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The discovery of epidermal growth factor receptor mutations in non–small cell lung cancer (NSCLC) launched the era of personalized medicine in advanced NSCLC, which led to a dramatic shift in the therapeutic landscape of this disease. [ABSTRACT FROM AUTHOR]

Background: The PACIFIC trial established consolidative durvalumab after concurrent chemoradiation as standard‐of‐care in patients with stage III or unresectable non–small cell lung cancer (NSCLC). Black patients, however, comprised just 2% (n = 14) of randomized patients in this trial, warranting real‐world evaluation of the PACIFIC regimen in these patients. Methods: This single‐institution, multi‐site study included 105 patients with unresectable stage II/III NSCLC treated with concurrent chemoradiation followed by durvalumab between 2017 and 2021. Overall survival (OS), progression‐free survival (PFS), and grade ≥3 pneumonitis‐free survival (PNFS) were compared between Black and non‐Black patients using Kaplan–Meier and Cox regression analyses. Results: A total of 105 patients with a median follow‐up of 22.8 months (interquartile range, 11.3–37.3 months) were identified for analysis, including 57 Black (54.3%) and 48 (45.7%) non‐Black patients. The mean radiation prescription dose was higher among Black patients (61.5 ± 2.9 Gy vs. 60.5 ± 1.9 Gy; p =.031), but other treatment characteristics were balanced between groups. The median OS (not‐reached vs. 39.7 months; p =.379) and PFS (31.6 months vs. 19.3 months; p =.332) were not statistically different between groups. Eight (14.0%) Black patients discontinued durvalumab due to toxicity compared to 13 (27.1%) non‐Black patients (p =.096). The grade ≥3 pneumonitis rate was similar between Black and non‐Black patients (12.3% vs. 12.5%; p =.973), and there was no significant difference in time to grade ≥3 PNFS (p =.904). Three (5.3%) Black patients and one (2.1%) non‐Black patient developed grade 5 pneumonitis. Conclusions: The efficacy and tolerability of consolidative durvalumab after chemoradiation appears to be comparable between Black and non‐Black patients. Consolidative durvalumab after concurrent chemoradiation has similar efficacy and tolerability between Black and non‐Black patients with unresectable stage II/III non–small cell lung cancer. [ABSTRACT FROM AUTHOR]

Celebrating 75 years of publication, Cancer continues to serve as a beacon for scientific research that is fundamental to achieving cures for cancer. Heading into the future, the journal will continue to maintain its unique identity and strive to bring the best of science to the broadest of the audience. [ABSTRACT FROM AUTHOR]

Background: Poly(ADP‐ribose) polymerase (PARP) inhibitors may synergize with programmed cell death receptor‐1 (PD‐1) inhibitors to enhance adaptive and innate antitumor immune responses. In the phase 2 JASPER study (NCT04475939), the PARP inhibitor niraparib was evaluated in combination with the PD‐1 inhibitor pembrolizumab in patients with metastatic and/or locally advanced non–small cell lung cancer (NSCLC). Methods: Patients whose tumors had programmed cell death ligand 1 (PD‐L1) tumor proportion scores (TPS) ≥50% (cohort 1) or 1%‐49% (cohort 2) received first‐line niraparib (200 mg once daily) plus pembrolizumab (200 mg every 3 weeks). The primary end point was investigator‐assessed objective response rate (ORR). Secondary end points included duration of response (DoR), progression‐free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Results: Thirty‐eight patients were enrolled in cohorts 1 and 2. In cohort 1, ORR (95% confidence interval [CI]) was 56.3% (9 of 16 patients; 29.9%‐80.2%); 2 of 16 patients had complete responses and 7 of 16 had partial responses (PRs). In cohort 2, ORR was 20.0% (5.7%‐43.7%) with 4 of 20 PRs. In cohorts 1 and 2, the median DoR was 19.7 months (95% CI, 4.2 months to not estimable [NE]) and 9.4 months (95% CI, 4.2 months to NE), the median PFS was 8.4 months (95% CI, 3.9‐22.1 months) and 4.2 months (95% CI, 2.0‐6.2 months), and the median OS was NE (95% CI, 6.0 months to NE) and 7.7 months (95% CI, 4.0‐12.5 months), respectively. Grade ≥3 treatment‐emergent adverse events occurred in 88.2% and 85.7% of patients in cohorts 1 and 2, respectively. Safety was consistent with known profiles of single‐agent niraparib and pembrolizumab. Conclusions: Niraparib plus pembrolizumab showed clinical activity in patients with advanced and/or metastatic NSCLC. Lay Summary: The JASPER clinical trial studied a new combination treatment for advanced or metastatic non–small cell lung cancer (NSCLC).Pembrolizumab, a drug approved for NSCLC, was given with niraparib.Previous research showed that these 2 drugs together might work better than either drug alone.This study found that more than half of patients with high levels of a tumor marker responded to the combination, and one‐fifth of patients with lower levels of the marker responded.The types of side effects from the combination were similar to side effects from both drugs alone.These results support more research on this combination. The poly(ADP‐ribose) polymerase inhibitor niraparib, in combination with the programmed cell death receptor 1 inhibitor pembrolizumab, shows clinical activity and a manageable safety profile in patients with advanced or metastatic non–small cell lung cancer (NSCLC) in the phase 2 JASPER study. These results warrant further evaluation of this novel combination in NSCLC. [ABSTRACT FROM AUTHOR]

Background: To the authors' knowledge, race‐based differences in efficacy for the treatment of patients with advanced non–small cell lung cancer (NSCLC) have not been studied to date due to the underrepresentation of patients of minority backgrounds in pivotal trials. In the current study, the authors examined real‐world differences in outcome in a diverse patient population. Methods: The authors retrospectively analyzed the clinical outcomes of patients with advanced NSCLC who were treated with single‐agent immune checkpoint blockade (ICB) between 2013 and July 2018 at Winship Cancer Institute of Emory University in Atlanta, Georgia. Primary efficacy comparison between Black patients and White patients was performed using bivariate and multivariate analyses for overall survival (OS) and progression‐free survival (PFS). Results: Data from 257 patients were analyzed. The median age of the patients was 69 years; 50.6% of the patients were female, 63.4% were White, 29.5% were Black, and 7.1% of the patients were of "other" race. ICB was the first‐line treatment in 51 patients (19.9%), the second‐line treatment in 161 patients (62.6%), and the third‐line treatment in 33 patients (12.9%). The most commonly used agents were nivolumab (49.0%), pembrolizumab (25.2%), and atezolizumab (21.3%). No differences with regard to OS (P =.839) and PFS (P =.235) were noted between Black and White patients. The sample overall response rate was 20.6% (15.2% in Black patients and 23.1% in White patients). No differences with regard to OS (P =.081) and PFS (P =.176) were observed between female and male patients. The rate of immune‐related adverse events was found to be similar in Black and White patients (20.0% vs 29.9%; P =.148). On multivariate analysis, race was not found to be significantly associated with OS or PFS. Conclusions: Real‐world analysis of the authors' institutional experience demonstrated similar efficacy and tolerability of ICB in Black versus White patients with advanced NSCLC. Larger multi‐institutional studies including other US minority populations would make the findings of the current study more generalizable. In the current study, the authors perform a retrospective analysis of overall survival (OS) and progression‐free survival (PFS) among patients with non–small cell lung cancer who were treated with single‐agent immune checkpoint blockade between 2013 and 2018. The data indicate similar outcomes between Black and White patients with regard to OS, PFS, and the rate of immune‐related adverse events. Large studies are needed to make these findings more generalizable. [ABSTRACT FROM AUTHOR]

Background: The majority of patients with non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations respond well to osimertinib (AZD9291), a third-generation, mutation-selective EGFR inhibitor. The current study focuses on determining whether targeting MEK/ERK signaling prevents or delays the development of acquired resistance to osimertinib.Methods: Drug effects on cell survival were determined by measuring cell number alterations. Apoptosis was assessed with flow cytometry for the detection of annexin V-positive cells and with Western blotting for protein cleavage. Alterations of proteins in cells were detected with Western blotting. Drug effects on delaying the emergence of osimertinib resistance were evaluated with colony formation in vitro and xenografts in nude mice in vivo.Results: Osimertinib combined with an MEK or ERK inhibitor synergistically decreased cell survival with enhanced induction of apoptosis in EGFR-mutant NSCLC cells but not in EGFR wild-type NSCLC cells. These combinations were also very effective in killing cell clones with primary intrinsic resistance to osimertinib. Continuous and intermittent pharmacologic inhibition of MEK/ERK signaling delayed the emergence of osimertinib resistance both in vitro and in vivo.Conclusions: These results provide strong preclinical evidence in support of targeting MEK/ERK signaling as a strategy for delaying or preventing acquired resistance to osimertinib in the clinic to improve the long-term therapeutic efficacy of osimertinib. From a clinical standpoint, the data support the evaluation of an intermittent treatment schedule of osimertinib in combination with an MEK or ERK inhibitor in patients with EGFR-mutated NSCLC. [ABSTRACT FROM AUTHOR]

Background: Intratumoral heterogeneity is defined by subpopulations with varying genotypes and phenotypes. Specialized, highly invasive leader cells and less invasive follower cells are phenotypically distinct subpopulations that cooperate during collective cancer invasion. Because leader cells are a rare subpopulation that would be missed by bulk sequencing, a novel image-guided genomics platform was used to precisely select this subpopulation. This study identified a novel leader cell mutation signature and tested its ability to predict prognosis in non-small cell lung cancer (NSCLC) patient cohorts.Methods: Spatiotemporal genomic and cellular analysis was used to isolate and perform RNA sequencing on leader and follower populations from the H1299 NSCLC cell line, and it revealed a leader-specific mutation cluster on chromosome 16q. Genomic data from patients with lung squamous cell carcinoma (LUSC; n = 475) and lung adenocarcinoma (LUAD; n = 501) from The Cancer Genome Atlas were stratified by 16q mutation cluster (16qMC) status (16qMC+ vs 16qMC-) and compared for overall survival (OS), progression-free survival (PFS), and gene set enrichment analysis (GSEA).Results: Poorer OS, poorer PFS, or both were found across all stages and among early-stage patients with 16qMC+ tumors within the LUSC and LUAD cohorts. GSEA revealed 16qMC+ tumors to be enriched for the expression of metastasis- and survival-associated gene sets.Conclusions: This represents the first leader cell mutation signature identified in patients and has the potential to better stratify high-risk NSCLC and ultimately improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background: The major clinical obstacle that limits the long‐term benefits of treatment with osimertinib (AZD9291) in patients with epidermal growth factor receptor‐mutant non–small cell lung cancer is the development of acquired resistance. Therefore, effective strategies that can overcome acquired resistance to osimertinib are urgently needed. The authors' current efforts in this direction have identified LBH589 (panobinostat), a clinically used histone deacetylase inhibitor, as a potential agent in overcoming osimertinib resistance. Methods: Cell growth and apoptosis in vitro were evaluated by measuring cell numbers and colony formation and by detecting annexin V‐positive cells and protein cleavage, respectively. Drug effects on tumor growth in vivo were assessed with xenografts in nude mice. Alterations of tested proteins in cells were monitored with Western blot analysis. Gene knockout was achieved using the CRISPR/Cas9 technique. Results: The combination of LBH589 and osimertinib synergistically decreased the survival of different osimertinib‐resistant cell lines, including those harboring C797S mutations, with greater inhibition of cell colony formation and growth. The combination enhanced the induction of apoptosis in osimertinib‐resistant cells. Importantly, the combination effectively inhibited the growth of osimertinib‐resistant xenograft tumors in nude mice. Mechanistically, the combination of LBH589 and osimertinib enhanced the elevation of Bim in osimertinib‐resistant cells. Knockout of Bim in osimertinib‐resistant cells substantially attenuated or abolished apoptosis enhanced by the LBH589 and osimertinib combination. These results collectively support a critical role of Bim elevation in the induction of apoptosis of osimertinib‐resistant cells for this combination. Conclusions: The current findings provide strong preclinical evidence in support of the potential for LBH589 to overcome osimertinib resistance in the clinic. The major clinical obstacle that limits the long‐term benefits of treatment with osimertinib in patients with epidermal growth factor receptor–mutant non–small cell lung cancer is the development of acquired resistance. This study provides strong preclinical evidence in support of the potential for histone deacetylase inhibition to overcome osimertinib resistance in the clinic. [ABSTRACT FROM AUTHOR]

Background: Body mass index (BMI) is used to define obesity, but it is an imperfect measure of body composition. In the current study, the authors explored the association between types of fat and survival in patients treated with immunotherapy.Methods: A retrospective analysis of 90 patients who were treated with immunotherapy on phase 1 clinical trials at the Winship Cancer Institute in Atlanta, Georgia, from 2009 through 2017 was performed. Overall survival (OS) and progression-free survival (PFS) were used to measure clinical outcomes. Baseline BMI and radiographic images at the middle of the third lumbar vertebrae were obtained. Fat densities were calculated and converted to indices (subcutaneous fat index [SFI], intermuscular fat index [IFI], and visceral fat index [VFI]) after dividing by height in meters squared. Risk groups were created using recursive partitioning and the regression trees method for SFI and IFI, which were selected by stepwise variable selection among all fat-related variables. The Cox proportional hazards model and Kaplan-Meier method were used for the association with OS and PFS.Results: The majority of patients (59%) were male and diagnosed with melanoma (33%) or gastrointestinal cancers (22%). The median BMI was 27.4 kg/m2 , the median SFI was 62.78, the median IFI was 4.06, and the median VFI was 40.53. Low-risk patients (those with an SFI ≥73) had a significantly longer OS (hazard ratio, 0.20; 95% CI, 0.09-0.46 [P < .001]) and PFS (hazard ratio, 0.38; 95% CI, 0.20-0.72 [P = .003]) compared with patients at intermediate risk (those with an SFI <73 and IFI <3.4) and poor risk (those with an SFI <73 and IFI ≥3.4). The Uno concordance statistics were found to be higher for fat risk groups than BMI in predicting OS (0.603 vs 0.574; P = .581) and PFS (0.602 vs 0.586; P = .71).Conclusions: Increased BMI, increased SFI, and decreased IFI may be associated with prolonged survival in patients with cancer who are treated with immunotherapy. Further studies are needed to elucidate the effect of adiposity on the host immune response to immunotherapy. [ABSTRACT FROM AUTHOR]

Background: This study assesses different technologies for detecting epidermal growth factor receptor (EGFR) mutations from circulating tumor DNA in patients with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) from the AURA3 study (NCT02151981), and it evaluates clinical responses to osimertinib and platinum-pemetrexed according to the plasma T790M status.Methods: Tumor tissue biopsy samples were tested for T790M during screening with the cobas EGFR Mutation Test (cobas tissue). Plasma samples were collected at screening and at the baseline and were retrospectively analyzed for EGFR mutations with the cobas EGFR Mutation Test v2 (cobas plasma), droplet digital polymerase chain reaction (ddPCR; Biodesix), and next-generation sequencing (NGS; Guardant360, Guardant Health).Results: With cobas tissue test results as a reference, the plasma T790M positive percent agreement (PPA) was 51% (110 of 215 samples) by cobas plasma, 58% (110 of 189) by ddPCR, and 66% (136 of 207) by NGS. Plasma T790M detection was associated with a larger median baseline tumor size (56 mm for T790M-positive vs 39 mm for T790M-negative; P < .0001) and the presence of extrathoracic disease (58% for M1b-positive vs 39% for M0-1a-positive; P = .002). Progression-free survival (PFS) was prolonged in randomized patients (tissue T790M-positive) with a T790M-negative cobas plasma result in comparison with those with a T790M-positive plasma result in both osimertinib (median, 12.5 vs 8.3 months) and platinum-pemetrexed groups (median, 5.6 vs 4.2 months).Conclusions: PPA was similar between ddPCR and NGS assays; both were more sensitive than cobas plasma. All 3 test platforms are suitable for routine clinical practice. In patients with tissue T790M-positive NSCLC, an absence of detectable plasma T790M at the baseline is associated with longer PFS, which may be attributed to a lower disease burden. [ABSTRACT FROM AUTHOR]

Cancer, among the oldest and most prestigious oncology journals, is well positioned to bring the best of science to the broadest audience with a strong focus on featuring research that directly affects the lives of patients with cancer. [ABSTRACT FROM AUTHOR]

Overall survival data from the PACIFIC trial have reaffirmed earlier US Food and Drug Administration approval of durvalumab in patients with stage III non–small cell lung cancer. In the current commentary, the authors provide a brief historical perspective on stage III disease as well as a further analysis of the strengths and weaknesses of the trial. [ABSTRACT FROM AUTHOR]

Background: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is selective for both EGFR-TKI-sensitizing and T790M (threonine-to-methionine substitution at codon 790)-resistance mutations. The authors present long-term follow-up data from a preplanned, pooled analysis of phase 2 studies, the AZD9291 First Time in Patients Ascending Dose Study (AURA) extension trial (clincialtrials.gov identifier NCT01802632) and the AURA2 trial (NCT02094261).Methods: Patients with centrally confirmed, T790M mutation-positive, advanced non-small cell lung cancer received osimertinib 80 mg once daily until disease progression or study discontinuation. Response was assessed by a blinded, independent, central review using Response Evaluation Criteria in Solid Tumors, version 1.1. The primary endpoint was the objective response rate.Results: In total, 411 patients received osimertinib (second line, 129 patients; third line or later, 282 patients). At the data cutoff date of November 1, 2016, the median treatment exposure was 16.4 months (range, 0-29.7 months), the objective response rate was 66% (95% confidence interval [CI], 61%-70%), the median response duration was 12.3 months (95% CI, 11.1-13.8 months), and the median progression-free survival was 9.9 months (95% CI, 9.5-12.3 months). At the data cutoff date of May 1, 2018, 271 patients (66%) had died, and 140 patients (34%) had discontinued before death. The median overall survival was 26.8 months (95% CI, 24.0-29.1 months); and the 12-month, 24-month, and 36-month survival rates were 80%, 55%, and 37%, respectively. Grade ≥3 possibly causally related (investigator assessed) adverse events were reported in 65 patients (16%), and the most common were rash (grouped terms; 42%; grade ≥3, 1%) and diarrhea (39%; <1%).Conclusions: This pooled analysis represents the most mature clinical trial data for osimertinib in patients with pretreated, T790M-positive, advanced non-small cell lung cancer, further establishing osimertinib as a standard of care for this patient population. [ABSTRACT FROM AUTHOR]

Background: Optimal prognostic and predictive biomarkers for patients with advanced-stage cancer patients who received immunotherapy (IO) are lacking. Inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), and the platelet-to-lymphocyte ratio (PLR), are readily available. The authors investigated the association between these markers and clinical outcomes of patients with advanced-stage cancer who received IO.Methods: A retrospective review was conducted of 90 patients with advanced cancer who received treatment on phase 1 clinical trials of IO-based treatment regimens. NLR, MLR, and PLR values were log-transformed and treated as continuous variables for each patient. Overall survival (OS), progression-free survival (PFS), and clinical benefit were used to measure clinical outcomes. For univariate associations and multivariable analyses, Cox proportional-hazards models or logistic regression models were used.Results: The median patient age was 63 years, and most were men (59%). The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). High baseline NLR, MLR, and PLR values were associated significantly with worse OS and PFS (P < .05) and a lower chance of benefit (NLR and PLR; P < .05). Increased NLR, MLR, and PLR values 6 weeks after baseline were associated with shorter OS and PFS (P ≤ .052).Conclusions: Baseline and early changes in NLR, MLR, and PLR values were strongly associated with clinical outcomes in patients who received IO-based treatment regimens on phase 1 trials. Confirmation in a homogenous patient population treated on late-stage trials or outside of trial settings is warranted. These values may warrant consideration for inclusion when risk stratifying patients enrolled onto phase 1 clinical trials of IO agents. [ABSTRACT FROM AUTHOR]

Background: Treatment for advanced lung adenocarcinoma (AC) has become increasingly personalized based on molecular results. However, for patients with AC brain metastases (BMs), intracranial outcomes based on molecular subtype and the frequency of molecular aberrations are less well defined. This study sought to report targeted next-generation sequencing results and investigate molecularly based outcomes for patients with AC-BMs treated with radiotherapy.Methods: The records of 132 patients with AC-BMs treated at Emory University from September 2008 to August 2016 with successful next-generation sequencing were reviewed. Rates of local disease recurrence, distant brain failure (DBF), and salvage whole-brain radiotherapy (WBRT) were estimated using cumulative incidence with competing risk analysis. Univariate and multivariate analyses were performed.Results: The most common aberrations included tumor protein 53 (TP53) (60%), KRAS (29%), epidermal growth factor receptor (EGFR) (20.5%), phosphatase and tensin homolog (PTEN) loss (15.5%), and MET amplification (13%). The majority of patients (62%) were treated with stereotactic radiosurgery alone. In these patients, KRAS mutation, anaplastic lymphoma kinase (ALK) rearrangement, and having ≥ 6 BMs were associated with an increased risk of salvage WBRT (P < .05). KRAS mutation remained significant for an increased risk of salvage WBRT when compared with EGFR/ALK/KRAS-negative patients (hazard ratio, 5.17; P < .05), despite a similar risk of DBF. PTEN loss was associated with increased risk of DBF (P < .05), whereas EGFR and ALK aberrations were associated with a decreased risk of local disease recurrence (P < .05).Conclusions: The results of the current study quantified the frequency of genetic aberrations in patients with AC-BMs and demonstrated their association with intracranial outcomes. In particular, a cohort of patients with KRAS mutations and ≥6 BMs were identified to be at high risk of requiring salvage WBRT after undergoing upfront stereotactic radiosurgery. [ABSTRACT FROM AUTHOR]

Background: To the authors' knowledge, the practice patterns for patients aged more than 80 years with stage III non-small cell lung cancer (NSCLC) is not well known. The purpose of the current study was to investigate factors predictive of and the impact on overall survival (OS) after concurrent chemoradiation (CRT) among patients aged ≥80 years with American Joint Committee on Cancer stage III NSCLC in the National Cancer Data Base (NCDB).Methods: In the NCDB, patients aged ≥80 years who were diagnosed with stage III NSCLC from 2004 to 2013 with complete treatment records were identified. Multivariable logistic regression and Cox proportional hazard models were generated and propensity score-matched analysis was used.Results: A total of 12,641 patients met the entry criteria: 6018 (47.6%) had stage IIIA disease and 6623 (52.4%) had stage IIIB disease. The median age at the time of diagnosis was 83.0 years (range, 80-91 years). A total of 7921 patients (62.7%) received no therapy. Black race (odds ratio [OR], 1.23; 95% confidence interval [95% CI], 1.06-1.43) and living in a lower educated census tract of residence (OR, 1.20; 95% CI, 1.03-1.40) were found to be associated with not receiving care, whereas treatment at an academic center (OR, 0.80; 95% CI, 0.70-0.92) was associated with receiving cancer-directed therapy. Receipt of no treatment (hazard ratio [HR], 2.69; 95% CI, 2.57-2.82) or definitive radiation alone (HR, 1.15; 95% CI, 1.07-1.24) compared with CRT was associated with worse OS. On propensity score matching, not receiving CRT was found to be associated with worse OS (HR, 1.58; 95% CI, 1.44-1.72).Conclusions: In this NCDB analysis, approximately 62.7% of patients aged ≥80 years with stage III NSCLC received no cancer-directed care. Black race and living in a lower educated census tract were associated with not receiving cancer-directed care. OS was found to be improved in patients receiving CRT. Cancer 2018;124:775-84. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

The emergence of immune checkpoint inhibitors for the treatment of cancer has led to major changes to the therapeutic landscape of lung cancer. Improvements in overall survival relative to standard chemotherapy have been observed in the first-line and second-line therapy settings for patients with advanced non-small cell lung cancer (NSCLC) who are treated with immune checkpoint inhibitors. Consequently, every patient with advanced-stage NSCLC is now a candidate for immune checkpoint inhibitor therapy. However, it is clear that the benefit from therapy is not universal, and identification of biomarkers to select therapy has assumed importance. In addition to programmed cell death receptor ligand 1 expression, both tissue-based and blood-based markers are under evaluation to select patients. In an era of increasing costs of care and potential for toxicities related to immune checkpoint inhibition, proper patient selection is critical to the optimal use of this new class of agents. In addition, development of novel combination approaches has also emerged as an important way to improve the efficacy of immune checkpoint inhibition. Studies in earlier stages of NSCLC are already underway with the hope of improving the cure rate. In this article, the authors review the current landscape of immune checkpoint inhibitors in the treatment of advanced NSCLC. Cancer 2018;124:248-61. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Monoclonal antibodies against programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) are effective therapies in patients with non-small cell lung cancer (NSCLC). Herein, the authors performed a systematic review investigating differences in the toxicities of PD-1 and PD-L1 inhibitors.Methods: An electronic literature search was performed of public databases (MEDLINE, Excerpta Medica dataBASE [EMBASE], and Cochrane) and conference proceedings for trials using PD-1 inhibitors (nivolumab and pembrolizumab) and PD-L1 inhibitors (atezolizumab, durvalumab, and avelumab) in patients with NSCLC. A formal systematic analysis was conducted with Comprehensive Meta-Analysis software (version 2.2). Clinical and demographic characteristics, response, and toxicity data were compared between both groups.Results: A total of 23 studies reported between 2013 and 2016 were eligible for analysis. The total number of patients evaluated for toxicities was 3284 patients in the PD-1 group and 2460 patients in the PD-L1 group. The baseline patient characteristics of the 2 groups were similar, although there was a trend toward increased squamous histology in the group treated with PD-L1 (32% vs 25%; P = .6). There was no difference in response rate noted between PD-1 (19%) and PD-L1 (18.6%) inhibitors (P = .17). The incidence of overall adverse events (AEs) was comparable between the PD-1 and PD-L1 inhibitors (64% [95% confidence interval (95% CI), 63%-66%] vs 66% [95% CI, 65%-69%]; P = .8). Fatigue was the most frequently reported AE with both classes of drugs. Patients treated with PD-1 inhibitors were found to have a slightly increased rate of immune-related AEs (16% [95% CI, 14%-17%] vs 11% [95% CI, 10%-13%]; P = .07) and pneumonitis (4% [95% CI, 3%-5%] vs 2% [95% CI, 1%-3%]; P = .01) compared with patients who received PD-L1 inhibitors.Conclusions: In this systematic review involving 5744 patients with NSCLC, the toxicity and efficacy profiles of PD-1 and PD-L1 inhibitors appear to be similar. Cancer 2018;124:271-7. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Human epidermal growth factor receptor 2 (HER2) mutations have been reported in lung adenocarcinomas. Herein, the authors describe the prevalence, clinical features, and outcomes associated with HER2 mutations in 1007 patients in the Lung Cancer Mutation Consortium (LCMC).Methods: Patients with advanced-stage lung adenocarcinomas were enrolled to the LCMC. Tumor specimens were assessed for diagnosis and adequacy; multiplexed genotyping was performed in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories to examine 10 oncogenic drivers. The LCMC database was queried for patients with HER2 mutations to access demographic data, treatment history, and vital status. An exploratory analysis was performed to evaluate the survival of patients with HER2 mutations who were treated with HER2-directed therapies.Results: A total of 920 patients were tested for HER2 mutations; 24 patients (3%) harbored exon 20 insertion mutations (95% confidence interval, 2%-4%). One patient had a concurrent mesenchymal-epithelial transition factor (MET) amplification. The median age of the patients was 62 years, with a slight predominance of females over males (14 females vs 10 males). The majority of the patients were never-smokers (71%) and presented with advanced disease at the time of diagnosis. The median survival for patients who received HER2-targeted therapies (12 patients) was 2.1 years compared with 1.4 years for those who did not (12 patients) (P = .48). Patients with HER2 mutations were found to have inferior survival compared with the rest of the LCMC cohort with other mutations: the median survival was 3.5 years in the LCMC population receiving targeted therapy and 2.4 years for patients not receiving targeted therapy.Conclusions: HER2 mutations were detected in 3% of patients with lung adenocarcinoma in the LCMC. HER2-directed therapies should be investigated in this subgroup of patients. Cancer 2017;123:4099-4105. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Genetic aberrations are well characterized in lung adenocarcinomas (LACs) and clinical outcomes have been influenced by targeted therapies in the advanced setting. Stereotactic body radiotherapy (SBRT) is the standard-of-care therapy for patients with nonoperable, early-stage LAC, but to the authors' knowledge, no information is available regarding the impact of genomic changes in these patients. The current study sought to determine the frequency and clinical impact of genetic aberrations in this population.Methods: Under an Institutional Review Board-approved protocol, the records of 242 consecutive patients with early-stage lung cancers were reviewed; inclusion criteria included LAC histology with an adequate tumor sample for the successful use of next-generation sequencing and fluorescence in situ hybridization testing. Univariate analysis was performed to identify factors associated with clinical outcomes.Results: LAC samples from 98 of the 242 patients were reviewed (40.5%), of whom 45 patients (46.0%) had genetic testing. The following mutations were noted: KRAS in 20.0% of samples, BRAF in 2.2% of samples, SMAD family member 4 (SMAD4) in 4.4% of samples, epidermal growth factor receptor (EGFR) in 15.6% of samples, STK1 in 2.2% of samples, tumor protein 53 (TP53) in 15.6% of samples, and phosphatase and tensin homolog (PTEN) in 2.2% of samples. The following gene rearrangements were observed: anaplastic lymphoma kinase (ALK) in 8.9% of samples, RET in 2.2% of samples, and MET amplification in 17.8% of samples. The median total delivered SBRT dose was 50 grays (range, 48-60 grays) over a median of 5 fractions (range, 3-8 fractions). The KRAS mutation was associated with worse local control (odds ratio [OR], 3.64; P<.05). MET amplification was associated with worse regional (OR, 4.64; P<.05) and distant (OR, 3.73; P<.05) disease control.Conclusions: To the authors' knowledge, the current series is the first to quantify genetic mutations and their association with clinical outcomes in patients with early-stage LAC treated with SBRT. KRAS mutations were associated with worse local control and MET amplification was associated with worse regional and distant disease control, findings that need to be validated in a prospective setting. Cancer 2017;123:3681-3690. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND Patients with resectable esophageal cancer (rEC) are managed with either concurrent chemoradiotherapy followed by surgery (CRSx) or concurrent chemoradiotherapy alone (cCR). To the authors' knowledge, there is insufficient evidence comparing the overall survival of patients treated with these 2 options. METHODS The National Cancer Data Base was queried for rEC cases diagnosed from 2003 through 2011. Patients with previous cancers, cervical rEC, clinical stage T1N0 disease, or metastasis were excluded. cCR was defined as radiotherapy administered within 30 days of chemotherapy. CRSx was defined as cCR followed by esophagectomy within 90 days. Overall survival was compared using Kaplan-Meier methods, propensity score matching, and extended Cox proportional hazards models. RESULTS Of the 11,122 eligible patients, 8091 (72.7%) received cCR and 3031 (27.3%) received CRSx. The odds of receiving CRSx were higher among patients with American Joint Committee on Cancer stage II disease (vs stage III), adenocarcinoma (vs squamous cell carcinoma), lesions of the lower one-third of the esophagus, private insurance, and those living >25 miles from the treating facility or in areas with a higher median income or a greater percentage of high school-educated residents. Patients aged >70 years, female patients, African-American patients, those with ≥2 comorbidities, or those treated at community programs were more likely to receive cCR. After propensity score matching, the median and 10-year survival rates were found to be significantly better with CRSx (32.5 months [95% confidence interval (95% CI), 29.6-34.8 months] and 23.8% months [95% CI, 20.0-27.9 months], respectively) compared with cCR (14.2 months [95% CI, 13.4-15.5 months] and 6.1% months [95% CI, 3.9-9.0 months], respectively). CONCLUSIONS Data from the National Cancer Data Base support the inclusion of surgery after concurrent chemoradiotherapy for patients with locally advanced rEC. Cancer 2017;123:3476-85. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Molecular testing to inform treatment and clinical trial choices is now the standard of care for several types of cancer. However, no established guidelines exist for the type of information physicians should cover during discussions with the patient about the test or its results. The objectives of this study were to identify physician and patient preferences regarding information and who should communicate this information and how to inform guidelines for these conversations.Methods: Physicians and patients who participated in discussions regarding molecular testing were asked to choose 8 topics of most relevance out of a list of 18. The McNemar test was used to determine their top preferences. Patients were asked to identify what information they wanted to receive and who should inform them, and physicians were asked to identify the best aid to communication.Results: Sixty-six patients identified 12 preferred topics: the benefits of testing (88%), how testing determines treatment (88%), implications for family (71%), whether a test indicates the seriousness of disease (68%), purpose of the test (64%), incidental findings (56%), explanation of cancer genetics (53%), how the test is done (46%), limitations (44%), explanation of biomarker (42%), risks (42%), and uninformative results (38%). Physicians added cost (59%). Patients preferred receiving information about molecular testing from their nurse or physician (85%), and physicians preferred using a pamphlet (67%) to augment communication.Conclusions: The topics identified as important to discuss can inform future guidelines and can contribute to effective communication regarding molecular testing. Cancer 2017;123:1610-1616. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Phase 1 clinical trials introduce new therapies to humans with the goal of establishing their safety. A prior Children's Oncology Group (COG) study analyzed the proportional enrollment of patients by race, ethnicity, sex, and age for all trial phases. The current study evaluated the representation of patients by race, ethnicity, sex, and age in phase 1 clinical trials.Methods: This study evaluated 1348 children with 128 diagnoses enrolled in COG and Pediatric Brain Tumor Consortium phase 1 clinical trials in the United States from February 28, 2000 to December 29, 2008. Observed and expected proportions were calculated according to an established methodology with a representative population from Surveillance, Epidemiology, and End Results data, which included 27,766 children with the same International Classification of Diseases for Oncology (third edition) diagnostic codes.Results: Underrepresentation in phase 1 trials was seen for lymphohematopoietic (LH) tumors (9.3% observed vs 37% expected) versus solid tumors (90.6% observed vs 63% expected). Although representation was fairly proportional, Hispanics (12.6% observed vs 27% expected), particularly Hispanic females (6% observed vs 18% expected), were significantly underrepresented. The 0- to 4-year age group was underrepresented (11.7% observed vs 36.5% expected). By tumor type, the most significantly underrepresented groups were 0- to 4-year-old children and Hispanics for both solid cancers (11% observed vs 34.4% expected for 0- to 4-year-old children and 12% observed vs 24% expected for Hispanics) and LH cancers (16% observed vs 40% expected for 0- to 4-year-old children and 19.4% observed vs 33% expected for Hispanics).Conclusions: Although sex and racial/ethnic groups are mostly proportionally represented in phase 1 trials, some specific subgroups such as Hispanic children are underrepresented and may benefit from focused accrual. Cancer 2016;122:3207-14. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Preclinical targeting of the hedgehog pathway by vismodegib and of insulin-like growth factor 1 receptor by cixutumumab enhances the efficacy of chemotherapy and also demonstrates activity against the tumor cell fraction responsible for disease recurrence in small cell lung cancer.Methods: Patients with newly diagnosed extensive-stage small cell lung cancer (SCLC-ED) were randomized to receive four 21-day cycles of cisplatin and etoposide alone (cisplatin at 75 mg/m(2) on day 1 and etoposide at 100 mg/m(2) on days 1-3; arm A) or in combination with either vismodegib (150 mg/d by mouth; arm B) or cixutumumab (6 mg/kg/wk intravenously on day 1; arm C). The primary endpoint was progression-free survival (PFS). Circulating tumor cells (CTCs) were isolated/enumerated with the Veridex CellSearch platform at the baseline.Results: One hundred fifty-two eligible patients were treated. Patient demographics and disease characteristics were well balanced between the 3 arms except for the higher rate with a performance status of 0 in arm B (P = .03). The median PFS times in arms A, B, and C were 4.4, 4.4, and 4.6 months, respectively; the median overall survival (OS) times were 8.8, 9.8, and 10.1 months, respectively; and the response rates were 48%, 56%, and 50%, respectively. None of the comparisons of these outcomes were statistically significant. The median OS was 10.5 months for those with low CTC counts (≤100/7.5 mL) at baseline and 7.2 months for those with high CTC counts (hazard ratio, 1.74; P = .006).Conclusions: There was no significant improvement in PFS or OS with the addition of either vismodegib or cixutumumab to chemotherapy in patients with SCLC-ED. A low baseline CTC count was associated with a favorable prognosis. Cancer 2016;122:2371-2378. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: The discovery of oncogenic drivers has ushered in a new era for lung cancer, but the role of these mutations in different racial/ethnic minorities has been understudied. The Lung Cancer Mutation Consortium 1 (LCMC1) database was investigated to evaluate the frequency and impact of oncogenic drivers in lung adenocarcinomas in the racial/ethnic minority patient population.Methods: Patients with metastatic lung adenocarcinomas from 14 US sites were enrolled in the LCMC1. Tumor samples were collected from 2009 through 2012 with multiplex genotyping performed on 10 oncogenic drivers (KRAS, epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase (ALK) rearrangements, ERBB2 [formerly human epidermal growth factor receptor 2], BRAF, PIK3CA, MET amplification, NRAS, MEK1, and AKT1). Patients were classified as white, Asian, African American (AA), or Latino. The driver mutation frequency, the treatments, and the survival from diagnosis were determined.Results: One thousand seven patients were included. Whites represented the majority (n = 838); there were 60 AAs, 48 Asians, and 28 Latinos. Asian patients had the highest rate of oncogenic drivers with 81% (n = 39), and they were followed by Latinos with 68% (n = 19), whites with 61% (n = 511), and AAs with 53% (n = 32). For AAs, the EGFR mutation frequency was 22%, the KRAS frequency was 17%, and the ALK frequency was 4%. Asian patients were most likely to receive targeted therapies (51% vs 27% for AAs). There were no significant differences in overall survival.Conclusions: Differences were observed in the prevalence of oncogenic drivers in lung adenocarcinomas and in subsequent treatments among racial groups. The lowest frequency of drivers was seen for AA patients; however, more than half of AA patients had a driver, and those treated with targeted therapy had outcomes similar to those of other races. Cancer 2016;122:766-772. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: The last 3 decades have witnessed limited therapeutic advances in small cell lung cancer (SCLC) management. This study evaluated real-world trends in the use of systemic therapies and the impact on patient outcomes in the United States.Methods: The Surveillance, Epidemiology, and End Results-Medicare database was used to find patients diagnosed with SCLC between 1985 and 2005. The 1985-1990 period served as the baseline for a temporal analysis conducted at 5-year intervals (1985-1990, 1991-1995, 1996-2000, and 2001-2005). Cox proportional models were used to estimate the effect of chemotherapy on survival. Results were validated with a propensity-matched analysis.Results: There were 47,351 eligible patients: 52% were male; the median age was 71 years; and 87% were white, 7% were black, and 1.4% were Asian. The proportion of patients treated with chemotherapy was low but increased over time (38%, 55%, 50%, and 53%; P < .001). Race, diagnosis period, age, stage, and location of residence significantly predicted chemotherapy use. Females (51%), Asians (53%), and rural residents (60%) were more likely to receive chemotherapy. The median overall survival with and without chemotherapy was 9.6 and 3.6 months, respectively. Linear trend analyses showed a modest reduction in the impact of chemotherapy on survival for patients treated with chemotherapy versus untreated patients (hazard ratios [HRs], 0.59, 0.61, 0.64, and 0.62; P < .001) but an overall trend of improved survival for treated (HRs, 1.0, 1.03, 1.00, and 0.96; P = .005) and untreated patients (HRs, 1.0, 0.99, 0.94, and 0.92; P < .001). There was no survival difference between patients treated with carboplatin and patients treated with cisplatin (HR, 0.99; confidence interval [CI], 0.81-1.19; P = .875). Additional therapy beyond platinum-based chemotherapy was associated with a survival benefit (HR, 0.78; CI, 0.75-0.81; P < .001).Conclusions: Chemotherapy use was associated with a survival benefit in Medicare patients with SCLC treated in a real-world setting. [ABSTRACT FROM AUTHOR]

Background: Stereotactic body radiation therapy (SBRT) has demonstrated high rates of local control with low morbidity and has now emerged as the standard of care for medically inoperable, early stage non-small cell lung cancer (NSCLC). However, the impact of lung SBRT on survival in the elderly population is less clear given competing comorbid conditions. An analysis of the National Cancer Data Base (NCDB) was undertaken to determine whether definitive SBRT improves survival relative to observation alone patients ages 70 years and older.Methods: The NCDB, a retrospective national database that captures approximately 70% of all patients treated for cancer, was queried for patients aged 70 years or older with early stage (T1-T3N0M0) NSCLC from 2003 to 2006. Overall survival was compared between patients who received stereotactic body radiotherapy alone and those who received no treatment. An extended Cox proportional hazards model was applied to estimate the treatment effect of SBRT.Results: In total, 3147 patients met the selection criteria for this analysis. SBRT was delivered to 258 patients (8.2%), and 2889 patients (91.8%) received no treatment. There was no significant difference in the distribution of Charlson/Deyo comorbidity index scores between the 2 groups (P = .076). Multivariable analysis revealed improved overall survival with SBRT compared with observation for the entire cohort (hazard ratio, 0.64; P < .001).Conclusions: SBRT is associated with improved survival in elderly patients with early stage NSCLC who have concurrent comorbid conditions compared with observation alone. The current data support the use of SBRT for the treatment of elderly patients with early stage NSCLC who have limiting comorbid conditions. [ABSTRACT FROM AUTHOR]

The 1971 National Cancer Act paved the way for a collective national approach to improve outcomes for patients with cancer. This editorial reviews the impact of this major legislation and discusses opportunities for the future. [ABSTRACT FROM AUTHOR]

Although the burden of lung cancer has started to decline in the United States in recent years, in China, the world's most populous nation, nearly 650,000 new cases are diagnosed each year. These staggering statistics call for urgent action at multiple levels of society to reduce the burden of lung cancer in China. [ABSTRACT FROM AUTHOR]

As the burden of lung cancer grows dramatically in China, efforts towards prevention and early detection are urgently needed. Implementation of an effective tobacco‐control policy will have to go hand‐in‐hand with other actions. [ABSTRACT FROM AUTHOR]

Background: Preclinical evidence supports the clinical investigation of inhibitors to the insulin-like growth factor receptor (IGFR) and the epidermal growth factor receptor (EGFR) either alone or in combination as treatment for patients with non-small cell lung cancer (NSCLC).Methods: Patients with chemotherapy-naïve, advanced NSCLC who had an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomized to receive carboplatin intravenously at an area under the plasma drug concentration-time curve of 6.0 plus paclitaxel 200 mg/m(2) intravenously on day 1 every 3 weeks combined with either intravenous cetuximab weekly (arm A), intravenous cixutumumab every 2 weeks (arm B), or both (arm C). Patients who had nonprogessing disease after 12 weeks of therapy were permitted to continue on maintenance antibody therapy until they developed progressive disease. The primary endpoint was progression-free survival (PFS). The study design required 180 eligible patients and had 88% power to detect a 60% increase in median PFS for either comparison (arm A vs arm C or arm B vs arm C) using the log-rank test.Results: From September 2009 to December 2010, 140 patients were accrued. The study was closed to accrual early because of an excessive number of grade 5 events reported on arms A and C. Thirteen patients died during treatment (6 patients on arm A, 2 patients on arm B, and 5 patients on arm C), including 9 within approximately 1 month of starting therapy. The estimated median PFS for arms A, B, and C were similar at 3.4 months, 4.2 months, and 4 months, respectively.Conclusions: On the basis of the apparent lack of efficacy and excessive premature deaths, the current results do not support the continued investigation of carboplatin, paclitaxel, and cixutumumab either alone or in combination with cetuximab for patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

The discovery of 'driver' genomic alterations in patients with non-small cell lung cancer (NSCLC) has dramatically changed the field of thoracic oncology in recent years. The best understood of these molecular drivers are those involving the epidermal growth factor receptor ( EGFR), which when aberrantly activated are integral to the development of a subset of NSCLC tumors. First-generation and second-generation tyrosine kinase inhibitors (TKIs) specific to the activated EGFR have shown significant efficacy and have brought about the era of targeted therapy for NSCLC. The most common resistance mechanism is a threonine-to-methionine substitution (T790M) in exon 20 of the EGFR gene. Although the previous standard of care in patients with EGFR-mutated NSCLC that progressed on initial TKI therapy was chemotherapy, third-generation EGFR TKIs have now been developed and have yielded promising results for this population of patients with NSCLC. This article reviews the emerging data regarding third-generation agents in the treatment of patients with advanced NSCLC. Cancer 2015;121:E1-E6. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND Platinum-based therapy combined with cetuximab is standard first-line therapy for recurrent or metastatic squamous cell carcinoma of the head and neck (RMSCCHN). Preclinical studies have suggested that mammalian target of rapamycin inhibitors may overcome resistance to epidermal growth factor receptor blockers and may augment cetuximab antitumor activity. We conducted a phase 1b trial of carboplatin, cetuximab, and everolimus for untreated RMSCCHN. METHODS Patients received carboplatin (area under the curve = 2 mg/ml/min; 3 weeks on, 1 week off), cetuximab (with a loading dose of 400 mg/m2 and then 250 mg/m2 weekly), and dose-escalating everolimus (2.5, 5.0, 7.5, and 10 mg/day) with a 3+3 design. After 4 cycles, patients without progression continued cetuximab/everolimus until progression or intolerable toxicity. Patients (age ≥ 18 years) had previously untreated, unresectable RMSCCHN not amenable to radiotherapy and an Eastern Cooperative Oncology Group performance status of 0 to 2. RESULTS The study enrolled 20 patients (male/female = 18/2) with RMSCCHN; the median age was 65 years (44-75 years). Thirteen patients received everolimus (male/female = 92%). Two of 6 patients receiving 2.5 mg/day experienced dose-limiting toxicity (DLT) with grade 3 hyponatremia and nausea. In 7 patients receiving de-escalated everolimus (2.5 mg every other day), grade 3 hyperglycemia produced DLT in 1 of 6 patients. The objective response rate (RR) was 61.5% (all partial responses). Progression-free survival (PFS) was 8.15 months. The pharmacokinetics of everolimus was described with a 2-compartment mixed-effects model. There was a significant correlation between tumor p-p44/42 staining and response ( P = .044) and a marginally significant correlation between phosphorylated mammalian target of rapamycin and overall survival. CONCLUSIONS The maximum tolerated dose of everolimus with cetuximab and carboplatin was 2.5 mg every other day. The regimen was associated with an encouraging RR and PFS, and this suggested possible clinical efficacy in a select group of patients with squamous cell carcinoma of the head and neck. Cancer 2014;120:3940-3951. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Targeted therapy has emerged as an effective treatment option for certain molecular subsets of advanced stage non-small cell lung cancer (NSCLC). The discovery of the echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) translocation as an oncogenic driver has led to the development of novel therapies with activity in vitro and in the clinic. The first-in-class tyrosine kinase inhibitor crizotinib is effective against ALK-positive NSCLC and is currently used as first-line or salvage therapy in the setting of advanced disease. However, resistance inevitably develops through a variety of mechanisms, including point mutations affecting the fusion protein, activation of bypass signaling pathways, copy number gain of ALK, and other means. Increased understanding of these pathways is essential for tailoring treatment choices to improve outcomes and minimize toxicities. Potent second-generation ALK inhibitors currently in trials are producing encouraging results in ALK-positive NSCLC, even in patients with acquired resistance to crizotinib. The success in identifying the ALK translocations and rapidly developing targeted drugs to exploit it paves the way for a better understanding of NSCLC biology and the quest to provide effective, personalized treatment for lung cancer patients. Cancer 2014;120:2392-2402. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND Epigenetic events play a major role in the carcinogenesis of tobacco-related cancers. The authors conducted a retrospective cohort study to evaluate the effects of exposure to the anticonvulsant agent valproic acid (VPA), a histone deacetylase inhibitor, on the risk of developing cancers of the lung, head and neck, prostate, bladder, and colon. METHODS The study was based on the 2002 through 2008 National Veterans Affairs (VA) medical SAS data set linked to the VA Central Cancer Registry. The cohort was defined as subjects aged > 40 years who were followed in the VA system for at least 1 year for 1 of 4 diagnoses for which a VPA indication exists (bipolar disorder, posttraumatic stress disorder, migraines, and seizures). Multivariable Cox proportional hazards models were used to estimate hazards ratios (HR) and 95% confidence intervals (95% CI) reflecting the association between use of VPA and cancer incidence. RESULTS VPA use was associated with a significant reduction in the risk of cancers of the head and neck (HR, 0.66; 95% CI, 0.48-0.92). Additional associations were noted with the duration of treatment and median VPA drug levels. No significant differences in cancer incidence were observed for cancers of the lung (HR, 1.00; 95% CI, 0.84-1.19), bladder (HR, 0.86; 95% CI, 0.64-1.15), colon (HR, 0.95; 95% CI, 0.74-1.22), and prostate (HR, 0.96; 95% CI, 0.88-1.12). CONCLUSIONS Use of VPA is associated with a lower risk of developing head and neck cancers. Cancer 2014;120:1394-1400. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND Prophylactic cranial irradiation (PCI) improves survival in patients with limited-stage small cell lung cancer (SCLC) who have a complete response to chemotherapy and radiotherapy, yet to the best of the authors' knowledge, data specific to the elderly population are lacking. METHODS Using the Surveillance, Epidemiology, and End Results (SEER) database, the authors identified 1926 patients aged ≥ 70 years who were diagnosed with limited-stage SCLC between 1988 and 1997. Overall survival (OS) for patients who received PCI versus those who did not were estimated using the Kaplan-Meier method and compared with the log-rank test. A Cox proportional hazards model was further fitted to estimate the effect of PCI on OS after adjusting for age, race, sex, tumor size, lymph node status, stage of disease, and receipt of thoracic radiotherapy and surgery. RESULTS The median age of the patients was 75 years (range, 70 years-94 years) and 138 patients (7.2 %) received PCI. The 2-year and 5-year OS rates were 33.3% (95% confidence interval [95% CI], 25.6%-41.2%) and 11.6% (95% CI, 6.9%-17.6%), respectively, among patients who received PCI versus 23.1% (95% CI, 21.2%-25.1%) and 8.6% (95% CI, 7.3%-9.9%), respectively, among patients who did not receive PCI ( P = .028). On multivariable analysis, PCI was found to be an independent predictor of OS (hazards ratio, 0.72; 95% CI, 0.54-0.97 [ P = .032]). On subgroup analysis, PCI remained an independent predictor of OS among patients aged ≥ 75 years, but not among patients aged ≥ 80 years. CONCLUSIONS The receipt of PCI is associated with improved OS in patients aged ≥ 70 years with SCLC, suggesting that the benefit of PCI is maintained in the elderly population. Cancer 2013;119:3753-3760. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: Reliable predictive biomarkers are required to address the challenge of disease recurrence after thyroid cancer surgery. For this study, the authors assessed the association of cellular-based and serum-based immunologic mediators with thyroid cancer recurrence. METHODS: Leukocyte subset counts and immune regulatory cytokine levels were determined in peripheral blood samples using multiparameter flow cytometry and 51-panel, multiplex enzyme-linked immunosorbent assays, respectively. The functional activity of circulating B-lymphocytes, T-lymphocytes, and natural killer lymphocytes was assessed ex vivo. Differences in mean biomarker levels between defined patient groups and correlations between biomarkers and cancer recurrence were assessed using t tests or Wilcoxon tests and by univariate and multivariate analyses with Cox models. Optimal cutoff values of significantly correlated biomarkers that best predicted disease recurrence after surgery were established by receiver operating characteristics and were validated by using an optimal cutpoint determination algorithm. RESULTS: In total, 35 patients were enrolled (median age, 49.4 year), including 24 women and 15 patients with recurrent disease; and there were 21 individuals in the control group. Patients without recurrence had higher levels of soluble FAS (tumor necrosis receptor superfamily, member 6) ligand (sFASL), transforming growth factor-β, regulatory T cells, and programmed death 1/ programmed death ligand 1-expressing leukocytes. sFASL (hazard ratio, 0.60; 95% confidence interval, 0.38-0.95; P = .031) and interferon-α (hazard ratio, 1.55; 95% confidence interval, 1.03-2.34; P = .038) were associated significantly with disease recurrence. There was a significant difference in progression-free survival between patient groups stratified by an sFASL optimal cutpoint of 15 pg/mL (log-rank P = .0009). CONCLUSIONS: sFASL and IFN-α levels were correlated significantly with thyroid cancer recurrence and may be useful for risk-adapted surveillance strategies in patients with thyroid cancer. Cancer 2013. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: Lung cancer is the leading cause of death among non-acquired immunodeficiency syndrome (AIDS)-defining malignancies. Because highly active antiretroviral therapy (HAART) has improved the survival of patients with human immunodeficiency virus (HIV), the authors evaluated lung cancer outcomes in the HAART era. METHODS: HIV-positive patients who were diagnosed with lung cancer at the authors' institution during the HAART era (1995-2008) were analyzed. Patient charts were reviewed for clinical and laboratory data. The CD4 count at diagnosis was treated as a continuous variable and subcategorized into distinct variables with 3 cutoff points (50 cells/mL, 200 cells/mL, and 500 cells/mL). Pearson correlation coefficients were estimated for each covariate studied. Survival was determined by using the Kaplan-Meier method. RESULTS: Of 80 patients, 73 had nonsmall cell lung cancer. Baseline characteristics were as follows: median patient age, 52 years; male, 80%; African Americans, 84%; injection drug users, 25%; smokers, 100%; and previous exposure to antiretroviral agents, 55%. At the time of cancer diagnosis, the mean CD4 count was 304 cells/mL, and the mean viral load was 82,420 copies/mL. The latency between HIV diagnosis and lung cancer diagnosis was significantly shorter among women (4.1 years vs 7.7 years; P = .02), and 71% of patients received anticancer therapy. The 1-year and 3-year survival rates for stage IIIB/IV were 25% and 0%, respectively. Grade 3/4 toxicities occurred in 60% of patients who received chemoradiation versus 36% of patients who received chemotherapy. Cancer-related survival was better for patients with CD4 counts >200 cells/mL ( P = .0298) and >500 cells/mL ( P = .0076). CONCLUSIONS: The latency from diagnosis of HIV to lung cancer was significantly shorter for women. Although outcomes for patients with lung cancer who have HIV remain poor, a high CD4 count was associated with improved lung cancer-related survival. Cancer 2012;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: Lonafarnib (LNF) is a protein farnesyl transferase (FTase) inhibitor that has shown synergistic activity with taxanes in preclinical models and early stage clinical trials. Preclinical findings suggested tubulin acetylation and FTase expression levels may be important determinants of drug sensitivity that would help identify patient populations more likely to benefit from this regimen. This pilot study evaluated the biological effects of LNF and docetaxel (DTX) combination therapy in refractory solid tumors by comparing pretreatment and post-treatment tumor biopsies. METHODS: Patients with histologically confirmed locally advanced or metastatic solid malignancies refractory to standard therapies or with no effective therapies available were eligible. Patients were randomized to 1 of 4 dosing cohorts: 1) 30 mg/m2, 100 mg; 2) 36 mg/m2, 100 mg; 3) 30 mg/m2, 150 mg; or 4) 36 mg/m2, 150mg of DTX intravenously weekly, LNF orally twice daily, respectively. RESULTS: Of the 38 patients enrolled, 36 were treated, and 29 were evaluable for toxicity and response assessment. The combination of LNF and DTX was tolerated in all cohorts with the exception of a 28% incidence of grade 3/4 diarrhea, which was manageable with aggressive antidiarrheal regimens. Seven patients derived clinically meaningful benefit from this combination treatment; these patients had significantly lower basal FTase-beta mRNA expression levels than the mean study population level ( P < .05). Correlation of clinical benefit with tubulin acetylation content as well as basal acetyl-tubulin content were evaluated. However, no significant correlation was found. CONCLUSIONS: Despite the small number of patients, these findings support our preclinical mechanistic studies and warrant further clinical investigations using FTase-beta mRNA expression as a potential predictive biomarker to select for an enriched patient population to study the effects of taxane and FTase inhibitor combination therapies. Cancer 2011. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: Everolimus is a novel inhibitor of the mammalian target of rapamycin pathway, which is aberrantlyactivated in nonsmall cell lung cancer (NSCLC). The authors conducted a phase 1 and pharmacokinetic study of everolimus and docetaxel for recurrent NSCLC. METHODS: Patients with advanced stage NSCLC and progression after prior platinum-based chemotherapy were eligible. Sequential cohorts were treated with escalating doses of docetaxel(Day 1) and everolimus (orally daily, Days 1-19) every 3 weeks. Pharmacokinetic sampling of everolimus and docetaxelwas done in Cycle 1. The primary endpoint was determination of the recommended phase 2 doses of the combination. RESULTS: Twenty-four patients were enrolled (median age, 62 years; women, 11; number of prior regimens, 1 [n = 13], 2 [n = 6], ≥3[ n = 5]; Eastern Cooperative Oncology Group performance status, 0 [n = 6], 1 [n = 17]). Thedose-limiting toxicities (DLTs) were fever with grade 3/4 neutropenia, grade 3 fatigue, and grade 3 mucositis. Noneof the 7 patients treated at the recommended phase 2 dose (docetaxel 60 mg/m² and everolimus 5 mg daily) experienced DLT. Everolimus area under the concentration time curve (AUC) was not different with 60 or 75 mg/m² docetaxel. Mean ± standard deviation AUC-based accumulation factors for everolimus on Days 8 and 15 were 1.16 ± 0.37and 1.42 ±0.42, respectively. Docetaxel Day 1 half-life was 9.4 ± 3.4 hours. Among 21 patients evaluable, 1 had a partial response, and 10 had disease stabilization. CONCLUSIONS: The recommended phase 2 doses of docetaxel and everolimus for combination therapy are 60 mg/m² and 5 mg orally daily, respectively. Promising anticancer activityhas been noted. [ABSTRACT FROM AUTHOR]

The article presents a phase 2 study which evaluates the effectiveness of the combination therapy of Paclitaxel and Irinotecan in patients with refractory or recurrent small cell lung cancer (SCLC). It mentions that the Irinotecan and Paclitaxel were administered for days one and eight of each three-week treatment cycle in the 51 patients out of 55. Results show that the therapy has a slow progress in the patients with a response rate of 21% but it was well tolerated by SCLC patients.

The article presents a study which investigated the significant role of maintenance therapy after combination therapy in patients with nonsmall-cell lung cancer (NSCLC). It notes that the use of anticancer agents in maintenance therapy has been recognized as a new treatment for NSCLC. Likewise, molecular targeted agents such as erlotinib have shown potential as effective maintenance therapy for NSCLC through maintaining tumor regression after an initial response to chemotherapy.

Background: Cetuximab, an immunoglobulin (Ig) G1 chimeric monoclonal antibody against the epidermal growth factor receptor, has demonstrated evidence of activity in nonsmall cell lung cancer (NSCLC). When administered in combination with carboplatin and docetaxel, a commonly used regimen for advanced NSCLC, cetuximab has exhibited synergistic interaction in preclinical studies. Therefore, a phase 2 study was conducted to evaluate the efficacy of the combination of cetuximab, carboplatin, and docetaxel for the treatment of advanced NSCLC.Methods: Chemotherapy-naïve patients aged >or=18 years with stage IIIB (with effusion) or stage IV NSCLC received cetuximab (at a dose of 400 mg/m(2) on Day 1 and 250 mg/m(2) on Days 8 and 15) plus docetaxel (at a dose of 75 mg/m(2) on Day 1) and carboplatin (area under the concentration vs time curve [AUC]=6 on Day 1) every 21 days for up to 6 cycles (graded according to the American Joint Committee on Cancer Staging System). Thereafter, patients without evidence of disease progression were continued on single-agent cetuximab for a maximum of 1 year or until disease progression. The primary endpoint was response rate.Results: Eighty patients were enrolled. The median number of cycles administered was 4 (range, 1-6 cycles). The objective response rate was 15.2%, with a median progression-free survival of 4.6 months and a median overall survival of 10.3 months. The salient grades 3 of 4 adverse events were neutropenia (30%), hypotension (3%), hypokalemia (4%), and hypomagnesemia (3%). Twenty-five patients received single-agent cetuximab (median duration, 12 weeks) and this was well tolerated.Conclusions: The results of this large, multicenter, phase 3 study indicate that the novel combination of cetuximab with docetaxel and carboplatin demonstrate modest anticancer activity for patients with advanced and metastatic NSCLC and has an acceptable toxicity profile. [ABSTRACT FROM AUTHOR]

In this editorial, the Editor‐in‐Chief and Section Editor for Chest and Lung Disease explain why Cancer will no longer consider any work that is funded directly or indirectly from tobacco companies or their subsidiaries. [ABSTRACT FROM AUTHOR]

The author reflects on the Crizotinib therapy associated with the hypogonadism. He informs that the Crizotinib is a small molecule of tyrosine kinase inhibitor and recently approved by the U.S. Food and Drug Administration for the treatment of patients who are suffering from advanced nonsmall cell lung cancer (NSCLC). He also opines that the Crizotinib therapy is one of the effective and safe treatments for patients suffering from lung cancer.

The article focuses on a study conducted to observe disease complications in the patients suffering with lung cancer and also with genetic translocation in anaplastic lymphoma kinase gene. It informs that oncogenic mutations in the epidermal growth factor receptor are found to be 15 percent of all the cases of adenocarcinoma. It also discusses the usage of histological techniques in the diagnosis of several cancerous cells.