tbuckley/cabot-search huggingface dataset:
Malignant pleural mesothelioma (MPM) genomic profile in the randomized phase II RAMES Study.
Authors: Maria Pagano, Roberta Gnoni, Candida Bonelli, Francesca Zanelli, Marina Chiara Garassino, Giovanni Luca Ceresoli, Giulia Pasello, Marcello Tiseo, Hector J. Soto Parra, Federica Grosso, Paolo Andrea Zucali, Federica Torricelli, Carmine Pinto
Journal: Journal of Clinical Oncology (2019)

8547 Background: Since MPM is an uncommon neoplasia, its rarity has limited available data on molecular drivers. Methods: RAMES study evaluated the second-line efficacy of gemcitabine/ramucirumab treatment vs. gemcitabine/placebo. From December 2016 to July 2018 (end of enrolment), 164 patients (pts) were admitted to this study, which involved the collection of tumor samples - with diagnosis - to evaluate 34 genes by NGS (ACTB, ACTG1, ACTG2, ACTR1A, BAP1,CDH8, CDK4, CDKN2A, CDKN2B, COL3A1, COL5A2, CUL1, DHFR, GOT1, KDR, KIT, MXRA5, NF2, NFRKB, NKX6,-2, NOD2, PCBD2, PDZK1IP1, PIK3CA, PIK3CB, PSMD13, RAPGEF6, RDX, SETDB1, TAOK1, TP53,TXNRD1, UQCRC1, XRCC6). We reported the results of the first 87 pts (54%): hystotype was epithelioid in 70 pts (80%), biphasic in 14 pts (16%) and sarcomatoid in 3 pts (4%). Median age was 63 years (range 45-81). 70 pts were male (80%) and 17 pts were female (20%). In the present analysis, we included 55 pts in stage III (63%), 26 pts in stage IV (30%) and 6 pts whose stage was unknown. Median first-line PFS platinum/pemetrexed therapy was for 5.75 months (I.C. 95% 4.75-6.76). PFS was ≤6 months for 40 pts (49%), and 6 months for 41 pts (51%). Results: 187 functional somatic mutations were identified. Genomic alterations/patient were 1 gene in 29 pts (33%), 3 genes in 18 pts (21%) and ≥5 genes in 2 pts (2%). The most frequent somatic mutations were RDX in 35 pts (40%), MXRA5 in 20 pts (23%), BAP1 in 13 pts (15%) and ACTG 1 in 9 pts (11%). When patients were collated by stage, the most frequent mutations were: MXRA5 in 16 pts in stage III (29%), BAP1 in 5 pts in stage IV (19%) and RDX in 16 pts in stage IV (62%). The percentage of somatic mutations in patients with PFS as first-line chemotherapy for ≤6 and &gt;6 months was 2.2 and 1.6 (p=0.032), respectively. The most frequent mutations/patient for ≤6 and &gt;6 months PFS were: RDX in 14 pts (35%) with PFS &lt; 6, RDX in 19 pts (46%) with PFS &gt;6 and MXRA5 in 11 pts (27%) with PFS &gt;6. Conclusions: This preliminary data suggests a possible role that a genetic signature may play in distinguishing MPM with different clinical-pathological features. The results are expected to be clarified further in the second step of the study, which is ongoing. Clinical trial information: 2016-001132-36.
The efficacy and safety of lenvatinib in patients who did not meet the inclusion criteria of the phase 3 trial (REFLECT trial) in real-world practice in Japan: A nationwide multicenter study in Japan.
Authors: Kaoru Tsuchiya, Masayuki Kurosaki, Hiroyuki Marusawa, Takehiko Abe, Chikara Ogawa, Tetsuro Sohda, Hiroyuki Kimura, Masahiko Kondo, Keiji Tsuji, Koichiro Furuta, Masaya Shigeno, Kouji Joko, Ryoichi Narita, Yasushi Uchida, Hideo Yoshida, Takehiro Akahane, Haruhiko Kobashi, Akeri Mitsuda, Yuji Kojima, Namiki Izumi
Journal: Journal of Clinical Oncology (2019)

e15629 Background: Lenvatinib (LEN) has been approved as a single agent for patients with unresectable hepatocellular carcinoma (u-HCC) since Mar 2018 in Japan. We conducted a nationwide multicenter study and especially focused on the efficacy and safety in the patients who did not meet the inclusion criteria of the phase 3 trial (REFLECT trial). Methods: A total of 202 patients received LEN from March 2018 at 21 sites in Japan was registered. Tumour assessments in accordance with modified RECIST were done using dynamic CT or MRI within 4-8 weeks and every 6-8 weeks thereafter. Adverse events (AEs) were graded according to the CTCAE ver4.0. Results: In this study, 128 of 202 (63%) patients did not meet the inclusion criteria of the REFLECT trial. For the reasons, 69 patients received TKI therapy before LEN, 37 patients were Child-Pugh B, 6 patients showed main portal vein invasion,13 patients had HCC which occupied ≥ 50% of liver, and 22 patients were with lower platelet ( &lt; 75 × 10⁹ per L) . Median observation time was 4.1 months in all patients, 22 patients died, and median overall survival (OS) was not reached. As the 2nd-line therapy (after sorafenib), 45 patients received LEN and 24 patients did as the 3rd-line (after regorafenib). The OS between TKI naïve and experienced patients was not significantly different, even though baseline albumin level and ALBI score were significantly lower in TKI experienced patients than TKI naïve (p = 0.001 and 0.005). Objective response rate (ORR) and disease control rate (DCR) of TKI naïve patients were 37% and 84%, while those of TKI experienced were 27% and 76%. Child-Pugh B patients (n = 36) had significantly shorter OS than Child-Pugh A (p = 0.01) and median OS in Child-Pugh B patients was 6.1 months. Drug discontinuation due to AEs and elevated aspartate aminotransferase were significantly higher in Child-Pugh B patients (p = 0.005 and 0.001). The OS, treatment duration and drug discontinuation were not significantly different between patients with or without lower platelets. ORR and DCR in patients with lower platelets (n = 22) were 18% and 63%. Conclusions: The response rate of LEN in patients who experienced TKI therapies was similar to that in TKI naïve patients. The median OS in Child-Pugh B patients was 6.1 months and elevated aspartate aminotransferase during LEN was frequently reported in such patients. The OS and treatment duration were not significantly different between patients with or without lower platelets at the cut off of &lt; 75 × 10⁹ per L.
Prospective assessment of the risk for colorectal neoplasia in a Mexican population according to risk categories.
Authors: Vanessa Rosas Camargo, Edgar Omar Martos Armendariz, Mauricio Rivera Aguilar, Jorge Humberto Hernandez-Felix, Monica Lily Cordon, Angela Rosales Sotomayor, Mónica Isabel Meneses Medina, Fidel David Huitzil Melendez
Journal: Journal of Clinical Oncology (2019)

e15158 Background: General population screening can reduce colorectal cancer (CRC) mortality. International guidelines recommend CRC screening for asymptomatic people over 50 years. There is no established national screening program in Mexico. Even in countries with low incidence of CRC such as Mexico, targeted screening of subjects at high risk could decrease resource utilization and cost. Our aim was to describe the distribution among an average-risk population based on risk for colorectal neoplasia (CRN). Methods: We performed a prospective assessment of the risk for CRN among asymptomatic people over 50 years at Instituto Nacional de Ciencias Médicas y Nutrición between 2017-2018. The inclusion was competitive consistent with our age-sex pyramid. We included workers, non-family attendants and patients (internal medicine consultation). Each subject answered a standardized questionnaire, which included information on their age, gender, family history of CRC, diabetes, body mass index (BMI), smoking status and drinking habits. In order to stratify the population according to their risk for CRN, we used the Asia-Pacific Colorectal Screening (APCS) score. Results: We included 256 subjects. Median age was 59 y/o (50-93), 52% were female. 5% had a first-degree relative with CRC. 44% were current or ex-smoker and 9% reported alcohol consumption. 21% had diabetes. The median BMI was 27.3 (17-51). According to the APCS score, 60% were assigned as average risk (AR) and 40% as high risk (HR) for CRN. We observed a higher proportion of HR compared to our previous retrospective data (Table). Conclusions: We prospectively confirmed that using basic clinical information (age, gender, smoking status, family history of CRC, BMI and diabetes), it is possible to identify a subset of asymptomatic subjects at high risk for CRN in whom screening strategies should be prioritized. In developing countries with limited resources, a focus on high risk groups could improve cost effectiveness of screening colonoscopy. Risk stratification based on APCS score. [Table: see text]
Safety and efficacy of adoptive cell transfer using autologous tumor infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical carcinoma.
Authors: Amir A. Jazaeri, Emese Zsiros, Rodabe Navroze Amaria, Andrew S. Artz, Robert P. Edwards, Robert Michael Wenham, Brian M. Slomovitz, Axel Walther, Sajeve Samuel Thomas, Jason Alan Chesney, Robert Morris, Koji Matsuo, Stephanie Gaillard, Peter Graham Rose, Jesus Garcia Donas, Jacqueline Maria Tromp, Fatemeh Tavakkoli, Huiling Li, Maria Fardis, Bradley J. Monk
Journal: Journal of Clinical Oncology (2019)

2538 Background: There is a high unmet medical need for effective treatments for patients with recurrent, metastatic, or persistent cervical cancer. Most patients are young and survival rates are poor. ORR for second line therapies is between 4 and 14% for chemotherapy and recently approved immunotherapy. Adoptive cell transfer using tumor infiltrating lymphocytes (TIL) have demonstrated durable responses in some patients with recurrent cervical cancer thus offering the potential for long-term disease control. Methods: Study C-145-04 is an ongoing, open-label, multicenter Phase 2 clinical trial evaluating the safety and efficacy of LN-145 TIL therapy in patients with advanced cervical cancer who have undergone at least one prior line of chemotherapy. Prior checkpoint inhibitor therapy is an exclusion criterion. The primary endpoint is ORR per RECIST 1.1; secondary endpoints include duration of response (DOR), disease control rate (DCR), and LN-145 safety. Tumors surgically harvested at local institutions are shipped to central GMP facilities for TIL generation in a 22-day manufacturing process. Final LN-145 TIL product is cryopreserved and shipped to sites. Patients receive one week of preconditioning lymphodepletion (cyclophosphamide, fludarabine), a single LN-145 infusion, followed by up to 6 doses of IL-2 (600,000 IU/kg). Results: As of 4 Feb 2019, 27 efficacy-c patients have received Gen 2 of LN-145, with a mean age of 47 years and 2.6 mean prior lines of therapy. Preliminary efficacy results: ORR was 44% (1 CR, 9 PR, 2 uPR), DCR was 89% at 3.5-month median study follow-up with 11/12 patients maintaining their response. Improved responses were observed in 4 patients with longer follow-up. Mean TIL cells infused was 28x10 9 . Median IL-2 doses administered was 6.0. The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens. Conclusions: LN-145 results in 44% ORR in previously treated cervical cancer patients with acceptable safety and efficacy profile. LN-145 offers patients a viable therapeutic option warranting further investigation. Clinical trial information: NCT03108495.
Expression of PD-L1 and IDO in hormone receptor negative DCIS.
Authors: Sneha Deepak Phadke, Gerald H. Clamon, Amani Bashir, Matthew Keeney, Timothy Ginader
Journal: Journal of Clinical Oncology (2019)

e14116 Background: Although outcomes from ductal carcinoma in situ (DCIS) are generally excellent, hormone receptor (HR) negative DCIS is associated with a higher rate of recurrence. There is no chemopreventative agent that has been effective in this subgroup. The aim of our study was to evaluate expression of PD-L1 and IDO (Indoleamine 2,3-Dioxygenase) in HR negative DCIS, in an effort to identify a possible target for prevention using immunotherapy. Methods: Using pathology databases at the University of Iowa, we identified 60 cases of HR negative DCIS from 1995-2017, and 41 of these cases had adequate DCIS tissue for immunostaining. Immunohistochemical staining with antibodies against PD-L1 and IDO was performed on slides prepared from formalin-fixed paraffin-embedded tissue blocks retrieved from pathology archives. IDO was assessed by IHC using the mouse monoclonal antibody clone 10.1 (Millipore Sigma). An initial assessment for PD-L1 (M3653 mouse monoclonal antibody clone 22C3, DAKO) was negative. A repeat assessment for PD-L1 on a smaller sample in a different laboratory was also negative. Clinical data was abstracted from the medical record of each patient. Results: Of the 41 subjects with enough tissue for staining, the median age at diagnosis was 56.76 years, and median BMI was 26.59 kg/m 2 . Most common method of DCIS detection was screening mammogram (80.5%) versus a patient detected breast finding (19.5%). Most subjects had high grade DCIS (92.7%) and none had low grade DCIS. Six subjects (16.7%) had an ipsilateral in situ recurrence while another 6 subjects developed ipsilateral invasive cancer. Most of the subjects had HER2+ DCIS (63.9%). None of the 41 cases stained positive for IDO or PD-L1, thus no statistical analysis was done to analyze associations with clinicopathologic characteristics. Conclusions: Our sample of HR negative DCIS tumors did not express PD-L1 or IDO, making these receptors unlikely targets for immunopreventative efforts. It is still possible that tumor mutation burden, expression of PD-L2, PD-L1 or IDO expression on TILs, or expression of CTLA-4 may be future considerations for work in the DCIS microenvironment.
Immunotherapeutic efficacy in NSCLC and patients’ smoking status: A meta-analysis.
Authors: Shanshan Wang, Guoqiang Wang, Yu Xu, Shangli Cai, Jianping Xiong
Journal: Journal of Clinical Oncology (2019)

e20510 Background: In non-small cell lung cancer (NSCLC), tumour mutational burden (TMB) has been validated in predicting the clinical benefit of immunotherapy. Smoke, delivering the carcinogens that form covalently bound DNA adducts into respiratory system, is the critical cause of miscoding events and mutational burden in NSCLC. However, the predictive potential of tobacco consumption in immunotherapy remains controversial. Here, we did a meta-analysis to assess the heterogeneity of immune checkpoint inhibitor (ICI) efficacy in NSCLC patients with or without smoking habit. Methods: We systematically searched PubMed, the Cochrane Central library and Embase, for the randomized controlled trials (RCTs) of ICIs (inhibitors of PD-1, PD-L1, CTLA-4, or combination) in NSCLC. The studies were excluded due to the unpublished hazard ratio (HR) for both progression-free survival (PFS) and overall survival (OS) according to smoking status. Pooled estimates of survival HR and 95% confidence interval (CI) in smokers and non-smokers were performed using a random-effects model, and the heterogeneity between the two estimates was assessed using an interaction test by Review Manager. Results: In total, 13 eligible RCTs of FDA-approved ICIs (concerning ipilimumab, nivolumab, pembrolizumab, atezolizumab, and avelumab) containing 8154 patients with NSCLC (6800 [83.4%] smokers and 1354 [16.6%] non-smokers) were included for analysis. Compared to standard treatment, a prolonged PFS was observed in smokers treated with ICIs (pooled HR, 0.72, 95% CI 0.63-0.81, P &lt; 0·001) instead of non-smokers (pooled HR, 0.98, 95% CI 0.73-1.31, P = 0·90). The pooled HR of OS between immunotherapy and standard treatment was 0.77 (95% CI 0.69-0.86, P &lt; 0·001) in smokers and 0.78 (95%CI 0.59-1.02, P = 0·07) in non-smokers. Similar results were observed among sub-groups according to the different histology (squamous and non-squamous), class of ICIs (anti-PD-1 or PD-L1) and lines of treatment (first-line or subsequent). The difference in efficacy between smokers and non-smokers treated with ICIs was also significant (HR 0.75, 95% CI 0.62-0.92, P = 0·005). Conclusions: ICIs can improve PFS and OS for patients with advanced NSCLC, but the magnitude of benefit depends on smoking history, especially for PFS. Future clinical trials are supposed to include more non-smokers and concentrate on enhancing the efficacy of ICIs in the NSCLC patients without cigarette consumption, possibly discovering distinctive immunotherapeutic approaches in smokers and non-smokers.
APOBEC3B interaction with PRC2 modulates microenvironment to promote HCC progression
Authors: Duowei Wang, Xianjing Li, Jiani Li, Yuan Lu, Sen Zhao, Xinying Tang, Xin Chen, Jiaying Li, Yan Zheng, Shuran Li, Rui Sun, Ming Yan, Decai Yu, Guangwen Cao, Yong Yang
Journal: Gut (2019)

Objective APOBEC3B (A3B), a cytidine deaminase acting as a contributor to the APOBEC mutation pattern in many kinds of tumours, is upregulated in patients with hepatocellular carcinoma (HCC). However, APOBEC mutation patterns are absent in HCC. The mechanism of how A3B affects HCC progression remains elusive. Design A3B ­promoter luciferase reporter and other techniques were applied to elucidate mechanisms of A3B upregulation in HCC. A3B overexpression and knockdown cell models, immunocompetent and immune-deficient mouse HCC model were conducted to investigate the influence of A3B on HCC progression. RNA­seq, flow cytometry and other techniques were conducted to analyse how A3B modulated the cytokine to enhance the recruitment of myeloid­-derived suppressor cells (MDSCs) and tumour­-associated macrophages (TAMs). Results A3B upregulation through non-classical nuclear factor-κB (NF-κB)signalling promotes HCC growth in immunocompetent mice, associated with an increase of MDSCs, TAMs and programmed cell death1 (PD1) exprssed CD8 + T cells. A CCR2 antagonist suppressed TAMs and MDSCs infiltration and delayed tumour growth in A3B and A3B E68Q/E255Q ­ expressing mouse tumours. Mechanistically, A3B upregulation in HCC depresses global H3K27me3 abundance via interaction with polycomb repressor complex 2 (PRC2) and reduces an occupancy of H3K27me3 on promoters of the chemokine CCL2 to recruit massive TAMs and MDSCs. Conclusion Our observations uncover a deaminase-independent role of the A3B in modulating the HCC microenvironment and demonstrate a proof for the concept of targeting A3B in HCC immunotherapy.
Cardiovascular morbidity in a randomized trial comparing GnRH-agonist and antagonist among patients with advanced prostate cancer.
Authors: David Margel, Avivit Peer, Yaara Ber, Sivan Sela, Liat Shavit Grievink, Tzlil Tabachnik, Guy Witberg, Jack Baniel, Daniel Kedar, Wilhelmina CM Duivenvoorden, Eli Rosenbaum, Jehonathan H Pinthus
Journal: Journal of Clinical Oncology (2019)

5015 Background: Androgen-deprivation therapy (ADT) used in prostate-cancer may increase risk of cardiovascular disease (CVD). Limited preclinical and retrospective clinical data suggest that use of gonadotrophin-releasing hormone (GnRH)-antagonist may be associated with lower risk of CVD compared to GnRH-agonist. Methods: We conducted a randomized open-label study comparing the one year incidence of major cardiovascular and cerebrovascular event (MACCE) in prostate-cancer patients with pre-existing CVD commencing on GnRH-agonists or antagonists. Patients were followed every 3 months for the development of MACCE defined as either death, myocardial infarction (MI), cerebrovascular event (CVA), or percutaneous-coronary intervention (PCI). Serum levels of N-terminal pro-B-type natriuretic peptide (NTproBNP) were analyzed at baseline, 3, 6 and 12-months. Results: Eighty patients were enrolled (41 randomized to GnRH-antagonist, 39 to GnRH-agonist). Patients in both arms had similar age, baseline cardiovascular and prostate-cancer characteristics. During follow-up 15 patients developed a new cardiovascular event. Of these, nine patients developed MACCE (two deaths, one MI, two CVAs, and four PCI). Twenty percent (n = 8) of patients randomized to GnRH-agonists had a MACCE compared to 3% (n = 1) randomized to antagonists (log-rank p = 0.013). The absolute risk reduction for MACCE at 12 months using GnRH-antagonist was 18% (95%CI 5-31). Baseline levels of NTproBNP predicted events (AUC = 0.73 95%CI 0.54-0.91 p = 0.03) and increased over time only among patients with CV events. Conclusions: This is the first prospective study to test cardiovascular outcome among prostate-cancer patients receiving ADT. We demonstrated that in patients with pre-existing CVD, GnRH-antagonists was associated with development of fewer cardiovascular events compared to GnRH-agonists. Clinical trial information: NCT02475057.
Determination of the recommended phase II dose of birinapant in combination with pembrolizumab: Results from the dose-escalation phase of BPT-201.
Authors: Russell J. Schilder, Mark Albertella, James Fredric Strauss, Malin Sydvander, Dung T. Le, Stefan Norin, Monica M. Mita, Emma Boström, Siqing Fu, Linda Basse, Richard Bethell
Journal: Journal of Clinical Oncology (2019)

2506 Background: Birinapant is a bivalent SMAC mimetic targeting cIAP1. Synergistic effects of combining birinapant with immune checkpoint inhibitors have been demonstrated in preclinical models. Based on these observations, a clinical trial with birinapant and pembrolizumab was initiated (NCT02587962). Methods: Patients ≥18 years with advanced solid tumors without further suitable standard therapeutic options were eligible for inclusion. Birinapant (5.6-22 mg/m 2 ) was administered IV on day 1 and 8 in addition to pembrolizumab 200 mg on day 1 in a 21-day cycle until disease progression using standard 3+3 dose-escalation. The primary objective was to determine the safety and tolerability of the recommended phase 2 dose (RP2D) of birinapant in combination with pembrolizumab. Secondary and exploratory objectives included antitumor activity assessed by RECIST 1.1 and iRECIST, pharmacokinetics and assessment of biomarkers including serum cytokines, cIAP1, PD-L1 expression and tumor infiltrating lymphocytes. Results: Nineteen patients were enrolled at 4 dose levels of 5.6 (n = 3), 11 (n = 3), 17 (n = 6) and 22 (n = 7) mg/m 2 . Most common tumors were pancreatic (n = 5), colorectal (n = 4), ovarian (n = 3) and sarcoma (n = 3). Median prior therapies were 4 (0-12). The most common AE related to any of the study drugs was rash occurring in 3 patients. Ten patients had 17 SAE's of which only one (stomatitis) was judged related to birinapant. Increased ALT/AST (G3/G2) leading to missed day 8 dose constituted a DLT at 22 mg/m 2 . Grade 2 lipase increases were seen in 2 patients. No cases of Bell’s palsy were detected. ORR by RECIST 1.1 was 5.6% (n = 1) in 18 evaluable patients. The responding patient had microsatellite stable colorectal carcinoma (MSS-CRC)) and remains on therapy 13+ months after first dose. By iRECIST, ORR was 11.1%. CBR (PR+SD) by RECIST was 22.2%. The exposure to birinapant generally increased with dose. The RP2D was determined to be 22 mg/m 2 . Conclusions: Birinapant and pembrolizumab is a safe and tolerable combination that has shown encouraging signals of efficacy. A phase 2 study evaluating efficacy of this combination in MSS-CRC is ongoing. Clinical trial information: NCT02587962.