Trends in Subpopulations at High Risk for Lung Cancer

AbstractIntroductionTwo-thirds of patients in the United States with newly diagnosed lung cancer would not meet the current U.S. Preventive Services Task Force (USPSTF) screening criteria, which suggests a need for amendment of the definition of high risk. To provide evidence of additional high-risk subpopulations and estimated gains and losses from using different criteria for screening eligibility, we conducted a two-step study using three cohorts.MethodsThe two prospective cohorts comprised 5988 patients in whom primary lung cancer was diagnosed between 1997 and 2011 (the hospital cohort) and 850 defined-community residents (the community cohort); the retrospective cohort consisted of the population of Olmsted County, Minnesota, which was observed for 28 years (1984–2011). Subgroups of patients with lung cancer who might have been identified using additional determinates were estimated and compared between the community and hospital cohorts. The findings were supported by indirect comparative projections of two ratios: benefit to harm and cost to effectiveness.ResultsFormer cigarette smokers who had a smoking history of 30 or more pack-years and 15 to 30 quit-years and were 55 to 80 years old formed the largest subgroup not meeting the current screening criteria; they constituted 12% of the hospital cohort and 17% of community cohort. Using the expanded criteria suggested by our study may add 19% more CT examinations for detecting 16% more cases when compared with the USPSTF criteria. Meanwhile, the increases in false-positive results, overdiagnosis, and radiation-related lung cancer deaths are 0.6%, 0.1%, and 4.0%, respectively.ConclusionsCurrent USPSTF screening criteria exclude many patients who are at high risk for development of lung cancer. Including individuals who are younger than 81 years, have a smoking history of 30 or more pack-years, and have quit for 15 to 30 years may significantly increase the number of cases of non-overdiagnosed screen-detected lung cancer, does not significantly add to the number of false-positive cases, and saves more lives with an acceptable amount of elevated exposure to radiation and cost

MET and EGFR Mutations Identified in ALK-Rearranged Pulmonary Adenocarcinoma: Molecular Analysis of 25 ALK-Positive Cases

IntroductionOncogenic ALK kinase activity associated with ALK gene rearrangement is the target of crizotinib, an ALK inhibitor recently approved by the Food and Drug Administration for the treatment of ALK-rearranged (ALK+) non–small cell lung cancers. ALK+ status is generally thought to be mutually exclusive of epidermal growth factor receptor (EGFR) and KRAS mutations. However, the mutation status of other genes is not widely known in ALK+ tumors. The aim of this study is to survey for mutations involving other genes in 25 ALK+ cases confirmed by fluorescent in situ hybridization.MethodsUsing the DNA extracted from formalin-fixed paraffin-embedded tumor samples, a MassArray-based Lung Cancer Mutations Screening Panel was performed to test for 179 individual mutations in 10 genes, including EGFR, KRAS, BRAF, ERBB2, JAK2, AKT1, AKT2, KIT, MET and PIK3CA, which have been implicated in lung carcinogenesis and/or considered as potential therapeutic targets.ResultsFive of 25 ALK+ cases showed additional genetic abnormalities, which were verified by gene sequencing. One patient had EGFR del L747-S752. The remaining four mutations were in the MET gene: MET N375S (n = 2) and MET R988C (n = 2). No MET amplification was found by fluorescent in situ hybridization in the four cases with MET mutation. No mutations were detected in the other genes tested.ConclusionsIn summary, additional mutations were found in 20% of ALK+ cases involving two of the 10 genes tested. Our study highlights that EGFR mutation can be present in ALK+ tumors, though uncommon. Clinical implication of MET mutation in our cases is uncertain and further study is needed

Worse Disease-Free Survival in Never-Smokers with ALK+ Lung Adenocarcinoma

IntroductionThe EML4–anaplastic lymphoma kinase (ALK) translocation is a recognized oncogenic driver in non-small cell lung cancer. We investigated immunohistochemistry (IHC) screening with fluorescence in situ hybridization (FISH) confirmation for ALK detection and estimated the prevalence of ALK positivity in our patient cohort of never-smokers, together with differences in clinical outcomes and prognostic factors for patients with ALK-positive and ALK-negative tumors.MethodsWe designed a three-phase study (training, validation, and testing) in 300 never-smokers with lung adenocarcinoma from the observational Mayo Clinic Lung Cancer Cohort. Tumor samples were tested using IHC and FISH, and concordance between the methods was assessed. Clinical outcomes were assessed via 5-year progression- or recurrence-free survival from diagnosis. Prognostic factors for ALK-positive tumors and metastases were also investigated.ResultsALK-positive patients were significantly (p < 0.05) younger and had higher grade tumors than ALK-negative patients. ALK positivity was 12.2% by IHC and confirmed at 8.2% of tumors by FISH, with complete concordance between IHC 3+/0 and FISH+/− assessments, respectively. Five-year risk of progression or recurrence was doubled for patients with ALK-positive compared with ALK-negative tumors; ALK-positive tumors also appeared to be associated with a higher risk of brain and liver metastases.ConclusionsOur findings suggest that ALK positivity is associated with a significantly poor outcome in nonsmoking-related adenocarcinoma and that ALK-positive tumors may be associated with an increased risk of brain and liver metastases compared with ALK-negative disease. Consequently, an unmet medical need exists in ALK-positive lung cancer patients, and effective ALK-specific therapies are needed

Secondhand tobacco smoke exposure and lung adenocarcinoma in situ/minimally invasive adenocarcinoma (AIS/MIA)

The aim of this study was to estimate the effect of exposure to secondhand tobacco smoke on the incidence of lung adenocarcinoma in situ/minimally invasive adenocarcinoma (AIS/MIA). Data from seven case-control studies participating in the International Lung Cancer Consortium (ILCCO) were pooled, resulting in 625 cases of AIS/MIA and 7,403 controls, of whom 170 cases and 3,035 controls were never smokers. Unconditional logistic regression was used to estimate adjusted ORs (ORadj) and 95% confidence intervals (CI), controlling for age, sex, race, smoking status (ever/never), and pack-years of smoking. Study center was included in the models as a random-effects intercept term. Ever versus never exposure to secondhand tobacco smoke was positively associated with AIS/MIA incidence in all subjects (ORadj = 1.48; 95% CI, 1.14-1.93) and in never smokers (ORadj = 1.45; 95% CI, 1.00-2.12). There was, however, appreciable heterogeneity of ORadj across studies (P = 0.01), and the pooled estimates were largely influenced by one large study (40% of all cases and 30% of all controls). These findings provide weak evidence for an effect of secondhand tobacco smoke exposure on AIS/MIA incidence. Further studies are needed to assess the impact of secondhand tobacco smoke exposure using the newly recommended classification of subtypes of lung adenocarcinoma