tbuckley/cabot-search huggingface dataset:
The mutational landscape of MSI-H and MSS colorectal cancer.
Authors: Enxiao LI, Ying Hu, Wenbo Han, Tianshu Liu, Fang Lv, Lili Zhao, Yang Liu, Yanhui Chen, Henghui Zhang
Journal: Journal of Clinical Oncology (2019)

e15122 Background: The microsatellite instability-high (MSI-H) phenotype confers good prognosis and greater response to immunotherapy in colorectal cancer(CRC). The mutational landscape of MSI-H CRC is unclear. This study was designed to illustrate the difference mutation profile between the MSI-H and microsatellite stable (MSS) CRC. Methods: Tumor tissue and matched blood samples from 40 patients with colorectal cancer were collected. Microsatellite instability (MSI) status were detected by PCR-amplified for five mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27). Mutation profiles were sequenced by a cancer gene-targeted NGS panel. Results: The tumor mutation burden(TMB) of the MSI-H CRC patients was significantly higher than those MSS CRC patients. Compared with the MSS CRC, MSI-H CRC involved more genes and pathways. Furthermore, we found the copy number variation (CNV) was different between the two groups. The copy number instability (CNI) score of MSI-H CRC patients was significantly lower than those MSS CRC patients. MSI-H CRC patients showed a higher frequency of TP53 gene CNV gain compared with MSS CRC (41% (7/17) in MSI-H CRC versus 13% (3/23) in MSS CRC). Conclusions: The mutational landscape are different between the MSI-H and MSS colorectal cancer. Compared with MSS colorectal cancer, the MSI-H colorectal cancer patients have higher tumor mutation burden(TMB) and lower copy number instability (CNI) score. Keywords: colorectal cancer, microsatellite instability, tumor mutation burden, copy number instability. Abbreviations CRC, colorectal cancer; TMB, tumor mutation burden; MSI-H, The microsatellite instability-high; MSS, microsatellite stable; CNV, copy number variation.
Treatment patterns and outcomes among patients with advanced cutaneous squamous cell carcinoma (CSCC) in a US community oncology setting.
Authors: C. Lance Cowey, Nicholas J. Robert, Kalatu Davies, Janet L. Espirito, Jennifer R. Frytak, Israel Lowy, Matthew G. Fury
Journal: Journal of Clinical Oncology (2019)

e21033 Background: Advanced CSCC is a term that encompasses the locally advanced (laCSCC) and metastatic (mCSCC) condition. For advanced CSCC patients who receive conventional anticancer systemic treatment, there are limited data regarding treatment patterns and clinical outcomes. Methods: This was a retrospective, observational study of adult patients with laCSCC and mCSCC who initiated first-line (1L) systemic treatment from 1/1/2008 to 12/31/2015, with follow-up to 9/30/2017. Data were abstracted from the US Oncology Network’s iKnowMed SM electronic health record database, supplemented by chart review. ECOG performance status (PS) of 0 or 1 was required for inclusion. Exclusion criteria included tumor of unknown primary site, treatment with an anti-PD-1/anti-PD-L1 agent, participation in clinical trial, and concurrent primary cancer. Duration of therapy (DOT) and overall survival (OS) were analyzed by Kaplan-Meier method. Response rate was calculated as the proportion of patients who achieved physician assessed-response. Results: 82 patients met inclusion criteria (17 laCSCC and 65 mCSCC). Median age at start of 1L treatment was 75y; 85% were male, 79% Caucasian, 88% of patients had an ECOG PS of 1, 90% had prior surgery, 84% prior radiotherapy, and 8.5% had prior organ transplant. The most common 1L regimens were carboplatin + paclitaxel (27% of patients) and cetuximab monotherapy (24%). Median 1L DOT was 2.4 mo for the overall population; 4.1 mo for laCSCC, 2.3 mo for mCSCC. Physician-assessed response rate for 1L therapy was 18.3% overall; 17.6% for laCSCC, and 18.5% for mCSCC. Median OS from the start of 1L treatment was 15.3 mo (95% CI, 10.4-21.0) overall; 16.2 mo for laCSCC, and 15.3 mo for mCSCC. Only 24 patients (29%) received 2L therapy. Conclusions: This is the largest retrospective data set regarding advanced CSCC patients treated with conventional chemotherapy. Efficacy was low in both laCSCC and mCSCC. These data provide historic benchmarks for outcomes in advanced CSCC patients prior to the FDA approval of cemiplimab-rwlc.
Aflibercept (Afl) for patients (pts) with metastatic colorectal cancer (mCRC): Clinical predictors of nonhematologic (nonhem) toxicity.
Authors: Liubov Yu Vladimirova, Mikhail Fedyanin, Viacheslav Chubenko, Olga Fakhrudinova, Larisa Bolotina, Fedor Vladimirovich Moiseenko, Alfiya Khasanova, Alexandr Belonogov, Hedi Musaeva, Olga Novikova, Irina Stradaeva, Guzel Mukhametshina, Rashida Orlova, Polina Feoktistova, Evgeniya Kuzmina, Elena Karabina, Oksana Nekrasova, Viktor Sherstnev, Andrey Micshenko, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2019)

e15007 Background: Afl is one of the antiagiogenic agents used for the treatment for mCRC. Cardiovascular toxicity of Afl is shown to be a main reason of the drug discontinuation but there are no studies on factors associated with nonhem adverse events(AEs). The aim of the study was to define clinical factors associated with the development of Gd.3-4 nonhem AEs. Methods: Pts with mCRC treated with FOLFIRI+Afl were included in a multicenter prospective base from 2016-18. Multivariative regression analysis was performed with Chicago, IL v.22.0. Factors studied included demographic, disease characteristics, data about concomitant diseases(CD) and concomitant medications. Results: 278 pts with mCRC from 18 centers were included. Mean age – 58.7, 48.6% were male, mean number of metastases– 2. ECOG 0-1–97.5%pts. RASm had 133 (47.8%) pts. Afl+FOLFIRI was used as the 2nd line therapy–in 67.6%. CD were in 194 (69.8%), cardiovascular–in 175 (62.9%). ORR(CR+PR)17.3%, SD-43.9%. MedPFS was 6.0 mos. Afl discontinuation due to AEs 11.9%. AE were reported in 201 (72.3%), Gd3-4 – in 69 (24.8%); nonhem AEs – in 178 (64%), Gd3-4–52 (18.8%)pts. Among Gd3-4 nonhem AEs were arterial hypertension Gd1-2–77 (27.7%), Gd3-4-in 36 (12.9%), vomiting Gd1-2–45 (16.2%), diarrhea Gd1-2–in 32 (11.5%), asthenia Gd1-2 –in 29 (10.4%), hepatotoxicity Gd1-2–in 2(5%), thrombosis–in 2 (5%) pts. Multivariate regression analysis showed that among the factors studied number of lines of treatment (OR1.4,95%CI1.1-2.1,p=0.03) and CD requiring medical support (OR 2.0,95%CI1.1-3.7,p=0.03) were found as independent factors of nonhem AE Gd3-4 development. ACE-inhibitors (OR2.2,95%CI1.2-4.3,p=0.02), calcium-channel blockers (CCB)(OR4.1,95%CI1.6-10.4,p=0.003 ) were the medical drugs considered to be significant. Conclusions: Number of lines and CD requiring medical support, especially with ACE-inhibitors or CCB, identifies a significant risk of developing cardiovascular non-hem AEs Gd3-4 with FOLFIRI + Afl.
Validation of G8 and its acuracy as a predictor of object in oncological patients with age of ≥ 60 YEARS. prospective cohort of 889 brazilian elderly cancer patients.
Authors: Jurema Telles O Lima, Raissa Viana, Letícia telles Sales, Mirella Rebello, José Natal Figueiroa, Anke Bergmann, Zilda Cavalcanti, Amanda L LINS Mello, Maria Julia Gonçalves Mello, Luiz Claudio Santos Thuler
Journal: Journal of Clinical Oncology (2019)

e23036 Background: The G8, a questionnaire with 8 questions, has been specifically developed as a screening tool for vulnerability in older patients (70+) with cancer, with results suggesting 14 points as a threshold (equivalent to 90% sensitivity and 60% specificity). Its prognostic value for early death was not evaluated in Brazilian population. Methods: Cancer patients (60 years or older) with solid organ malignancies were included in a prospective cohort in a Brazilian Geriatric Oncology Clinic, between 2015 and 2017. Before the start of any oncologic therapy, a Comprehensive Geriatric Assessment (CGA) with 12 questionnaires was performed. For this study, we analyzed the G8 (Figure 1) considering items from Mini Nutritional Assessment (MNA), polypharmacy ( &gt; 3 medications per day), self reported health status and the age of patient. G8 score was considered abnormal if ≤14, and early death (within six months of surveillance) was the gold standard for the study accuracy. Cox proportional hazard risk and Kaplan-Meier survival curves were performed. Results: 889 patients were enrolled and there were 145 (16.3 %) early deaths. Overall, 52% were male, the extremes of age were from 60 to 97 (mean 72.5 ± 0.24), and 38% were &lt; 70 years old. The most common cancers were prostate (31.2%), digestive tract (21.9%) and breast (16.0%); 30.4% were metastatic. 470 (52,9%) from all patients had abnormal (≤ 14) G8 score; 128 (27.2%) who had abnormal G8 score died within the first 6 months, versus 17 (4.1%) with normal score (Table 1). At cut point 14, the G8 sensitivity was 88.3% (CI95% 81.9 - 93.0); specificity 54.0% (CI95% 50.4 - 57.7); positive predictive value 27.2% (CI95% 23.3 - 31.5); negative predictive value 95.9% (CI95% 93.6 - 97.5); area under ROC curve was 0.819 (Figure 2). For those older than 70, the G8 sensitivity was 91% (CI95% 83.4 - 96.1). Abnormal scores showed significant differences in survival probability (Figure 3). Conclusions: G8 score is a strong and consistent predictor of overall 6-month survival, regardless of age, metastatic status or tumor site in Brazilian older (60 or older) oncologic patients. This finding strengthens the clinical utility of this instrument in the Geriatric Oncology and may be an option to extend the practice of Geriatric Assessment in countries with medium-low economic development, even in the younger elderly population.
Development and clinical validation of Lantern Pharma’s AI engine: Response algorithm for drug positioning and rescue (RADR).
Authors: Umesh Kathad, Yuvanesh Vedaraju, Aditya Kulkarni, Gregory Tobin, Panna Sharma
Journal: Journal of Clinical Oncology (2019)

3114 Background: The Response Algorithm for Drug positioning and Rescue (RADR) technology is Lantern Pharma's proprietary Artificial Intelligence (Al)-based machine learning approach for biomarker identification and patient stratification. RADR is a combination of three automated modules working sequentially to generate drug- and tumor type-specific gene signatures predictive of response. Methods: RADR integrates genomics, drug sensitivity and systems biology inputs with supervised machine learning strategies and generates gene expression-based responder/ non-responder profiles for specific tumor indications with high accuracy, in addition to identification of new correlations of genetic biomarkers with drug activity. Pre-treatment patient gene expression profiles along with corresponding treatment outcomes were used as algorithm inputs. Model training was typically performed using an initial set of genes derived from cancer cell line data when available, and further applied to patient data for model tuning, cross-validation and final gene signature development. Model testing and performance computation were carried out on patient records held out as blinded datasets. Response prediction accuracy and sensitivity were among the model performance metrics calculated. Results: On average, RADR achieved a response prediction accuracy of 80% during clinical validation. We present retrospective analyses performed as part of RADR validation using more than 10 independent datasets of patients from selected cancer types treated with approved drugs including chemotherapy, targeted therapy and immunotherapy agents. For an instance, the application of the RADR program to a Paclitaxel trial in breast cancer patients could have potentially reduced the number of patients in the treatment arm from 92 unselected patients to 24 biomarker-selected patients to produce the same number of responders. Also, we cite published evidence correlating genes from RADR derived biomarkers with increased Paclitaxel sensitivity in breast cancer. Conclusions: The value of RADR platform architecture is derived from its validation through the analysis of about ~17 million oncology-specific clinical data points, and ~1000 patient records. By implementing unique biological, statistical and machine learning workflows, Lantern Pharma's RADR technology is capable of deriving robust biomarker panels for pre-selecting true responders for recruitment into clinical trials which may improve the success rate of oncology drug approvals.
Ondansetron versus palonosetron as a marker of non-adherence to antiemetic prophylaxis guidelines in highly emetogenic chemotherapy.
Authors: Eric Roeland, Kathryn Jean Ruddy, Thomas William LeBlanc, Rebecca Anne Clark-Snow, Rita S. Wickham, Gary Binder, Silvia Sebastiani, Ravi C. Potluri, Eros Papademetriou, Luke M. Schmerold, Rudolph M. Navari
Journal: Journal of Clinical Oncology (2019)

e23108 Background: ASCO antiemetic guidelines recommend upfront triple prophylaxis (NK1 receptor antagonist (RA) + 5HT3 RA + dexamethasone) for patients receiving highly emetogenic chemotherapy (HEC). Physicians exhibit high variation in HEC guideline adherence, principally involving inclusion of NK1 RA. Whether adherence is associated with selection of the specific 5HT3 RA agent remains inadequately studied. Methods: In the IBM Explorys electronic health record database, we used procedure and diagnosis codes to identify HEC courses and related nausea/vomiting (NV) from 2012 to 2018. We defined HEC guideline adherence as triple prophylaxis at chemotherapy initiation. We assigned HEC courses for ≥ 7 day cycles of cisplatin or anthracycline + cyclophosphamide (AC), or carboplatin (≥ 14 day cycles as a proxy for AUC ≥ 4) to prescribing oncologists based on encounter frequency. We categorized 5HT3 RA use of each physician treating ≥ 5 HEC courses based on their most commonly used 5HT3 and performed descriptive statistics. Results: Of 12,262 HEC courses, 57% involved physicians having greater use of ondansetron (OND) (mean OND to palonosetron (PALO) ratio of 3.9:1). These courses had lower guideline adherence (due to NK1 RA omission) and higher rates of NV for combined HEC, AC, and carboplatin. NV rates for cisplatin did not vary by 5HT3 agent used. Courses involving physicians with greater PALO use (mean OND:PALO ratio of 0.2:1) had superior adherence and NV rates, despite involving a slightly higher risk population (younger and/or female). Conclusions: According to HEC antiemetic guidelines, NK1 RA use should occur independent of 5HT3 RA agent selection. However, we observed less NK1 RA use where OND was preferred, which may have caused the observed higher rates of NV with OND. Further evaluation should assess whether pharmacy cost minimization is a driver of both OND preference and NK1 omission in HEC. [Table: see text]
Immune Responses in Context
Authors: Bram Slütter, Johan Kuiper
Journal: Circulation (2019)

Atherosclerosis is now known as an inflammatory disease that proceeds in the context of dyslipidemia.The role of inflammation in the process of cardiovascular disease (CVD) has more recently been shown in the CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study), in which patients with a high level of inflammation, as determined by their plasma high-sensitivity C-reactive protein levels, benefited from neutralization of the proinflammatory cytokine interleukin (IL)-1β. 1 The CANTOS trial merely shows the role of the innate immune response in CVD, but the role of T cells as important components of the adaptive immune response has been studied intensively in the context of CVD.In human lesions, T cells are abundantly present from early lesions until the stage of advanced complicated and ruptured lesions. 2 Of the various classes of T cells, CD4 + T cells have received the most attention in atherosclerosis research.CD4 + T cells are presumed to be activated via antigens derived from modified proteins that are associated with CVD such as oxidized low-density lipoprotein presented via major histocompatibility complex (MHC) class II (HLA II) molecules in the context of costimulatory molecules and cytokine signaling.Early studies already demonstrated that CD4 + T cells derived from human atherosclerotic lesions respond to oxidized low-density lipoprotein in an HLA class II-dependent manner, indicating that T cells in patients with CVD have been primed to respond to oxidized low-density lipoprotein in a proinflammatory manner. 3Since then, the role of CD4 + T cells has been studied mainly in experimental (mouse) models of atherosclerosis, and both the proatherogenic and antiatherogenic roles of various CD4 + T helper cell subsets such as Th1, Th2, Th17, and regulatory T cells (Tregs) have been described in detail.Th1 cells, characteristically expressing the transcription factor Tbet, are activated in the context of IL-12 derived from dendritic cells and macrophages and produce interferon-γ.Studies using transgenic mice lacking Tbet or interferon-γ or the use of IL-12-blocking strategies clearly show the proatherogenic nature of the Th1 CD4 + T-cell subset.Th17 cells have been intensively studied and are predominantly considered to be proatherogenic on the basis of various IL-17-blocking strategies such as anti-IL-17 antibodies, soluble IL-17 receptors, and IL-17-deficient mice, although under specific conditions, IL-17 may have an atheroprotective function.Th2 cells are known mainly for their B-cell help, and in that respect, they are able to act proatherogenic by inducing immunoglobulin E antibodies that activate mast cells to increase lesion size.The Treg subset finally is clearly antiatherogenic.Many studies that were designed to activate the functionality of Tregs such as tolerization against oxidized low-density lipoprotein or parts thereof, clearly show that this subset can limit atherosclerosis, whereas mice deficient in Tregs develop larger lesions.
Identification of new targets and biomarkers in lung cancer.
Authors: Ioannis Papasotiriou, Panagiotis Parsonidis, Dimitrios-Athanasios Ntanovasilis, Aggelos C Iliopoulos, Georgios Beis, Panagiotis Apostolou
Journal: Journal of Clinical Oncology (2019)

e14656 Background: Lung cancer is the second most common type of cancer in both genders; however is the leading cause of cancer deaths. Adenocarcinoma constitutes more than 60% of non-small cell lung cancer (NSCLC), and accounts for approximately 40% of lung cancers. Therefore, early prediction, prognosis of the disease and treatment strategy is of primary importance. Molecular biology assays, including microarrays, enable identification of new targets. The above targets can be used either as biomarkers, useful for early prediction and prognosis of the disease, or as drugable targets, upon proof of their biological action. The present study aimed to identify new biomarkers and/or targets in lung cancer. Methods: Whole genome gene expression microarrays have been performed for 12 lung cancer cell lines (provided be ECACC, ATCC), representing non-small cell lung (adenocarcinoma, squamous, large cell) and small cell lung cancer. Real-time experiments were followed for validation of thirty genes that were overexpressed. The experiments were performed including other cell lines, representing breast, colon, prostate, hepatocellular, melanoma and pancreatic cancer. Sample from healthy donors, as well as normal lung epithelial cell were used. Results: Among the genes that were studied, there was observed downregulation or none expression in normal donors as well as in normal lung epithelia cells. VSIG10 overexpressed in adenocarcinoma and large cells, while no expression observed in breast, prostate, melanoma and pancreatic cancer. DCBLD2 overexpressed in all NSCLC samples, but not in small cells. LIFR was overexpressed mainly in squamous cells, while no expression or downregulation observed in the other types of cancer. The same expression profile was mentioned for PDGFC. Conclusions: Taking everything into consideration, it is obvious that the identification of new biomarkers and/or targets for lung cancer is of primary importance. The present study revealed different genes, with different biological function that might be used primary as biomarkers. Their role need to be clarified also in clinical samples as to be used as drugable targets. However, the above data are encouraging for identification of new therapeutic models in lung cancer.
Pembrolizumab in MMR-proficient metastatic colorectal cancer pharmacologically primed to trigger dynamic hypermutation status: The ARETHUSA trial.
Authors: Salvatore Siena, Andrea Sartore-Bianchi, Nicola Personeni, Filippo Pietrantonio, Giovanni Germano, Alessio Amatu, Emanuela Bonoldi, Emanuele Valtorta, Ludovic Barault, Federica Di Nicolantonio, Giulia Siravegna, Giovanni Crisafulli, Lorenza Rimassa, Filippo G. De Braud, Armando Santoro, Luca Lazzari, Paolo Luraghi, Nabil Amirouchene-Angelozzi, Alberto Bardelli, Silvia Marsoni
Journal: Journal of Clinical Oncology (2019)

TPS2659 Background: Metastatic colorectal cancer (CRC) harbouring genetic defects in the mismatch-repair pathway (MMRd) presents with a high tumor mutational burden (TMB), and is highly sensitive to anti–programmed cell death protein 1 (PD-1) immune checkpoint inhibitors. We recently showed in preclinical models that the pharmacological treatment with temozolomide (TMZ) can induce the inactivation of MMR genes, and consequently the increase of TMB and immunogenic neoantigens, thus suggesting that TMZ could be used to prime MMR proficient (MMRp) tumors for response to checkpoint inhibitors. Accordingly, mCRC patients recruited in previous clinical trials where TMZ was administered, acquired alterations of MMR genes upon treatment and showed remarkable increase in TMB at disease progression (PD). We thus designed the ARETHUSA clinical trial to test whether a priming course with TMZ in patients can sensitize mCRC to the anti-PD1 inhibitor pembrolizumab. Methods: Arethusa (NCT03519412) is a 2-cohorts, phase II trial consisting of three different phases. In the SCREENING, 348 mCRC RAS-mutated patients will be tested for MMR status. MMRd patients will proceed directly to TRIAL for immediate pembrolizumab treatment (expected 14). MMR-proficient (MMRp) patients will be further tested for expression of O 6 -methylguanine-DNA methyltransferase (MGMT) by immunohistochemistry and by promoter methylation analysis. IHC-negative, promoter methylation-positive MMRp patients (expected 67) will enter in the PRIMING phase and will be treated with TMZ until PD. TMB will then be assessed on tumor biopsies at resistance. Those patients that will have &gt; 20 mutations/megabase will proceed to TRIAL (expected 20) and will be treated with pembrolizumab. Overall response rate (primary outcome), Progression Free, and Overall Survival, and treatment related toxicities (secondary outcomes) in MMRp pembrolizumab-treated patients will be estimated., while the MMRd cohort will be used for comparison. Tissue biopsies, longitudinal blood and stool collection will be used for discovery of predictive molecular biomarkers and assessment of tumor evolution. Clinical trial information: NCT03519412.