The ROS-1 gene plays a major role in the oncogenesis of numerous tumors. ROS-1 rearrangement is found in 0.9–2.6% of non-small-cell lung cancers (NSCLCs), mostly lung adenocarcinomas, with a significantly higher rate of women, non-smokers, and a tendency to a younger age. It has been demonstrated that ROS-1 is a true oncogenic driver, and tyrosine kinase inhibitors (TKIs) targeting ROS-1 can block tumor growth and provide clinical benefit for the patient. Since 2016, crizotinib has been the first-line reference therapy, with two-thirds of the patients’ tumors responding and progression-free survival lasting ~20 months. More recently developed are ROS-1-targeting TKIs that are active against resistance mechanisms appearing under crizotinib and have better brain penetration. This review summarizes current knowledge on ROS-1 rearrangement in NSCLCs, including the mechanisms responsible for ROS-1 oncogenicity, epidemiology of ROS-1-positive tumors, methods for detecting rearrangement, phenotypic, histological, and molecular characteristics, and their therapeutic management. Much of this work is devoted to resistance mechanisms and the development of promising new molecules.

Introduction: Despite recent therapeutic advances, lung cancer remains the primary cause of cancer deaths worldwide, and early lung mortality was poorly studied. Area covered: Early lung-cancer mortality reflects local therapy (surgery or radiotherapy) impact (localized forms), and metastatic disease evolution, comorbidities and healthcare-system accessibility. The definition of early lung cancer mortality is not consensual; thresholds range from 1 to 12 months post-diagnosis. This systematic review was undertaken to identify and analyze factors significantly associated with early lung cancer mortality. Age, male sex, non-adenocarcinoma histology, advanced stage at diagnosis and ECOG performance status are the main clinical factors of early lung cancer mortality. Active/ex-smoking also seems to favor early mortality, despite heterogeneous definitions of smoker status. For radio-chemotherapy treated locally advance disease, the early mortality rate increases according to tumor volume. Less well studied, socioeconomic characteristics (rurality and social deprivation index) yielded contradictory results, partially because definitions vary over studies. However, early lung cancer mortality is significantly higher for lower socioeconomic class patients. Expert opinion: Prospective, observational, general population studies are needed to better evaluate early lung-cancer mortality. International consensus concerning the patient-, disease- or healthcare system-linked factors of interest to be collected would facilitate comparisons among countries.

To evaluate how comorbidities affect mortality benefits of lung cancer screening (LCS) with low-dose computed-tomography (LDCT). We developed a comorbidity index (PLCO-ci) using LCS-eligible participants' data from the Prostate Lung Colorectal and Ovarian (PLCO) trial (training set) and the National Lung Screening Trial (NLST) (validation set). PLCO-ci predicts 5-year non-lung cancer (LC) mortality using a regularized Cox model; with performance evaluated by the area under the ROC curve (ROC_AUC). In NLST, LC mortality (per original publication) was compared between LDCT and chest X-ray arms across PLCO-ci quintile (Q1-5) using cause-specific hazard ratio (csHR) with 95% confidence intervals [95%CI]. Analyses included 34,690 PLCO and 53,452 NLST participants (mean age: 62 (±5) and 61 (±5) years old, 58% and 59% males, 39% and 41% active smokers, respectively). PLCO-ci predicted 5-year non-LC mortality with ROC_AUC [95%CI] of 0.72 [0.71-0.74] in PLCO and 0.69 [0.67-0.70] in NLST. In NLST, at median follow-up of 6.5 years, LC mortality was significantly reduced for participants with intermediate comorbidity (Q2-Q3-Q4): csHR [95% CI] 0.62 [0.41-0.95], 0.68 [0.48-0.96] and 0.72 [0.54-0.96] respectively, with a non-statistically significant reduction for Q1 (csHR=0.72 [0.45-1.17]) and no reduction for Q5 participants (csHR=0.99 [0.79-1.23]). Participants in Q2-Q3-Q4 (60%) accounted for 89% of LC deaths averted among all NLST participants. Q1 participants had low LC incidence, while Q5 had higher localized LC lethality, more squamous cell carcinomas, and untreated LC. The PLCO-ci developed in this work shows that individuals with intermediate comorbidity benefited the most from LCS, highlighting the need of addressing comorbidities to achieve LC mortality benefits.

Background: Lung cancer screening programs concern smokers at risk for cardiovascular diseases (CVDs) and chronic obstructive pulmonary disease (COPD). The LUMASCAN (LUng Cancer Screening, MArkers and low-dose computed tomography SCANner) study aimed to evaluate the acceptability and feasibility of screening for these 3 diseases in a community population with centralized organization and to determine low-dose computed tomography (CT) markers associated with each disease. Methods: This cohort enrolled participants meeting National Comprehensive Cancer Network criteria (v1.2014) in an organized lung cancer–screening program including low-dose CT scans; spirometry; evaluations of coronary artery calcifications (CACs); and a smoking cessation plan at inclusion, 1, and 2 years; then telephone follow-up. Outcomes were the participation rate and the proportion of participants affected by lung cancer, obstructive lung disease, or CVD events. Logistic-regression models were used to identify radiological factors associated with each disease. Results: Between 2016 and 2019, a total of 302 participants were enrolled: 61% men; median age 58.8 years; 77% active smoker; 11% diabetes; 38% hypertension; and 27% taking lipid-lowering agents. Inclusion, 1-year, and 2-year participation rates were 99%, 81%, 79%, respectively. After a median follow-up of 5.81 years, screenings detected 12 (4%) lung cancer, 9 of 12 via low-dose CT (78% localized) and 3 of 12 during follow-up (all stage IV), 83 (27%) unknown obstructive lung disease, and 131 (43.4%) moderate to severe CACs warranting a cardiology consultation. Preexisting COPD and moderate to severe CACs were associated with major CVD events with odds ratios of 1.98 (95% confident interval [CI] = 1.00 to 3.88) and 3.27 (95% CI = 1.72 to 6.43), respectively. Conclusion: The LUMASCAN study demonstrated the feasibility of combined screening for lung cancer, COPD, and CVD in a community population. Its centralized organization enabled high participation and coordination of healthcare practitioners.