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Quantitative imaging biomarkers (QIB) are increasingly used in clinical research to advance precision medicine approaches in oncology. Computed tomography (CT) is a modality of choice for cancer diagnosis, prognosis, and response assessment due to its reliability and global accessibility. Here, we contribute to the cancer imaging community through The Cancer Imaging Archive (TCIA) by providing investigator-initiated, same-day repeat CT scan images of 32 non–small cell lung cancer (NSCLC) patients, along with radiologist-annotated lesion contours as a reference standard. Each scan was reconstructed into 6 image settings using various combinations of three slice thicknesses (1.25 mm, 2.5 mm, 5 mm) and two reconstruction kernels (lung, standard; GE CT equipment), which spans a wide range of CT imaging reconstruction parameters commonly used in lung cancer clinical practice and clinical trials. This holds considerable value for advancing the development of robust Radiomics, Artificial Intelligence (AI) and machine learning (ML) methods. [ABSTRACT FROM AUTHOR]

Background: Direct KRASG12C inhibitors are approved for patients with non-small cell lung cancers (NSCLC) in the second-line setting. The standard-of-care for initial treatment remains immune checkpoint inhibitors, commonly in combination with platinum-doublet chemotherapy (chemo-immunotherapy). Outcomes to chemo-immunotherapy in this subgroup have not been well described. Our goal was to define the clinical outcomes to chemo-immunotherapy in patients with NSCLC with KRASG12C mutations. Patients and Methods: Through next-generation sequencing, we identified patients with advanced NSCLC with KRAS mutations treated with chemo-immunotherapy at 2 institutions. The primary objective was to determine outcomes and determinants of response to first-line chemo-immunotherapy among patients with KRASG12C by evaluating objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). We assessed the impact of coalterations in STK11/KEAP1 on outcomes. As an exploratory objective, we compared the outcomes to chemo-immunotherapy in KRASG12C versus non-G12C groups. Results: One hundred and thirty eight patients with KRASG12C treated with first-line chemo-immunotherapy were included. ORR was 41% (95% confidence interval (CI), 32-41), median PFS was 6.8 months (95%CI, 5.5-10), and median OS was 15 months (95%CI, 11-28). In a multivariable model for PFS, older age (P =.042), squamous cell histology (P =.008), poor ECOG performance status (PS) (P <.001), and comutations in KEAP1 and STK11 (KEAP1MUT/STK11MUT) (P =.015) were associated with worse PFS. In a multivariable model for OS, poor ECOG PS (P =.004) and KEAP1MUT/STK11MUT (P =.009) were associated with worse OS. Patients with KRASG12C (N = 138) experienced similar outcomes to chemo-immunotherapy compared to patients with non-KRASG12C (N = 185) for both PFS (P =.2) and OS (P =.053). Conclusions: We define the outcomes to first-line chemo-immunotherapy in patients with KRASG12C, which provides a real-world benchmark for clinical trial design involving patients with KRASG12C mutations. Outcomes are poor in patients with specific molecular coalterations, highlighting the need to develop more effective frontline therapies. This study aimed to define the clinical outcomes of first-line chemo-immunotherapy in patients with non-small cell lung cancer with KRASG12C mutations and to examine the significance of PD-L1 tumor proportion score and comutation status (KEAP1 and STK11) on outcomes. [ABSTRACT FROM AUTHOR]

PURPOSE: Patients with EGFR- mutant lung cancer have no approved targeted therapies after disease progression on first-line osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Preclinical studies suggest that tumors with both EGFR -sensitizing alteration and acquired second-site EGFR resistance alterations after treatment with osimertinib retain sensitivity to second-generation EGFR TKIs. We hypothesized that dacomitinib, a pan-human epidermal growth factor receptor TKI, may be effective in this setting. METHODS: In this phase II study, patients who had progressed on first-line osimertinib were treated with dacomitinib 45 mg orally daily until disease progression or intolerability. The primary end point was objective response rate. RESULTS: We enrolled 12 patients. Two partial responses were documented (17% objective response rate; 95% CI, 5 to 45). The median progression-free survival was 1.8 months (95% CI, 1.6 to not reached). One patient with an original sensitizing EGFR G719A mutation and one patient without molecular testing available had partial responses, whereas 0 of the 3 patients with second-site acquired EGFR resistance mutations (two C797S and one G724S) met the response criteria. The patient with EGFR G719A has an ongoing response at 17 months, which exceeds prior time on osimertinib (11 months). CONCLUSION: In the first trial evaluating a second-generation EGFR TKI after first-line third-generation osimertinib, we found that dacomitinib after disease progression on osimertinib has limited benefit. [ABSTRACT FROM AUTHOR]

PURPOSE: Although MET exon 14 (MET ex14)–altered lung cancers were first identified more than a decade and a half ago, the frequency of CNS metastatic disease remains poorly defined. Furthermore, the seminal trial of crizotinib in these patients (PROFILE 1001) did not report patterns of CNS response or progression. PATIENTS AND METHODS: Patients with pathologically confirmed, advanced non–small-cell lung cancers (NSCLC) harboring a MET ex14 alteration by targeted DNA/RNA sequencing were studied. The incidence of brain metastases and the outcomes of MET inhibition with crizotinib were analyzed. RESULTS: Eighty-three patients with MET ex14-altered metastatic NSCLC were identified. The incidence of CNS metastases at diagnosis was 17% (95% CI, 10% to 27%). The lifetime incidence was 36% (95% CI, 26% to 47%); 83% of patients had parenchymal disease, and 17% had leptomeningeal disease. The probability of having brain metastasis at 1, 2, and 3 years was 24%, 35%, and 38%, respectively. Fifty-four patients received crizotinib. The median time to radiologic CNS progression was 5.8 months (range, 3.7-20.0 months). Patterns of crizotinib progression were as follows: intracranial only in 10% of patients, intracranial and extracranial in 12%, and extracranial only in 78%. In patients with brain metastases before treatment, the median time on crizotinib was 7.5 months (range, 7.2-11.7 months). CONCLUSION: CNS metastases, including leptomeningeal disease, occurred in more than a third of patients with MET ex14-altered lung cancers. In crizotinib-treated patients with or without CNS metastases, CNS failure was seen in less than a quarter of patients on progression. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 33-year-old female never-smoker presented with cough and dyspnea. It notes the identification of the RET fusion-positive lung cancer with brain and leptomeningeal metastases; and mention the impactful intracranial response of patient to selective RET inhibition with LOXO-292.

Background: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) is commercially available and increasingly adopted in clinical practice despite a paucity of prospective data to support its use.Methods: Patients with advanced lung cancers who had no known oncogenic driver or developed resistance to current targeted therapy (n = 210) underwent plasma NGS, targeting 21 genes. A subset of patients had concurrent tissue NGS testing using a 468-gene panel (n = 106). Oncogenic driver detection, test turnaround time (TAT), concordance, and treatment response guided by plasma NGS were measured. All statistical tests were two-sided.Results: Somatic mutations were detected in 64.3% (135/210) of patients. ctDNA detection was lower in patients who were on systemic therapy at the time of plasma collection compared with those who were not (30/70, 42.9% vs 105/140, 75.0%; OR = 0.26, 95% CI = 0.1 to 0.5, P < .001). The median TAT of plasma NGS was shorter than tissue NGS (9 vs 20 days; P < .001). Overall concordance, defined as the proportion of patients for whom at least one identical genomic alteration was identified in both tissue and plasma, was 56.6% (60/106, 95% CI = 46.6% to 66.2%). Among patients who tested plasma NGS positive, 89.6% (60/67; 95% CI = 79.7% to 95.7%) were also concordant on tissue NGS and 60.6% (60/99; 95% CI = 50.3% to 70.3%) vice versa. Patients who tested plasma NGS positive for oncogenic drivers had tissue NGS concordance of 96.1% (49/51, 95% CI = 86.5% to 99.5%), and directly led to matched targeted therapy in 21.9% (46/210) with clinical response.Conclusions: Plasma ctDNA NGS detected a variety of oncogenic drivers with a shorter TAT compared with tissue NGS and matched patients to targeted therapy with clinical response. Positive findings on plasma NGS were highly concordant with tissue NGS and can guide immediate therapy; however, a negative finding in plasma requires further testing. Our findings support the potential incorporation of plasma NGS into practice guidelines. [ABSTRACT FROM AUTHOR]

The article focuses on the impact of immunotherapy being provided to the patients with RET-rearranged lung cancer which has a lower success rate than systemic therapy. It talks about the RET rearrangements being targeted with the help of next-generation DNA sequencing. It tells about the time to treatment discontinuation (TTD) which defines the therapy initiation.

The article presents several case reports to study the acquired ALK and RET gene fusions for resistance to osimertinib in epidermal growth factor receptor (EGFR)-mutant lung cancers. The reports include a case report of a 68-year-old woman who had EGFR T790M mutation that was revealed through digital polymerase chain reaction. EGFR L858R and T790M mutations were also revealed by next-generation sequencing (NGS). She started receiving treatment with osimertinib.

In ~30% of patients with EGFR-mutant lung adenocarcinomas whose disease progresses on EGFR inhibitors, the basis for acquired resistance remains unclear. We have integrated transposon mutagenesis screening in an EGFR-mutant cell line and clinical genomic sequencing in cases of acquired resistance to identify mechanisms of resistance to EGFR inhibitors. The most prominent candidate genes identified by insertions in or near the genes during the screen were MET, a gene whose amplification is known to mediate resistance to EGFR inhibitors, and the gene encoding the Src family kinase YES1. Cell clones with transposon insertions that activated expression of YES1 exhibited resistance to all three generations of EGFR inhibitors and sensitivity to pharmacologic and siRNA-mediated inhibition of YES1. Analysis of clinical genomic sequencing data from cases of acquired resistance to EGFR inhibitors revealed amplification of YES1 in five cases, four of which lacked any other known mechanisms of resistance. Preinhibitor samples, available for two of the five patients, lacked YES1 amplification. None of 136 postinhibitor samples had detectable amplification of other Src family kinases (SRC and FYN). YES1 amplification was also found in 2 of 17 samples from ALK fusion-positive lung cancer patients who had progressed on ALK TKIs. Taken together, our findings identify acquired amplification of YES1 as a recurrent and targetable mechanism of resistance to EGFR inhibition in EGFR-mutant lung cancers and demonstrate the utility of transposon mutagenesis in discovering clinically relevant mechanisms of drug resistance. [ABSTRACT FROM AUTHOR]

Background: In a phase 1 study of pulse/continuous-dose erlotinib, no patient had disease progression in the central nervous system (CNS). This expansion cohort of the phase 1 study tested the same regimen in a cohort of individuals with epidermal growth factor receptor (EGFR)-mutant lung cancers with untreated brain metastases.Methods: Patients had not received EGFR tyrosine kinase inhibitors or radiation for brain metastases. All received 1200 mg of erlotinib on days 1 and 2 and 50 mg on days 3 to 7 weekly. The primary endpoints were the overall and CNS response rates (according to version 1.1 of the Response Evaluation Criteria in Solid Tumors).Results: Between May 2015 and August 2016, 19 patients were enrolled. Forty-two percent of the patients had target brain lesions, and the median size of the target brain lesions was 13 mm. Overall, 14 patients (74%; 95% confidence interval [CI], 51%-89%) had partial responses. The response rate in brain metastases was 75%. The overall median progression-free survival was 10 months (95% CI, 7 months to not reached). Only 3 patients (16%) had CNS progression. To date, 4 patients required CNS radiation at some time during their course. The adverse events (any grade) seen in 10% or more of the patients were rash, diarrhea, nausea, an increase in alanine aminotransferase, and fatigue.Conclusions: Pulse/continuous-dose erlotinib produced a 74% overall response rate and a 75% response rate in brain metastases in patients with EGFR-mutant lung cancers and untreated brain metastases. CNS control persisted even after progression elsewhere. Although this regimen did not improve progression-free survival or delay the emergence of EGFR T790M, it prevented progression in the brain and could be useful in situations in which CNS control is critical. Cancer 2018;124:105-9. © 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]

The article presents the update to the 2007 Cancer Care Ontario (CCO) and American Society of Clinical Oncology (ASCO) clinical practice guideline. It states that the updates incorporate published research on adjuvant therapy in patients with resected stage I to IIIA lung cancers. It mentions that a panel of clinical experts used evidence-based recommendations for adjuvant radiation therapy to modify the joint guidelines.

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 Prognostic variables are independently associated with survival and are fundamental to clinical trial design. In the current study, the authors evaluated the impact of stage of disease at the time of the initial diagnosis on overall survival (OS) in 2 independent, oncogene-defined cohorts. METHODS All patients with epidermal growth factor receptor ( EGFR)-mutant and KRAS-mutant metastatic lung adenocarcinomas were identified through routine molecular testing from January 2005 through January 2011. Clinical characteristics were obtained. OS from the date of diagnosis of recurrent or de novo metastatic disease was estimated using the Kaplan-Meier method. RESULTS A total of 635 patients with KRAS-mutant and 496 patients with EGFR-mutant metastatic lung adenocarcinomas were identified. Among patients with KRAS-mutant lung adenocarcinomas, those with de novo metastatic disease were found to have a shorter median OS compared with those with recurrent metastatic disease (13 months vs 18 months; P = .003). In a multivariable analysis of patients with KRAS-mutant lung adenocarcinomas, de novo metastatic disease at the time of diagnosis (TNM stage IV vs stage I-III: hazard ratio, 1.5 [95% confidence interval, 1.2-1.8]; P<.001) was independently associated with shorter OS. In patients with EGFR-mutant lung adenocarcinomas, after controlling for age and Karnofsky performance status, de novo metastatic disease at the time of diagnosis (stage IV vs stage I-III: hazard ratio, 1.3 [95% confidence interval, 1.0-1.7]; P = .03) was found to be independently associated with shorter OS. CONCLUSIONS Among patients with KRAS-mutant lung adenocarcinomas, stage of disease at diagnosis was associated with OS from the time of diagnosis of recurrent/metastatic disease. In multivariable analyses, in both patients with EGFR-mutant and KRAS-mutant lung adenocarcinomas, advanced stage at the time of diagnosis was found to be independently associated with shorter survival. Stage at diagnosis is a prognostic variable that should be accounted for in prospective studies in patients with metastatic lung adenocarcinomas. Cancer 2015;121:2078-2082. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND The advent of effective targeted therapy for BRAFV600E-mutant lung adenocarcinomas necessitates further exploration of the unique clinical features and behavior of advanced-stage BRAF-mutant lung adenocarcinomas. METHODS Data were reviewed for patients with advanced lung adenocarcinomas enrolled in the Lung Cancer Mutation Consortium whose tumors underwent testing for mutations in epidermal growth factor receptor ( EGFR), Kirsten rat sarcoma viral oncogene homolog ( KRAS), human epidermal growth factor receptor 2 ( HER2), AKT1, BRAF, dual-specificity mitogen-activated protein kinase kinase 1 ( MEK1), neuroblastoma RAS viral (v-ras) oncogene homolog ( NRAS), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α ( PIK3CA); for anaplastic lymphoma kinase ( ALK) translocations; and for MET amplification. RESULTS Twenty-one BRAF mutations were identified in 951 patients with adenocarcinomas (2.2%; 95% confidence interval [CI], 1.4%-3.4%): 17 (81%; 95% CI, 60%-92%) were BRAFV600E mutations, and 4 were non- BRAFV600E mutations. Among the 733 cases tested for all 10 genes, BRAF mutations were more likely to occur than most other genotypic abnormalities in current or former smokers ( BRAF vs sensitizing EGFR, 82% vs 36%, mid- P < .001; BRAF vs ALK, 39%, mid- P = .003; BRAF vs other mutations, 49%, mid- P = .02; BRAF vs patients with more than 1 oncogenic driver [doubleton], 46%, mid- P = .04.) The double-mutation rate was 16% among patients with BRAF mutations but 5% among patients with other genomic abnormalities (mid- P = .045). Differences were not found in survival between patients with BRAF mutations and those with other genomic abnormalities ( P > .20). CONCLUSIONS BRAF mutations occurred in 2.2% of advanced-stage lung adenocarcinomas, were most commonly V600E, and were associated with distinct clinicopathologic features in comparison with other genomic subtypes and with a high mutation rate in more than 1 gene. These findings underscore the importance of comprehensive genomic profiling in assessing patients with advanced lung adenocarcinomas. Cancer 2015;121:448-456. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: Serum biomarkers are not in routine clinical use for diagnosis, prognosis, or treatment selection in lung cancer. OBJECTIVE: We examined serum protein biomarkers from patients with metastatic lung cancer to determine whether they correlate with progression-free survival (PFS), overall survival (OS), or histologic subtype. METHODS: Serum samples were collected prior to chemotherapy from 153 patients with metastatic lung cancer treated at Memorial Sloan-Kettering Cancer Center. Serum biomarkers were selected for ELISA testing based on their availability in a CLIA-certified clinical laboratory: ProGRP, SCC-Ag, NSE, CYFRA 21-1, TIMP1, and HE4. Pretreatment biomarker levels were correlated with outcome using proportional hazards analysis and tumor histology using logistic regression analysis. RESULTS: Univariate analysis indicated that only higher levels of CYFRA 21-1 were significantly associated with worsened PFS (HR 1.3, 95% CI 1.1--1.5, p< 0.01) and OS (HR 1.4, 95% CI 1.2-1.7, p< 0.001). Multivariate analysis of NSE, CYFRA 21-1, and TIMP1 indicated that CYFRA 21-1 remained independently associated with lower OS (HR 1.3, 95% CI 1.1-1.6, p< 0.01). Univariate analysis indicated that ProGRP (OR 3.3, 95% CI 1.7-6.5, p< 0.001) and NSE (OR 4.8, 95% CI 2.6-8.8, p< 0.0001) had the highest probabilities of differentiating SCLC from NSCLC. Multivariate analysis of these two markers demonstrated that they predicted SCLC histology with 94% accuracy. Univariate analysis showed that only SCCL-Ag distinguished squamous cell histology from adenocarcinoma (OR 4.4, 95% CI 1.7-11.5, p< 0.01). CONCLUSIONS: Serum CYFRA 21-1 may be useful in predicting patient survival, and serum ProGRP, NSE 21-1, and SCCL-Ag may be helpful in distinguishing between lung cancer sub-types. [ABSTRACT FROM AUTHOR]

Objective: The genes KRAS and EGFR have emerged as potential targets for therapy in lung adenocarcinoma; mutations in these genes can be found in almost half of patients. In anticipation of the clinical importance of molecularly defined adenocarcinoma subgroups for the treatment of patients with resected stages I through III lung adenocarcinoma, the Memorial Sloan–Kettering Cancer Center (MSKCC) Departments of Surgery and Pathology have collaborated since 2006 to conduct reflex testing of tumor specimens for EGFR and KRAS mutations. Methods: Using established methods, the identification of EGFR exon 19 deletions and exon 21 L858R mutations was performed. In samples lacking these 2 sensitizing EGFR mutations, KRAS analysis was done. Results: We studied a total of 1831 patients who had stage I through IV lung adenocarcinomas and detected 448 KRAS and 364 EGFR mutations. Of these patients, a subset of 855 (78%) patients with stages I through III adenocarcinoma of the lung who underwent curative surgical resection at MSKCC were tested. In patients with early stage disease, 158 EGFR mutations and 207 KRAS mutations were detected. Conclusions: The results of the first 3 years of reflex testing at MSKCC reported here demonstrate the feasibility, clinical utility, and potential of this approach. This information allowed for enrollment of patients into clinical trials to explore mutation-specific, directed therapy and led to retrospective studies related to patient outcome. In addition, it may inform selection of chemotherapy for recurrent disease and may help to distinguish multiple primary tumors from metastatic disease. [ABSTRACT FROM AUTHOR]

The article provides information on a study that determined a daily dose of everolimus with gefitinib in patients with advanced nonsmall-cell lung cancer. It describes methodology used in the study. It concludes that everolimus at a dose of 5 milligrams (mg) daily in combination with daily gefitinib 250 mg is recommended.

Background: Lung adenocarcinomas from patients who respond to the tyrosine kinase inhibitors gefitinib (Iressa) or erlotinib (Tarceva) usually harbor somatic gain-of-function mutations in exons encoding the kinase domain of the epidermal growth factor receptor (EGFR). Despite initial responses, patients eventually progress by unknown mechanisms of "acquired" resistance. Methods and Findings: We show that in two of five patients with acquired resistance to gefitinib or erlotinib, progressing tumors contain, in addition to a primary drug-sensitive mutation in EGFR, a secondary mutation in exon 20, which leads to substitution of methionine for threonine at position 790 (T790M) in the kinase domain. Tumor cells from a sixth patient with a drug-sensitive EGFR mutation whose tumor progressed on adjuvant gefitinib after complete resection also contained the T790M mutation. This mutation was not detected in untreated tumor samples. Moreover, no tumors with acquired resistance had KRAS mutations, which have been associated with primary resistance to these drugs. Biochemical analyses of transfected cells and growth inhibition studies with lung cancer cell lines demonstrate that the T790M mutation confers resistance to EGFR mutants usually sensitive to either gefitinib or erlotinib. Interestingly, a mutation analogous to T790M has been observed in other kinases with acquired resistance to another kinase inhibitor, imatinib (Gleevec). Conclusion: In patients with tumors bearing gefitinib- or erlotinib-sensitive EGFR mutations, resistant subclones containing an additional EGFR mutation emerge in the presence of drug. This observation should help guide the search for more effective therapy against a specific subset of lung cancers. [ABSTRACT FROM AUTHOR]

Background Somatic mutations in the gene for the epidermal growth factor receptor (EGFR) are found in adenocarcinomas of the lung and are associated with sensitivity to the kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Lung adenocarcinomas also harbor activating mutations in the downstream GTPase, KRAS, and mutations in EGFR and KRAS appear to be mutually exclusive. Methods and Findings We sought to determine whether mutations in KRAS could be used to further enhance prediction of response to gefitinib or erlotinib. We screened 60 lung adenocarcinomas defined as sensitive or refractory to gefitinib or erlotinib for mutations in EGFR and KRAS. We show that mutations in KRAS are associated with a lack of sensitivity to either drug. Conclusion Our results suggest that treatment decisions regarding use of these kinase inhibitors might be improved by determining the mutational status of both EGFR and KRAS. [ABSTRACT FROM AUTHOR]

Background: Overexpression of squamous cell carcinoma–related oncogene (SCCRO) is associated with invasive progression and poor outcomes in non–small cell lung cancer. We assessed the role of SCCRO as a tumor marker in bronchioloalveolar carcinoma (BAC), a subtype of adenocarcinoma exhibiting evidence of histologic tumor progression. We hypothesized that SCCRO expression would correlate with invasive tumor phenotypes and worse survival in BAC.Methods: We classified 150 tumors as pure BAC, BAC with focal invasion, or adenocarcinoma with BAC features. A tissue microarray was constructed from areas of benign lung, BAC, and invasive adenocarcinoma in these tumors. Squamous cell carcinoma–related oncogene expression was graded by immunohistochemistry from 0 to 3 (absent, low, moderate, or high), with positive SCCRO phenotype defined as grade 3. Squamous cell carcinoma–related oncogene specificity was determined by Wilcoxon rank test and area under the receiver-operator curve, survival by the Kaplan-Meier method, and correlation with prognostic factors by log-rank test.Results: Of the 86.0% (129 of 150) of specimens suitable for analysis, positive SCCRO phenotype was seen in 16.3% (21 of 129) and was 100.0% specific for tumor versus benign tissue (area under receiver-operator curve, 0.92). Positive SCCRO phenotype was greater in tumors with increasing degrees of invasive histologic type (7.0% pure BAC, 13.6% BAC with focal invasion, and 28.6% adenocarcinoma with BAC features; p = 0.02). Low-level SCCRO expression was present in 83.9% (99 of 118) of benign tissues and correlated with tobacco use and poor survival (p = 0.05).Conclusions: Squamous cell carcinoma–related oncogene is a marker of invasive tumor progression in BAC. Low-level expression in adjacent benign lung predicts worse survival, and may represent field cancerization or host–tumor effects. [Copyright &y& Elsevier]

Lung cancer is the leading cause of cancer death in US women and is responsible for as many deaths as breast cancer and all gynecological cancers combined. Most lung cancer is caused by cigarette smoke. Despite all that is known about the devastating effects of cigarettes, one quarter of women in the United States continue to smoke. Women are targeted in tobacco advertising, and teenage girls are often drawn to cigarette smoking under a variety of social pressures. Following the increase in smoking, the death rate from lung cancer in US women rose 600% from 1930 to 1997. Women may be more susceptible than men to the carcinogenic properties of cigarette smoke. In addition, differences in the biology of lung cancer exist between the 2 sexes with higher levels of DNA adduct formation, increased CYP1A1 expression, decreased DNA repair capacity, and increased incidence of K-ras gene mutations in women. The novel estrogen receptor β has also been detected in lung tumors and suggests that estrogen signaling may have a biological role in tumorigenesis. Given these differences and given the enormous toll this disease has on US women, undertaking sex-specific research in lung cancer is crucial. Finally, disseminating information about this epidemic may prevent a similar epidemic in other parts of the world where women are just now becoming addicted to tobacco. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer death in the U.S. At the time of diagnosis, most patients are older than 65 years and have Stage III or IV disease. More than 80% of patients have non-small cell lung cancer and the rest have small cell lung cancer. Age is not a significant prognostic factor for overall survival and response to treatment for patients with either type of lung cancer. Treatment options should be tailored to older patients based on the same selection process and benefits seen in the population as a whole.

Context: More persons in the United States die from non–small cell lung cancer (NSCLC) than from breast, colorectal, and prostate cancer combined. In preclinical testing, oral gefitinib inhibited the growth of NSCLC tumors that express the epidermal growth factor receptor (EGFR), a mediator of cell signaling, and phase 1 trials have demonstrated that a fraction of patients with NSCLC progressing after chemotherapy experience both a decrease in lung cancer symptoms and radiographic tumor shrinkages with gefitinib. Objective: To assess differences in symptomatic and radiographic response among patients with NSCLC receiving 250-mg and 500-mg daily doses of gefitinib. Design, Setting, and Patients: Double-blind, randomized phase 2 trial conducted from November 2000 to April 2001 in 30 US academic and community oncology centers. Patients (N = 221) had either stage IIIB or IV NSCLC for which they had received at least 2 chemotherapy regimens. Intervention: Daily oral gefitinib, either 500 mg (administered as two 250-mg gefitinib tablets) or 250 mg (administered as one 250-mg gefitinib tablet and 1 matching placebo). Main Outcome Measures: Improvement of NSCLC symptoms (2-point or greater increase in score on the summed lung cancer subscale of the Functional Assessment of Cancer Therapy-Lung [FACT-L] instrument) and tumor regression (>50% decrease in lesion size on imaging studies). Results: Of 221 patients enrolled, 216 received gefitinib as randomized. Symptoms of NSCLC improved in 43% (95% confidence interval [CI], 33%-53%) of patients receiving 250 mg of gefitinib and in 35% (95% CI, 26%-45%) of patients receiving 500 mg. These benefits were observed within 3 weeks in 75% of patients. Partial radiographic responses occurred in 12% (95% CI, 6%-20%) of individuals receiving 250 mg of gefitinib and in 9% (95% CI, 4%-16%) of those receiving 500 mg. Symptoms improved in 96% of patients with partial radiographic responses. The overall survival at 1 year was 25%. Th... [ABSTRACT FROM AUTHOR]

Background: Although there is no proven benefit associated with screening for lung cancer, screening programs are attracting many individuals who perceive themselves to be at high risk due to smoking. We sought to determine whether the risk of lung cancer varies predictably among smokers. Methods: We used data on 18172 subjects enrolled in the Carotene and Retinol Efficacy Trial (CARET)—a large, randomized trial of lung cancer prevention—to derive a lung cancer risk prediction model. Model inputs included the subject's age, sex, asbestos exposure history, and smoking history. We assessed the model's calibration by comparing predicted and observed rates of lung cancer across risk deciles and validated it by assessing the extent to which a model estimated on data from five CARET study sites could predict events in the sixth study site. We then applied the model to evaluate the risk of lung cancer among smokers enrolled in a study of lung cancer screening with computed tomography (CT). Results: The model was internally valid and well calibrated. Ten-year lung cancer risk varied greatly among participants in the CT study, from 15% for a 68-year-old man who has smoked two packs per day for 50 years and continues to smoke, to 0.8% for a 51-year-old woman who smoked one pack per day for 28 years before quitting 9 years earlier. Even among the subset of CT study participants who would be eligible for a clinical trial of cancer prevention, risk varied greatly. Conclusions: The risk of lung cancer varies widely among smokers. Accurate risk prediction may help individuals who are contemplating voluntary screening to balance the potential benefits and risks. Risk prediction may also be useful for researchers designing clinical trials of lung cancer prevention. [ABSTRACT FROM AUTHOR]

Background: All-trans-retinoic acid (all-trans RA) induces complete remission in most patients with acute promyelocytic leukemia (APL). However, continuous oral dosing results in progressive decline in plasma drug concentrations, which is associated with relapse and resistance to this retinoid. We speculated that the decline in drug levels, indicating acquired resistance, resulted partly from inducible cytochrome-P450 oxidative enzymes, which can catabolize all-trans RA.Purpose: We studied the clinical pharmacology of all-trans RA in cancer patients to determine possible mechanisms of acquired resistance and evaluated the potential for reversal by ketoconazole, an inhibitor of cytochrome-P450 oxidative enzymes.Methods: Serial plasma samples were obtained from 54 patients with APL or advanced lung cancer after a single oral dose of all-trans RA (45 mg/m2). In the 34 patients with advanced lung cancer, all-trans RA (45 mg/m2) was administered twice daily for 4 weeks, and, on days 2, 28, and 29, serial plasma samples were again obtained after a single 45-mg/m2 dose. One hour prior to drug administration on days 2 and 29, a single oral dose (200-1200 mg) of ketoconazole was administered. Endogenous plasma concentrations of all-trans RA and 13-cis-retinoic acid were measured in a subset of these patients and in 11 with early-stage lung cancer.Results: The mean area under the curve for plasma drug concentration times time (AUC) for all-trans RA on day 1 varied substantially among patients. Compared with patients with APL, the 28 patients with advanced lung cancer who completed therapy demonstrated significantly lower AUC levels on day 1 (P = .06); a subgroup with levels less than 300 ng/mL per hour on day 1 had lower endogenous plasma all-trans RA concentrations than patients with APL or early-stage lung cancer or 14 normal subjects. Following continuous oral treatment, the mean day 28 AUC for all-trans RA was significantly lower than that on day 1 (213 ng/mL per hour versus 467 ng/mL per hour; P < .01), a decline significantly attenuated by ketoconazole, which increased the mean plasma all-trans RA AUC on day 29 to 375 ng/mL per hour (P < .01).Conclusion: Reported variability for the pharmacokinetics of all-trans RA may result from disease-related or population-based differences in basal catabolic rates influenced by genetic or environmental factors. However, the pattern of inducible catabolism of all-trans RA is not disease specific. Ketoconazole attenuates this accelerated catabolism, suggesting that oxidation by cytochrome-P450 enzymes is an important pathway for both constitutive and induced pathways of all-trans RA metabolism. [ABSTRACT FROM AUTHOR]

Explores the role of phosphatidylinositol 3-kinase/Akt in predicting sensitivity of non-small-cell lung cancer (NSCLC) to gefitinib. Inhibition of epidermal growth factor receptor (EGFR) by gefitinib; Association of mutations in the tyrosine kinase domain of EGFR with gefitinib sensitivity in persons with NSCLC; Use of immunohistochemistry to predict sensitivity or resistance to gefitinib.

The article focuses on a study which deals with the analysis of tumor samples for the evaluation of mutations in genes including KRAS, NRAS, MEK1 and BRAF. It mentions of the resistance to tyrosine kinase inhibitors (TKIs) by the study of epidermal growth factor receptor (EGFR) mutant lung cancer. It informs about a cohort study for the analysis of mutation and reports mutation only in BRAF gene.

Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) are effective for many patients with lung cancer with EGFR mutations. However, not all patients are responsive to EGFR TKIs, including even those harboring EGFRsensitizing mutations. In this study, we quantified the cells and cellular interaction features of the tumor microenvironment (TME) using routine H&E-stained biopsy sections. These TME features were used to develop a prediction model for survival benefit from EGFR TKI therapy in patients with lung adenocarcinoma and EGFR-sensitizing mutations in the Lung Cancer Mutation Consortium 1 (LCMC1) and validated in an independent LCMC2 cohort. In the validation data set, EGFR TKI treatment prolonged survival in the predicted-to-benefit group but not in the predicted-not-to-benefit group. Among patients treated with EGFR TKIs, the predicted-to-benefit group had prolonged survival outcomes compared with the predicted not-to-benefit group. The EGFR TKI survival benefit positively correlated with tumor-tumor interaction image features and negatively correlated with tumor-stroma interaction. Moreover, the tumor-stroma interaction was associated with higher activation of the hepatocyte growth factor/MET-mediated PI3K/AKT signaling pathway and epithelial-mesenchymal transition process, supporting the hypothesis of fibroblast-involved resistance to EGFR TKI treatment. [ABSTRACT FROM AUTHOR]

Gefitinib (ZD1839, Iressa®), a selective drug inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase (TK), was recently approved for the treatment of patients with advanced non-small cell lung cancer (NSCLC). This article reviews the identification of EGFR as a therapeutic target and the steps in the development of gefitinib as “targeted” monotherapy for patients with NSCLC. Whether EGFR is required for the maintenance of lung tumor survival is also discussed. Finally, strategies to identify predictors of response to gefitinib are explored. [Copyright &y& Elsevier]

• HSP90 inhibitor SNX-5422 with carboplatin/paclitaxel is safe in advanced lung cancer. • The preliminary efficacy of this combination is encouraging in an enriched subpopulation of lung cancers with oncogenic drivers. • Future development of current and next-generation HSP90 inhibitors should consider the inclusion of oncogene-driven lung cancers. Single-agent heat shock protein 90 (HSP90) inhibition has demonstrated activity in oncogene-driven non-small cell and small cell lung cancers. SNX-5422 is an oral HSP90 inhibitor with increased activity in vitro with the addition of carboplatin and paclitaxel. Therefore, we conducted a phase 1, open-label, multicenter study to evaluate SNX-5422, carboplatin and paclitaxel followed by SNX-5422 maintenance in patients with advanced lung cancers. In part 1 (3 + 3 dose escalation), SNX-5422 (50/75/100-mg/m2) was dosed every other day (qod) for 21 days (28-day cycle) for ≤4 cycles; carboplatin (AUC 5)-paclitaxel (175 mg/m2) was administered once every 3 weeks for ≤6 courses. In part 2 (maintenance), subjects who achieved at least stable disease in part 1 received 100 mg/m2 SNX-5422 monotherapy qod for 21 days (28-day cycle). Twenty-three patients with advanced non-small cell lung cancer (NSCLC, n = 20) and small cell lung cancer (SCLC, n = 3) were enrolled. The median age was 60 years and 61% (n = 14/23) had ≥1 prior treatment regimens. The maximum tolerated dose of SNX-5422 was 100 mg/m2 qod in combination with carboplatin-paclitaxel. The most common treatment-related grade 3/4 adverse events (part 1/part 2) were diarrhea (26%/15%) and nausea (9%/0%). In response-evaluable patients with NSCLC, 33% (6/18) had a partial response, 56% (10/18) stable disease, and 11% (2/18) progressive disease. Patients who remained on single-agent SNX-5422 maintenance therapy ≥2 months (n = 9) had cancers enriched for oncogenic drivers (n = 3 KRAS mutation, n = 1 EGFR exon 20 mutation, n = 1 HER2 mutation, and n = 1 RET fusion). The triplet combination of SNX-5422, carboplatin and paclitaxel followed by maintenance SNX-5422 therapy was well-tolerated and showed anti-tumor activity. Cancers for which disease control on single-agent SNX-5422 maintenance was observed were enriched for oncogene-driven NSCLCs. [ABSTRACT FROM AUTHOR]

Objectives Reports of the prognostic significance of ALK -rearrangement in resected non-small cell lung cancer (NSCLC) have been contradictory. We aimed to determine the prognosis of early-stage ALK -positive lung cancers relative to KRAS - and EGFR -mutant lung cancers. Material and methods We reviewed medical records of patients with resected NSCLC harboring an ALK rearrangement (n = 29) or a driver mutation in EGFR (n = 255) or KRAS (n = 480). Recurrence-free survival (RFS) was estimated for each genotype with the differences reported as a hazard ratio (HR). Results Among the 764 patients, 555 (73%), 101 (13%), and 108 (14%) had stage I, II, and III NSCLC, respectively. ALK -positive patients were distributed across all stages: 10 (34%) stage I, 6 (21%) stage II, and 13 (45%) stage III. Median RFS was not reached for EGFR -mutant patients, 24.3 months (95%CI 11.4–65.3) for ALK -positive patients, and 72.9 months (95%CI 59.7 to undefined) for KRAS -mutant patients. When adjusted for stage, ALK -positive NSCLC remained associated with worse RFS compared to EGFR -mutant (HR 1.8, 95%CI: 1.1-3.1), but not when compared to KRAS -mutant (HR 1.3, 95%CI: 0.8-2.1) NSCLC. Conclusions In this large series of resected NSCLC, ALK rearrangements were associated with a trend toward inferior disease outcomes compared to other clinically relevant genomic subsets. These data support the need for clinical trials evaluating use of ALK inhibitors among ALK -positive patients with localized or locally-advanced disease. [ABSTRACT FROM AUTHOR]

Objectives Thyroid transcription factor 1 (TTF-1) is routinely tested in the diagnostic evaluation of suspected lung cancers, is commonly expressed by lung adenocarcinomas, and may modulate lung cancer biology. We examined the role of TTF-1 as a predictive and prognostic marker in patients with advanced lung adenocarcinomas. Materials and methods We analyzed clinical, pathologic, and molecular features, treatments received, and overall survival obtained from the medical records of 479 consecutive patients at a single site with stage IV lung adenocarcinomas and evaluable TTF-1 expression. TTF-1 expression was determined by immunohistochemistry using antibody 8G7G3/1. Results and conclusion TTF-1 expression was evaluable in 479 (75%) of all patients reviewed, and was positive in 383 (80%, 95% CI 76–83%). Clinicopathologic features were similar between TTF-1 positive and TTF-1 negative tumors, except EGFR mutations were more common in TTF-1 positive cases (24% vs 6%, p < 0.001). In univariate analysis, overall survival was significantly longer in patients with TTF-1 positive versus TTF-1 negative tumors (18 months vs 9 months, p < 0.0001). In multivariate analysis, TTF-1 positivity remained associated with better overall survival (HR = 0.38, p < 0.0001), exceeding the prognostic impact of Karnofsky performance status >/= 80% (HR 0.62, p = 0.0003) and receipt of first-line combination chemotherapy or targeted therapy (HR relative to first-line single agent chemotherapy 0.59, p = 0.05 and 0.51, p = 0.05 respectively). Both patients with TTF-1 positive and TTF-1 negative cancers had longer durations of initial therapy when treated with pemetrexed-based chemotherapy. In patients with advanced lung adenocarcinomas, TTF-1 expression is associated with better survival but is not predictive of distinct benefit from pemetrexed-based chemotherapy. [ABSTRACT FROM AUTHOR]

Background: RET rearrangements are found in 1-2% of non-small-cell lung cancers. Cabozantinib is a multikinase inhibitor with activity against RET that produced a 10% overall response in unselected patients with lung cancers. To assess the activity of cabozantinib in patients with RET-rearranged lung cancers, we did a prospective phase 2 trial in this molecular subgroup.Methods: We enrolled patients in this open-label, Simon two-stage, single-centre, phase 2, single-arm trial in the USA if they met the following criteria: metastatic or unresectable lung cancer harbouring a RET rearrangement, Karnofsky performance status higher than 70, and measurable disease. Patients were given 60 mg of cabozantinib orally per day. The primary objective was to determine the overall response (Response Criteria Evaluation in Solid Tumors version 1.1) in assessable patients; those who received at least one dose of cabozantinib, and had been given CT imaging at baseline and at least one protocol-specified follow-up timepoint. We did safety analyses in the modified intention-to-treat population who received at least one dose of cabozantinib. The accrual of patients with RET-rearranged lung cancer to this protocol has been completed but the trial is still ongoing because several patients remain on active treatment. This study was registered with ClinicalTrials.gov, number NCT01639508.Findings: Between July 13, 2012, and April 30, 2016, 26 patients with RET-rearranged lung adenocarcinomas were enrolled and given cabozantinib; 25 patients were assessable for a response. KIF5B-RET was the predominant fusion type identified in 16 (62%) patients. The study met its primary endpoint, with confirmed partial responses seen in seven of 25 response-assessable patients (overall response 28%, 95% CI 12-49). Of the 26 patients given cabozantinib, the most common grade 3 treatment-related adverse events were lipase elevation in four (15%) patients, increased alanine aminotransferase in two (8%) patients, increased aspartate aminotransferase in two (8%) patients, decreased platelet count in two (8%) patients, and hypophosphataemia in two (8%) patients. No drug-related deaths were recorded but 16 (62%) patients died during the course of follow-up. 19 (73%) patients required dose reductions due to drug-related adverse events.Interpretation: The reported activity of cabozantinib in patients with RET-rearranged lung cancers defines RET rearrangements as actionable drivers in patients with lung cancers. An improved understanding of tumour biology and novel therapeutic approaches will be needed to improve outcomes with RET-directed targeted treatment.Funding: Exelixis, National Institutes of Health and National Cancer Institute Cancer Center Support Grant P30 CA008748. [ABSTRACT FROM AUTHOR]

Objectives The role of anti-angiogenic tyrosine kinase inhibitors (AATKI) for patients with non-small-cell lung cancers (NSCLC) is uncertain. We conducted a comprehensive meta-analysis to assess the overall utility of adding AATKI to chemotherapy. Materials and Methods We included 15 randomized controlled trials (RCTs) of AATKI plus chemotherapy versus chemotherapy involving 7997 patients with advanced NSCLC. Meta-analysis was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for objective response rate (ORR) and grade 3 or greater toxicity. Pre-specified subgroup analyses were performed according to line of chemotherapy, chemotherapeutic regimen and histology. Results The addition of AATKI to chemotherapy significantly increased progression-free survival (PFS) (HR 0.83, 95% CI 0.79, 0.87; P < 0.00001) and ORR [OR 1.63, 95% CI 1.45, 1.84; P < 0.00001], but not overall survival (OS) (HR 0.96, 95% CI 0.91, 1.01; P = 0.14). OS benefit was seen in the subset of patients with adenocarcinomas (HR 0.86; 95% CI 0.79, 0.95; P = 0.002), especially in the second line setting (HR 0.85; 95% CI 0.76, 0.96; P = 0.008). However, both grade ≥3 toxicity (HR 2.08, 95% CI 1.59, 2.73; P < 0.00001) and treatment-related deaths (OR 2.37, 95% CI 1.58, 3.56; P<0.0001) were significantly higher with the addition of AATKI. Conclusion The addition of AATKI to chemotherapy in patients with advanced NSCLC significantly increased PFS and ORR but not OS, and did so at the expense of increased toxicity and treatment-related deaths. Preclinical and translational research in predictive biomarkers are essential for the clinical development of this class of drugs. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 ( HER2, ERBB2 ) mutations occur in 3% of lung adenocarcinomas. While case reports and series have shown activity of HER2 targeted agents in these patients, little is known about outcomes of chemotherapies. Patients with stage IV HER2 -mutant lung cancers at Memorial Sloan Kettering were reviewed. Patient demographics, types of HER2 mutations, duration of systemic treatments and survival were analyzed. We identified 38 patients with HER2- mutant lung cancers: median age 62; majority were women (n = 24), never smokers (n = 22), and all had adenocarcinomas. A 12 base pair in-frame insertion YVMA in exon 20 (p.A775_G776insYVMA) was present in 24 (63%, 95% CI 46–78%) patients. In addition, there were four 9 base pair insertions, one 6 base pair insertion, and five 3 base pair insertions in exon 20, and four single bp substitutions (exon 20 L755F, V777L, D769H, exon 8 S310F). The median overall survival from date of diagnosis of stage IV disease was 2.3 years (95% CI 1.2-2.6). The median duration of chemotherapy was 4.3 months (68 treatments, range 0–21 months): 6.2 months for pemetrexed ±platinum/bevacizumab, 4 months for taxane ±platinum/bevacizumab, 2.6 months for gemcitabine, 3.5 months for vinorelbine. The median duration of HER2 tyrosine kinase inhibitors was 2.2 months (28 treatments, range 0.3-16.3 months). As we search for better targeted therapies for patients with HER2 -mutant lung cancers, chemotherapy remains an important component of care. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To compare preoperative size of stage I and stage II lung adenocarcinoma as measured by Computed Tomography (CT) and as assessed on gross pathology specimens. Materials and methods: 47 patients diagnosed with stage I or II lung adenocarcinoma were evaluated. Institutional Review Board permission was obtained. Tumor contours were delineated using a semi-automated segmentation algorithm and adjusted based on a radiologist''s input. Based on the tumor perimeter, maximal in-plane tumor diameter was calculated automatically. The largest single diameter from the pathology gross report was utilized. A paired t-test was used to examine the measurement difference between CT and pathology. Results: The mean largest diameter of the tumors at CT and pathology was 29.53mm and 24.04mm, respectively. There was a statistically significant difference between the mean CT measurement and mean pathology measurement of 5.49mm (standard deviation 9.08mm, p <0.001). The percent relative difference between the two measurements was 18.3% (standard deviation 28.2%). Conclusion: There is a statistically significant difference between the tumor diameter as measured by CT and on pathology gross specimen. These differences could have implications in the treatment and prognosis of patients with early stage lung adenocarcinoma. [Copyright &y& Elsevier]

Abstract: Background: GD2/GM2 synthase is a key enzyme in the synthesis of GD2 and GM2 gangliosides found on the surface of neuroblastoma and small cell lung carcinoma (SCLC) cells. In neuroblastoma, persistent levels of GD2/GM2 synthase RNA in bone marrow (BM) following therapy portend poorer progression-free and overall survival. We conducted this study to determine if GD2/GM2 synthase RNA could be detected in SCLC cell lines and human tissues, and whether mRNA transcript levels corresponded with disease status. Experimental design: Initially, a pilot study enrolled patients with SCLC to determine the rate of GD2 expression at various points in the patients’ disease course. Peripheral blood (PB), bone marrow and tumor tissues were used to measure GD2/GM2 synthase levels. In addition, SCLC cell lines were analyzed for GD2/GM2 synthase expression. Based on data from that initial analysis, a prospective trial was developed enrolling patients with newly diagnosed SCLC and following them serially. GD2/GM2 synthase transcript was determined by a sensitive quantitative reverse transcription-PCR (qRT-PCR) assay and normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Results: Six SCLC cell lines were assayed for expression of GD2/GM2 synthase, and high expression was detected in all. GD2/GM2 synthase transcript levels were obtained from tumor tissue, BM, or PB of 29 patients in the pilot study. 6/10 (60%) tumor tissues or BM samples were positive (median 332.7 units; range 13–2323 units); 8/19 (42%) untreated patients were GD2/GM2 synthase positive in their PB prior to beginning therapy (median 10.2; range 5.1–32.2); 3/4 (75%) patients who were first tested when they developed recurrent disease were positive in their PB (median 16.1; range 8.5–19.9). The fourth patient had an initial value of 2.0 (negative), which increased to 8.4 (positive) within 1 month without treatment. Seven of 12 patients with baseline positive GD2/GM2 synthase values had post-treatment levels measured, all of which were ≤5 or showed a >50% decrease following successful treatment. Patients in the prospective trial demonstrated lower rates of positivity, with only 3/26 (12%) patients exhibiting detectable transcript levels in the peripheral blood prior to treatment. All 3 of these patients had their transcript levels fall below 5 after treatment. 11/26 patients had baseline levels of zero. Bone marrow was drawn at baseline on 7 patients in the prospective trial and 3 (43%) had transcript levels above 5 (range 0.65–27.43 units). There was no correlation between elevated levels in the BM and elevated levels in the PB. Conclusions: Although initial studies demonstrated that GD2/GM2 synthase transcripts were measurable in the peripheral blood of SCLC patients at diagnosis and declined with successful treatment, in a separate prospective study, these results could not be confirmed. Thus, GD2/GM2 is not a reliable biomarker in SCLC. [Copyright &y& Elsevier]

Surgical series of non-small cell lung cancer (NSCLC) pathologic samples have shown that the expression of the proteins bcl-2 and bax, which regulate cell death, may have prognostic implications. Laboratory data also suggests that these proteins may impact chemotherapy response. In order to determine the rate of bcl-2 and bax expression in advanced NSCLC and assess the impact on chemotherapy response and patient survival, we performed immunohistochemistry on biopsy samples from patients enrolled in a phase I/II trial of vinorelbine plus docetaxel. We chose to study the pathology of patients in this specific trial because both docetaxel and vinorelbine phosphorylate bcl-2 and we hypothesized that this mechanism may affect clinical outcome. The goal of this study was to determine the feasibility of this analysis, and to observe any differences in response rate or survival based on bcl-2 or bax staining results. Unstained slides from paraffin blocks were obtained for 31 patients (55%) on the phase I/II trial. The patient characteristics for this subgroup did not differ significantly from the entire cohort of patients on the trials. Bcl-2 staining was positive in 5/31 samples (16%, 95% CI 3–29%) and bax was positive in 19/28 samples (68%, 95% CI 51–85%). Bcl-2 and bax staining did not correlate with response (p=0.65 and 1.00 respectively, Fisher''s exact test), or survival (by Kaplan–Meier curves). In conclusion, bcl-2 and bax expression was similar in this population with advanced NSCLC to previously reported results for early stage disease, but did not predict response to vinorelbine plus docetaxel in this series. [Copyright &y& Elsevier]

Human epidermal growth factor 2 ( HER2, ERBB2 ) mutations in lung cancers are oncogenic drivers that respond to HER2 targeted therapies. Little is known about the sensitivity of subtypes of HER2 mutant lung cancers to targeted agents. We present a patient with HER2 mutant lung cancer with a 12 base pair insertion YVMA (p.A775_G776insYVMA), who had a long natural history and durable partial response to afatinib. We demonstrate that afatinib has activity in patients with HER2 mutant lung cancers with exon 20 YVMA insertions, the most common variant. [ABSTRACT FROM AUTHOR]

The clinical success of EGFR inhibitors in EGFR -mutant lung cancer is limited by the eventual development of acquired resistance. We hypothesize that enhancing apoptosis through combination therapies can eradicate cancer cells and reduce the emergence of drug-tolerant persisters. Through high-throughput screening of a custom library of ∼1,000 compounds, we discover Aurora B kinase inhibitors as potent enhancers of osimertinib-induced apoptosis. Mechanistically, Aurora B inhibition stabilizes BIM through reduced Ser87 phosphorylation, and transactivates PUMA through FOXO1/3. Importantly, osimertinib resistance caused by epithelial-mesenchymal transition (EMT) activates the ATR-CHK1-Aurora B signaling cascade and thereby engenders hypersensitivity to respective kinase inhibitors by activating BIM-mediated mitotic catastrophe. Combined inhibition of EGFR and Aurora B not only efficiently eliminates cancer cells but also overcomes resistance beyond EMT. [Display omitted] • Aurora kinase inhibitors combined with osimertinib prevent and overcome resistance • Concurrent inhibition of EGFR and AURKB maximizes BIM- and PUMA-mediated apoptosis • EMT activates ATR-CHK1-AURKB and sensitizes cancer cells to these kinase inhibitors • Mitotic catastrophe triggered by ATR-CHK1-AURKB inhibitors involves BIM and BAX/BAK Tanaka et al. identify Aurora kinase inhibitors as potent enhancers of osimertinib-induced apoptosis by HTS. Concurrent inhibition of EGFR and AURKB maximizes BIM- and PUMA-mediated apoptosis to eradicate cancer cells. Osimertinib resistance caused by EMT activates ATR-CHK1-AURKB and engenders hypersensitivity to these kinase inhibitors by activating BIM-mediated mitotic catastrophe. [ABSTRACT FROM AUTHOR]