1559 Background: Low-dose computer tomography (LDCT) screening for individuals at high risk for developing lung cancer has led to earlier detection of suspicious nodules, rapid diagnosis, and a reduction in deaths due to lung cancer. Unfortunately, the majority of lung cancers are diagnosed at advanced stages where most patients will still die from their disease. We conducted a pilot study to evaluate whether chest CT scans performed routinely during emergency room (ER) visits for general medical conditions could be used to identify patients with incidental lung cancers. Methods: NLP software was used to review all CT scans obtained in 3 community-based hospital ERs in Nashville, TN and Dallas, TX from October, 2014 through December, 2015. All CT radiology reports containing key words such as: ‘nodule’, ‘opacity’, or ‘mass’ were identified by NLP software and collected by nurse navigators. Corresponding images were then reviewed by cancer center multi-disciplinary tumor boards (MDTB). Repeat imaging or biopsy was recommended based on National Comprehensive Cancer Network (NCCN) guidelines. Results: NLP software identified 1212 CT scans for MDTB review, which led to 64 biopsies (5% of NLP-identified cases). There were 37 cancer diagnoses (3% of NLP-identified cases) -26 (70%) lung cancers and 11 (30%) other cancers (including: head and neck, lymphoma, sarcoma, hepatic, breast, pancreatic, and gynecologic). Among the diagnosed lung cancers, 7 (27%) were early stage (TNM I or II) and were surgically treated for potential cure. Conclusions: The use of NLP software to review CT scans performed during routine ER encounters led to early diagnosis and successful treatment of patients whose cancers might otherwise have gone undetected until potentially much later. This pilot study is expanding to include multiple community hospitals across additional markets.
e19022 Background: A NGS program was launched in 10/2012 at a single community practice in middle Tennessee. This program was designed to discover molecular alterations with proven/potential therapeutic significance for patients (pts) with advanced cancers. We report the lung cancer cohort findings. Methods: Pts with advanced lung cancer who were candidates for systemic treatment (ECOG ≤ 2) were consented for molecular profiling. Tissue specimens were tested by NGS with 1,000X coverage in a CLIA/CAP-certified lab. Oncogenic hotspot mutations in 35 genes were tested. Results were reported to the treating M.D. <12 days of tissue procurement. Results were stored in a database to enable correlation with clinical outcomes. Results: From 10/2012-12/2013, 1,040 tumor samples were profiled across tumor types; 238 (23%) were from pts with lung cancer (all histologies). 18% (43/238) of the lung samples were inadequate for testing. Of the 195 samples with sufficient tissue, 80 (41%) had >1 mutation: 55 (28%) with single mutations and 25 (13%) with multiple mutations. The mutation frequency by histology was: adenocarcinoma 59% (54/91 pts), squamous 22% (10/45 pts), large cell 67% (4/6 pts), and small-cell 18% (5/28 pts). The most frequent mutations were KRAS and EGFR (16% and 12%, respectively). Other alterations identified included: STK11 5%, MET 4%, BRAF 3%, RUNX1 2%, FGFR3 2%, MEK1 2%, PIK3CA 2%, and KIT 2%. 24% (47/195) of profiled pts were enrolled to clinical trials after receiving NGS results (25 without discoverable mutations, 22 with mutations.) Conclusions: NGS in lung cancer is feasible in the community. 41% of pts with lung cancer had a mutation, and a third of these pts had multiple alterations. As NGS panels expand and tissue procurement improves, genomic profiling in the community could potentially broaden treatment and clinical trial options for patients with lung cancer. KRAS and EGFR Mutations. Gene Codons tested Mutated codons # of mutations % of detected mutations KRAS 12, 13, 61, 146 12 29 91% 13 1 3% 61 2 6% EGFR 709-719, exon 19 deletion, 768-790, exon 20 insertion, 833, 858-861 727 1 4% 768 1 4% 769 2 8% 790 1 4% 796 1 4% 833 1 4% 834 1 4% 852 1 4% 858 5 19% Deletion/insertion 12 46%
e20658 Background: CPIs have led to improved survival and response duration for patients (pts) with NSCLC. Tumor PDL1 expression using IHC is a method for predicting benefit from CPIs, but more reliable biomarkers are needed. Other clinicopathologic features for predicting benefit have been suggested, including heavy smoking history, high mutation burden, and exposure to radiation (RT). Here we report a retrospective analysis of pts with NSCLC treated with CPI monotherapy. Methods: We sought to identify clinical and molecular characteristics associated with benefit from CPI treatment (tx) in a database of pts with NSCLC treated in the community from March, 2013 through October, 2014. We identified pts with a highly favorable (HFR, ‘best’) response to CPI tx as those having partial response to tx (per RECIST 1.1) or duration of tx > 1 year; and pts with unfavorable responses (UFR, ‘worst’) as those whom came off CPI tx due to progressive disease at the first disease evaluation after ≥ 3 doses of tx. Next-Generation Sequencing (NGS) results were assessed where available. Results: As of Sept 2015, 152 pts were treated with CPI (median time on tx 117 days (range 1-849)). 28 pts were classified in the HFR cohort; 29 pts in the UFR cohort. Baseline characteristics including age, gender, smoking history, and RT exposure were similar between cohorts (Table). NGS revealed similar numbers of genomic alterations (GA)/variants of unknown significance (VUS) between HFR and UFR cohorts. Driver oncogenes were noted in both groups (2 EGFR mutations in the HFR group and 3 ALK rearrangements in the UFR group) as well as individual outliers-including one pt with 42 GA and 134 VUS who remains on tx for 2.5+ years. Conclusions: In this analysis, there was no clear clinical or molecular differences identified between two groups of pts with distinct responses to CPI tx. Additional work is needed to identify predictive factors for response to immunotherapy. HFR N = 28 UFR N = 29 Median Age 67 (53-86) 63 (50-88) Male 20 21 Female 8 8 Smoking History (median pack years) 46 (0 -135) 40 (0 - 0.92) 0 - 20 9 7 > 20 19 22 Prior RT exposure 13 19 No RT exposure 15 10 # GA by NGS (median) 3.5 5.5 # of total mutation burden (GA+VUS) (median) 12 12
The GAGE protein is detected only in cancer and in testis and is expressed from a cluster of nearly identical gene copies on the X-chromosome. We determined the lengths of these GAGE gene clusters from human families, identical twins, and in clinical samples from cancer patients. The GAGE cluster lengths proved to be highly heterogeneous, ranging from 13 to 39 gene copies, with an average content of 20 GAGE genes per cluster. Low levels of mei-otic rearrangement in families and mitotic rearrangement in adult solid tumors are detectable. Analysis of Rothmund -Thomson syndrome (RTS) kindreds and probands showed GAGE cluster inheritance and stability indistinguishable from that found in non-RTS individuals. These observations support the concept of evolutionarily rapid rearrangement of clustered repetitive sequences in the human genome.
Abstract Defects in the human BLM gene cause Bloom syndrome, notable for early development of tumors in a broad variety of tissues. On the basis of sequence similarity, BLM has been identified as one of the five human homologs of RecQ from Escherichia coli . Nevertheless, biochemical characterization of the BLM protein indicates far greater functional similarity to the E. coli RecG protein and there is no known RecG homolog in human cells. To explore the possibility that the shared biochemistries of BLM and RecG may represent an example of convergent evolution of cellular function where in humans BLM has evolved to fulfill the genomic stabilization role of RecG, we determined whether expression of RecG in human BLM-deficient cells could suppress established functional cellular Bloom syndrome phenotypes. We found that RecG can indeed largely suppress both the definitive elevated sister chromatid exchange phenotype and the more recently demonstrated gene cluster instability phenotype of BLM-deficient cells. In contrast, expression of RecG has no impact on either of these phenotypes in human cells with functional BLM protein. These results suggest that the combination of biochemical activities shared by RecG and BLM fill the same evolutionary niche in preserving genomic integrity without requiring exactly identical molecular mechanisms.
TPS5608 Background: WEE1 is DNA damage cell-cycle checkpoint protein that inactivates cyclin-dependent kinase 1 (CDC2) and is overexpressed in a variety of malignancies. Pts with deficient p53 expression rely on the WEE1 kinase to arrest cell-cycle progression at the G2 checkpoint for DNA repair. AZD1775, a highly selective, adenosine-triphosphate (ATP) competitive, small-molecule inhibitor of the WEE1 kinase, is being developed for the treatment of advanced solid tumors with TP53-mutated malignancies. Inhibition of WEE1 allows CDC2 phosphorylation and subsequent cell-cycle progression despite DNA damage. This G2 checkpoint abrogation thus sensitizes cells to cytotoxic agents. Preliminary efficacy data have been promising when AZD1775 is used in combination with chemotherapy. In this randomized, phase II trial in pts with platinum-resistant, TP53-mutated cancers, AZD1775 will be added to a standard chemotherapy regimens (paclitaxel, gemcitabine, or carboplatin), with the goal of improving efficacy when compared to chemotherapy alone. The primary endpoints are response rate (Part 1), and progression-free survival (Part 2). Methods: In Part 1, up to 69 pts will be randomized to receive AZD1775 plus paclitaxel, gemcitabine or carboplatin (Arm A: AZD1775 175 mg PO BID Days 1, 2, 8,9,15, and 16 plus gemcitabine 1000 mg/m2 IV Days 1, 8, and 15; Arm B: AZD1775, 5 doses of 225 mg PO BID Days 1-3, 8-10, and 15-17 plus paclitaxel 80 mg/m2 IV Days 1, 8, and 15; Arm C: AZD1775, 5 doses of 225 mg PO BID Days 1-3 plus carboplatin AUC 5 IV Day 1). In Part 2, up to 108 pts will be randomized 1:1 to the most efficacious AZD1775/chemotherapy combination identified in Part 1, or chemotherapy alone. Pts will be restaged every 2 cycles and continue treatment until disease progression or unacceptable toxicity. Key eligibility includes: platinum-resistant TP53-mutated epithelial ovarian, fallopian tube, or primary peritoneal cancer, measurable disease per RECIST v 1.1, ECOG PS 0 or 1, QTc < 470 msec, and no known CNS disease. Tumor samples will be collected for evaluation of specific biomarkers. Clinical trial information: NCT02272790.
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