Search

Supplemental Table 7: Cases with two or more oncogenic driver alterations. Supplemental Table 8. Comparison of LCMC I and LCMC II.

Purpose: Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas.Experimental Design: Sixteen U.S. institutions enrolled 1,367 patients with lung cancer in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and IHC.Results: The use of targeted therapies in patients with EGFR, ERBB2, or BRAF p.V600E mutations, ALK, ROS1, or RET rearrangements, or MET amplification was associated with a survival increment of 1.5 years compared with those with such mutations not receiving targeted therapy, and 1.0 year compared with those lacking a targetable driver. Importantly, 60 patients with a history of smoking derived similar survival benefit from targeted therapy for alterations in EGFR/ALK/ROS1, when compared with 75 never smokers with the same alterations. In addition, coexisting TP53 mutations were associated with shorter survival among patients with EGFR, ALK, or ROS1 alterations.Conclusion: Patients with adenocarcinoma of the lung and an oncogenic driver mutation treated with effective targeted therapy have a longer survival, regardless of prior smoking history. Molecular testing should be performed on all individuals with lung adenocarcinomas irrespective of clinical characteristics. Routine use of massively parallel sequencing enables detection of both targetable driver alterations and tumor suppressor gene and other alterations that have potential significance for therapy selection and as predictive markers for the efficacy of treatment. Clin Cancer Res; 24(5); 1038–47. ©2017 AACR.

Supplemental Table 5. All subjects with all molecular results in LCMC2.

PTEN and MET IHC methods

Supplemental Figure Legends

Supplementary Figure 1 Sample Analysis Flowchart Supplementary Figure 2 LOMC2 Gene List Supplementary Figure 3 PTEN Immunohistochemistry analysis of LCMC II samples. Supplementary Figure 4 Mutation Frequency by Mutation and Smoking Status

OBJECTIVES To determine the factors that shape utilization of social media-based online support communities (OSCs) and study the influence of these communities on medical decision-making in patients with Idiopathic Subglottic Stenosis (iSGS). STUDY DESIGN Survey study. METHODS A survey investigating OSC use was sent to the 1,056 members of the North American Airway Collaborative (NoAAC) iSGS1000 cohort in January 2018. Responses were merged with the existing NoAAC data set containing extensive demographic data, disease-specific history, and responses to validated patient-reported outcome measures. RESULTS A total of 755 individuals with iSGS and mean age of 51.8 ± 11.6 years were included (99% female, 98% white, 63% college educated) and 58% were OSC users. Younger age, female gender, and college education were each associated with OSC use (P

Mutations in the KRAS gene are the most common driver oncogenes present in lung adenocarcinomas. We analyzed the largest multi-institutional database available containing patients with metastatic KRAS-mutant lung adenocarcinomas.The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional collaboration to study the genomic characteristics of lung adenocarcinomas, treat them with genomically directed therapeutic approaches, and assess their outcomes. Since its inception in 2009, the LCMC has enrolled more than 1900 patients and has performed pretreatment, multiplexed, molecular characterization along with collecting clinical data. We evaluated the characteristics of patients with KRAS mutation in the LCMC and the association with overall survival.Data from 1655 patients with metastatic lung adenocarcinomas were analyzed. Four hundred fifty (27%) patients had a KRAS mutation, 58% were female, 93% were smokers, and there was a median age of 65 years. Main KRAS subtypes were: G12C 39%; and G12D and G12V at 18% each. Among patients with KRAS mutation, G12D had a higher proportion of never-smokers (22%, p0.001). Patients with KRAS-mutant tumors had a trend toward shorter median survival compared to all others in the series (1.96 versus 2.22; P = 0.08) and lower 2-year survival rate (49% [95% confidence interval: 44%-54%] and 55% [95% confidence interval: 52%-58%], respectively).In the LCMC study, 27% of lung adenocarcinomas patients harbored a KRAS mutation and up to one-third of them had another oncogenic driver. Patients with both KRAS and STK11 mutations had a significantly inferior clinical outcome.

e13568 Background: Crowdsourcing as a means of codifying the knowledge of many individuals can be an effective way to build models where data do not exist to inform these models. Risk for health complications during cancer survivorship is one area where there are limited large datasets that track detailed outcomes. While many survivorship care expert groups such as the National Comprehensive Cancer Network (NCCN) and Children’s Oncology Group (COG) Survivorship Guidelines Panels recognize the need for a stratified system of assigning survivorship care, criteria for assigning risk to individuals at the end of active cancer treatment are not well agreed upon. To build a model for risk of health complications during survivorship care, we created an online crowdsourcing platform called Follow-up Interactive Long-Term Expert Ranking (FILTER). With FILTER we invite oncologists from a range of backgrounds to determine which case, among two cases, is higher risk. This process is repeated many times by many oncologists to achieve a consensus rating for risk for each case. The purpose of this preliminary study was to understand the characteristics of oncologists who were willing to participate in pilot testing FILTER and the number of cases they were able to adjudicate. Methods: We released the FILTER application in November 2021 to members of the NCCN Survivorship Guidelines Panel, COG Survivorship Guidelines Panel, and Vanderbilt-Ingram Cancer Center oncologists. Through the registration process, we collected institution and specialty information about each expert to determine whether a diverse range of experts were contributing their experience to the risk model. Results: Out of over 100 oncologists who were invited to participate in pilot testing of FILTER, 29 users have signed up for an account and adjudicated at least one matchup. These experts came from 13 institutions and have adjudicated a total of 1665 matchups generating risk scores for 78 synthetic cases. The median number of matchups adjudicated per expert was 45. There were 15 medical oncologists, 3 radiation oncologists, a surgical oncologist, and 10 pediatric oncologists who participated in pilot testing. Conclusions: We succeeded in recruiting a limited number of experts to date from a diverse range of oncology specialties, institutions, and backgrounds to pilot test FILTER. However, recruitment has been inadequate to meet the needs of the project. We therefore will seek to recruit more oncologists to refine these scores and will use meetings of oncology groups such as ASCO to achieve this goal. With enough adjudications by oncologists, a reliable ranking of cases by risk score will allow us to create a model to inform a survivorship risk calculator. This calculator, which will be made publicly available once finalized and validated, will provide another resource to help triage cancer survivors to appropriate survivorship care needs.

TPS8596 Background: Comprehensive genomic profiling (CGP) has transformed the care of patients with advanced non-small cell lung cancer (NSCLC), giving many patients access to precision targeted treatment and immunotherapy with remarkable improvements in outcomes. Studies show that patients with lung cancers with oncogenic drivers are the least likely group to benefit from checkpoint inhibitors and are better served by enrollment in studies of targeted therapies. Early-stage NSCLC is now poised to benefit from these precision approaches with the regulatory approval of the first tyrosine kinase inhibitors and checkpoint inhibitors for the adjuvant treatment of resected NSCLC, each requiring testing for precision biomarkers. Neoadjuvant precision therapy for NSCLC has the potential to further improve treatment outcomes. Methods: The LCMC4 Evaluation of Actionable Drivers in EaRly Stage Lung Cancer (LEADER) Neoadjuvant Screening Trial (NCT04712877) is a collaborative diagnostic study developed by the Lung Cancer Mutation Consortium (LCMC), supported by the Thoracic Surgery Oncology Group and the Lung Cancer Research Foundation. The primary objective is to determine the proportion of patients with stage IA2-III lung cancers who possess actionable oncogenic drivers, defined as 1 of 11 actionable genomic alterations: mutations in EGFR, BRAFV600E, MET exon 14, KRAS G12C, and HER2, rearrangements in ALK, RET, NTRK, and ROS1, and amplification of MET and HER2. The study will also assess the feasibility of CGP to detect actionable oncogenic drivers in patients with suspected early-stage lung cancers scheduled to undergo biopsies to establish the diagnosis of lung cancer. The protocol will enroll 1000 patients with operable stage IA2-III (TNM 8th edition) lung cancer who will undergo CGP utilizing the Foundation Medicine 324 gene assay as well as paired liquid biopsy analysis. Results will enable selection of neoadjuvant therapy and enrollment onto independent therapeutic trials with genomically matched neoadjuvant treatment, standard therapies, or other trials if no driver is detected. The approach will be considered feasible if >35% of non-squamous NSCLCs have 1 of the 11 actionable alterations. Tumor mutational burden and PD-L1 IHC will be assessed. Plasma specimens collected pre- and post neoadjuvant treatment and post-surgery will be used for research to study the ability of circulating tumor DNA to assess neoadjuvant treatment response and minimal residual disease. 26 academic sites in the US plan to enroll patients. Clinical trial information: NCT04712877.

Objectives To develop an online crowdsourcing platform where oncologists and other survivorship experts can adjudicate risk for complications in follow-up. Materials and Methods This platform, called Follow-up Interactive Long-Term Expert Ranking (FILTER), prompts participants to adjudicate risk between each of a series of pairs of synthetic cases. The Elo ranking algorithm is used to assign relative risk to each synthetic case. Results The FILTER application is currently live and implemented as a web application deployed on the cloud. Discussion While guidelines for following cancer survivors exist, refinement of survivorship care based on risk for complications after active treatment could improve both allocation of resources and individual outcomes in long-term follow-up. Conclusion FILTER provides a means for a large number of experts to adjudicate risk for survivorship complications with a low barrier of entry.

Most colorectal cancers (CRCs) develop from either adenomas (ADs) or sessile serrated lesions (SSLs). The origins and molecular landscapes of these histologically distinct pre-cancerous polyps remain incompletely understood. Here, we present an atlas at single-cell resolution of sporadic conventional tubular/tubulovillous ADs, SSLs, hyperplastic polyps (HPs), microsatellite stable (MSS) and unstable (MSI-H) CRC, and normal colonic mucosa. Using single-cell transcriptomics and multiplex imaging, we studied 69 datasets from 33 participants. We also examined separate sets of 66 and 274 polyps for RNA and targeted gene sequencing, respectively. We performed multiplex imaging on a tissue microarray of 14 ADs and 15 CRCs, and we integrated pre-cancer polyp data with published single-cell and The Cancer Genome Atlas (TCGA) bulk CRC data to establish potential polyp-cancer relationships. Striking differences were observed between ADs and SSLs that extended to MSS and MSI-H CRCs, respectively, reflecting their distinct origins and trajectories. ADs arose from WNT pathway dysregulation in stem cells, which aberrantly expanded and expressed a Hippo and ASCL2 regenerative program. In marked contrast, SSLs were depleted of stem cell-like populations and instead exhibited a program of gastric metaplasia in the setting of elevated cytotoxic inflammation. Using subtype-specific gene regulatory networks and shared genetic variant analysis, we implicated serrated polyps, including some HPs conventionally considered benign, as arising from a metaplastic program in committed absorptive cells. ADs and SSLs displayed distinct patterns of immune cell infiltration that may influence their natural history. Our multi-omic atlas provides novel insights into the malignant potential of colorectal polyps and serves as a framework for precision surveillance and prevention of sporadic CRC.

Recent studies have shown that disease-susceptibility variants frequently lie in cell-type-specific enhancer elements. To identify, interpret, and prioritize such risk variants, we must identify the enhancers active in disease-relevant cell types, their upstream transcription factor (TF) binding, and their downstream target genes. To address this need, we built HACER (http://bioinfo.vanderbilt.edu/AE/HACER/), an atlas of Human ACtive Enhancers to interpret Regulatory variants. The HACER atlas catalogues and annotates in-vivo transcribed cell-type-specific enhancers, as well as placing enhancers within transcriptional regulatory networks by integrating ENCODE TF ChIP-Seq and predicted/validated chromatin interaction data. We demonstrate the utility of HACER in (i) offering a mechanistic hypothesis to explain the association of SNP rs614367 with ER-positive breast cancer risk, (ii) exploring tumor-specific enhancers in selective MYC dysregulation and (iii) prioritizing/annotating non-coding regulatory regions targeting CCND1. HACER provides a valuable resource for studies of GWAS, non-coding variants, and enhancer-mediated regulation.

Introduction Overexpression of the mesenchymal-epithelial transition (MET) receptor, a receptor tyrosine kinase, can propel the growth of cancer cells and portends poor prognoses for patients with lung cancer. Evaluation of MET by immunohistochemistry is challenging, with MET protein overexpression varying from 20% to 80% between lung cancer cohorts. Clinical trials using MET protein expression to select patients have also reported a wide range of positivity rates and outcomes. Materials and methods To overcome this variability, the Lung Cancer Mutation Consortium Pathologist Panel endeavored to standardize the evaluation of MET protein expression with "Round Robin" conferences. This panel used randomly selected Aperio-scanned formalin-fixed paraffin-embedded lung cancer specimens stained by MET immunohistochemistry for the Lung Cancer Mutation Consortium 2.0 study (N=838). Seven pathologists in separate laboratories scored images of 5 initial cases and 2 subsequent rounds of 39 cases. The pathologists' scores were compared for consistency using the intraclass correlation coefficient. Issues affecting reproducibility were discussed in Round Robin conferences between rounds, and steps were taken to improve scoring consistency, such as sharing reference materials and example images. Results The overall group intraclass correlation coefficient comparing the consistency of scoring improved from 0.50 (95% confidence interval, 0.37-0.64) for the first scoring round to 0.74 (95% confidence interval, 0.64-0.83) for the second round. Discussion We found that the consistency of MET immunohistochemistry scoring is improved by continuous training and communication between pathologists.

Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC.

Introduction MNNG HOS Transforming gene (MET) amplification and MET exon 14 (METex14) alterations in lung cancers affect sensitivity to MET proto-oncogene, receptor tyrosine kinase (MET [also known by the alias hepatocyte growth factor receptor]) inhibitors. Fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and immunohistochemistry (IHC) have been used to evaluate MET dependency. Here, we have determined the association of MET IHC with METex14 mutations and MET amplification. Methods We collected data on a tri-institutional cohort from the Lung Cancer Mutation Consortium. All patients had metastatic lung adenocarcinomas and no prior targeted therapies. MET IHC positivity was defined by an H-score of 200 or higher using SP44 antibody. MET amplification was defined by copy number fold change of 1.8x or more with use of NGS or a MET-to–centromere of chromosome 7 ratio greater than 2.2 with use of FISH. Results We tested tissue from 181 patients for MET IHC, MET amplification, and METex14 mutations. Overall, 71 of 181 patients (39%) were MET IHC–positive, three of 181 (2%) were MET-amplified, and two of 181 (1%) harbored METex14 mutations. Of the MET-amplified cases, two were FISH positive with MET-to–centromere of chromosome 7 ratios of 3.1 and 3.3, one case was NGS positive with a fold change of 4.4x, and one of the three cases was MET IHC–positive. Of the 71 IHC-positive cases, one (1%) was MET-amplified and two (3%) were METex14-mutated. Of the MET IHC–negative cases, two of 110 (2%) were MET-amplified. Conclusions In this study, nearly all MET IHC–positive cases were negative for MET amplification or METex14 mutations. MET IHC can also miss patients with MET amplification. The limited number of MET-amplified cases in this cohort makes it challenging to demonstrate an association between MET IHC and MET amplification. Nevertheless, IHC appears to be an inefficient screen for these genomic changes. MET amplification or METex14 mutations can best be detected by FISH and a multiplex NGS panel.

2578 Background: Combination strategies to improve the efficacy of single agent immune checkpoint inhibitors (ICIs) are increasingly being explored, with one strategy being the addition of vascular endothelial growth factor (VEGF) inhibition. Having shown promise in the treatment of hepatocellular carcinoma and renal cell carcinoma, NCT03583086 is a multi-institutional, phase I/II study of combination vorolanib and nivolumab in both naïve and refractory thoracic tumors that progressed on at least one prior line of platinum-based chemotherapy. Though structurally similar to the tyrosine kinase inhibitor, sunitinib, vorolanib was designed to have a more favorable safety profile with comparable efficacy. Here we present safety data across all cohorts and interim efficacy analyses of the SCLC and NSCLC with primary resistance to ICI-based therapy cohorts, both of which have now completed enrolment. Methods: The maximum tolerated dose determined in phase I was vorolanib 200mg daily and nivolumab 240mg q2 weeks. Phase II uses a two-stage MinMax design across 5 cohorts with objective response rate (ORR) as the primary endpoint: NSCLC (ICI naïve, primary refractory, and acquired resistance), SCLC, and thymic carcinoma. Primary refractory is defined as radiographic progression of disease within 12 weeks of ICI initiation. Results: As of January 2021, 75 patients have been enrolled across all cohorts. Stage 1 of the SCLC and primary refractory NSCLC cohorts have completed accrual at 18 and 15 patients, respectively. In the SCLC cohort, disease-control rate (DCR) was 7% and no objective responses were achieved among 14 evaluable patients. In the primary refractory NSCLC cohort, DCR was 57% and ORR 7% (1 partial response) among 14 evaluable patients. A total of 140 treatment-related adverse events (TRAEs) have been reported, 13 (9%) were grade 3 and there were no grade 4/5 events. Fatigue (9%), nausea (6%), diarrhea (6%), ALT elevation (5%), and AST elevation (5%) were the most common all grade TRAEs. The most common grade 3 TRAEs were ALT elevation and hypertension. Conclusions: This therapeutic strategy of nivolumab plus vorolanib appears to be a well-tolerated combination with a manageable safety profile. Adding VEGF inhibition may offer additional disease control in the setting of NSCLC with primary resistance to ICIs, but neither the SCLC or primary refractory NSCLC cohorts achieved the pre-determined target number of objective responses for progression to stage 2 of the study. Enrolment in the other 3 cohorts as well as exploratory correlatives are ongoing. Clinical trial information: NCT03583086.

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 2015. © 2015 American Cancer Society.

e21019 Background: VEGF inhibition is suggested to enhance innate T cell function, activate dendritic cells, block recruitment of regulatory T cells, and decrease myeloid-derived suppressor cells. Vorolanib is a tyrosine kinase inhibitor that is structurally similar to sunitinib but designed to improve safety without compromising efficacy. Response to checkpoint inhibitors in patients with thoracic tumors is limited, thus we designed this multi-institutional, phase I/II study (NCT03583086) to explore safety and efficacy of combining vorolanib and nivolumab. Here we present updated results in the NSCLC, thymic, and SCLC cohorts, including patients previously treated with single agent IO. Methods: The Phase I maximum tolerated dose was 200 mg vorolanib and 240 mg nivolumab q2w. Phase II is ongoing and uses a two-stage MinMax design to assess the objective response rate (RR) in SCLC, thymic carcinoma, and three NSCLC cohorts: 1) IO naïve; 2) primary refractory, defined as radiographic progression < 12 weeks of starting IO; and 3) acquired resistance, defined as achieving at least stable disease ≥12 weeks to IO followed by progression. Results: As of December 2019, 37 patients had enrolled, 38% female, 11% never smokers, median age 66. The disease control rate (DCR) across all cohorts is 65% (20/31 evaluable patients) and the RR is 13% (4/31). In the NSCLC cohort, the overall RR is 14% (3/21); the RR is 33% (2/6) in IO naïve patients, including 2 on therapy > 17 months. RR in the NSCLC patients with acquired resistance is 14% (1/7) with an 86% (6/7) DCR. No responses in the primary refractory cohort but the DCR is 50% (4/8). DCR in the SCLC and thymic cohorts is 40% (2/5) and 50% (2/4), respectively; 1 thymic patient had a partial response with a complete response in target lesions. Exploratory correlatives, including mass cytometry analysis and single cell gene expression, are being performed in order to understand changes in macrophages and T cell activation markers to differentiate the underlying biology of the tumor and the microenvironment between responders and nonresponders. Conclusions: The addition of vorolanib nearly doubled the RR in the IO naïve NSCLC patients compared to historical data with single agent nivolumab. Additionally, 67% of NSCLC patients with prior IO achieved at least stable disease, 1 patient with acquired resistance had a response. Correlatives that may help define biomarkers of response to therapy will be presented among different cohorts of patients. Clinical trial information: NCT03583086 .

Importance Surgical treatment comparisons in rare diseases are difficult secondary to the geographic distribution of patients. Fortunately, emerging technologies offer promise to reduce these barriers for research. Objective To prospectively compare the outcomes of the 3 most common surgical approaches for idiopathic subglottic stenosis (iSGS), a rare airway disease. Design, Setting, and Participants In this international, prospective, 3-year multicenter cohort study, 810 patients with untreated, newly diagnosed, or previously treated iSGS were enrolled after undergoing a surgical procedure (endoscopic dilation [ED], endoscopic resection with adjuvant medical therapy [ERMT], or cricotracheal resection [CTR]). Patients were recruited from clinician practices in the North American Airway Collaborative and an online iSGS community on Facebook. Main Outcomes and Measures The primary end point was days from initial surgical procedure to recurrent surgical procedure. Secondary end points included quality of life using the Clinical COPD (chronic obstructive pulmonary disease) Questionnaire (CCQ), Voice Handicap Index-10 (VHI-10), Eating Assessment Test-10 (EAT-10), the 12-Item Short-Form Version 2 (SF-12v2), and postoperative complications. Results Of 810 patients in this cohort, 798 (98.5%) were female and 787 (97.2%) were white, with a median age of 50 years (interquartile range, 43-58 years). Index surgical procedures were ED (n = 603; 74.4%), ERMT (n = 121; 14.9%), and CTR (n = 86; 10.6%). Overall, 185 patients (22.8%) had a recurrent surgical procedure during the 3-year study, but recurrence differed by modality (CTR, 1 patient [1.2%]; ERMT, 15 [12.4%]; and ED, 169 [28.0%]). Weighted, propensity score–matched, Cox proportional hazards regression models showed ED was inferior to ERMT (hazard ratio [HR], 3.16; 95% CI, 1.8-5.5). Among successfully treated patients without recurrence, those treated with CTR had the best CCQ (0.75 points) and SF-12v2 (54 points) scores and worst VHI-10 score (13 points) 360 days after enrollment as well as the greatest perioperative risk. Conclusions and Relevance In this cohort study of 810 patients with iSGS, endoscopic dilation, the most popular surgical approach for iSGS, was associated with a higher recurrence rate compared with other procedures. Cricotracheal resection offered the most durable results but showed the greatest perioperative risk and the worst long-term voice outcomes. Endoscopic resection with medical therapy was associated with better disease control compared with ED and had minimal association with vocal function. These results may be used to inform individual patient treatment decision-making.

IntroductionIdiopathic subglottic stenosis (iSGS) is an unexplained progressive obstruction of the upper airway that occurs almost exclusively in adult, Caucasian women. The disease is characterised by mucosal inflammation and localised fibrosis resulting in life-threatening blockage of the upper airway. Because of high recurrence rates, patients with iSGS will frequently require multiple procedures following their initial diagnosis. Both the disease and its therapies profoundly affect patients’ ability to breathe, communicate and swallow. A variety of treatments have been advanced to manage this condition. However, comparative data on effectiveness and side effects of the unique approaches have never been systematically evaluated. This study will create an international, multi-institutional prospective cohort of patients with iSGS. It will compare three surgical approaches to determine how well the most commonly used treatments in iSGS ‘work’ and what quality of life (QOL) trade-offs are associated with each approach.Methods and analysisA prospective pragmatic trial comparing the ‘Standard of Care’ for iSGS at multiple international institutions. Patients with a diagnosis of iSGS without clinical or laboratory evidence of vasculitis or a history of endotracheal intubation 2 years prior to symptom onset will be included in the study. Prospective evaluation of disease recurrence requiring operative intervention, validated patient-reported outcome (PRO) measures as well as patient-generated health data (mobile peak flow recordings and daily steps taken) will be longitudinally tracked for 36 months. The primary endpoint is treatment effectiveness defined as time to recurrent operative procedure. Secondary endpoints relate to treatment side effects and include PRO measures in voice, swallowing, breathing and global QOL as well as patient-generated health data.Ethics and disseminationThis protocol was approved by the local IRB Committee of the Vanderbilt University Medical Center in July 2015. The findings of the trial will be disseminated through peer-reviewed journals, national and international conference presentations and directly to patient with iSGS via social media-based support groups.Trial registration numberNCT02481817.

Purpose: Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas. Experimental Design: Sixteen U.S. institutions enrolled 1,367 patients with lung cancer in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and IHC. Results: The use of targeted therapies in patients with EGFR, ERBB2, or BRAF p.V600E mutations, ALK, ROS1, or RET rearrangements, or MET amplification was associated with a survival increment of 1.5 years compared with those with such mutations not receiving targeted therapy, and 1.0 year compared with those lacking a targetable driver. Importantly, 60 patients with a history of smoking derived similar survival benefit from targeted therapy for alterations in EGFR/ALK/ROS1, when compared with 75 never smokers with the same alterations. In addition, coexisting TP53 mutations were associated with shorter survival among patients with EGFR, ALK, or ROS1 alterations. Conclusion: Patients with adenocarcinoma of the lung and an oncogenic driver mutation treated with effective targeted therapy have a longer survival, regardless of prior smoking history. Molecular testing should be performed on all individuals with lung adenocarcinomas irrespective of clinical characteristics. Routine use of massively parallel sequencing enables detection of both targetable driver alterations and tumor suppressor gene and other alterations that have potential significance for therapy selection and as predictive markers for the efficacy of treatment. Clin Cancer Res; 24(5); 1038–47. ©2017 AACR.

Introduction Molecular genetic analyses of lung adenocarcinoma have recently become standard of care for treatment selection. The Lung Cancer Mutation Consortium was formed to enable collaborative multi-institutional analyses of 10 potential oncogenic driver mutations. Technical aspects of testing and clinicopathologic correlations are presented. Methods Mutation testing in at least one of the eight genes ( epidermal growth factor receptor [ EGFR ], KRAS, ERBB2 , AKT1, BRAF, MEK1, NRAS , and PIK3CA ) using SNaPshot, mass spectrometry, Sanger sequencing+/− peptide nucleic acid and/or sizing assays, along with anaplastic lymphoma kinase ( ALK ) and/or MET fluorescence in situ hybridization, were performed in six labs on 1007 patients from 14 institutions. Results In all, 1007 specimens had mutation analysis performed, and 733 specimens had all 10 genes analyzed. Mutation identification rates did not vary by analytic method. Biopsy and cytology specimens were inadequate for testing in 26% and 35% of cases compared with 5% of surgical specimens. Among the 1007 cases with mutation analysis performed, EGFR , KRAS, ALK , and ERBB2 alterations were detected in 22%, 25%, 8.5%, and 2.4% of cases, respectively. EGFR mutations were highly associated with female sex, Asian race, and never-smoking status; and less strongly associated with stage IV disease, presence of bone metastases, and absence of adrenal metastases. ALK rearrangements were strongly associated with never-smoking status and more weakly associated with presence of liver metastases. ERBB2 mutations were strongly associated with Asian race and never-smoking status. Two mutations were seen in 2.7% of samples, all but one of which involved one or more of PIK3CA, ALK , or MET . Conclusion Multi-institutional molecular analysis across multiple platforms, sample types, and institutions can yield consistent results and novel clinicopathological observations.

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).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.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.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.

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 .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.

The incidence of esophageal adenocarcinoma (EAC) has been increasing steadily over the past few decades,1 despite widespread recognition of the problem and a vast body of research. This disease is believed to originate in the broadest sense from Barrett’s Esophagus (BE), the recognized precursor of EAC, but current methods for surveillance have not been found to be effective in defining patients at risk. While a number of molecular and cellular mechanisms that underlie the transformation of BE to EAC have been outlined, their utility in understanding and preventing the progression of this cancer or in managing the intervention-resistant clones has not been demonstrated in a number of proposed models. As the rate of progression of BE to EAC is very low, estimated at

Mesenchymal-epithelial transition factor gene (MET) gene copy number gain may be a predictive biomarker for mesenchymal-epithelial transition factor (MET) inhibition in lung cancer, but the most appropriate method and criteria for defining MET positivity are uncertain.MET copy number was assessed by fluorescence in situ hybridization in lung adenocarcinoma. Positivity criteria included mean MET per cell values greater than 5 (low [≥5 to6], intermediate [≥6 to7], and high [≥7]) and mean MET-to-chromosome 7 centromere ratios (MET/CEP7) of at least 1.8 (low [≥1.8 to ≤2.2], intermediate [2.2 to5], and high [≥5]). Associated clinical and molecular characteristics were captured.Of 686 cases, 99 (14%) had a mean MET per cell value of 5 or greater, 52 of 1164 (4.5%) had a MET/CEP7 ratio of 1.8 or higher. Other oncogenic drivers (in EGFR, KRAS, anaplastic lymphoma receptor tyrosine kinase gene [ALK], erb-b2 receptor tyrosine kinase 2 gene [ERBB2], BRAF, NRAS, ROS1, or ret proto-oncogene [RET]) were detectable in 56% of the group with a mean MET per cell value of 5 or higher and 47% of the group with a MET/CEP7 ratio of 1.8 or higher, suggesting that many MET-positive cases are not truly MET addicted. The rates of concomitant drivers in the groups of patients in the low, indeterminate, and high categories of mean MET per cell were 32 of 52 (62%), 12 of 19 (63%), and 11 of 27 (41%) (p = 0.2), and the rates of concomitant drivers in the low, intermediate, and high categories of MET/CEP7 ratios were 15 of 29 (52%), 9 of 18 (50%), and 0 of 4 (0%), respectively (p = 0.04). A MET/CEP7 ratio of 1.8 or higher in the absence of other oncogenes was associated with a higher rate of adrenal metastases (p = 0.03) but not with never-smoking status.A fluorescence in situ hybridization MET/CEP7 ratio of 5 or higher defined a "MET-positive" group with no oncogenic overlap. As this method and criteria are also associated with the highest response rate to MET inhibition, it represents the clearest definition of a MET copy number gain-addicted state. However, a MET-associated phenotype may also exist across cases with a MET/CEP7 of 1.8 or higher when no other oncogene overlap occurs.

Numerous predictive factors for cutaneous melanoma metastases to sentinel lymph nodes have been identified; however, few have been found to be reproducibly significant. This study investigated the significance of factors for predicting regional nodal disease in cutaneous melanoma using a large multicenter database.Seventeen institutions submitted retrospective and prospective data on 3463 patients undergoing sentinel lymph node (SLN) biopsy for primary melanoma. Multiple demographic and tumor factors were analyzed for correlation with a positive SLN. Univariate and multivariate statistical analyses were performed.Of 3445 analyzable patients, 561 (16.3%) had a positive SLN biopsy. In multivariate analysis of 1526 patients with complete records for 10 variables, increasing Breslow thickness, lymphovascular invasion, ulceration, younger age, the absence of regression, and tumor location on the trunk were statistically significant predictors of a positive SLN.These results confirm the predictive significance of the well-established variables of Breslow thickness, ulceration, age, and location, as well as consistently reported but less well-established variables such as lymphovascular invasion. In addition, the presence of regression was associated with a lower likelihood of a positive SLN. Consideration of multiple tumor parameters should influence the decision for SLN biopsy and the estimation of nodal metastatic disease risk.

9021 Background: To better understand outcome heterogeneity in pts with KRAS mutant lung cancers, we analyzed the largest multi-institutional database of pts with metastatic KRAS mutant lung adenocarcinomas. Methods: We reviewed data of all pts who consented to LCMC between 2009-2015. Pts with known KRAS status were included in analyses. Mutation data along with co-mutations were obtained along with clinical outcomes. We evaluated baseline characteristics and association of KRAS data with overall survival (OS), calculated from date of distant metastasis to death, in a univariate and multivariable analyses. The median follow-up was 2.15 years (95% CI: 2.01-2.27). Results: 1655 (86%) of 1918 pts’ data were analyzed. Comparative characteristics are summarized in the Table. Among 450 (23%) pts with KRAS mutations: 58% female, 93% ever smokers, and median age 65 years. Main KRAS subtypes: G12C 39%, G12D and G12V were 18% each. Never smokers with KRAS mutation were more likely to have G12D subtypes (18%; p < 0.001). Pts with KRAS mutation, the median OS was 1.96 years, with 2-year OS rate of 49%. Co-mutations (1-16) were checked in all KRAS mutant pts. Co-mutations were rare (14 pts; 3%). KRAS co-mutations were associated with improved OS in multivariable analyses (HR 0.35; 95% CI: 0.13-0.97; p = 0.04), but not KRAS main subtypes / codons. Co-mutation STK-11 in particular (17 of 92 pts; 18%) was associated with poor OS in univariate (HR 2.16; 95% CI: 1.03-4.54; p = 0.04) and multivariable analyses (HR 2.31; 95% CI: 1.18-5.50; p = 0.02). Pts with KRAS mutations had a trend towards a shorter survival (median OS 1.96 vs. 2.22 years; p = 0.08) and a decreased 2-year OS when compared to KRAS wildtype [49% (95% CI: 44-54%) vs. 55% (95% CI: 52-58%)], respectively. Conclusions: KRAS mutation is a significant predictor of worse survival outcomes in pts with metastatic lung adenocarcinomas. The presence of STK-11 co-mutation was associated with especially poor OS. [Table: see text]

Background: Therapies for myelofibrosis (MF) are limited and most are palliative. The JAK1/2 inhibitor ruxolitinib reduces spleen size and MF-related symptoms and improves survival, but can be limited by dose-dependent anemia and thrombocytopenia. Moreover, nearly half of ruxolitinib responders relapse within 5 years. PI3Kd is highly expressed in MF patient samples, independent of ruxolitinib pre-exposure. In JAK2-mutated cell lines, inhibition of PI3K/AKT signaling reduced proliferation and clonogenic potential. The once daily, next generation PI3Kd inhibitor TGR-1202 inhibited PI3K/AKT signaling and led to apoptosis in leukemia and lymphoma cell lines and was well-tolerated in clinical studies, with a toxicity profile distinct from that of ruxolitinib and other PI3Kd inhibitors. We hypothesized that adding TGR-1202 to ruxolitinib could resensitize or augment the response of MF patients with lost or suboptimal response to single-agent ruxolitinib. Objective: To assess safety of TGR-1202 in combination with ruxolitinib in MF patients Secondary Objectives: Hematologic response, symptom assessment Methods: MF patients who had sub-optimal responses to ruxolitinib continued their highest tolerated dose of ruxolitinib without change for ≥ 8 weeks, and were assigned to escalating doses of TGR-1202 in a standard 3+3 algorithm. Adverse events (AEs) were graded by NCI-CTCAE v4.03. Efficacy was assessed according to IWG-MRT consensus response criteria. Symptoms were assessed by the MPN symptom assessment form total symptom score (TSS). All patients received Pneumocystis pneumonia prophylaxis after cycle 1. Results: Eleven MF patients were enrolled and received 400 mg (n=3), 800 mg (n=6), or 600 mg TGR-1202 (n=2) daily. Nine were evaluable for response. Median age was 66y, 73% were male. All had ECOG PS 0-1. Five patients had mutations in JAK2, 4 in CALR, and 3 in MPL; these were mutually exclusive with exception of 1 patient with CALR and MPL mutations (Table 1). Median number of cycles of TGR-1202 + ruxolitinib treatment was 5 (1-13). Grade 2 anemia was the most common AE (Table 2). Two patients had asymptomatic Grade 3 elevations in amylase and lipase that persisted after drug was held, meeting criteria for dose limiting toxicities (DLTs) in 2 separate cohorts (TGR-1202 800mg+ruxolitinib 15mg BID and TGR-1202 800mg+ruxolitinib 10mg BID). Both patients had peak plasma TGR-1202 concentrations 1.5-2x higher than the other patients receiving 800mg TGR-1202, although steady-state levels were equivalent. The maximum tolerated dose (MTD) of TGR-1202 in combination with ruxolitinib was not established. Two patients went off-study due to AEs, and 3 due to progressive disease. One of 9 evaluable patients achieved complete remission and 7 had stable disease. Seven of the 9 evaluable patients had improvement in hematologic parameters and 8 had reduced MF symptoms with a median 33% decrease in TSS (Fig. 1). Conclusions: TGR-1202 + ruxolitinib was well-tolerated. Pharmacokinetic data were consistent with single-agent TGR-1202 (unpublished data), indicating that ruxolitinib does not alter absorption or metabolism of TGR-1202. Grade 3 elevations in amylase and lipase were considered DLTs, per protocol. Although the clinical significance of these asymptomatic laboratory findings is not clear, the protocol was amended to further assay these labs and to exclude concomitant medications with the potential to increase amylase/lipase. Importantly, no grade ≥3 hepatotoxicity, colitis, or thrombocytopenia was seen and no MTD was found. Although only one patient achieved CR, 89% demonstrated clinical benefit with the addition of TGR-1202 to ruxolitinib, supporting further exploration of this combination. Disclosures Strickland: Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Miskin:TG Therapeutics, Inc: Employment, Equity Ownership. Cavers:TG Therapeutics: Employment, Equity Ownership. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Michaelis:Pfizer: Equity Ownership; Cellgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria. Mesa:CTI: Research Funding; Promedior: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Savona:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Sunesis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

Purpose Indications for sentinel lymph node biopsy (SLNB) for thin melanoma are continually evolving. We present a large multi-institutional study to determine factors predictive of sentinel lymph node (SLN) metastasis in thin melanoma. Patients and Methods Retrospective review of the Sentinel Lymph Node Working Group database from 1994 to 2012 identified 1,250 patients who had an SLNB and thin melanomas (≤ 1 mm). Clinicopathologic characteristics were correlated with SLN status and outcome. Results SLN metastases were detected in 65 (5.2%) of 1,250 patients. On univariable analysis, rates of Breslow thickness ≥ 0.75 mm, Clark level ≥ IV, ulceration, and absence of regression differed significantly between positive and negative SLN groups (all P < .05). These four variables and mitotic rate were used in multivariable analysis, which demonstrated that Breslow thickness ≥ 0.75 mm (P = .03), Clark level ≥ IV (P = .05), and ulceration (P = .01) significantly predicted SLN metastasis with 6.3%, 7.0%, and 11.6% of the patients with these respective characteristics having SLN disease. Melanomas < 0.75 mm had positive SLN rates of < 5% regardless of Clark level and ulceration status. Median follow-up was 2.6 years. Melanoma-specific survival was significantly worse for patients with positive versus negative SLNs (P = .001). Conclusion Breslow thickness ≥ 0.75 mm, Clark level ≥ IV, and ulceration significantly predict SLN disease in thin melanoma. Most SLN metastases (86.2%) occur in melanomas ≥ 0.75 mm, with 6.3% of these patients having SLN disease, whereas in melanomas < 0.75 mm, SLN metastasis rates are < 5%. By using a 5% metastasis risk threshold, SLNB is indicated for melanomas ≥ 0.75 mm, but further study is needed to define indications for SLNB in melanomas < 0.75 mm.

Purpose: We sought to determine the frequency and clinical characteristics of patients with lung cancer harboring NRAS mutations. We used preclinical models to identify targeted therapies likely to be of benefit against NRAS-mutant lung cancer cells. Experimental Design: We reviewed clinical data from patients whose lung cancers were identified at six institutions or reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) to harbor NRAS mutations. Six NRAS-mutant cell lines were screened for sensitivity against inhibitors of multiple kinases (i.e., EGFR, ALK, MET, IGF-1R, BRAF, PI3K, and MEK). Results: Among 4,562 patients with lung cancers tested, NRAS mutations were present in 30 (0.7%; 95% confidence interval, 0.45%–0.94%); 28 of these had no other driver mutations. 83% had adenocarcinoma histology with no significant differences in gender. While 95% of patients were former or current smokers, smoking-related G:C>T:A transversions were significantly less frequent in NRAS-mutated lung tumors than KRAS-mutant non–small cell lung cancer [NSCLC; NRAS: 13% (4/30), KRAS: 66% (1772/2733), P < 0.00000001]. Five of 6 NRAS-mutant cell lines were sensitive to the MEK inhibitors, selumetinib and trametinib, but not to other inhibitors tested. Conclusion: NRAS mutations define a distinct subset of lung cancers (∼1%) with potential sensitivity to MEK inhibitors. Although NRAS mutations are more common in current/former smokers, the types of mutations are not those classically associated with smoking. Clin Cancer Res; 19(9); 2584–91. ©2013 AACR.

Cell cycle control in the fission yeast Schizosaccharomyces pombe involves interplay amongst a number of regulatory molecules, including the cdc2, cdc13, cdc25, wee1, and mik1 gene products. Cdc2, Cdc13, and Cdc25 act as positive regulators of cell cycle progression at the G2/M boundary, while Wee1 and Miky1 play a negative regulatory role. Here, we have screened for suppressors of the lethal premature entry into mitosis, termed mitotic catastrophe, which results from simultaneous loss of function of both Wee1 and Mik1. Through such a screen, we hoped to identify additional components of the cell cycle regulatory network, and/or G2/M-specific substrates of Cdc2. Although we did not identify such molecules, we isolated a number of alleles of both cdc2 and cdc13, including a novel wee allele of cdc2, cdc2-5w. Here, we characterize cdc2-5w and two alleles of cdc13, which have implications for the understanding of details of the interactions amongst Cdc2, Cdc13, and Wee1.

11510Background: EGFR mutation (MT) and ALK rearrangement (RR) testing is standard of care for advanced stage LUCA due to effective targeted therapies. Testing for additional driver alterations in ...

8094 Background: LCMC 1.0 demonstrated that multiplexed genomic platforms can assay 10 oncogenic drivers at diagnosis in tumor specimens from patients with lung adenocarcinomas and this information...

Non–small-cell lung cancer (NSCLC) is the secondmost common cancer diagnosed in the United States and the leading cause of cancer-related mortality, with an estimated 221 200 newcases and 158 040deaths anticipated in2015.1Despite advances in treatment, 5-year survival remains lowat 16.8% across all patients, and only 2% in patients with stage 4 disease, indicating a need for novel therapies that affect survival. The identification of driver mutations in lung adenocarcinoma has dramatically changed the therapeutic landscape and improved treatment options for patients with advanced-stage disease, specifically, targeted options for patients with tumors that harbor mutations in the epidermal growth factor receptor (EGFR) gene or rearrangement in the anaplastic lymphoma kinase (ALK) gene. Whereas some targetedagentshavebeenapprovedon thebasisofdata fromrandomized phase 3 trials, theALK inhibitors crizotinib and ceritinibwere grantedpreliminary approval by theFoodandDrug Administration on the basis of early phase 1 data2,3; efficacy of crizotinibwas latervalidated in randomizedphase3 trials.4,5 In this issueof JAMAOncology, Lakdawallaandcolleagues6 discuss the incremental social value of providing early access to newNSCLC treatment on the basis of progression-free survival (PFS) alone. Their analysis finds that early access based on any PFS benefit produces an overall loss of greater than $170 000pernewly treatedpatient permonth,whereas granting access to drugs with PFS benefit between 1 and 3 months is more cost-effective. They also note that PFS benefit correlates with overall survival (OS) benefit in 71% of studies. Thisanalysis raises importantquestions regardingdrugapproval and treatment decisionmodels in the context of inherently limitedhealth care resources. Particularlywith regard to NSCLC, the analysis further raises questions of how to evaluate cost-benefit in the era of targeted therapy. In the Food and Drug Administration’s new drug approvalprocess, cost considerationsare taboo;approval isbased strictly on a thorough assessment of whether the protocolspecified primary end point wasmet, and PFS is increasingly common as a primary end point. At the same time, everincreasing costs of health care have long been the focus of nationwide attention and attempts at reform, begging the question, should such reform give greater weight to incremental social valueof access to treatment?Furthermore, givennet social value as a consideration, which parameters should be included in the value calculation? In the analysis presented by Lakdawalla and colleagues,6 indirect cost of treatment is considered, although not comprehensively; a more accurate picture may require a model with more detailed adjustment for net changes in overall treatment-related costs, such as differences inadverseevents,need for additional clinicvisits orhospitalizations due to therapy, and family member burden. Amore sophisticatedmodel, to consider treatment crossover as well as more detailed consideration of indirect costs, may be particularly important in the era of targeted therapy, given that (1) when purchase price alone is considered, tarRelated article page 196 Research Original Investigation Modeling Access DecisionsWith Surrogate End Points

Importance Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials. Objectives To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival. Design, Setting, and Participants From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival. Interventions Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies. Main Outcomes and Measures Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival. Results From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR , 122 (17%); ALK rearrangements, 57 (8%); other EGFR , 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2 ), 19 (3%); BRAF , 16 (2%); PIK3CA , 6 ( MET amplification, 5 ( NRAS , 5 ( MEK1 , 1 ( AKT1 , 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range [IQR], 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who did not receive genotype-directed therapy (propensity score–adjusted hazard ratio, 0.69 [95% CI, 0.53-0.9], P = .006). Conclusions and Relevance Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival. Trial Registration clinicaltrials.gov Identifier:NCT01014286.

8060 Background: A variety of somatic mutations and gene rearrangements have been described in patients with lung adenocarcinoma. The Lung Cancer Mutation Consortium (LCMC) tested for the presence ...

In a screen for second site mutations capable of reducing the restrictive temperature of the fission yeast mutant cdc2-D217N, we have isolated a novel temperature-sensitive mutant, dim1-35. When shifted to restrictive temperature, dim1-35 mutant cells arrest before entry into mitosis or proceed through mitosis in the absence of nuclear division, demonstrating an uncoupling of proper DNA segregation from other cell cycle events. Deletion of dim1 from the Schizosaccharomyces pombe genome produces a lethal G2 arrest phenotype. Lethality is rescued by overexpression of the mouse dim1 homolog, mdim1. Likewise, deletion of the Saccharomyces cerevisiae dim1 homolog, CDH1, is lethal. Both mdim1 and dim1+ are capable of rescuing lethality in the cdh1::HIS3 mutant. Although dim1-35 displays no striking genetic interactions with various other G2/M or mitotic mutants, dim1-35 cells incubated at restrictive temperature arrest with low histone H1 kinase activity. Morevoer, dim1-35 displays sensitivity to the microtubule destabilizing drug, thiabendazole (TBZ). We conclude that Dim1p plays a fundamental, evolutionarily conserved role as a protein essential for entry into mitosis as well as for chromosome segregation during mitosis. Based on TBZ sensitivity and failed chromosome segregation in dim1-35, we further speculate that Dim1p may play a role in mitotic spindle formation and/or function.

8019 Background: The detection of driver mutations in the EGFR and ALK genes and targeted therapy has transformed treatment of lung cancer. The LCMC was established in 2009 to assay lung adenocarcinomas for driver genomic alterations in 10 genes and to study and treat patients by their molecular subtypes. Methods: The 14-member LCMC enrolled patients with metastatic adenocarcinoma of the lung and tested their tumors in CLIA laboratories for KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, MEK1, and NRAS mutations using multiplexed assays, and for ALK rearrangements and MET amplifications using fluorescence in situ hybridization (FISH). Results: 1,102 eligible patients were enrolled; 1,007 underwent testing for at least one genomic alteration with 733 undergoing testing for all 10 genes. 600 patients were women (60%) with a median age of 63; 341 were never smokers (34%) and 589 former smokers (58%). A driver alteration was detected in 622 (62%) of the 1,007 with any genotyping, and in 465 (63%) of the 733 fully genotyped cases. Among the tumors with full genotyping, drivers were found as follows: KRAS 182 (25%), sensitizing EGFR 107 (15%), ALK rearrangements 56 (8%), other EGFR 43 (6%), two genes 29 (4%), BRAF 16 (2%), HER2 15 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (

8085 Background: Somatic T790M mutations are detected in 62% of EGFR-mutant lung cancers with acquired resistance to EGFR TKIs, and have rarely been identified in the tumor at diagnosis and/or within the germline DNA. Multiplexed genotyping by the LCMC permitted us to evaluate the incidence of T790M at diagnosis, co-mutations, and survival of patients with this driver. Methods: The 14 member LCMC prospectively tested tumors of patients with lung adenocarcinomas in CLIA laboratories for mutations in EGFR and 9 other genes. We assayed T790Mby Sequenom, Snapshot, or Sanger sequencing. Germline DNA was not collected. Results: In the 987 tumors tested, 209 had mutations in EGFR alone: 25 T790M (2.5%) , 157 sensitizing EGFR mutations (exon 19 del, L858R, L861Q, G719X) without T790M, 23 exon 20 ins, 4 other mutations. 13 additional cases harbored mutations in EGFR and another driver; 2 with both T790M and PIK3CA. In each of the 27 EGFR-mutant cases with T790M, a coincident EGFR mutation was detected (18 exon 19 del, 9 L858R, 1 exon 20 ins). EGFR T790M was found more often than EGFR exon 20 ins or mutations in HER2 (1.9%), BRAF (1.6%), or PIK3CA (0.7%). Patients with T790M: 77% women, 81% never smokers, median age 55 (range 38-79), stage IV at diagnosis 81%, PS 0/1 100%. Characteristics did not differ from persons with sensitizing mutations and no T790M. Median survival from the diagnosis of metastatic disease for patients with EGFR-mutant lung cancers was 3.5 yrs with T790Mand 4.0 yrs without (p=0.926). Conclusions: T790M mutations were detected at diagnosis in 3% of adenocarcinomas and always coincident with another EGFR mutation. Cases with T790M represent 13% of all cases of EGFR- mutant lung cancer. Characteristics and survival for patients with EGFR- mutant lung cancers with T790M at diagnosis were similar to individuals with sensitizing mutations and no T790M. The observed incidence of T790M exceeded that of the other actionable targets HER2, BRAF, and PIK3CA. Trials should study this unique population identified by routine multiplexed genotyping. Supported by 1RC2CA148394-01 and the National Lung Cancer Partnership. Clinical trial information: NCT01014286.

Here we discuss members of a new family of serine/threonine protein kinases with a likely role in cell cycle control. These kinases are referred to as polo-like kinases, after the prototypic founding member of the family, the polo gene product of Drosophila melanogaster. The polo kinase was originally identified in mutants that display abnormal mitotic spindle organization. Subsequently, potential homologues of Drosophila polo have been identified in yeasts (Cdc5p in Saccharomyces cerevisiae; plo1+ in Schizosaccharmoyces pombe) and in mammals (polo-like kinase 1; Plk1). Genetic and biochemical studies suggest that polo, Cdc5p and plo1+ may be required for mitotic spindle organization and, possibly, for cytokinesis. Likewise, the patterns of expression, activity and subcellular localization of Plk1 strongly suggest that this mammalian kinase functions also during mitosis, possibly in spindle assembly and function. In addition to Plk1, however, more distantly related members of the polo-like kinase family have been identified in mammalian cells, and the available data are consistent with the idea that some of these may act earlier in the cell cycle, possibly during G1. If this hypothesis is correct, different members of the polo-like kinase family would act at several points during the cell cycle, reminiscent of the behaviour of Cdk/cyclin complexes.

The highly conserved Cdc2 serine/threonine kinase plays a central role in cell cycle progression. Although Cdc2 levels remain constant throughout the cell cycle, Cdc2 kinase activity peaks at the G2/M boundary, in order to drive entry into mitosis. In the model organism Schizosaccharotnysces pombe, potentially active Cdc2/Cdc13 kinase complex accumulates throughout the S and G2 phases of the cell cycle. This complex, however, is maintained in an inactive state by Weel/Mik1-mediated phosphorylation at Y15 (and, possibly, T14). At the G2/M boundary, the Cdc25 protein phosphatase is activated to dephosphorylate the Cdc2/Cdcl3 complex, resulting in abrupt activation of Cdc2 kinase activity and entry into mitosis.

7589 Background: The Lung Cancer Mutation Consortium (LCMC) consisting of 14 US Cancer Centers was established to evaluate a panel of molecular mutations in advanced lung adenocarcinoma. ALK gene fusions and MET gene amplification were assessed by FISH in CLIA certified laboratories. Methods: Molecular tests were performed in stage IIIB or IV lung adenocarcinoma. To date, FISH assays have been completed in 901 patients for ALK (ALK break-apart, Abbott Molecular) and in 654 patients for MET (in house/Abbott Molecular reagents). ALK+ specimens were defined by split 3’ALK/5’ALK signals (gap >2 signal diameters) or single 3’ALK signals in >15% of tumor cells. MET gene amplification (MET+) was defined by ratio mean MET/mean CEP7 ≥2. Results: The ALK+ patient subset (N=75, 8.3%) compared to the ALK- had significantly lower age at diagnosis (52 vs. 60, p