tbuckley/cabot-search huggingface dataset:
Actionable coalterations in breast tumors with pathogenic mutations in the homologous recombination DNA damage repair pathway.
Authors: Arielle Lutterman Heeke, Joanne Xiu, Filipa Lynce, Paula Raffin Pohlmann, Gregory A. Vidal, Claudine Isaacs, Sandra M. Swain, Lee S. Schwartzberg, Antoinette R. Tan
Journal: Journal of Clinical Oncology (2019)

3132 Background: Homologous recombination (HR) deficient breast tumors may have genomic alterations that suggest responsiveness to targeted therapies other than PARP inhibitors. Methods: Comprehensive molecular profiles of 4,647 breast tumors performed at Caris Life Sciences using 592-gene NGS (average read depth 500X) were reviewed to identify somatic pathogenic mutations in HR genes ARID1A, ATM, ATRX, BAP1, BLM, BRCA1/2, BRIP1, CHEK1/2, FANCA/C/D2/E/F/G/L, KMT2D, MRE11, NBN, RAD50/51/51B &amp; PALB2, as well 41 markers associated with treatment response. Results: Overall, 17.9% of breast tumors have HR mutations (HR-MT, 831/4647). HR-MT is seen most in HER2– disease [hormone receptor (hr)+/HER2– (18.3%, n=2183), TNBC (18.2%, n=1568), hr–/HER2+ (12.9%, n=217)]. Mean TMB is higher for HR-MT tumors across subtypes (9.2 mut/Mb vs 7.6 WT, p=&lt;0.0001) &amp; independent of MS status. HR-MT hr–/HER2+ tumors are more likely to have PD-L1 overexpression (25% vs 13.1% hr–/HER2+ WT, p=0.10), whereas MSI is more prevalent in HR-MT HER2– (hr+/HER2– 2.3%, TNBC 1.4%, HER2+ 0%). Mutations in chromatin remodeling genes (*) are more common in HR-MT. Additional co-alterations are outlined in the Table. Conclusions: In breast cancer, HR-MT is associated with HER2– disease &amp; markers of response to immunotherapy. Clinical trials combining HRD targeted agents &amp; immunotherapy are underway &amp; could be enriched through comprehensive molecular profiling. Mutations were identified in both HR-MT &amp; HR WT tumors that suggest other targets for treatment. [Table: see text]
Significance of examined lymph node number in accurate staging and long-term survival in resected stage I-II pancreatic cancer: More is better? A large international population-based cohort study.
Authors: Lei Huang, Lina Jansen, Yesilda Balavarca, Lydia van der Geest, Valery Lemmens, Bas Groot Koerkamp, Hjalmar van Santvoort, Robert Grützmann, Marc G. Besselink, Petra Schrotz-King, Hermann Brenner
Journal: Journal of Clinical Oncology (2019)

6503 Background: Examined lymph node (ELN) number is an important quality metric in cancer care. This large international cohort study aimed to investigate the associations of ELN number with accurate staging and long-term survival in pancreatic cancer (PaC) and to robustly determine the minimal and optimal ELN thresholds. Methods: Population-based data on patients with stage I-II PaC resected in 2003-2015 from the US Surveillance, Epidemiology, and End Results (SEER)-18 Program and Netherlands National Cancer Registry (NCR) were analyzed. Associations of ELN number with stage migration and survival were evaluated using multivariable-adjusted logistic and Cox regression models, respectively. The series of odds ratios (ORs) for stage migration and hazard ratios (HRs) for survival with more ELNs were fitted using a LOWESS smoother, and structural breakpoints were determined by Chow test. Results: Overall 18,303 patients were analyzed. With increasing ELN number, both cohorts exhibited significant proportional increases from node-negative to node-positive disease (OR SEER-18 = 1.05, 95% CI = 1.04-1.05; OR NCR = 1.10, 95% CI = 1.08-1.12) and serial improvements in survival (HR SEER-18 = 0.98, 95% CI = 0.98-0.99; HR NCR = 0.98, 95% CI = 0.97-0.99) per additional ELN after controlling for confounders. Associations for stage migration and survival remained significant in most stratifications by patient, tumor, and treatment factors. Cut-point analyses suggested a minimal threshold ELN number of 12 and an optimal number of 19, which were validated both internally in the derivative US cohort and externally in the Dutch cohort with the ability to well discriminate different probabilities of both survival and stage migration. Conclusions: In stage I-II PaC, more ELNs are associated with more precise nodal staging, which might largely explain the survival association. Our results robustly conclude 12 ELNs as the minimal and suggest 19 ELNs as the optimal cut-points, for evaluating quality of lymph node examination and possibly for stratifying postoperative prognosis. Our findings provide important references for defining population-based quality metrics in PaC care.
Tumor mutational burden (TMB) profile of <i>K-RAS/TP-53</i> co-mutation in metastatic non-small cell lung cancer (m-NSCLC).
Authors: Abdul Rafeh Naqash, Paul R. Walker, Mahvish Muzaffar, Rebecca Feldman, Maida Hafiz, Stephen V. Liu, Hirva Mamdani, Anokhi Patel, Hossein Borghaei, Nitika Sharma, Jorge J. Nieva, Yanis Boumber, Ari M. Vanderwalde, Patrick C. Ma, Ihab Eldessouki, David Craig Portnoy, Alexander I. Spira, Li V. Yang, Nagla Fawzy Abdel Karim
Journal: Journal of Clinical Oncology (2019)

2626 Background: Early data suggests that co-occurring genetic events define biological heterogeneity in K-RAS mutant NSCLC, with K-RAS/ TP-53 (KP) co-mutated subset having potential therapeutic vulnerabilities to immune checkpoint blockade (ICB). To explore the immunological basis for these findings, we evaluated the immune biomarker profile (TMB/PD-L1) in KP mutant m-NSCLC using a large next-generation sequencing (NGS) dataset. Methods: Caris life sciences NGS dataset consisting of 1317 m-NSCLC tissue samples from 2016-18 was queried. PD-L1 pos was defined as ≥ 1% staining using 22c3 Dako assay. TMB was measured by counting all somatic non-synonymous missense mutations using targeted NGS (592 genes). TMB-high (H) was defined as ≥ 10 mutations/Megabase (mut/Mb). P-values were calculated using Chi-square and Mann-Whitney test. Results: K-RAS mutations were identified in 28.7% (378/1317). Within this K-RAS mutant group, KP subset constituted 49.4% (187/378), remaining were K-RAS mutated/ TP-53 wild type (K-Pwt). 72.2 % (135/187) of KP had PD-L1 pos with 51.9% (97/187) having PD-L1 ≥ 50%. KP had higher median TMB vs. K-Pwt (14.5 vs. 9.0 mut/Mb, p&lt;0.001) and higher % of TMB-H vs. K-Pwt (79.9 vs. 45.1%, p&lt;0.001; Table). Even in the PD-L1 neg group, KP had higher % of TMB-H vs. K-Pwt (86.5 vs. 41.5%, p&lt;0.001). K-RAS or TP-53 exon-subtypes had no difference in median TMB or % of TMB-H. Across metastatic sites, brain tissue had the highest % of KP subset (38.3%, 68/187) followed by bone (28.9%, 54/187). Within KP subset, brain tissue had higher median TMB vs. bone (16 vs. 11 mut/Mb, p&lt;0.01) as well as greater % of TMB-H vs. bone (86.5 vs. 68.5%, p=0.01). Conclusions: This is the largest dataset to date highlighting the unique immune profile of KP mutant m-NSCLC. Our results show that KP subset has a significantly higher TMB than K-Pwt, especially in the PD-L1 neg subgroup. Metastatic site-specific variations in TMB were also observed for the KP subset. These findings could have therapeutic implications in guiding patient selection for ICB and merit prospective investigation.[Table: see text]
The role of anticoagulants for the primary prophylaxis of venous thromboembolism in patients with malignancy: A systematic review and meta-analysis of randomized controlled trials.
Authors: Mahmoud Barbarawi, Yazan Zayed, Babikir Kheiri, Inderdeep Gakhal, Owais Barbarawi, Areeg Bala, Ahmad Alabdouh, Ahmed Abdalla, Tarek Haykal, Sowmya Goranta, Ghassan Bachuwa, Khalil Katato
Journal: Journal of Clinical Oncology (2019)

e14691 Background: Venous thromboembolism (VTE) is a common cause of morbidity and mortality in cancer patients. Despite this, pharmacologic prophylaxis for the primary prevention of VTE is not offered for most medical oncology patients, likely due to the competing risk of bleeding. Recent trials may offer new insight into the role of anticoagulants for the prevention of cancer associated thrombosis (CAT). Accordingly, we conducted a meta-analysis of randomized controlled trials (RCTs) that evaluated anticoagulants for the primary prophylaxis of VTE in cancer patients. Methods: A literature search of Pubmed/MEDLINE, Embase, and Cochrane library was done by two investigators. All RCTs that used anticoagulant in cancer patients for primary prevention of VTE were included. The primary outcomes were VTE events and all-cause mortality; VTE related mortality and major bleeding were secondary outcomes. A random effects model was used to report the risk ratios (RR) with 95% confidence intervals (CIs), and odds ratios (ORs) with Bayesian 95% credible intervals for both direct and network meta-analysis, respectively. Results: Twenty-four RCTs were included with a total of 13,338 patients (7,197 received anticoagulants and 6,141 received placebo). Of these trials, 19 used low-molecular weight heparin (LMWH), 3 used direct oral anticoagulants (DOACs), 2 used warfarin, and 1 used heparin. Mean age ranged between 54.6 to 68.1 years, with 50.5% male. Compared with placebo, LMWH or DOACs were associated with reduced VTE events (RR 0.58; 95% CI 0.48-0.69, p &lt; 0.001) and (RR 0.39; 95% CI 0.24-0.63, p &lt; 0.001), respectively. LMWH compared with placebo was associated with decreased VTE, and all-cause mortality (P &lt; 0.05). While DOACs was associated with decreased PE events only compared with placebo (RR 0.28; 95% CI 0.11-0.71, P = 0.008). Regarding the safety outcome, LMWH and DOACs were associated with an increased risk of major bleeding compared with placebo, but this did not reach statistical significance in this study (RR 1.26; 95% CI 0.92-1.74, p = 0.16 and RR 1.76; 95% CI 0.83-3.73, p = 0.14). Results regarding VTE events and major bleeding were consistent in both lung and pancreatic cancers. Conclusions: Both LMWH and DOACs were associated with a lower number of VTE events compared with placebo. However, this potentially protective effect must be balanced against a possible increased risk of bleeding for some patients.
A phase I study of oncolytic immunotherapy of metastatic neuroendocrine tumors using intralesional rose bengal disodium: Cohort 1 results.
Authors: Timothy Jay Price, Gabby Cehic, Eric Andrew Wachter, Ian Kirkwood, Rubin Sebbon, Lisa Leopardi, Jessic Reid, Anas Alawawdeh, Susan J Neuhaus, Guy Maddern
Journal: Journal of Clinical Oncology (2019)

4102 Background: Metastatic neuroendocrine neoplasms (mNEN’s) originating in the gastrointestinal tract are frequently slow growing yet both symptom and disease control remain important. Treatment options include resection, chemoablation, systemic somatostatin analogues (SSA) or peptide receptor radionuclide therapy (PRRT), but additional options are needed and one such option is hepatic intralesional (IL) rose bengal disodium (PV-10), an oncolytic immunotherapy under development for solid tumours. Methods: This phase 1 study is evaluating the safety, tolerability and reduction of biochemical markers and symptoms resulting from percutaneous administration of PV-10 in 12 subjects with progressive mNEN with hepatic lesions not amenable to resection or other potentially curative therapy. Target lesion(s) must be 1.0 - 3.9 cm in longest diameter. In Cohort 1 (n = 6) subjects receive PV-10 to a single hepatic lesion per treatment cycle, and can receive PV-10 to additional uninjected hepatic lesions ≥6 weeks after prior injection. Cohort 2 (n = 6) subjects may receive injection of multiple lesions per treatment cycle. The primary endpoint is safety. Secondary endpoints include objective response rate (ORR) assessed by contrast enhanced CT and 68 Ga-DOTATATE PET, biochemical response (CgA) and patient-reported outcome (EORTC QLQ-C30 and GI.NET21). Results: Cohort 1 has fully enrolled, with 4 of 6 subjects male, median age 65yrs, range 47-72. Primary sites were: small bowel 3, pancreas 2, caecal 1; grade: Gd1 = 5, Gd2 = 1. All patients received prior SSA and PRRT. Median CgA was 645 (range 30-2819). To date 1 subject has received 4 PV-10 treatment cycles, 1 has received 2 cycles, and 4 have received a single cycle. Toxicity has been acceptable, including pain post procedure, carcinoid flare and nausea. LFT’s have remained stable. Overall QOL score was stable for 5 of 6 subjects. ORR in injected lesions is 50% (progression in 1 subject), with overall disease control of 84%. CgA response: 5 stable, 1 progression. One subject with “carcinoid pellagra” had rash resolution. Response follow-up is ongoing and additional efficacy and functional data will be presented. Conclusions: Hepatic IL PV-10 elicited no safety concerns with encouraging evidence of both local and systemic disease control. Enrolment to Cohort 2 is underway. Clinical trial information: NCT02693067.
Retrospective study of neuroendocrine breast cancer cases from a single institution in Québec.
Authors: Marie-Michèle Plante, Paul-Michel Houle, Catherine C. M. Prady, Samuel Martel, Sameh Geha, Michel Pavic
Journal: Journal of Clinical Oncology (2019)

e12588 Background: Within numerous breast cancer types, the neuroendocrine subtype distinguishes itself from the others by its rarity. Most of the actual data comes from European and Asian retrospective studies, whom were mostly published before the 2012 WHO classification. Methods: The aim of our study was to describe a North American cohort of neuroendocrine breast cancer tumors homogenized for the latest WHO classification of 2012. We describe the clinical presentation, diagnostic, therapeutic management and prognosis of our population recensed between 2006 and 2016 at the CHUS in Sherbrooke, Québec. A pathological review of the cases was done to unify the cohort by the latest WHO classification. Results: 59 cases were identified from the 5238 cases of breast cancer evaluated between 2006 and 2016. After review from the pathologist, 9 cases were discarded since they did not meet the diagnostic criterias. 47 patients had invasive breast carcinoma with neuroendocrine differentiation, 4 patients had poorly differentiated/small cell carcinoma and none had well differentiated neuroendocrine tumor. 44 patients were not metastatic whereas 7 patients were metastatic at disease onset with a mean age at diagnosis of 70 and 67 years respectively. 10% (4/44) developed a metastatic disease with a median time of 30 months. The mean size of the tumor was 26,1 mm and had a mean Ki67% of 28,3%. All of our patients were ER+, 98% PR+ and 4% Her2+. None had a triple negative disease. 6 patients were SBR grade 1, 31 were grade 2 and 12 were grade 3. The median follow-up for the non-metastatic patients was 42 months and 23 months for the metastatic patients. The median overall survival of our metastatic cohort was 30 months. The histologic subtype did not statistically influence the overall survival and the progression-free survival. Conclusions: Our study is the largest North American cohort of neuroendocrine breast cancer tumors classified with the latest WHO classification of 2012. More details about each subgroup analysis will be presented at the meeting. Even with this classification, the histologic diagnosis remains challenging. Further studies are needed to better characterize these patients and define their optimal management.
Next-generation sequencing of primary prostate cancer tumors to reveal actionable opportunities for clinical management.
Authors: Daniel James Crona, Anthony Drier, Jing Daisy Zhu, Emily Fox Bell, Margaret Rose Sketch, Alexandra Boland, Amy Garrett, Lin Wang, Khalis Mitchell, Scott A. Tomlins, Elizabeth Claire Dees, Paul Alphonso Godley, Mary Dunn, Tracy L Rose, Ethan M. Basch, Matthew I. Milowsky, Young E. Whang
Journal: Journal of Clinical Oncology (2019)

e16582 Background: The Strata Trial (NCT03061305) is a multi-institutional precision oncology collaboration structured as an observational protocol that aims to match patients to genomically guided therapies. Methods: Selected University of North Carolina (UNC) metastatic prostate cancer (mPC) patients were enrolled on this IRB-approved study. Formalin fixed paraffin-embedded primary tumor specimens, without matched germline controls, were sent for targeted next generation sequencing (NGS) to detect actionable variants, including: mutations in 87 genes, copy number variations in 31 genes, gene fusions in 46 gene drivers, and microsatellite instability (MSI) status. mPC-related genes of specific interest included: AR, ATM, BRCA1/2, ERG, MSH2, MSH6, PTEN, RB1, and TP53. Results: Of the 108 cases sequenced, 6 (6%) failed testing. Of the 102 mPC patients with sequence data, the median age was 69 (47-86), 60 (59%) were white, 35 (34%) were black, 1 (1%) was Asian, and 6 (6%) declined to identify race. NGS data revealed 122 variants in 27 genes: 73 patients (71%) had at least one variant. Among those 73 patients, 38 (52%) had only 1 variant, 24 (33%) had 2 variants, 8 (11%) had 3 variants, and 3 (4%) had 4 variants. TMPRSS2-ERG fusions occurred most frequently (51%), followed by TP53 variants (38%), and PTEN variants (16%). Only 8% of patients had variants in DNA damage repair genes, including ATM (3%), BRCA2 (3%) and MSH2 (2%). Two patients with MSI high tumors were treated with pembrolizumab, while 4 patients with deep BRCA2 or ATM deletions were eligible for trials of PARP inhibition. Conclusions: Our UNC experience shows that a high proportion of primary prostate cancer tumors from mPC patients have genomic variants, and two patients were treated based on these data. Limited actionability may reflect the landscape of currently FDA approved mPC treatments available clinical trials, or due to short duration of follow-up after enrollment on the Strata Trial.
Clonal tumor evolution under induction chemotherapy and concurrent radiochemotherapy (RCHT) in patients with resectable stage IIIA (N2) and selected IIIb non-small cell lung cancer (NSCLC): Molecular analysis of the ESPATUE randomized phase III trial.
Authors: Sayedmohammad Hasheminasab, Maximilian Knoll, Christian Schwager, Ali Nowrouzi, Nicole Pfarr, Wilko Weichert, Stefan Rieken, Christoph Pöttgen, Thomas Christoph Gauler, Wilfried Eberhardt, Martin H. Schuler, Dirk Theegarten, Clemens Aigner, Juergen Debus, Martin Stuschke, Amir Abdollahi
Journal: Journal of Clinical Oncology (2019)

8543 Background: A better understanding of molecular mechanisms governing clonal tumor evolution under RCHT is of utmost importance for development of novel biomarker and targeted therapies. We report here the first attempt to decipher RCHT induced cellular and molecular perturbation in NSCLC on an integrative multiscale level. Methods: Patients with stage III disease received induction chemotherapy with cisplatin and paclitaxel followed by concurrent RCHT with 45 Gy (1.5 Gy twice daily) and cisplatin/vinorelbine according to the ESPATUE protocol. Tumor tissue was sampled from tumor enriched areas marked by pathologists at diagnosis (biopsies, n= 23) and post RCHT during surgical resection (n=22, ESPATUE-Arm B) corresponding to 16 paired samples (PS). Transcriptome analysis (n=45, 16PS), methylome analysis (n=35, 12PS), deep whole exome sequencing (WES) including copy number variation (CNV) analysis by low-pass whole genome sequencing (WGS, n=34, 13PS) were performed. A confirmatory targeted ultra-deep NGS for 41 genes was conducted (n=20PS). Results: Similarity plots of delta transcriptome data identified three distinct clusters of tumor evolution under RCHT. Cluster 1 was highly enriched for STS (5 out of 7 Pat.) compared to cluster 3 enriched for LTS (4 out of 6), p&lt;0.02. 146 transcripts were differentially expressed as the function of RCHT (FDR &lt;0.05). Among them, 61 genes were upregulated and enriched for ECM and tissue remodeling (COL6A3/4, Col14A1, LAMA2, PAI1, MMP2), p53 signaling (p21, GADD45B) and stress response (FOSB, EGR1) pathways, p&lt;0.01. 39 downregulated genes were enriched for genes attributed to cell cycle- and DDR signaling (FANCI, SLX1A) p&lt;0.05. 4221 CpG were differentially methylated (FDR&lt;0.05). Seven inversely regulated genes were found with SLIT3 and TBX5 being among upregulated and hypomethylated genes. WES analysis revealed patterns of tumor evolution with a range of clonal diversity. In 5/13 pairs the clonal composition remained unchanged after RCHT. Approximately 500 post RCHT exclusive mutations were found. Conclusions: Clonal, transcriptional and methylome dynamic of tumor evolution towards RCHT selection pressure is unrevealed in patients with locally advanced NSCLC. This multi-scale dynamic approach provides novel means for development of biomarker and therapeutic targets. Clinical trial information: ESPATUE.
SP0171 THE NEW COMPLEMENT THERAPEUTICS
Authors: Claire Harris
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> Despite a wealth of knowledge in the complexities of the complement cascade, and many decades of endeavour, very few drugs have progressed to the clinic. Recently, strong genetic associations of complement with common diseases have emerged and fuelled the fire of complement drug discovery leading to an explosion in complement therapies in development; while many of these agents and others before them have failed to progress, their legacy is key to future success. Obstacles to successful drug development include target concentration and turnover rates, and ability to target to the appropriate site. The drug development landscape is littered with agents that have failed at the preclinical or early clinical stage; their modes of action and modalities are wide-ranging. It is becoming increasingly clear that an understanding of disease mechanism and matching of drug modality and mode of action to the right disease and patient population (or stratified sub-population) is critical to success. A number of drugs are now in phase 3 clinical development for a number of different diseases. In this talk, innovative approaches that are emerging to overcome obstacles blocking success will be explored, highlighting drugs in development which employ new state-of-the-art strategies. These include 'homing" drugs and a new generation of orally bioavailable molecules. Complement biomarkers that can decipher disease mechanism and be applied for patient stratification will be discussed. It is clear that a range of different drugs, or combination of drugs, will be needed for effective management of the many and diverse complement-mediated diseases. <h3>Disclosure of Interests:</h3> None declared