tbuckley/cabot-search huggingface dataset:
Mutations in TSC1/TSC2 genes are prevalent in sporadic renal angiomyolipoma and insulinoma tumors, supporting their responsiveness to mTOR inhibitors
Authors: K.I. Anoshkin, I.A. Vasilyev, C. Mosyakova, A.S. Tanas, K. Karandasheva, N. Bagmet, G.A. Karagyozyan, Y.V. Doludin, E.B. Kuznetsova, L. Gurevich, A. Vinarov, D.V. Zaletaev, M. Sekacheva, V.V. Strelnikov
Journal: Annals of Oncology (2018)

Background: The products of TSC1 and TSC2 genes, hamartin and tuberin respectively, form a complex that is the natural inhibitor of mammalian target of rapamycin (mTOR). Mutations in these genes are associated with such diseases as tuberous sclerosis (TS) and lymphangioleiomyomatosis, for which the main pharmacologic treatment at present is everolimus, the mTOR kinase inhibitor. Benign tumors like renal angiomyolipoma and pancreatic neuroendocrine tumors (PNET) can occur in tuberous sclerosis in 70% and 10% patients, respectively, but the overwhelming majority of them is sporadic. Despite the benign character, these tumors can be life-threatening. At the present time, the pathogenesis of sporadic renal angiomyolipoma (sRA) and PNETs is largely unknown but is growing as a research topic. Referring to cases of the tumors that occur in tuberous sclerosis, we assumed that TSC1 and TSC2 genes might play a key role in the development of sRA and PNETs. Methods: NGS was performed on 20 sRA and 12 PNETs (insulinomas) tumor samples, respectively. Results:Table: 74PTumor sample1st hit2nd hitsRA-10TSC2:c.1509_1510insGTCC: p.Q503fs–sRA-12TSC2:c.G1832A:p.R611QLOH 16p13.3sRA-13TSC2:c.204delA:p.A68fs–sRA-14TSC2:c.C1372T:p.R458XTSC2:c.G3367C:p.G1123RsRA-16TSC2:c.1454delT:p.I485fsTSC2:c.C5126G:p.P1709RsRA-17TSC2:c.5171dupA:p.Q1724fsTSC2:c.A1793G:p.Y598CsRA-18TSC2:c.C4713A:p.Y1571X–sRA-19TSC2:c.G4829A:p.W1610XLOH 16p13sRA-1TSC2:c.C1111T:p.Q371X–sRA-2TSC2:c.976-3_41del–sRA-3TSC2:c.500delG:p.W167X–sRA-6TSC2:c.629dupC:p.A210fsLOH 16p13.3sRA-7TSC2:c.1283delC:p.S428fsLOH 16p13.3sRA-9TSC2:c.G4289A:p.W1430XLOH 16p13.3PNET-3TSC2:c.600-4G>TTSC2:c.G4760A:p.C1587YPNET-4TSC2:c.649-1G>ATSC1:c.C1075T:p.P359SPNET-5TSC2:c.G997A:p.V333MLOH 16p13.3PNET-6–LOH 16p13.3PNET-8TSC2:c.2838-1G>ATSC2:c.C2164T:p.L722FPNET-9TSC2:c.C1306T:p.P436SLOH 16p13.3PNET-10TSC2:p.Q883Xc.C2671T:p.H891YPNET-11TSC2:c.2355 + 1G>ALOH 16p13.3PNET-12TSC2 c.C2753T:p.S918FLOH 16p13.3 Open table in a new tab Conclusions: Mutations found in tuberous sclerosis complex genes in sporadic renal angiomyolipoma and insulinomas strongly suggest involvement of these genes in the development of these tumors. These findings assume the possibility of using non-invasive treatment, namely the use of such drugs as everolimus for the treatment of these diseases. Legal entity responsible for the study: Research Centre for Medical Genetics. Funding: The research was carried out within the state assignment. Disclosure: All authors have declared no conflicts of interest.
Treatment of metastatic uveal melanoma (mUM) directed by a comprehensive molecular tumour analysis program (CMTA).
Authors: Serge Leyvraz, Thomas Kessler, Moritz Schütte, Mario Lamping, Susen Burock, Sebastian Ochsenreither, Vyacheslav Amstislavskiy, Christoph Wierling, Korinna Jöhrens, Frederick Klauschen, Caroline-Anna Peuker, Felix Kiecker, Reinhold Schäfer, Bodo Lange, Hans Lehrach, Antonia Joussen, Damian Tobias Rieke, Konrad Friedrich Klinghammer, Ulrich Keilholz, Marie-Laure Yaspo
Journal: Journal of Clinical Oncology (2018)

9566 Background: There is a lack of active treatment against mUM. Such “hard-to-treat” tumour might benefit from treatment decisions driven by a complete genomic and transcriptomic analysis program. Methods: From 1.3.2016 to 1.12.2017, mUM were included in the prospective TREAT20Plus study and were subjected to a CMTA including WGS, WES, RNAseq, cell culture and systems biological/pharmacodynamic modelling. Treatment recommendations were made by a molecular tumour board. Results: Twenty six patients (12 F, 14M). Age: 61 (32-80). PS: 0 (0-2). Metastases: 4 (1-10). Abnormal LDH: 19. Pre-treatment: 1 (0-5) and type: iv chemotherapy: 11, checkpoint-inhibitors (-i): 7, intra-hepatic: 13, vaccine: 1. Insufficient material in 3 patients. The mutation burden was low: 32 (15-449). The treatment recommendations (TRec) were based on the different mutations or activation profiles: A) MEK-i. for mutations of GNAQ: 11, GNA11: 13. B) a MET-i. for MET overexpression: 17. ALK-i. for the oncogenic ALK ATI isoform: 3. C) CDK4/6-i. for CDKN2A loss: 1. D) checkpoint-i. for mutation burden > 100: 3. E) For the other alterations no off-label treatment was available: mutation of BAP1: 8 or SF3B1: 10, overexpression of MYC: 14, BCL2: 24, CCND2: 16, ERBB3: 5 , biallelic loss of TNFAIP3: 1. Among novel non-recurring gene-fusions: inactivating gene fusion affecting MITF: 1. In 1 patient repeated biopsies at time of recurrence after MEK-i disclosed biallelic loss of CDKN2A. The pharmacodynamic modeling confirmed TREc in 10 and helped with the decision in 8 patients. A treatment was initiated in 15 patients: Trametinib: 6, Cabozantinib: 3, Crizotinib: 6, Palbociclib: 1. A treatment was not initiated for 8 patients: 4 too early, 4 rapid progression. Among the 12 evaluable patients the antitumor response was: minor response: 2, stable disease: 4, progressive disease: 5, too early: 1. Median PFS of the treated patients: 5,5 months. Conclusions: Precision medicine in mUM is clinically feasible. It leads to a better understanding of the biology of the tumour and of the potential therapeutic targets. Its clinical efficacy is limited by the non-availability of drugs as single agent or in combination. Clinical trial information: EA4/063/13.
A randomized, open label, phase II study comparing pemetrexed plus cisplatin followed by pemetrexed versus pemetrexed alone in EGFR mutant NSCLC patients who have failed first-line EGFR TKI: KCSG-LU12-13.
Authors: Kwai Han Yoo, Jinhyun Cho, Ki Hyeong Lee, Keon Uk Park, Ki Hwan Kim, Eun Kyung Cho, Kyung A. Kwon, Heuijune Ahn, HyeRyun Kim, Hoon-Gu Kim, Ha Yeon Lee, Hwan Jung Yun, Jin-Hyoung Kang, Jaeheon Jeong, Moon Young Choi, Sin-Ho Jung, Jong-Mu Sun, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
Journal: Journal of Clinical Oncology (2016)

9043 Background: Various therapeutic strategies are available for NSCLC patients who develop disease progression on first-line EGFR-TKI. However, it has not been established which cytotoxic regimens are preferable for these patients. We conducted a prospective randomized phase II trial to compare the clinical outcomes between pemetrexed plus ciplatin (PC) combination therapy with pemetrexed (P) monotherapy after failure of first-line EGFR-TKI. Methods: Patients with non-squamous NSCLC harboring activating EGFR mutation (Del 19 or L858R mutation) who have progressed on first-line EGFR-TKI were randomly assigned in a ratio of 1:1 to PC arm or P arm. Patients were treated with pemetrexed 500 mg/m2 and cisplatin 70 mg/m2 for four cycles, followed by pemetrexed maintenance every 3 weeks or treated with pemetrexed 500 mg/m2monotherapy every 3 weeks until progression. Primary objective was PFS, and secondary objectives include overall response rate (ORR), OS, safety profile. Results: 96 patients were randomized and 91 patients were treated. The baseline characteristics of PC arm (N = 48) and P arm (N = 48) were well balanced in the age, sex, ECOG PS and EGFR mutation status. The ORR of PC arm (N = 46) was 34.8% (16/46), while P arm (N = 45) was 17.8% (8/45). With 20.4 months of median follow-up, the median PFS was 5.4 months (95% CI, 4.5-6.3) in PC arm and 6.4 months (95% CI, 3.6-9.2) in P arm (p = .313). 1-year survival rate was 77% for PC arm, 68% for P arm, respectively. The most common adverse events include anorexia (N = 34, 37.4%), nausea (N = 24, 26.4%), neuropathy (N = 10, 11.0%) and skin change (N = 10, 11.0%). Adverse events ≥ Grade 3 were in 12 patients (26.1%) in PC arm and 8 patients (17.8%) in P arm. Dose reduction (5 vs. 2 patients) and delay (10 vs. 4 patients) were required more often in PC arm. Further analysis including OS and quality of life (QoL) will be updated. Conclusions: PC combination therapy showed higher response rate than P monotherapy. However, there was no significant difference in PFS between two arms. Further genetic and molecular-based analyses are warranted to evaluate the contributing factors for long-term responders. Clinical trial information: KCSG-LU12-13.
Influence of the comprehensive geriatric assessment (CGA) in elderly metastatic cancer patients. Analysis from a prospective cohort of 1048 patients.
Authors: Rabia Boulahssass, Sebastien Gonfrier, Bereder Isabelle, Ludovic Evesque, Andre Gary, Jean Michel Hannoun Levi, Delphine Borchiellini, Patrice Brocker, Gerard Cavaglione, Emmanuel Barranger, Emmanuel Benizri, Anne-Claire Frin, Anne Creisson, Thomas Kreitmann, jean-Louis Bernard, Gilles Poissonnet, Jean Amiel, Joel Guigay, Eric Francois, Olivier Guerin
Journal: Journal of Clinical Oncology (2016)

10045 Background: Previous studies were shown that the CGA influence the therapeutic decision and help in the care plan.Aims of this study are :1) Determine the influence of the CGA for the therapeutic decision in elderly metastatic cancers (MC). 2) To determine the impact of the CGA on guided geriatric interventions in MC Methods: The PACA East cohort is a multicentric and prospective cohort study approved by an ethics committee. At the baseline, a standardized CGA was performed (MMSE,MNA,Grip strength, ADL, IADL ,CIRSg,Charlson,lee,PS,Gait speed, QLQc30,G8,Balducci). During the follow up from April 2012 to October 2014, treatments made and guided interventions were collected. We collected the final decision, the rate and the type of modification according to the CGA in MC and in non MC for making a comparison. Results: In the cohort 312 patients had a MC with a median age of 82y. The CGA influence the therapeutic decision in 28% in MC (n = 312) versus 20% (n = 736) in non MC (p = 0,004).The CGA modified the decision for best supportive care (BSC) for 10% (n = 106) in this cohort (n = 1048) and in 17% (n = 55/312) in MC versus 7%(n = 51/736) in non MC (p < 0,001). The dependence on ADL and IADL was more found in elderly patients with MC (p = 0,042 /p = 0,007) and they had more nursing interventions (p < 0,001). Patients with MC had a worse QoL (p < 0,001) , more depression (p = 0,012) , poor PS (p < 0,001) and they have more psychological interventions (p = 0,01) and more specialized pain evaluation (p = 0,007). The G8 and the nutritional status assessed by the MNA were worse for patients with MC (p < 0,001) and they had more nutritional interventions (p = 0,001).We observed no significant differences regarding gait speed, isolation, balducci score and cognitive function but also no difference on rate of physiotherapist interventions, of social interventions and on modification of care course for rehabilitation by the geriatric team between the 2 groups. Conclusions: Guided geriatric interventions seems to be correlated to deficits assessed by the geriatrian. This study confirms the importance of the CGA in the decision , but also in the global care plan in patients with MC.
TCT-255 Results of the percutaneous coronary intervention with overlapping stents with homogeneous or heterogeneous drug for the treatment of diffuse coronary disease in real clinical practice.
Authors: José Abellán-Huerta, Alfonso Jurado-Román, Juan Antonio Requena, Ignacio Sanchez-Perez, María López-Lluva, Jesus Piqueras-Flores, Ramón Maseda Uriza, Pedro Pérez-Díaz, Raquel Frías, Fernando Lozano
Journal: Journal of the American College of Cardiology (2018)
Clinical outcomes after whole genome sequencing in patients with metastatic non-small cell lung cancer.
Authors: Erica S Tsang, Yaoqing Shen, Negar Chooback, Cheryl Ho, Martin Jones, Daniel John Renouf, Howard John Lim, Sophie Sun, Stephen Yip, Erin Pleasance, Yussanne Ma, Yongjun Zhao, Andrew J. Mungall, Richard Moore, Steven Jones, Marco Marra, Janessa J. Laskin
Journal: Journal of Clinical Oncology (2017)

e20563 Background: The Personalized OncoGenomics (POG) program at the BC Cancer Agency integrates whole genome (DNA) and RNA sequencing into practice for metastatic malignancies. We examine patients with metastatic NSCLC and report the prevalence of actionable targets, treatments, and outcomes. Methods: Between 2012-2016, 217 patients had a tumor biopsy and blood sample with comprehensive DNA (80X; 40X normal) and RNA sequencing followed by in-depth bioinformatics to identify potential cancer “drivers” and/or actionable/treatable targets. In NSCLC cases, we compared the progression-free survival (PFS) of “POG-informed therapies” with the PFS of the last regimen prior to POG (PFS ratio). Results: In 29 NSCLC cases, median age was 60.2 years (range 39.4-72.6), 11 were male (38%), and histologies were: adenocarcinoma (93%); squamous cell carcinoma (7%). Potential molecular targets (i.e. cancer “drivers”) were identified in 26 (90%), and 21 (72%) had actionable targets. 13 received POG-informed therapies, of which 3 had no therapy before POG. Of 10 patients with POG-informed therapy, median PFS ratio was 0.94 (IQR 0.2-3.4). 3 (30%) had a PFS ratio ≥1.3, and 3 (30%) had a PFS ratio ≥0.8 and &lt;1.3. Conclusions: In this NSCLC cohort, 30% demonstrated longer PFS with POG-informed therapies. Larger studies will help clarify the role of whole genome analysis in clinical practice. [Table: see text]
The privilege of age for people with cancer.
Authors: Ellen Sonet
Journal: Journal of Clinical Oncology (2016)

e21555 Background: The purpose of this study was to document and better understand the practical and psychosocial issues faced by cancer survivors. Methods: An online survey was completed during Sept-Nov 2015 by 505 US adults diagnosed with cancer. Respondents were recruited from consumer panels to achieve a nationally representative sample. Roughly equal numbers were from the Midwest (23%), Northeast (26%), Southeast (26%) and Southwest/West; (25%); 45% were diagnosed with breast, prostate, lung or colorectal cancer, 53% had other forms of cancer; 66% self-identified as white, 23% as African American; 23% were ages 65 and older, 22% were 55-64; 49% were diagnosed more than 2 years ago, the other half more recently. Significance testing was performed at the 90% confidence level. This abstract compares distress levels for various important aspects of life among survivors ages 55-64 to those ages 65-74. Results: See table below. The question asked was, “How distressed have you been due to the impact cancer has had on the following aspects of your life?” Conclusions: Much has been written about the high levels of general distress among those diagnosed with cancer. Holland et al have published research suggesting that older cancer patients report less distress than younger ones. This large, national study reveals quantitative data on how survivors in specific age segments experience the impact of cancer on certain aspects of their lives. Those ages 65-74 year report significantly less distress than those 10 years younger regarding finances, ability to work, physical health, ability to do the things they love, and how long they expect to live. The size and strength of the study supports that there is resiliency among older patients. Further study may lead to interventions that alleviate distress among younger people with cancer. Respondents reporting being extremely or highly distressed (5 pt scale). Total Age 55-64 Age 65-74 Total 505 110 114 100.0% 100.0% 100.0% The impact of your cancer on your family 177 28 19 35% 26% 17% Finances 154 33** 12 31% 30% 11% Ability to work 143 31** 7 28% 28% 6% How you feel physically 142 21** 9 28% 19% 8% Ability to do the things you love to do 134 21** 12 27% 19% 11% How long you expect to live 128 25** 9 25% 23% 8% Base: All Respondents (505); ** denotes significant difference between ages 55-64 and 65-74 at 90% CI
Phylogenetic analysis of longitudinal melanoma samples to reveal convergent evolution and markers of immunotherapy resistance.
Authors: David Liu, Gao Zhang, Alvin Shi, Benjamin Izar, Alexander Heyde, Gyulnara G. Kasumova, Dennie Tompers Frederick, Tabea Moll, Avinash Sahu, Eytan Ruppin, Martin Nowak, Manolis Kellis, Meenhard Herlyn, Donald P. Lawrence, Keith Flaherty, Eliezer Mendel Van Allen, Ryan J. Sullivan, Genevieve Marie Boland
Journal: Journal of Clinical Oncology (2018)

9581 Background: Immune checkpoint inhibitors (ICI) have revolutionized treatment in metastatic melanoma (MM), but progression occurs in the majority of patients (pts), and the evolution of resistance to immunotherapy in individual pts is not well characterized. Methods: Matched longitudinal tumor and germline samples from MM pts treated with ICI underwent whole exome sequencing (WES), bulk RNAseq, bisulfite sequencing, and multiplex immunofluorescence (IF) staining. Single nucleotide variants, small insertions and deletions, copy number alterations, tumor purity and ploidy, and tumor heterogeneity were inferred using standardized analytical pipelines. Phylogenetic analysis was conducted and validated using independent Bayesian clustering approaches. Results: 23 longitudinal tumor samples from a pt with delayed complete response to sequential ipilimumab and nivolumab were sequenced and analyzed. Samples spanned a three year time frame, from pre-treatment primary (n = 1), palliatively resected on-treatment lesions (n = 20), and escape lesions (n = 2, small bowel and brain) which appeared after a 2 year disease-free interval. Mutational load was similar (~500 somatic mutations per tumor) with 400 shared mutations, including driver mutations in IDH1, MAP2K1, CTNNB1, and ARID2. Phylogenetic analysis identified 5 melanoma lineages arising out of a common ancestor, with multiple spatially separated lineages co-existing in time. The escape lesions arose out of a lineage characterized by 15q arm loss (including B2M), with further acquisition of a genome doubling event as well as biallelic CDKN2A loss compared to earlier tumors within the lineage. Interestingly, biallelic PTEN loss was found across lineages and in 12/13 tumors after day 39 of therapy compared to 4/10 tumors prior (p = 0.02, Fisher's Exact), suggesting convergent evolution. Further analysis of tumor epigenetics, transcriptomics, functional proteomics, and IF is ongoing. Conclusions: Our results suggest that multiple mechanisms of immunotherapy resistance develop within the same pt. More broadly, phylogenetic analyses of longitudinal tumor samples may shed light on the clinical evolution of resistance.
Noninvasive molecular profiling of high-risk relapsed neuroblastoma by plasma cell-free DNA analysis.
Authors: Prachi Kothari, Julie Yang, Michael F. Berger, Neerav Narendra Shukla, Shakeel Modak, Dana Tsui
Journal: Journal of Clinical Oncology (2017)

10552 Background: Neuroblastoma (NB) is the most common extracranial solid tumor in children. 5-year survival rates for high-risk NB are &lt; 50% despite intense multimodality treatment. Recent studies revealed that as opposed to diagnostic samples, relapsed NB tumors have a significantly higher mutational burden as a result of clonal evolution. This poses a challenge for the development of personalized therapies and warrants molecular profiling at relapse. However, tumor samples are not always accessible at relapse. Our study evaluates the feasibility of using cell-free DNA (cfDNA) to noninvasively characterize tumor profiles at relapse to identify targetable genetic variants. Methods: Tumor specimens, plasma and matched control samples from 10 patients with high-risk stage 4 NB were collected during multimodality treatment. Samples were analyzed using the MSK-IMPACT platform, a targeted deep sequencing assay to interrogate the exons and selected introns of 410 actionable genes. Tumor samples were collected from surgeries performed either at diagnosis, disease progression, or relapse. Plasma samples were collected at a time of disease progression, at an average 395 days (range of 47-1597 days) from tumor collection. Matched control samples were used to filter germline variants. Results: We detected somatic mutations and copy number alterations in tumor tissues and cfDNA of 10/10 and 6/10 patients, respectively. These included recurrent NB drivers such as MYCN amplification and ATRX mutations. In 4 patients, cfDNA also revealed somatic variants that were not detected in the original tumor specimens, including potentially targetable mutations in NRAS, MLL2, CIC and IDH2 that were recently reported to be enriched in the relapse setting, as well as ARID1B mutation that is associated with poor prognosis. Conclusions: This study suggests that it is feasible to noninvasively profile the dynamic genetic heterogeneity of NB by plasma cfDNA analysis. Such analysis can potentially supplement tumor profiling especially in the relapse setting to guide treatment plans. Our findings call for incorporation of cfDNA analysis in clinical trials to further evaluate its utility for clinical management of NB patients.
Mutation profiling of cancer and stromal cells from patients with pancreatic ductal adenocarcinoma.
Authors: Liu Yang, Lianpeng Chang, Yaping Xu, Jiahong Jiang, Xiaoge Hu, Chao Ni, Dongsheng Huang
Journal: Journal of Clinical Oncology (2018)

e16238 Background: As one of the most lethal malignancy, pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stromal cells, which have been proven to interact with tumor cells. Exploring genomic profiling of stromal cells and its relation with cancer cells can provide novel evidence of tumorigenesis or metastasis mechanisms mediated by stromal cell. Methods: This prospective study enrolled 20 pts with operable PDAC in Zhejiang Provincial People's Hospital (Hangzhou, China) between 2016 to 2017. Formalin fixed and paraffin embedded (FFPE) tissue derived from fine-needle aspiration (FNA), surgically resected tumor tissue (T), and tumor cell/stromal cell divided from FFPE specimen by laser capture microdissection (LCM) (LCM-T/LCM-S) were collected. Target-capture deep sequencing with a panel covering 1021 genes was performed to detect somatic variants. Clonality of mutations was analyzed using PyClone with Bayesian algorithm. Results: The mean number of somatic mutations of LCM-T specimens was 4.53, higher than that of FFPE and T samples (2.38 and 2.86, p= 0.0479). Similarly, the allele frequency of variants detected in LCM-T were also significantly higher than those in FFPE and T specimens (p= 0.0120). KRAS (84.21%, 16/19) and TP53 (84.21%, 16/19) were the most recurrent mutated genes. Mutant frequency of top four genes (KRAS, TP53, SMAD4 and CDKN2A) were consistent with three published data of PDAC (QCMG, Nature, 2016; MSKCC, Nat Med, 2017; TCGA). For 13 paired LCM-T and LCM-S specimens, 42 (78%, 42/54) variants could be present in LCM-S, among which most were clonal mutations (67%). Mutations specifically detected in LCM-S, such as mutations in KRAS, ATRX, EZH2, ZMAT3, CBL, EWSR1 and MYCL1, had been reported to be related with tumorigenesis and metastasis. Conclusions: LCM-based method is an appropriate way to collected samples of PDAC. Genomic relation and discrepancy between cancer and stromal cell may bring new insight into the metastatic mechanisms and poor outcome of PDAC.