Citations

Context.— Autopsy rates have decreased dramatically despite providing important clinical information to medical practices and social benefits to decedents' families. Objective.— To assess the impact of an institutional Office of Decedent Affairs (ODA), a direct communication link between pathology and decedents' families, on hospital autopsy consent rates, autopsy-related communication, practitioner views, and next-of-kin experiences. Design.— A before and after study involving all hospital decedents whose deaths did not fall within the jurisdiction of the medical examiner's office from 2013 to 2018. A pathology-run ODA launched in May 2016 to guide next-of-kin through the hospital death process (including autopsy-related decisions) and serve as the next-of-kin's contact for any subsequent autopsy-related communication. Critical care and hematology/oncology practitioners were assessed for their autopsy-related views and decedents' next-of-kin were assessed for their autopsy-related experiences. Autopsy consent rates for non–medical examiner hospital deaths, autopsy-related communication rates, practitioner views on the role and value of autopsy, and next-of-kin autopsy experiences and decisions factors were compared prior to and after ODA launch. Results.— Autopsy consent rates significantly increased from 13.2% to 17.3% (480 of 3647 deaths versus 544 of 3148 deaths; P < .001). There were significant increases in the rate of autopsy-related discussions and bereavement counseling provided to decedents' families. Practitioner views on the positive role of autopsy for any hospital death and those with advanced stage cancer also significantly increased. Next-of-kin indicated more consistent autopsy-related discussions with the potential benefits of autopsy discussed becoming key decision factors. Conclusions.— An ODA improves hospital autopsy consent rates, autopsy-related communication, providers' autopsy-related views, and next-of-kins autopsy experiences.

e19013 Background: Mutation profiling to assess for potentially druggable mutations in NSCLC is being offered at an increasing number of cancer centers throughout North America and internationally. Although data continue to accumulate for the potential value of mutation testing in designing chemotherapeutic regimens, the treatment impact of obtaining information beyond assessment of EGFR and ALK status remains unclear. How best to obtain and clinically utilize these data, including information from exome and whole genome sequencing, also remains unclear. Methods: Patients were reviewed electronically in a multidisciplinary conference regarding indications for testing and results of mutation profiling from various methods, including the mass-spec based LungCarta test, targeted NexGen sequencing, exome, and whole genome sequencing. Outcomes of the multidisciplinary review were communicated back to treating physicians. Results: Mutation testing was performed on 200 patients using a variety of approaches. The majority (>150) were surgically resected stage I and II tumors. Mutations in at least 1 major cancer driver gene, including EGFR, KRAS, MET, BRAF and PIK3CA, were found in 47% of all patients tested. EGFR mutations were present in 14.8% of patients tested, KRAS 21.3%, BRAF 2.6%, PIK3CA 3.2%, and MET 4.5%. A total of 8 patients underwent either exome or whole genome sequencing. A limited number of patients (<10) had mutation results that impacted treatment decisions from this cohort. Conclusions: Mutation profiling can influence treatment decisions in NSCLC, but at a low frequency. The role of exome and or whole genome sequencing for patients with NSCLC is evolving and remains undefined.

11119 Background: Evaluation of prognostic factors in carcinoid tumors of the lung is limited due to the rarity of disease. This study assessed Ki-67 expression and other clinical variables as prognostic factors in 262 patients. Methods: A systematic search of Mayo Clinic lung cancer epidemiology and tumor registry databases from 1997 to 2009 identified 449 consecutive patients, with 262 having available tissue blocks [40 atypical carcinoids (AC) and 222 typical carcinoids (TC)]. Clinical data were collected by chart review. Tissue blocks were reviewed by 1/3 pathologists using WHO criteria. Tumors were tested for the Ki-67 index using digital image analysis (tumor tracing) by two operators. The association and predictive value of the factors with recurrence-free and overall survival (RFS and OS) were explored using univariable Cox proportional Hazards model and concordance (c) index. Results: Age, stage, smoking history, lymph node (LN) involvement and Ki-67 index were significant prognostic factors for RFS and OS. Median follow-up on alive-patients is 5 years (range: 0.006-5). Median percentage of Ki-67 index of AC and TC were 1.61% and 0.56% (P<0.0001), respectively. Patients with Ki-67 ≥ 1% had significantly worse RFS (HR=3.69, P<0.0001) and OS (HR=3.69, P=0.0007) compared with Ki-67 < 1% group. The c-index of Ki-67 (0.65) was comparable to the pathologic distinction between AC and TC (0.62 for original diagnosis and 0.63 for central-reviewed diagnosis). Conclusions: Ki-67 index cutoff value of 1% is a valuable prognostic biomarker for pulmonary carcinoids based on this large cohort. Our data also provide strong evidence for clinical variables such as age, stage, smoking history, and LN involvement as clinical prognostic factors in pulmonary carcinoids. A prognostic calculator incorporating Ki-67 and clinical variables is under development. [Table: see text]

7568 Background: The molecular events in the initiation and progression of invasive lung adenocarcinoma remain poorly characterized. These tumors are thought to develop through an adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), invasive adenocarcinoma (AD) sequence. The goal of our study was to assess lineage relationships between in situ and invasive components within adenocarcinomas with prominent lepidic growth patterns. Methods: Frozen tissue from fourteen lung adenocarcinomas with mixtures of AD together with an adjacent in situ component (AIS), varying in ratio between 40 to 80%, were selected from our Lung Specimen Registry. Laser capture microdissection (LCM) of each component was performed separately for each tumor. Genomic DNA was isolated using a direct in situ whole genome amplification (WGA) methodology, and Next Generation Sequencing performed using an Illumina Mate Pair (MP) library protocol. MP sequence reads were mapped to the human genome and primers spanning the fusion junctions were used in validation PCRs. Results: Genomic break points identical and unique to a specific patient were identified between the AIS and AD components in 13 (of 14) cases. The total number of events per case ranged from 4-215, and the number of identical events shared between the AIS and AD components ranged from 30 to 90%. Recurrent genomic breakpoints between cases were also observed, with the 2 most common involving 8q24.3 in 5 cases and FAM19A2 on chromosome 12 in 4 cases. PCR validation of selected genomic alterations confirmed the genomic break points identified from sequencing in both the AIS and AD in all cases. Interestingly, we also observed a limited number of genomic alterations present in a zonal distribution of surrounding normal lung around the tumor mass. Conclusions: Our study demonstrates unique chromosomal alterations present in both the AIS and AD components of individual lung tumors with features of lepidic growth. These data provide evidence for lineage relationship and clonal relatedness between the two components, and provide genomic evidence for a model of stepwise progression from AIS to invasive AD in this subset of lung adenocarcinomas.

7509 Background: NTX-010 is a naturally occurring replication-competent picornavirus with potent and selective tropism for SCLC tumor cells expressing neuroendocrine markers. A phase I study of NTX-010 showed evidence of antitumor activity in patients with SCLC. Methods: ES-SCLC patients (pts) with SD, PR or CR after at least 4 cycles of platinum-based chemotherapy were pre-registered to confirm diagnosis of SCLC with > 1 neuroendocrine marker by a central pathology review. Eligible pts were.randomized 1:1 to placebo (B) or NTX-010 (A). NTX-010 or placebo was administered intravenously as a 1-hour infusion in 100 mL normal saline as a single dose of 1 x1011vp/kg. Viral studies to determine distribution, clearance of the virus and the presence of neutralizing antibodies were done. The primary goal of this trial was to compare the progression-free survival (PFS) of arm A to B based on a sample size of 45 patients per arm to detect an improvement in median PFS from 3 to 5 months (m). A pre-planned interim futility analysis was done after 40 PFS events, and reported here. Results: The trial is permanently closed to accrual. One-hundred and twenty pts were pre-registered, of whom 58 were randomized. Baseline age, gender, ECOG performance status, and histology were balanced between arms. Median age was 63 (range: 44 - 82). 31% of pts had a PS of 0 and 69% of 1. Grade 4 adverse events were seen in 3 (12.5%) patients in arm A and none in arm B. Based on the interim futility analysis, PFS was 1.7 m (95% CI: 1.3-3.1) for arm A and 1.7 m (95% CI: 1.4-4.3) for arm B. Pts with viral RNA at 7 (7 pts) and 14 (6 pts) days had worse PFS compared to those with no detectable levels within arm A (1.0 vs 1.6 m, p=0.02; 0.9 vs. 1.2 m, p=0.06). Median follow-up in pts is 6.1 m. The 3-month OS estimates are 83% (95% CI: 69%-100%) and 85% (70%-100%) for arms A and B respectively. Conclusions: This phase II study showed no benefit in PFS for ES-SCLC patients receiving NTX-010. Pts with detectable virus at 7 and 14 days had worse PFS. Clinical trial information: NCT01017601.

1071 Background: N0234 is a phase II trial of gemcitabine at 1000 mg/m2 days 1 and 8 of a 21 day cycle and erlotinib at 150 mg daily in patients with previous therapy with either an anthracycline or a taxane for MBC. A partial response (PR) rate of 17% has been reported (ASCO 2005). Recent information suggests that over-expression of the EGFR pathway is frequent in patients with TNeg MBC. Methods: Tissue and serum were obtained for translational studies of ER, PR, HER2, and proteins related to EGFR pathway on tissue using immunohistochemistry; CK19, mammoglobin, and TTK on circulating tumor cells (CTCs). Markers were evaluated centrally, blinded to patient outcome. Complete data were available in 57 of 59 eligible patients; 20/57 patients (pts) were TNeg. Results: A PR rate of 25% and clinical benefit rate (PR + stable disease > 6 months)of 25% was observed in TNeg pts as compared to a PR rate of 14% (p = 0.30) and clinical benefit rate 22% (p= 0.75) for non-TNeg pts. Median progression free survival 72 days vs 98 days (p=0.13) and overall survival 227 days vs 738 days (p<0.001) were shorter for TNeg pts. Translational results for the EGFR pathway proteins and CTC analysis is forthcoming. Conclusions: The combination of gemcitabine and erlotinib appears to be as active in the non-TNeg and TNeg subset of patients on this trial. TNeg patients had an inferior clinical result, confirming the poor outcome seen in these patients. Data for the remaining biomarkers potentially predictive of activity will be presented. Supported by CA-25224, CA-37404. [Table: see text]

43 Background: Human leukocyte antigens (HLA) are crucial for cytotoxic T cell responses to cancer. Loss of HLA expression is a mechanism of tumor immune escape and may contribute to resistance to immunotherapy. In patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors we have observed discordant responses between brain metastases and extracranial disease and reported on differential PD-L1 expression and clonal T cell infiltration between paired primary lung lesions and brain metastases. In this project we sought to evaluate whether HLA expression was retained in metastatic NSCLC. Methods: Adult patients with paired primary NSCLC and brain metastases were identified from our institution’s tissue registry. HLA-A cell membrane expression on tumor cells was determined by immunohistochemistry with an anti-HLA-A antibody. Tumors with greater than 10% HLA expression were considered positive. Agreement statistics (κ) and Fisher’s exact test were used for analysis. Results: 51 patients with paired primary NSCLC and brain lesions were identified. The median HLA expression was 20% in the primary tumors (IQR 0-65%) and 10% in the brain metastases (IQR 5-40%). 27 primary tumors and 24 brain metastases were positive for HLA expression. There was disagreement in HLA positivity between paired lesions in 11 patients (22%, 95% CI 12-35%)(κ = 0.57, 95% CI 0.35-0.79)(p = 0.0001). There was no significant difference in the time between the primary tumor and brain metastasis resections in patients with HLA expression disagreement compared to those with HLA expression agreement. None of the patients received immune checkpoint inhibitors for treatment of these lesions. Conclusions: We found significant differences in HLA-A expression on tumor cells in nearly one quarter of paired primary lung cancers and brain metastases. Differences in HLA expression may help explain the discrepancies in response to immune checkpoint inhibitors at different sites of disease and warrants further study.

Objectives: The Ice Hockey Summit III provided updated scientific evidence on concussions in hockey to inform these 5 objectives: (1) describe sport related concussion (SRC) epidemiology; (2) classify prevention strategies; (3) define objective, diagnostic tests; (4) identify treatment; and (5) integrate science and clinical care into prioritized action plans and policy. Methods: Our action plan evolved from 40 scientific presentations. The 155 attendees (physicians, athletic trainers, physical therapists, nurses, neuropsychologists, scientists, engineers, coaches, and officials) voted to prioritize these action items in the final Summit session. Results: To (1) establish a national and international hockey database for SRCs at all levels; (2) eliminate body checking in Bantam youth hockey games; (3) expand a behavior modification program (Fair Play) to all youth hockey levels; (4) enforce game ejection penalties for fighting in Junior A and professional hockey leagues; (5) establish objective tests to diagnose concussion at point of care; and (6) mandate baseline testing to improve concussion diagnosis for all age groups. Conclusions: Expedient implementation of the Summit III prioritized action items is necessary to reduce the risk, severity, and consequences of concussion in the sport of ice hockey.

Abstract Background: Adenocarcinoma of the lung is the most common type of non-small cell lung cancer and is the subtype found in approximately 50% of all lung cancer cases. Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are thought to be precursor lesions of invasive disease. It has been hypothesized that there is a step-wise progression to lung adenocarcinoma, but little is known about genomic alterations in these precursor lesions. Methods: Genomic analysis including whole genome and exome sequencing, and SNP array analysis were performed on 9 AIS and 18 MIA pathologically confirmed samples to identify single nucleotide variants (SNVs), structural variations and copy number variations. Mutation significance and signature analysis were determined by MutSig and NMF analyses. Altered pathways were determined by Ingenuity variant effect pathway analysis. Results: The tumor mutation burden (TMB) for AIS and MIA ranged from 0.8 to 23.1 mut/Mb with a median of 3.0mut/Mb and a mean of 5.1mut/Mb. Highly mutated genes identified in AIS and MIA were RPL10, NBPF1, KRAS, GPR52, CAMK2A, ATOX1, STK11, TP53, MET and EGFR. Genes with recurrent mutations included SPTA1, USH2A, CACNA1E, EGFR, KRAS, MUC16, MUC17, OTOG, RYR2, COL20A1, CSMD3, RFX6 and XIRP2, which implicated pathways involving the EGFR-KRAS-TP53-MAPK axis. Somatic mutations were characterized by a C&gt;T, T&gt;C transitions and C&gt;A transversion signature. There were comparable structural variations in the AIS cases compared to MIA. Conclusion: In contrast to hypothesized models of tumor progression, AIS and MIA can harbor significant genomic alterations and tumor mutation burden, which suggests an intriguing concept of immunotherapeutic options for either treatment or chemoprevention. Deregulation of EGFR-KRAS-TP53-MAPK pathway indicates a role in early events of carcinogenesis. Citation Format: Michael K. Asiedu, Nanette R. Reed, Marie Christine Aubry, Anja C. Roden, Dennis A. Wigle. Genomic alterations in lung adenocarcinoma precursor lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 728.

Abstract Introduction: While most small cell lung cancer (SCLC) patients die within a few months, a sub-group of patients survive for many years. Factors determining long-term survivorship remain largely unknown. We present the first comprehensive comparative genomic and tumor microenvironment analyses of small cell lung cancer (SCLC) between patients with long term (LTS) and expected (EXS) survival times. Methods: We compared surgically resected tumors of 23 LTS (survival &gt; 4 years) and 18 EXS (survival ≤ 2 years). There were no differences in clinical variables including TNM staging and curative versus non-curative intend surgery between the groups. Gene expression profiling was performed by microarrays and tumor microenvironment analyses were by IHC of prominent immune related markers. Results: Immune related genes and pathways represented the majority of the differentially overexpressed genes in LTS compared to the EXS. The differences in the immunological tumor-microenvironment were confirmed by quantitative immuno-staining. Increased numbers of tumor infiltrating and associated lymphocytes were present throughout tumors of LTS. Several differentiating patterns of enhanced anti-tumor immunity were identified. While some areas of LTS tumors also harbored higher numbers of suppressive immune cells (monocytes, regulatory lymphocytes, and macrophages), ratios of these suppressive cells to CD3+ lymphocytes were generally lower in LTS tumors indicating a more tumor suppressive microenvironment. Conclusions: Our data demonstrate that long-term survivorship of SCLC patients is strongly influenced by the presence of anti-tumor immune cells in the tumor microenvironment. Characterization of the anti-tumor immune responses may identify opportunities for individualized immunotherapies for SCLC. Citation Format: Farhad Kosari, Prasuna Muppa, Simone Terra, Anurag Sharma, Aaron Mansfield, Marie Christine Aubry, Nafiseh Janaki, Aqsa Nasir, Tobias Peikert. Anti-tumor immunity is a key determinant of small cell lung cancer survivorship [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4577.