Comparison of SP263 and 22C3 immunohistochemistry PD-L1 assays for clinical efficacy of adjuvant atezolizumab in non-small cell lung cancer: results from the randomized phase III IMpower010 trial

Immune checkpoint inhibitors; Non-small cell lung cancer; Tumor biomarkersInhibidors del punt de control immunitari; Càncer de pulmó de cèl·lules no petites; Biomarcadors tumoralsInhibidores de puntos de control inmunológico; Cáncer de pulmón de células no pequeñas; Biomarcadores tumoralesBackground Tumor samples from the phase III IMpower010 study were used to compare two programmed death-ligand 1 (PD-L1) immunohistochemistry assays (VENTANA SP263 and Dako 22C3) for identification of PD-L1 patient subgroups (negative, positive, low, and high expression) and their predictive value for adjuvant atezolizumab compared with best supportive care (BSC) in resectable early-stage non-small cell lung cancer (NSCLC). Methods PD-L1 expression was assessed by the SP263 assay, which measured the percentage of tumor cells with any membranous PD-L1 staining, and the 22C3 assay, which scored the percentage of viable tumor cells showing partial or complete membranous PD-L1 staining. Results When examining the concordance at the PD-L1-positive threshold (SP263: tumor cell (TC)≥1%; 22C3: tumor proportion score (TPS)≥1%), the results were concordant between assays for 83% of the samples. Similarly, at the PD-L1–high cut-off (SP263: TC≥50%; 22C3: TPS≥50%), the results were concordant between assays for 92% of samples. The disease-free survival benefit of atezolizumab over BSC was comparable between assays for PD-L1-positive (TC≥1% by SP263: HR, 0.58 (95% CI: 0.40 to 0.85) vs TPS≥1% by 22C3: HR, 0.65 (95% CI: 0.45 to 0.95)) and PD-L1-high (TC≥50% by SP263: HR, 0.27 (95% CI: 0.14 to 0.53) vs TPS≥50% by 22C3: HR, 0.31 (95% CI: 0.16 to 0.60)) subgroups. Conclusions The SP263 and 22C3 assays showed high concordance and a comparable clinical predictive value of atezolizumab at validated PD-L1 thresholds, suggesting that both assays can identify patients with early-stage NSCLC most likely to experience benefit from adjuvant atezolizumab.This work was supported by F. Hoffmann-La Roche Ltd/Genentech, Inc, a member of the Roche Group. Editorial support, funded by the sponsor, was provided by an independent medical writer under the guidance of the authors

Cancer-testis gene expression is associated with the methylenetetrahydrofolate reductase 677 C\u3eT polymorphism in non-small cell lung carcinoma

BACKGROUND: Tumor-specific, coordinate expression of cancer-testis (CT) genes, mapping to the X chromosome, is observed in more than 60% of non-small cell lung cancer (NSCLC) patients. Although CT gene expression has been unequivocally related to DNA demethylation of promoter regions, the underlying mechanism leading to loss of promoter methylation remains elusive. Polymorphisms of enzymes within the 1-carbon pathway have been shown to affect S-adenosyl methionine (SAM) production, which is the sole methyl donor in the cell. Allelic variants of several enzymes within this pathway have been associated with altered SAM levels either directly, or indirectly as reflected by altered levels of SAH and Homocysteine levels, and altered levels of DNA methylation. We, therefore, asked whether the five most commonly occurring polymorphisms in four of the enzymes in the 1-carbon pathway associated with CT gene expression status in patients with NSCLC. METHODS: Fifty patients among a cohort of 763 with NSCLC were selected based on CT gene expression status and typed for five polymorphisms in four genes known to affect SAM generation by allele specific q-PCR and RFLP. RESULTS: We identified a significant association between CT gene expression and the MTHFR 677 CC genotype, as well as the C allele of the SNP, in this cohort of patients. Multivariate analysis revealed that the genotype and allele strongly associate with CT gene expression, independent of potential confounders. CONCLUSIONS: Although CT gene expression is associated with DNA demethylation, in NSCLC, our data suggests this is unlikely to be the result of decreased MTHFR function

Risk of Lung Carcinoma Among Users of Nonsteroidal Antiinflammatory Drugs

BACKGROUND; Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the development of lung tumors in experimental animals. To the authors' knowledge there are little data regarding whether regular use of NSAIDs reduces the risk of developing lung carcinoma in humans. METHOD; The association between lung carcinoma risk and regular use of NSAIDs, including aspirin, was evaluated in a hospital-based case–control study of 1038 patients and 1002 controls. RESULTS; The relative risk estimate of lung carcinoma associated with using NSAIDs 3 times a week or more for 1 or more years demonstrated an odds ratio (OR) of 0.68 (95% confidence interval [95% CI], 0.53–0.89). Results were similar when separated by lung histologic type. The association varied by smoking status. The OR was1.28 (95% CI, 0.73–2.25) in never-smokers and 0.60 (95% CI 0.45–0.80) in ever-smokers. The smoking-specific risk estimates for aspirin were similar to those for all NSAIDs. CONCLUSIONS; The results of the current study suggest a possible chemoprotective benefit with the use of NSAIDs among individuals who are former or current smokers

Predictors of recurrence and disease-free survival in patients with completely resected esophageal carcinoma

ObjectiveThe goal of this study was to analyze factors predictive of recurrence and disease-free survival in patients with completely resected esophageal carcinoma.MethodsWe conducted a retrospective review of a prospective database to identify patients with completely resected esophageal carcinoma. Medical records were reviewed. Recurrence rates, time to recurrence, and disease-free survival were analyzed. The Kaplan–Meier method was used for time to event estimation, and multivariate Cox regression models were constructed to analyze factors thought to be significant in determining both freedom from recurrence and disease-free survival.ResultsFrom 1988 to 2009, 465 of 500 patients underwent complete resection for esophageal carcinoma. Median follow-up for living patients was 49 months; 197 patients (42.4%) had recurrence, leading to 175 patients dying of cancer and 22 patients living with recurrent disease. Multivariate regression adjusted for P stage identified the following variables as independent predictors of freedom from recurrence: performance status greater than 0 (hazard ratio [HR], 1.84; 95 confidence interval [CI], 1.35–2.49]; P < .001), poor differentiation (HR, 1.50; CI, 1.12–2.01; P = .006), induction therapy (HR, 1.65; CI, 1.21–2.25]; P = .002), en bloc resection (HR, 0.61; CI, 0.43–0.88; P = .007), and advanced pathologic stages (II/III/IV) (HR, 5.46; CI, 3.05–9.78; P < .001). Independent predictors of disease-free survival adjusted for P stage were performance status greater than 0 (HR, 1.73; CI, 1.34–2.23; P < .001), en bloc resection (HR, 0.63; CI, 0.47–0.84; P = .002), induction therapy (HR, 1.34; CI, 1.02–1.76; P = .033), and advanced pathologic stages (II/III/IV) (HR, 3.16; CI, 2.15–4.65; P < .001).ConclusionsFor patients with completely resected esophageal cancer, independent predictors of improved freedom from recurrence and disease-free survival include good performance status, en bloc resection, and early pathologic stage

Cancer-testis gene expression is associated with the methylenetetrahydrofolate reductase 677 C>T polymorphism in non-small cell lung carcinoma

Background: Tumor-specific, coordinate expression of cancer-testis (CT) genes, mapping to the X chromosome, is observed in more than 60% of non-small cell lung cancer (NSCLC) patients. Although CT gene expression has been unequivocally related to DNA demethylation of promoter regions, the underlying mechanism leading to loss of promoter methylation remains elusive. Polymorphisms of enzymes within the 1-carbon pathway have been shown to affect S-adenosyl methionine (SAM) production, which is the sole methyl donor in the cell. Allelic variants of several enzymes within this pathway have been associated with altered SAM levels either directly, or indirectly as reflected by altered levels of SAH and Homocysteine levels, and altered levels of DNA methylation. We, therefore, asked whether the five most commonly occurring polymorphisms in four of the enzymes in the 1-carbon pathway associated with CT gene expression status in patients with NSCLC.Publisher's Versio

Sublobar resection is equivalent to lobectomy for clinical stage 1A lung cancer in solid nodules

ObjectivesA single randomized trial established lobectomy as the standard of care for the surgical treatment of early-stage non–small cell lung cancer. Recent advances in imaging/staging modalities and detection of smaller tumors have once again rekindled interest in sublobar resection for early-stage disease. The objective of this study was to compare lung cancer survival in patients with non–small cell lung cancer with a diameter of 30 mm or less with clinical stage 1 disease who underwent lobectomy or sublobar resection.MethodsWe identified 347 patients diagnosed with lung cancer who underwent lobectomy (n = 294) or sublobar resection (n = 53) for non–small cell lung cancer manifesting as a solid nodule in the International Early Lung Cancer Action Program from 1993 to 2011. Differences in the distribution of the presurgical covariates between sublobar resection and lobectomy were assessed using unadjusted P values determined by logistic regression analysis. Propensity scoring was performed using the same covariates. Differences in the distribution of the same covariates between sublobar resection and lobectomy were assessed using adjusted P values determined by logistic regression analysis with adjustment for the propensity scores. Lung cancer–specific survival was determined by the Kaplan–Meier method. Cox survival regression analysis was used to compare sublobar resection with lobectomy, adjusted for the propensity scores, surgical, and pathology findings, when adjusted and stratified by propensity quintiles.ResultsAmong 347 patients, 10-year Kaplan–Meier for 53 patients treated by sublobar resection compared with 294 patients treated by lobectomy was 85% (95% confidence interval, 80-91) versus 86% (confidence interval, 75-96) (P = .86). Cox survival analysis showed no significant difference between sublobar resection and lobectomy when adjusted for propensity scores or when using propensity quintiles (P = .62 and P = .79, respectively). For those with cancers 20 mm or less in diameter, the 10-year rates were 88% (95% confidence interval, 82-93) versus 84% (95% confidence interval, 73-96) (P = .45), and Cox survival analysis showed no significant difference between sublobar resection and lobectomy using either approach (P = .42 and P = .52, respectively).ConclusionsSublobar resection and lobectomy have equivalent survival for patients with clinical stage IA non–small cell lung cancer in the context of computed tomography screening for lung cancer