuk, Republic of Korea.
Hyun-Jung
HJ
Kim
Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Joo Hang
JH
Kim
Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: cbc1971@yuhs.ac.
Byoung Chul
BC
Cho
D000230:Adenocarcinoma / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality*; D000077548:Anaplastic Lymphoma Kinase; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics; D015321:Gene Rearrangement / Q000235:genetics; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D011013:Pneumonectomy; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012008:Recurrence; D012189:Retrospective Studies; D012907:Smoking; D016019:Survival Analysis; D018631:ras Proteins / Q000235:genetics
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C000626173:ALK protein, human; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
Anaplastic lymphoma kinase; C-ros oncogene 1; Lung adenocarcinoma; Never-smokers; Prognosis