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Cell membrane transporters and metabolic enzymes play a crucial role in the transportation of a wide variety of substrates that maintain homeostasis in biological processes. We explored associations between genetic variants in these genes and survival of nonsmall-cell lung cancer (NSCLC) patients by reanalyzing two datasets from published genome-wide association studies (GWASs). In the discovery by using the GWAS dataset of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, we evaluated associations of 1,245 single-nucleotide polymorphisms (SNPs) in genes of four transporter families and two metabolic enzyme families with survival of 1,185 NSCLC patients. We then performed a replication analysis in the Harvard University Lung Cancer study (LCS) with 984 NSCLC patients. Multivariate Cox proportional hazards regression and false discovery rate (FDR) corrections were performed to evaluate the associations. We identified that 21 genotyped SNPs in eight gene regions were significantly associated with survival with FDR ≤0.1 in the discovery dataset. Subsequently, we confirmed six SNPs, which were putative functional, in ABCG1 of the ATP-binding cassette transporter family in the replication dataset. In the pooled analysis, two tagging (at r² > 0.8 for linkage disequilibrium with other replicated SNPs)/functional SNPs were independently associated with survival: rs225388 G > A [adjusted hazards ratio (HR)51.12, 95% confidence interval (CI)51.03-1.20, Ptrend = 4.6 3 10-3] and rs225390 A > G (adjusted HR51.16, 95% CI51.07-1.25, Ptrend = 3.8 3 10-4). Our results indicated that genetic variants of ABCG1 may be predictors of survival of NSCLC patients. [ABSTRACT FROM AUTHOR]

BACKGROUND Tobacco use is the most important risk factor for the development of lung cancer. The objective of the current study was to determine the effect of smoking on the development of second primary lung cancers (SPLCs) and other clinical outcomes after surgery for non-small cell lung cancer (NSCLC). METHODS All patients who underwent surgery for NSCLC at the study institution from 1995 through 2008 were identified. Rates of SPLC were analyzed based on smoking status and pack-year exposure. Multivariate analysis was performed to determine risk factors for SPLC. Overall survival, local control, distant metastases, and postoperative mortality were also examined. RESULTS A total of 1484 patients were identified, including 98 never-smokers. The incidence of SPLC at 3 years, 5 years, and 8 years was 5%, 8%, and 16%, respectively. Only 1 never-smoker developed an SPLC. On multivariate analysis, which was restricted to ever-smokers with pack-years as a continuous variable, smoking history was found to be the only independent risk factor for SPLC (hazard ratio, 1.08; 95% confidence interval, 1.02-1.16 [ P = .031]), corresponding to an 8% increased risk per 10 pack-year exposure. There were no differences in rates of local control or distant metastases based on smoking status. There was a trend toward lower postoperative mortality in never-smokers compared with ever-smokers (0% vs 3.3%; P = .069). Overall survival was found to be significantly worse for current smokers compared with former and never-smokers. CONCLUSIONS SPLCs are rare in never-smokers. Increasing tobacco exposure is associated with a higher risk of SPLC in patients with a history of smoking. Current smokers have an increased risk of mortality whereas former and never-smokers have comparable survival. Cancer 2015;121:598-604. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: To evaluate the effect of diabetes mellitus (DM) on clinical outcomes in patients managed surgically for non-small cell lung cancer (NSCLC). Methods: Patients who underwent surgery for pathological I-IIIA NSCLC at Duke University from 1995-2005 were analyzed. Postoperative mortality was defined as any death occurring within 30 days of resection or during the initial hospitalization after surgery. Disease recurrence at the surgical margin, ipsilateral hilum, and/or mediastinum was considered a local/regional recurrence (LRR). Survival and LRR rates were estimated using the Kaplan-Meier method and compared using a log rank test. A multivariate regression analysis assessed the association between candidate factors, including DM, and disease recurrence and survival. Results: Of 957 patients, DM was present in 122 (13%). DM was associated with an increased risk of postoperative mortality (7.4% vs. 3.2%, P= 0.04). However, the proportion of patients undergoing sublobar resections, mediastinal lymph node dissection, and receiving adjuvant chemotherapy, was no different among patients with or without DM. Five-year LRR rates were 27% in patients with DM, versus 21% in patients without DM ( P= 0.23). Survival at five years was 43% for patients with DM, and 47% for patients without DM ( P= 0.10). On multivariate analysis, DM was not independently associated with a higher risk of LRR (hazard ratio [HR] 1.33, P= 0.34), distant recurrence (HR 0.86, P= 0.58), or overall survival (HR 1.08, P= 0.63). Conclusions: Although a higher risk of postoperative mortality was noted in patients with DM, a detriment in local or distant disease control or overall survival was not observed. [ABSTRACT FROM AUTHOR]

The article presents a study which evaluates the actuarial risk of local failure (LF) after stage I to II nonsmall cell lung cancer (NSCLC) surgery. It assesses surgical and pathologic factors associated with LF in the entire cohort and a subgroup who underwent stage IB and II surgery using a multivariate Cox regression analysis. It emphasizes that local sites were involved in more than half of the disease recurrences after early stage NSCLC surgery.

Purpose: To evaluate the clinical outcomes in patients with early-stage non-small-cell lung cancer (NSCLC) after combined treatment with thermal ablation and radiation therapy (RT). Materials and Methods: Forty-one patients with inoperable stage I/II NSCLC tumors underwent thermal ablation and RT at our institution between 1998 and 2005. Thirty-seven radiofrequency (RF) ablation procedures and four microwave ablation procedures were performed. Ablations were followed by standard-fraction external-beam RT within 90 days (n = 27) or postprocedural brachytherapy (n = 14). Survival and local recurrence were the primary endpoints evaluated by Kaplan-Meier analysis. Results: The median follow-up was 19.5 months. The overall survival rates were 97.6% at 6 months, 86.8% at 1 year, 70.4% at 2 years, and 57.1% at 3 years. Patients with tumors smaller than 3 cm (n = 17) had an average survival time of 44.4 +/- 5.4 months (SE). Patients with tumors 3 cm or larger (n = 24) had an average survival time of 34.6 +/- 7.0 months (P = .08). Local recurrence occurred in 11.8% of tumors smaller than 3 cm after an average of 45.6 +/- 4.1 months and in 33.3% of the larger tumors after an average of 34.0 +/- 7.8 months (P = .03). Outcomes in the brachytherapy and RT groups did not differ significantly. Nine of 15 pneumothoraces required chest tube drainage (22.0%). Conclusions: Thermal ablation followed by RT for inoperable stage I/II NSCLC has a relatively low rate of complications that are easily managed. Combined therapy may result in an improved survival compared with either modality alone. [ABSTRACT FROM AUTHOR]

Background Before the availability of immunotherapy, chemotherapy was standard first-line therapy for non–small-cell lung cancer (NSCLC) lacking actionable gene alterations. Preclinical evidence suggests chemotherapy is immunomodulatory, supporting chemotherapy/immunotherapy combinations. Atezolizumab, anti-programmed death ligand-1 (PD-L1) antibody, blocks programmed cell death protein-1 and B7.1 interaction with PD-L1. GP28328 ( NCT01633970 ) assessed atezolizumab with chemotherapy in multiple tumours; we report results for advanced, treatment-naïve NSCLC. Methods Patients received atezolizumab plus carboplatin with paclitaxel (Arm C: atezo/cb/pac), pemetrexed (Arm D: atezo/cb/pem, maintenance pemetrexed permitted), or nab-paclitaxel (Arm E: atezo/cb/nab-pac), four–six cycles, then atezolizumab maintenance. Primary end-point was safety; secondary end-points were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results Seventy-six NSCLC patients were enrolled (n = 25, 25 and 26 for Arms C, D and E, respectively). Common treatment-related grade III/IV adverse events were neutropenia (36% atezo/cb/pac, 36% atezo/cb/pem, 42% atezo/cb/nab-pac) and anaemia (16% atezo/cb/pac, 16% atezo/cb/pem, 31% atezo/cb/nab-pac). Confirmed ORRs were 36% atezo/cb/pac, 68% atezo/cb/pem (one complete response [CR]) and 46% atezo/cb/nab-pac (four CRs). Median PFS was 7.1 months, (95% confidence interval [CI]: 4.2–8.3), 8.4 months (95% CI: 4.7–11) and 5.7 months (95% CI: 4.4–14.8), respectively. Median OS was 12.9 months (95% CI: 8.8–21.3), 18.9 months (95% CI: 9.9–27.4) and 17.0 months (95% CI: 12.7–not evaluable), respectively. Conclusion Atezolizumab with chemotherapy was well tolerated with encouraging efficacy, though the analysis was limited by small numbers. NSCLC chemotherapy combination studies are ongoing. ClinicalTrials.gov identifier NCT01633970 . [ABSTRACT FROM AUTHOR]

Background: Nivolumab has shown improved survival in the treatment of advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. We assessed the safety and activity of combination nivolumab plus ipilimumab as first-line therapy for NSCLC.Methods: The open-label, phase 1, multicohort study (CheckMate 012) cohorts reported here were enrolled at eight US academic centres. Eligible patients were aged 18 years or older with histologically or cytologically confirmed recurrent stage IIIb or stage IV, chemotherapy-naive NSCLC. Patients were randomly assigned (1:1:1) by an interactive voice response system to receive nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 12 weeks, or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks until disease progression, unacceptable toxicities, or withdrawal of consent. Data from the latter two cohorts, which were considered potentially suitable for further clinical development, are presented in this report; data from the other cohort (as well as several earlier cohorts) are described in the appendix. The primary outcome was safety and tolerability, assessed in all treated patients. This ongoing study is registered with ClinicalTrials.gov, number NCT01454102.Findings: Between May 15, 2014, and March 25, 2015, 78 patients were randomly assigned to receive nivolumab every 2 weeks plus ipilimumab every 12 weeks (n=38) or nivolumab every 2 weeks plus ipilimumab every 6 weeks (n=40). One patient in the ipilimumab every-6-weeks cohort was excluded before treatment; therefore 77 patients actually received treatment (38 in the ipilimumab every-12-weeks cohort; 39 in the ipilimumab every-6-weeks cohort). At data cut-off on Jan 7, 2016, 29 (76%) patients in the ipilimumab every-12-weeks cohort and 32 (82%) in the ipilimumab every-6-weeks cohort had discontinued treatment. Grade 3-4 treatment-related adverse events occurred in 14 (37%) patients in the ipilimumab every-12-weeks cohort and 13 (33%) patients in the every-6-weeks cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (three [8%] and no patients), pneumonitis (two [5%] and one [3%] patients), adrenal insufficiency (one [3%] and two [5%] patients), and colitis (one [3%] and two [5%] patients). Treatment-related serious adverse events were reported in 12 (32%) patients in the ipilimumab every-12-weeks cohort and 11 (28%) patients in the every-6-weeks cohort. Treatment-related adverse events (any grade) prompted treatment discontinuation in four (11%) patients in the every-12-weeks cohort and five (13%) patients in the every-6-weeks cohort. No treatment-related deaths occurred. Confirmed objective responses were achieved in 18 (47% [95% CI 31-64]) patients in the ipilimumab every-12-weeks cohort and 15 (38% [95% CI 23-55]) patients in the ipilimumab every-6-weeks cohort; median duration of response was not reached in either cohort, with median follow-up times of 12·8 months (IQR 9·3-15·5) in the ipilimumab every-12-weeks cohort and 11·8 months (6·7-15·9) in the ipilimumab every-6-weeks cohort. In patients with PD-L1 of 1% or greater, confirmed objective responses were achieved in 12 (57%) of 21 patients in the ipilimumab every-12-weeks cohort and 13 (57%) of 23 patients in the ipilimumab every-6-weeks cohort.Interpretation: In NSCLC, first-line nivolumab plus ipilimumab had a tolerable safety profile and showed encouraging clinical activity characterised by a high response rate and durable response. To our knowledge, the results of this study are the first suggestion of improved benefit compared with anti-PD-1 monotherapy in patients with NSCLC, supporting further assessment of this combination in a phase 3 study.Funding: Bristol-Myers Squibb. [ABSTRACT FROM AUTHOR]

Purpose: To determine the maximum tolerated dose of radiation therapy (RT) given in an accelerated fashion with concurrent chemotherapy using intensity modulated RT.Methods and Materials: Patients with locally advanced lung cancer (non-small cell and small cell) with good performance status and minimal weight loss received concurrent cisplatin and etoposide with RT. Intensity modulated RT with daily image guidance was used to facilitate esophageal avoidance and delivered using 6 fractions per week (twice daily on Fridays with a 6-hour interval). The dose was escalated from 58 Gy to a planned maximum dose of 74 Gy in 4 Gy increments in a standard 3 + 3 trial design. Dose-limiting toxicity (DLT) was defined as acute grade 3-5 nonhematologic toxicity attributed to RT.Results: A total of 24 patients were enrolled, filling all dose cohorts, all completing RT and chemotherapy as prescribed. Dose-limiting toxicity occurred in 1 patient at 58 Gy (grade 3 esophagitis) and 1 patient at 70 Gy (grade 3 esophageal fistula). Both patients with DLTs had large tumors (12 cm and 10 cm, respectively) adjacent to the esophagus. Three additional patients were enrolled at both dose cohorts without further DLT. In the final 74-Gy cohort, no DLTs were observed (0 of 6).Conclusions: Dose escalation and acceleration to 74 Gy with intensity modulated RT and concurrent chemotherapy was tolerable, with a low rate of grade ≥3 acute esophageal reactions. [ABSTRACT FROM AUTHOR]