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UNLABELLED: Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. SIGNIFICANCE: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501.

BackgroundData from meta-analyses support the use of induction or adjuvant platinum-based chemotherapy for locally advanced non-small cell lung cancers (NSCLCs). This phase 2 study assessed the role of induction cisplatin and docetaxel followed by surgery in patients with resectable stage I to III NSCLCs, followed by 12 months of adjuvant erlotinib.MethodsPatients with resectable stage I to III NSCLCs received cisplatin 80 mg/m2, docetaxel 75 mg/m2 every 21 days for 3 cycles, followed by surgery, followed by adjuvant erlotinib for 12 months. The primary endpoint included safety. Long-term efficacy outcomes and exploratory analysis of intermediary endpoints are also reported (NCT00254384).ResultsForty-seven eligible patients received a median of 3 cycles of induction treatment, 37 underwent surgical resection, and only 21 received adjuvant erlotinib. Two patients died in the perioperative period (1 sepsis during chemotherapy, 1 acute respiratory distress syndrome postoperatively). Most common grade 3 to 5 toxicities during chemotherapy included hypokalemia (8%), infection (7%), and granulocytopenia (25%). During adjuvant erlotinib, 14% of patients experienced grade 2 rash. Median overall survival was 3.4 years. Major pathologic responses in the primary tumor were observed in 19% (7 of 37) of patients and correlated with improved long-term overall survival. Complete pathologic response in mediastinal/hilar nodes also correlated with superior survival.ConclusionsInduction cisplatin and docetaxel was well tolerated. Adjuvant erlotinib did not improve outcomes compared with historical controls. Major pathologic response predicted for improved long-term survival and is a suitable intermediary endpoint for future phase 2 studies.

BackgroundPopulation studies suggest that high body mass index (BMI) correlates with a reduced risk for death from lung cancer. The aim of our study was to evaluate definitively the influence of BMI on long-term overall survival (OS) in surgical patients with NSCLC.MethodsThe study population consisted of 1935 patients who underwent surgical resection for lung cancer at M. D. Anderson Cancer Center (2000-2014). Study variables included both patient- and treatment-related characteristics. Univariate and multivariate Cox regression analyses were performed to identify variables associated with OS.ResultsOn univariate analysis, significant predictors of improved survival were higher BMI, pathologic tumor stage (stage I versus stage II, III, or IV), type of surgical procedure (lobectomy/pneumonectomy versus wedge resection/segmentectomy), younger age, female sex, and adenocarcinoma histologic subtype (versus squamous) (all p < 0.05). Morbidly obese patients (BMI ≥ 35) demonstrated a trend toward better outcomes than those classified as obese (BMI ≥30 and <35 kg/m2) (p = 0.05), overweight (BMI ≥ 25 and <30 kg/m2) (p = 0.13), or healthy weight (BMI <25 kg/m2) (p = 0.37) (hazard ratio = 0.727, 0.848, 0.926, and 1, respectively). On multivariate analysis, BMI remained an independent predictor of survival (p = 0.02). Propensity matching analysis demonstrated significantly better OS (p = 0.003) in patients with a BMI of 30 kg/m2 or higher as compared with a BMI of 25 kg/m2.ConclusionsIn this large, retrospective, single-center series, after control for disease stage and other variables, higher BMI was associated with improved OS after surgical resection of NSCLC. Further studies are necessary to elucidate the precise relationship between BMI and treatment outcomes.

BackgroundWe hypothesized that telomere length in peripheral blood would have significant predictive value for risk of recurrence after curative resection in non-small-cell lung cancer (NSCLC).MethodsThis prospective study included 473 patients with histologically confirmed early stage NSCLC who underwent curative therapy at MD Anderson Cancer Center between 1995 and 2008. Relative telomere length (RTL) of peripheral leukocytes was measured by real-time polymerase chain reaction. The risk of recurrence was estimated as hazard ratios (HRs) and 95% confidence intervals (CIs) using a multivariable Cox proportional hazard regression model.ResultsMedian duration of follow-up was 61 months, and 151 patients (32%) had developed recurrence at time of analysis. Patients who developed recurrence had significantly longer mean RTL compared with those without recurrence (1.13 versus 1.07, p = 0.046). A subgroup analysis indicates that women had longer RTL compared with men (1.12 versus 1.06, p = 0.025), and the patients with adenocarcinoma demonstrated longer RTL compared with those with other histologic types (1.11 versus 1.05, p = 0.042). To determine whether longer RTL in women and adenocarcinoma subgroup would predict risk of recurrence, multivariate Cox analysis adjusting for age, sex, stage, pack year and treatment regimens was performed. Longer telomeres were significantly associated with higher risk of developing recurrence in women (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.02-4.96, p = 0.044) and adenocarcinoma subgroups (HR, 2.19; 95% CI, 1.05-4.55, p = 0.036). The increased risk of recurrence due to long RTL was more apparent in women with adenocarcinoma (HR, 2.67; 95% CI, 1.19-6.03, p = 0.018).ConclusionsThis is the first prospective study to suggest that long RTL is associated with recurrence in early stage NSCLC after curative resection. Women and adenocarcinoma seem to be special subgroups in which telomere biology may play an important role.

A new unit operation is presented that utilizes a rapid feed pressure swing cycle in a bed packed with catalyst and adsorbent to effect both reaction and separation. This hybrid device combines features of a cyclic-steady-state pressure swing adsorber with those of a flow-forced catalytic reactor. Feed sequences for the periodic separating reactor (PSR) are those of rapid, single-bed pressure swing adsorbers (PSA). Only the case of extremely fast reactions is considered here. A perturbed reaction-sorption equilibrium model is formulated and solved for isothermal operation for different equilibrium constants and reaction stoichiometries. The capacity and separation performance for an equilibrium-limited PSR (EPSR) can be of the same order of magnitude as PSA alone. For reactions involving a single reactant or single product, the principal component in a particular exit stream depends upon both the reaction stoichiometry and feed fraction of the process cycle. The pressure dependency of the reaction equilibrium expression is the cause of separation reversals as parameters are varied.

Neutrophil adherence to endothelial monolayers in multi-well plates can be rapidly quantitated, using a fluorescent plate reader. The number of adherent neutrophils which have been labeled with biscarboxyethyl carboxyfluorescein (BCECF) was calculated by comparing fluorescence of endothelial monolayers to a reference standard curve determined by fluorescence intensity of suspensions of labeled neutrophils. The limit of sensitivity approached 1000 cells, which is similar to that achieved by the most sensitive of alternate techniques. The assay, after isolation of the neutrophils, can be completed in 1.5 h. The ability to utilize microwell plates permits the use of large numbers of samples. This method has the advantage of being relatively simple and rapid while maintaining a sensitivity comparable to alternate approaches which employ radioactive labeling or counting of adherent or non-adherent cells.

Forced reactant cycling of carbon monoxide-nitrogen and oxygen-nitrogen streams over Pt---SnO2 in a differential reactor results in enhancements of the reaction rate of up to 9 times that of the optimal steady state. Dynamic features common to periodically forced reaction systems were experimentally observed. In addition, quasi-periodic behaviour under forced concentration cycling was also observed. Transient response experiments combined with see-through FTIR analysis confirm an underlying Langmuir-Hinshelwood-type mechanism. Spectral analysis of the quasi-periodic patterns identified at least three time constants of different orders of magnitude. The nature of the patterns also indicated a reaction mechanism which included one or more "reservoirs" of reactants and/or reaction intermediates.