Clinical and prognostic implications of ALK and ROS1 rearrangements in never-smokers with surgically resected lung adenocarcinoma.

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. 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. 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. This study shows significantly poorer DFS of ALK or ROS1 fusion-positive lung adenocarcinoma in never-smokers after curative surgery.

Kim MH ，Shim HS ，Kang DR ，Jung JY ，Lee CY ，Kim DJ ，Lee JG ，Bae MK ，Kim HR ，Lim SM ，Kim EY ，Park JS ，Chung KY ，Kim HJ ，Kim JH ，Cho BC ... -  《-》

Clinical characteristics associated with ALK rearrangements in never-smokers with pulmonary adenocarcinoma.

Anaplastic lymphoma kinase (ALK) rearrangement is a validated predictive marker to define patients with non-small cell lung cancer (NSCLC) who can benefit from selective ALK inhibitors. Therefore, accurate assessment of its prevalence and clinical characteristics is increasingly important in the treatment of NSCLC. Also, this ALK rearrangement was previously reported to be more common in patients with no smoking history or those with adenocarcinoma. Never-smokers with completely resected pulmonary adenocarcinoma were screened for ALK rearrangements using Nanostring's gene expression platform. Clinicopathologic data, such as information about epidermal growth factor receptor (EGFR) and KRAS mutation status were retrospectively reviewed. Of 231 tumors screened, 20 (9%) had an ALK rearrangement and all were confirmed to be positive with immunohistochemical and fluorescent in situ hybridization analysis. Of the tumors with available data on the EGFR/KRAS mutation status, EGFR and KRAS mutation rates were 64% (69/108) and 5% (5/102), respectively. Amongst the tumors that were free of EGFR and KRAS mutations, the proportion of ALK rearrangements reached up to 33%. At the time of data cut-off, total of 68 tumors were recurred. Although the recurrence rate was similar between the ALK-positive and negative groups (30% vs. 29%), there was a tendency for ALK-positive tumors to recur more frequently in the pleural space (15% vs. 5%). The five-year disease-free survival (61%) and overall survival rates (79%) in the ALK-positive group were similar to those in the ALK-negative group (51% and 83%, respectively). Even after excluding two patients treated with crizotinib after disease recurrence, overall survival was similar between the two groups. In an NSCLC subpopulation based on smoking history, histology, and EGFR and KRAS mutation status, the prevalence of ALK rearrangements is considerably high. However, ALK rearrangement status itself has no prognostic relevance in patients with completely resected NSCLC.

Sun JM ，Lira M ，Pandya K ，Choi YL ，Ahn JS ，Mao M ，Han J ，Park K ，Ahn MJ ，Kim J ... -  《-》

Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement.

The objectives of this study were to determine the proportions of major oncogenic alterations and to examine survival in genotype-specific subsets of never-smokers with nonsmall cell lung cancer (NSCLC). The authors concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes and investigated anaplastic lymphoma kinase (ALK) gene rearrangements in samples from 229 never-smokers with NSCLC. ALK rearrangements were identified by fluorescent in situ hybridization and were confirmed by immunohistochemistry. Mutations in EGFR (exons 18 to 21) and KRAS (codons 12 and 13) were determined by direct sequencing. Of 229 tumors, the frequency of EGFR mutations, ALK rearrangements, KRAS mutations, and no mutations (wild type [WT]) in any of the 3 genes (WT/WT/WT) was 48%, 8.3%, 3.5%, and 40.2%, respectively. All genetic alterations were mutually exclusive. The median progression-free survival after treatment with EGFR tyrosine kinase inhibitors (TKIs) was 12.8 months, 6.3 months, 2.1 months, and 1.6 months in patients with EGFR mutations, the WT/WT/WT genotype, KRAS mutations, and ALK rearrangements, respectively. In a Cox regression model, the adjusted hazard ratio for the risk of disease progression after treatment with EGFR TKIs was 0.59 (95% confidence interval [CI], 0.40-0.87; P = .008) for patients with EGFR mutations, 4.58 (95% CI, 2.07-10.15; P < .001) for patients with ALK rearrangements, and 4.23 (95% CI, 1.65-10.8; P = .003) for patients with KRAS mutations. Overall survival also differed significantly among genotypes. To the authors' knowledge, this was the largest comprehensive and concurrent analysis to date of 3 major oncogenic alterations in a cohort of East Asian never-smokers with NSCLC. Because survival outcomes differed among genotypes, and drugs that target specific alterations currently are available, genetic profiling to identify genotype-specific subsets can lead to successful treatment with appropriate kinase inhibitors.

Kim HR ，Shim HS ，Chung JH ，Lee YJ ，Hong YK ，Rha SY ，Kim SH ，Ha SJ ，Kim SK ，Chung KY ，Soo R ，Kim JH ，Cho BC ... -  《-》

On the relevance of a testing algorithm for the detection of ROS1-rearranged lung adenocarcinomas.

ROS1 proto-oncogene translocations define a new molecular subgroup in non-small cell lung cancers (NSCLC) and are associated with a response to the MET/ALK inhibitor, crizotinib. These rearrangements are described in 0.9-1.7% NSCLC, in wild-type EGFR, KRAS and ALK ("triple negative") lung adenocarcinomas. Rapid and efficient identification of these alterations is thus becoming increasingly important. In this study, 121 triple negative lung adenocarcinomas were screened by both IHC with the ROS1 D4D6 antibody, and FISH using two commercially available ROS1 break-apart probes. To address a possible cross-reactivity of the ROS1 antibody with other protein kinase receptors, we screened 80 additional cases with known EGFR, KRAS, PI3KCA, BRAF, HER2 mutations or ALK-rearrangement. We diagnosed 9 ROS1-rearranged adenocarcinomas, with both a positive FISH result (51-87% rearranged nuclei) and a positive IHC staining (2+/3+ cytoplasmic staining). Only one of the ROS1-positive FISH cases was characterized by a classical split pattern, the others showed a variant pattern, most commonly involving a loss of the 5' telomeric probe. Considering a positivity threshold of 2+ stained cells, the sensitivity of the ROS1 D4D6 antibody compared to FISH was 100% and the specificity 96.9%, as two HER2-mutated tumors were positive with D4D6 antibody, without any translocation in FISH. All the ROS1-positive cases were at an advanced stage, arising in never or light smokers. They were mainly solid cribriform and acinar adenocarcinomas, with signet ring cells noted in 5 cases, and calcifications in 3 cases. One positive case was an invasive mucinous carcinoma. Our results show that a screening algorithm based on an IHC detection of ROS1 fusion proteins, confirmed if positive or doubtful by a ROS1 break-apart FISH assay, is pertinent in advanced "triple negative" lung adenocarcinomas, since the prevalence of ROS1-positive cases in this selected population reaches 7.4% in our series.

Mescam-Mancini L ，Lantuéjoul S ，Moro-Sibilot D ，Rouquette I ，Souquet PJ ，Audigier-Valette C ，Sabourin JC ，Decroisette C ，Sakhri L ，Brambilla E ，McLeer-Florin A ... -  《-》

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

Kim HR ，Lim SM ，Kim HJ ，Hwang SK ，Park JK ，Shin E ，Bae MK ，Ou SH ，Wang J ，Jewell SS ，Kang DR ，Soo RA ，Haack H ，Kim JH ，Shim HS ，Cho BC ... -  《-》