tbuckley/cabot-search huggingface dataset:
Bespoke circulating tumor DNA (ctDNA) analysis as a predictive biomarker in solid tumor patients (pts) treated with single-agent pembrolizumab (P).
Authors: Marco Adelmo James Iafolla, Cindy Yang, Scott Dashner, Wei Xu, Aaron Richard Hansen, Philippe L. Bedard, Stephanie Lheureux, Anna Spreafico, Albiruni Ryan Abdul Razak, Hsin-Ta Wu, Svetlana Shchegrova, Zhihui (Amy) Liu, Pamela S Ohashi, Dax Torti, Maggie C Louie, Himanshu Sethi, Alexey Aleshin, Lillian L. Siu, Scott Victor Bratman, Trevor John Pugh
Journal: Journal of Clinical Oncology (2019)

2542 Background: Limited data exist in the clonal dynamics of serial ctDNA as a predictive biomarker in advanced solid tumor pts receiving immune checkpoint blockade. Methods: Pts with mixed solid tumors received single agent P (anti-PD-1) 200 mg IV Q3wks in the investigator-initiated phase II INSPIRE trial (NCT02644369). ctDNA was assayed at baseline (B) and start of cycle 3 (C3) using a pt-specific amplicon-based NGS assay (Signatera™). Samples were considered ctDNA positive if ≥2 of 16 pt-specific targets met the qualifying confidence score threshold. Results: Results of 70 pts are presented. Demographics: male 46%; median age=60 yrs (range 21–82); head and neck (20%), triple negative breast (14%) and ovarian (14%) cancers comprised the major malignancies. Median no. of P cycles=4 (range 2–35); follow up was 14m (range 2–29); RECIST responses: CR 2.9% (n=2), PR 17% (n=12), CBR (CR+PR+SD≥6 cycles) 31% (n=22), RECIST/clinical PD (n=43/10; 65%/15%). Median PFS=3.3m and median OS=17.8m. 68/70 pts had ctDNA detected at baseline (median=16/16 variants) demonstrating 97% sensitivity. Table shows correlation of ΔctDNA (ctDNA B compared to ctDNA C3 ) with clinical efficacy parameters, whereas ctDNA B values did not reach statistical significance. Conclusions: A strong correlation exists between ΔctDNA with OS, PFS, CBR and ORR with P, suggesting it is a potential predictive biomarker in pts with mixed solid tumors. Clinical trial information: NCT02644369. [Table: see text]
Potential biomarkers for targeted and immunotherapy in gliomas.
Authors: Jun Wu, Chen Chen, Zhengwen He, Pingping Dai, Longbo Zhang, Zhiqiang Liu, Jie Gao, Yan-Fang Guan, Xuefeng Xia, Ling Yang, Xin Yi
Journal: Journal of Clinical Oncology (2019)

e13523 Background: Glioma is the most common malignant brain tumor among adults. To explore biomarkers for efficient therapy, we describe mutational features and hypermutated nature among glioma. Methods: Analysis was performed on 119 tissues from patients diagnosed with glioma using panel of 1021 genes. We defined hypermutation as TMB-20 (TMB&gt;20 muts/Mb). Results: The most commonly observed alterations include mutations within promoter of TERT, catalytic domain of IDH1 and CDSs of TP53, EGFR, NOTCH1, CIC, ATRX, as well as amplifications of EGFR, 4q12 and deletions of 1p/19q, CDKN2A/B. Mutations in ATRX were mutually exclusive with TERT, but coexisted with TP53 mutations (p&lt;0.001). Targeted drugs had been developed for EGFR, CDKN2A/B and 4q12. Among 114 evaluable cases, TMB ranged from 0 to 298 muts/Mb, with a median of 4.32. Only 6% cases displayed TMB-20. MSI-H was 2.6%, with only one case had a germline mutation in MLH1. 2.6% cases harbored mutations in Pol genes. Only one case was positive for all three criteria. MSI-H cases all displayed TMB-20. The two biomarkers were extremely statistically significant (p=0.001) in gliomas. The case with highest TMB (298 muts/Mb) harbored five mutations in Pol genes, and germline frameshift mutations in MSH6. This was consistent with previous reports that mut Pol genes contributed to high TMB. High TMB may occur spontaneously or be induced by treatment. In our study, hypermutated cases in de novo and post-treatment groups were 11.1% and 11.5%, respectively. In IDH wild-type and mut groups, hypermutated cases were both 6.3%. However, extremely high TMB (TMB&gt;50) cases were all de novo and carried IDH mutations. While treatment-induced high TMB were always subclonal, which may not be sensitive to immunotherapy. This explained the limited efficiency of immunotherapy in gliomas to some extent. Conclusions: Most commonly observed mutations in gliomas may provide potential targets for targeted therapy. There is probably a trend that extremely higher TMB occurs in de novo patients, who may preferentially benefit from immunotherapy. Further research is needed on biomarkers for both effective targeted- and immuno-therapy.
Concurrent <i>TP53</i> mutation adversely impact the efficacy of crizotinib in <i>ROS1-</i>rearranged lung cancer patients.
Authors: Lin Gen, Huamin Xu, Jun Zhao, Jinliang Kong, Xinghao Ai, Fenglei Yu, Kaiqi Du, Lingjun Zhu, Lin Li, Hongxia Ma, Qiaoli Wang, Huanhuan Xiong, Rongrong Chen, Xuefeng Xia
Journal: Journal of Clinical Oncology (2019)

e20535 Background: ROS1 tyrosine kinase inhibitors (TKIs) are now standard of care for patients with advanced ROS1-rearranged NSCLC. But factors that may affect the efficacy of ROS1 TKIs remain to be explored. Methods: We conducted a retrospective multicenter study of lung cancer patients with ROS1 rearrangements. Treatment and survival follow-up was done and clinical records were reviewed. PFS distribution was analyzed by Kaplan-Meier method with log-rank test. Results: In total, we included 94 lung cancer patients with ROS1 fusion genes profiled by next-generation sequencing from May 2016 to September 2018. Fifty of them were female. The median diagnosis age was 54 (25-83). The most common histologic type was adenocarcinoma, which was confirmed in 75 of 78 patients with available pathological results. The most common fusion partners were CD74, EZR, SDC4 and SLC34A2 identified in 42, 19, 12 and 8 patients respectively. Concurrent actionable mutations were uncommon for ROS1 fusion-positive patients. The most frequent concomitant mutated gene was TP53, which was detected in 33% of all the patients. After excluding 29 patients who were lost to follow-up at the very start, the median follow-up time was 8.5 (0-28) months from the moment when mutation profiling was performed. Thirty-nine patients received treatment with crizotinib, among whom 27 were treatment-naïve patients. The median PFS of the 39 patients with crizotinib was not reached yet. Patients with baseline CNS metastasis tend to have shorter PFS compared to patients without (median, 12 vs NR, p = 0.0073). Besides, concurrent TP53 mutations were correlated with worse PFS (median, both NR, p = 0.0417). Mutation profiles of 10 patients were derived from ctDNA testing. No difference was found in PFS between these 10 patients with others whose genomic profiles were based on fresh tissue or FFPE specimens, suggesting that plasma ctDNA serves as good specimen source for mutation profiling to monitor clinical treatment. Conclusions: Concurrent TP53 mutation and presence of CNS metastasis are associated with decreased PFS of ROS1-positive patients treated with crizotinib.
A multicenter nonrandomized controlled trial to evaluate the efficacy of surgery versus radiofrequency ablation for small hepatocellular carcinoma (SURF cohort trial).
Authors: Ryosuke Tateishi, Kiyoshi Hasegawa, Yoshikuni Kawaguchi, Tadatoshi Takayama, Namiki Izumi, Naoki Yamanaka, Masatoshi Kudo, Mitsuo Shimada, Masafumi Inomata, Shuichi Kaneko, Kazuhiko Koike, Masao Omata, Masatoshi Makuuchi, Yutaka Matsuyama, Norihiro Kokudo
Journal: Journal of Clinical Oncology (2020)

4581 Background: In parallel with a multicenter randomized controlled trial that reported an equal recurrence-free survival (RFS) of early-stage hepatocellular carcinoma (HCC) patients who underwent either surgery (SUR) or radiofrequency ablation (RFA), we also enrolled HCC patients who fulfilled the enrollment criteria but did not give consent to participate in the RCT. Methods: All patients gave informed consent to participate in this study. Inclusion criteria were as follows: primary HCC with less than or equal to 3 tumors, each measuring 3 cm or smaller; without vascular invasion or extrahepatic metastasis; Child-Pugh score of 7 or less; and ages between 20 and 79 years. The feasibility for both treatments was confirmed by a joint chart review by surgeons and hepatologists. The primary endpoint was RFS and overall survival. A pre-specified interim analysis was performed to compare RFS. Results: Between April 2009 and August 2015, 740 patients (371 in SUR, 369 in RFA) were enrolled from 49 participating hospitals in Japan. The SUR group had significantly fewer patients with chronic hepatitis C (56.6% vs. 69.4%), higher median value of platelet count (145 vs. 120 × 10 9 /L), and more patients with &gt; 2 cm tumors (49.9% vs. 27.9%); most patients had a single tumor (91.1% vs. 88.3%). During the median follow-up period of 5 years, tumor recurrence was observed in 192 of SUR and 218 of RFA with 3-year RFS being 66.0% and 61.7%, respectively ( P = 0.091). In subgroup analysis, RFS was significantly better in SUR in patients with ≤ 2 cm tumors (62.9% vs. 51.7% in 3 years; hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.56-0.93; P = 0.014), whereas the difference was not significant in those with &gt; 2 cm tumors (52.7% vs. 46.4%; HR 0.85, 95% CI 0.63-1.18; P = 0.34). The adjusted HR for RFS using inversed probability of treatment weighting was 0.89 (95% CI, 0.72-1.10; P = 0.287). Conclusions: The imbalance in patient characteristics reflected a real-world practice. Factors related to background liver disease rather than tumor characteristics might have a larger impact on the recurrence in early HCC. Clinical trial information: C000001796 .
Cost-effectiveness of PD-L1 testing and tumor mutational burden testing of immune checkpoint inhibitors for non-small cell lung cancer.
Authors: Wenqian Li, Lingyu Li, Naifei Chen, Jiuwei Cui
Journal: Journal of Clinical Oncology (2019)

e20689 Background: Immunotherapy that targeted programmed death ligand 1 (PD-L1)–programmed death 1 (PD-1) pathway showed great benefit on survival compared with other therapies, especially with certain assessments before. However, the high costs limit its use. This cost-effectiveness analysis aimed to measure the significance of various assessments in immunotherapy. Methods: A decision-tree model was established based on the data of OAK study, we compared the economic benefit between immunotherapy and chemotherapy in no test group, PD-L1 test group and tumor mutational burden(TMB) test group respectively with a willingness-to-pay threshold of 3× the per capita gross domestic product ($29307/quality-adjusted life year [QALY]). Besides, we also balanced the benefit of immunotherapy among different groups. Furthermore, we also considered different costs of TMB tests due to the various methods of detection. Sensitivity analyses were conducted to evaluate the stability. Results: Immunotherapy was cost-effective compared with chemotherapy in all groups. Immunotherapy with PD-L1 test achieved economic benefit when comparing with both TMB test group and no test group. However, TMB test group was not cost-effective compared with no test group. The results from average CE and net benefit were consistent. Tissue-based TMB test was the most cost-effective TMB detection methods. One-way sensitivity analyses reflected the impact of utilities. Conclusions: Immunotherapy was cost-effective compared with chemotherapy. PD-L1 test was the most cost-effective immunotherapy test. [Table: see text]
Loss of the transcriptional repressor TGIF1 results in enhanced Kras-driven development of pancreatic cancer
Authors: Ching-Chieh Weng, Mei-Jen Hsieh, Chia-Chen Wu, Yu-Chun Lin, Yan-Shen Shan, Wen-Chun Hung, Li-Tzong Chen, Kuang-Hung Cheng
Journal: Molecular Cancer (2019)

The TG-interacting factor 1 (TGIF1) gene, which encodes a nuclear transcriptional corepressor of the TGFβ1/Smad signaling pathway, has been implicated in the pathogenesis of various types of human cancer; however, its role in pancreatic ductal adenocarcinoma (PDAC) has yet to be elucidated. The expression of TGIF1 in human and murine PDAC specimens were detected by IHC analysis. The functions of TGIF1 in in vivo PDAC growth, dissemination, and metastasis were assessed using conditional inactivation of TGIF1 in well-established autochthonous mouse models of PDAC. Primary cells from TGIF1 null or wild type PDAC mice were examined by assays for cell proliferation, migration, invasion, soft agar and xenograft tumorigenesis. Gene expression profiling, pathway analyses, epigenetic changes associated with TGIF1 loss, and in vitro and in vivo effects of 4-MU were assessed. Conditional deletion of TGIF1 in the mouse pancreas had no discernible effect on pancreatic development or physiology. Notably, TGIF1 loss induced KrasG12D-driven PDAC models exhibited shorter latency and greater propensity for distant metastases. Deciphering the molecular mechanisms highlighted the TGIF1 loss-induced activation of the hyaluronan synthase 2 (HAS2)-CD44 signaling pathway and upregulation of the immune checkpoint regulator PD-L1 to facilitate the epithelial–mesenchymal transition (EMT) and tumor immune suppression. We also founded that TGIF1 might function as an epigenetic regulator and response for aberrant EMT gene expression during PDAC progression. Our results imply that targeting the HAS2 pathway in TGIF1 loss of PDAC could be a promising therapeutic strategy for improving the clinical efficacy against PDAC metastasis.
Clinical, pathological and genetic predictors of patient-derived xenograft (PDX) engraftment in <i>EGFR</i>-mutated lung adenocarcinoma (LUAD).
Authors: Sebastiao N. Martins-Filho, Jessica Weiss, Nhu-An Pham, Michael Cabanero, Aline Fusco Fares, Erin L. Stewart, Devalben Patel, Judy McConnell, Penelope Ann Bradbury, Adrian G. Sacher, Natasha B. Leighl, Alexandria Grindlay, Frances Allison, Ming LI, Kazuhiro Yasufuku, Frances A. Shepherd, Nadeem Moghal, Ming Sound Tsao, Geoffrey Liu
Journal: Journal of Clinical Oncology (2019)

3110 Background: PDX are useful preclinical models to study drug response and resistance. Different specimen types have been used to generate PDX models including histological (surgery and CT-guided biopsy) and cytological preparations (EBUS and pleural effusions). We hypothesize that engraftment is not stochastic and is affected by many factors including sample type and tumor pathological and molecular properties. To improve sample selection and cost-effectiveness of PDX experiments, we investigated clinical, histological and genetic correlates of engraftment in EGFR-mutated LUAD. Methods: We assessed PDX engraftment from 96 surgical resections, 13 CT-guided biopsies, 21 EBUS and 14 pleural effusions of EGFR-mutated LUAD. Sixty-five samples, including 6 engrafted (XG) and 54 non-engrafted (noXG) were evaluated by exome sequencing. Results: Engraftment was successful in 9/96 (9%) surgical resections, 6/13 (46%) CT-guided biopsies, and 0/35 cytological samples. Biopsies taken at time of treatment failure (compared to treatment naive biopsies) correlated with greater engraftment (p=0.007, AUC = 0.68). Multivariable regression analysis of clinical variables at the time of sampling identified advanced (vs early) stage (p = 0.003) and histological (vs cytological) preparations (p &lt; 0.001) as the strongest predictors of engraftment (AUC = 0.79). Among tumor histologic features, solid (vs lepidic, acinar and papillary) pattern was associated with greater engraftment (p &lt; 0.001). Presence of EGFR-T790M (p = 0.004) and TP53 (p = 0.009) mutations were associated with greater engraftment; all XG samples carried TP53 mutations. EGFR-Ex19del (p = 0.076) showed a trend towards engraftment whereas EGFR-L858R (p = 0.086) trended towards non-engraftment. Conclusions: Advanced stage, post-therapy tumors, T790M+ and TP53+ EGFR-mutated LUAD samples obtained for histological processing are more likely to engraft as PDXs. Despite low engraftment rates, these models are useful to study novel therapeutic strategy and elucidation of resistance mechanisms.
AB0563 TRAUMA AND SLE-CONSIDERATIONS REGARDING A GROUP OF PATIENTS FROM ROMANIA
Authors: Ana Alwina Stan, Monica Copotoiu
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Systemic lupus erythematosus (SLE) represents a complex disease, which hasn't got a clear etiology established yet. Many genetic-susceptibility factors, environmental triggers, antigen-antibody (Ab) responses, B-cell and T-cell interactions, and immune clearance processes interact to generate and perpetuate autoimmunity. One of the triggers could be trauma-surgeries, serious infections or accidents. <h3>Objectives</h3> To assess the presence of history of trauma in patients diagnosed with SLE admitted in our Department, as well as the association with different co-morbidities. <h3>Methods</h3> We included 62 patients, admitted in the Rheumatology Department of the Tirgu-Mures Emergency Clinical County Hospital between 01.01.2018-29.01.2019, previously diagnosed with SLE. We performed a retrospective analysis of their medical documents, looking for evidence of traumatic risk factors. <h3>Results</h3> The majority of the patients were female (17=88.70%) and had some kind of trauma before being diagnosed with SLE (17=27.41%). Among the operations the most frequent were hysterectomy with bilateral oophorectomy and classical appendectomy, respectively (6=9.67% each), followed by cholecystectomy and tonsillectomy (2=3.22%). There were also one case of cerebral injury following a car accident and a complicated peritonitis-related to IUD extraction. The majority of co-morbidities was represented by neurologic involvement (16=25.80%), followed by thyroid (13=20.96%) and renal involvement (12=19.35%). <h3>Conclusion</h3> Patients with SLE from our department have a significant history of traumatic triggers, mainly open surgeries, which might explain the development of autoimmunity. They also have various organ involvement that sometimes warrants aggressive measures. Further studies have to be conducted in order to better examine the possible link between traumatic events and development of this multifaceted disease. <h3>References</h3> [1] Christie M Bartels- Systemic lupus erythematosus (SLE) on Medscape Drugs &amp; Diseases <h3>Disclosure of Interests</h3> Ana Alwina Stan Grant/research support from: Novartis, Monica Copotoiu Grant/research support from: Novartis
Clinical impact of comprehensive versus targeted genomic analysis for precision oncology.
Authors: Mario Lamping, Damian Tobias Rieke, Frederick Klauschen, Korinna Jöhrens, Ioannis Anagnostopoulos, Dido Lenze, Inge Tinhofer, Manuela Benary, Sebastian Ochsenreither, Konrad Friedrich Klinghammer, Susen Burock, Henning Jann, Anna Kathrin Stüven, Doreen Ditzen, Dieter Beule, Clemens Messerschmidt, Eric Blanc, Reinhold Schäfer, Ulrich Keilholz
Journal: Journal of Clinical Oncology (2019)

e13033 Background: Panel sequencing (PS) has become a standard-of-care in cancer diagnostics. More comprehensive analyses such as whole-exome (WES) or RNA sequencing (RNAseq) allow for the detection of rare and unknown genetic aberrations that are not covered by predefined assays. The clinical impact of targeted versus comprehensive genomic assays were analyzed in patients presented at the Charité Molecular Tumor Board (MTB). Methods: Patients (pts) with advanced and/or metastatic cancer for whom no standard therapy was available were discussed in the MTB to allocate diagnostic profiling and guide biomarker-based treatment (BBT). Pts had to be &lt; 50 years of age or diagnosed with a rare tumor entity to undergo WES/RNAseq, performed on fresh tissue. If ineligible, standard PS was performed on archival tissue. BBT recommendations, ranked by pre-specified evidence levels, were made by the MTB and pts were followed up. Results: 228 patients (median age 49 years, 108 female and 120 male) were discussed in the MTB between January 2016 and February 2019. We assigned 73 and 155 pts to PS and WES/RNAseq and results were obtained for 78.1% (n = 57/73) and 54.8% (n = 85/155) pts, respectively. Sequencing failed for 11 (PS; 15.1%) and 62 (WES/RNAseq; 40%) pts, most commonly due to insufficient tissue (n = 29). Sequencing was ongoing in 5 (PS) and 8 (WES/RNAseq) pts at the time of analysis. A median of 2 BBTs were recommended for 75.4% (43/57) of PS (range r: 1-3) and 90.6% (77/85) of WES/RNAseq pts (r: 1-6) each. 22% (n = 17/77) of WES/RNAseq pts had ≥4 BBTs made by the MTB. Treatment was initiated in 30.2% (n = 13/43) of PS and 40.2% (n = 31/77) of WES/RNAseq pts. Clinical benefit rates (CBRs) were 23.1% (2 PR, 1 SD) for PS and 45.2% (2 CR, 3 PR, 9 SD) for WES/RNAseq pts. Overall survival data was immature at the time of analysis. Conclusions: Utilizing WES/RNAseq is a feasible approach to perform tumor profiling in a heterogeneous cohort. We here show a higher rate of pts receiving confident evidence-based treatment recommendations in the WES/RNAseq group and a higher rate of treatment initiation. The CBR nearly doubled in the WES/RNAseq cohort when compared to standard PS pts, thus emphasizing the need for larger comparative analyses to guide diagnostic decision-making.
Patient characteristics, treatment received, and outcomes of non-metastatic breast cancer patients in Haiti: Report from retrospective cohort.
Authors: Temidayo Fadelu, Ruth Damuse, Liz Pecan, Cyrille Dubuisson, Lauren Greenberg, Satyre Danjoue, Joarly Kerwick Lormil, Timothy Rebbeck, Lawrence N. Shulman
Journal: Journal of Clinical Oncology (2019)

e18196 Background: Few studies have reported outcomes of breast cancer (BC) patients in Haiti. Since 2013, University Hospital Mirebalais, a tertiary government hospital, has offered treatment for BC, in partnership with Dana-Farber Cancer Institute and Zanmi Lasante, a Haitian non-profit. Standard chemotherapy and hormone therapy are available, but HER2 therapies and radiation are not. Here, we comprehensively describe patient characteristics, treatments delivered and outcomes of non-metastatic BC patients in this program. Methods: We conducted a retrospective observational study including 339 patients with non-metastatic BC, who presented between January 1, 2013 and June 30, 2016. We conducted detailed chart abstraction of patient characteristics, clinical diagnostic and treatment data, and outcomes. Our endpoint was disease-free survival (DFS) defined as time from presentation to cancer recurrence, progression or death. We used Kaplan-Meier estimation to plot survival curves, censoring at the time of last follow-up. Log-rank test was used to examine subgroup differences. Results: The median age in the cohort was 49, inter-quartile range of 42 to 58; 35.7% were post-menopausal. Invasive ductal carcinoma was the most common histology (65.5%). At presentation, 52.8% had T3/T4 disease, while 54.6% had locally advanced disease, and 37.5% were poorly differentiated. There was incomplete documentation of stage (18.3%), ER status (44.2%) and histologic grade (39.5%). 156 patients received neoadjuvant therapy with hormonal therapy (26.2%), chemotherapy (67.9%), or both (5.8%), while 227 received adjuvant therapy (25.5%, 26.5% and 48.0% respectively). 275 patients (81%) completed surgical resection. Median follow up time for the cohort was 24.8 months. 23 patients died; 75 had recurrences; and 9 had progression. Median DFS was 50.8 months (95% CI, 40.6 to 57.0). There was no DFS difference by ER status. Median DFS for early-stage patients was not reached compared to locally advanced patients of 40.4 months (95% CI, 34.0 to 49.7), P-value &lt; 0.0001. Conclusions: Non-metastatic BC patients in Haiti present with more advanced disease and have poorer prognostic factors compared to high-income countries. Although these patients have comparatively worse outcome, curative treatment is feasible in Haiti.