bluuebunny/crossref_metadata_2025_split huggingface dataset:
PDL1 landscape in checkpoint inhibitor ineligible patients by IHC and cfRNA.
Authors: Kato Shumei , Khalid Noor , Jimenez Rebecca , Lee Suzanna , Drusbosky Leylah , Szeto Christopher , Garner Chad , Reddy Sandeep K. , Kurzrock Razelle 
Published: May 2019

e14570 Background: Immune checkpoint inhibitors (ICT) are indicated in patients with PDL1+ IHC and restricted to certain histologies . Other tumor histologies express PDL1 at various frequencies with no established threshold for therapeutic efficacy. We evaluated traditionally ICT non-indicated histologies by IHC and cfRNA to determine potential therapeutic thresholds. Methods: A total of 97 pts (cancer of unknown primary [N = 10], appendix [N = 6], bile duct [N = 4], colorectal cancer [N = 25], esophageal [N = 6], ovary [N = 7], pancreas [N = 15], other [N = 24]) with IHC (Dako 76 22C3, 21 SP142) and cfRNA for PDL1 were available for analysis. cfRNA was a random draw not matched with the time of tissue collection and performed by qPCR. A cutoff of > 1.5x for PDL1 normalized to beta actin was defined as PDL1+ in cfRNA. IHC > 10% was used as the threshold for IHC+. Results: Most patients were PDL1- by IHC: 90/97 (93%), PDL1 TPS: 0% (N = 72), 1% (N = 7), 5% (N = 8), 10% (N = 3), > 10% (N = 3), > 50% (N = 4). No difference was seen between 22C3 and SP142 antibodies. PDL1+ cfRNA (N = 59), PDL1- cfRNA (N = 38). Positive concordance for cfRNA PDL1+ and IHC PDL1+ was 10.2% (6/59). Negative concordance for cfRNA PDL1 - and IHC PDL1- was 97.4% (37/38) (p = 0.079). Conclusions: In ICIs ineligible patients a > 50% IHC threshold is rarely met (4%). Random draw qPCR PDL1 is poorly correlated with IHC, with higher rates of PDL1+ in cfRNA in setting of IHC PDL1-. In the other hand, cfRNA PDL1- is strongly associated with an IHC negative result. Further investigation incorporating both cfRNA and IHC result to predict the response from ICIs are warranted.
Genetic mutation analysis of plasma circulating tumor DNA by ultra-deep sequencing in breast benign lesions and cancers.
Authors: Wu Qian , Jian Wenjing , Yao Xumei , Xie Xintong , Fang Hanjie , Geng Shengkai , Song Shufeng , Sheng Haiyan , Liu Xia , Cheng Fangsheng , Xie Wenling , Lu Shixin , Wang Yanhui , Deng Longhui , Li Xiaohua , Wang Xianming , Zhang HW , Xu Chuanbo 
Published: May 2019

e14572 Background: Mammography screening for breast cancer results in large number of impalpable lesions without clear determination of the malignancy. Analysis of breast cancer related gene mutations in blood circulating tumor DNA (ctDNA) may provide clarification. This analysis aims to provide insights into the feasibility of the approach. Methods: The clinical trial was conducted at top tier teaching hospitals in China to recruit patients with breast diseases for surgery. Eligible patients were consented and the breast lesions were pathologically diagnosed. Peripheral blood was collected prior to surgical resection. For breast cancer patients, samples of resected tissue were also collected. The samples were analyzed using our proprietary NGS technique called systematic error correction sequencing (Sec-Seq) (detailed in Abstract ##e23057, ASCO 2018). Results: In total, 69 patients with breast lesions (57 malignant and 12 benign) were included in this analysis. Tumor gDNA and plasma ctDNA were analyzed by deep NGS sequencing using a panel of 62 breast cancer-associated genes. The average sequencing depth is 35000. After deduplication, the average number of unique reads is 1500. Detection limit for mutant allele frequency was set at 0.2% for ctDNA and 1% for tumor tissue. For ctDNA mutation detection, 2 out of 12 patients with benign diseases were found with mutations while 10 out of 55 breast cancer patients had no mutations, resulting in an overall sensitivity of 82% and specificity of 83%. By cancer stage, the two Stage 0 (carcinoma in situ) patients had no mutation, and the range of mutations detected is between 53% to 75% from Stage I to III. The tumor tissue samples have higher rate of mutations (only 2 cancer patients, 1 Stage 0 and 1 Stage 2, had no mutations). 15% patients have at least one common mutation detected in both the tumor tissue and ctDNA, and 27% patients have mutations in the same genes in the two matching samples. The concordance increases as the clinical stage advances. The most commonly mutated genes are previously reported breast cancer drivers of PIK3CA (79% of tumor and 18% of ctDNA samples), TP53 (56% and 39%), and BRCA1 (6% and 15%). Conclusions: In this hypothesis generating analysis, we showed the feasibility of plasma ctDNA sequencing for gene mutation detection in early stage breast cancer and differentiation from the benign breast diseases. Although with limited number of samples, the data encourage further improvement of the gene panel and the validation of ctDNA assay as a non-invasive approach to the cancer screening. Clinical trial information: ChiCTR1800017345.
#earlydetection: Leveraging social media to recruit individuals at increased-risk of pancreas cancer for an early detection study.
Authors: Klute Kelsey , Hoy Christina , Larson Luann , Yu Fang , Hollingsworth Michael A. , Eberle Kirsten , Blase Terri , Boerner Brian , Shivaswamy Vijay , Singh Shailender 
Published: May 2019

e14577 Background: Social media (SM) could transform how individuals learn of clinical trials. In an ongoing, single-center cohort study to collect serial biospecimens and clinical data from high-risk individuals (HRIs) for pancreatic cancer (PC), we explored how HRIs learned of the study, surveyed relevant SM posts and compared those referred by SM vs. other means. Methods: Initial recruitment focused on HRIs with familial risk for PC. Referral method was self-reported. We identified relevant SM posts and compared those referred via SM vs. other means by ANOVA and t-test. Investigators did not create SM content but were featured in a relevant local news clip, institutional blog post and Project Purple podcast; study-related media was IRB-approved. Results: We enrolled 91 HRIs between Aug 2018 and Jan 2019. Over half self-referred; 55.0% of self-referrals came from SM. We identified 16 unique SM posts, all to Facebook. Authors were 2 administrators for local hereditary cancer organizations, Project Purple, UNMC and 2 study subjects (9,4, 3 and 2 posts). Content included links to a podcast, clinicaltrials.gov, local news story, blog post, live chat and anecdotes from subjects. Nine posts shared study contact information or clinicaltrials.gov link. The mean age of those referred via SM was younger than for other methods (mean 49.2 vs. 53.4y) but was not statistically significant (p = 0.19). SM was more likely to recruit HRIs with familial risk than other methods (100.0% vs. 76.3%; p < 0.01) Conclusions: SM effectively recruited HRIs with familial risk for PC; this group may be more likely to seek information online. Individuals may find studies via SM without investigator involvement. SM may be an effective tool to recruit HRIs to early detection research in PC and other conditions. Clinical trial information: NCT03568630. [Table: see text]
Business versus science: High drug prices conspire against oncological research.
Authors: Gercovich Felipe G. , Gil Deza Ernesto , Morgenfeld Eduardo L. , Muino Marcelo , Mizrahi Marvin Albert , Martin Reinas Gaston , Smolje Leonardo , Abal Mariana , Rivarola Edgardo G. J. 
Published: May 2019

e14580 Background: It has been consistently proven that pivotal clinical trials (PCT) for drug registration or new drug indications (NDI), sponsored by the pharmaceutical industry, obtain better results than independent confirmatory studies (ICS). The interplay between PCT and ICS has supported better treatment selections and more realistic expectations: hope vs hype.The aim of this paper is to analyze the amount of ICS publications in Oncology within the last decade. Methods: All new FDA approved oncological drugs or NDI for solid tumors between 2005 and 2017 were taken into account. The PCT that led to their approval were identified, and between October and November 2019 a thorough search for related ICS (published or ongoing) was conducted on MEDLINE, ASCO Abstracts, NEJM, Lancet Oncology, JAMA, JCO, Cancer, PLOS ONE, PLOS Medicine and www.Clinicaltrials.gov. Results: Fifty-five new drugs or NDI were analyzed (Abemaciclib, Abiraterone, Ado-trastuzumab emtasine, Afatinib, Alectinib, Atezolizumab, Avelumab, Axitinib, Bendamustine, Bevacizumab, Brigatinib, Cabozantinib, Ceritinib, Cobimetinib, Crizotinib, Dabrafenib, Degarelix, Denosumab, Durvalumab, Eribuline mesylate, Everolimus, Ipilimumab, Irinotecan liposome, Ixabepilone, Lapatinib, Lenvatinib, Necitumumab, Neratinib, Nilotinib, Niraparib, Nivolumab, Olaparib, Osimertinib, Paclitaxel protein bound, Palbociclib, Panitumumab, Pazopanib, Pembrolizumab, Pertuzumab, Ramucirumab, Regorafenib, Ribociclib, Rucaparib, SipuleucelT, Sonidegib, Sorafenib, Sunitinib, Topotecan, Trabectedin, Trametinib, Trastuzumab, Vandetanib, Vemurafenib, Vismodegib, Ziv-afilbercept). Until November 30, 2019, no published or ongoing ICS were found in any of the cases. Conclusions: a) For the past decade, none of the PCT used for approval of new oncological drugs or NDI were replicated by ICS (without pharmaceutical industry sponsorship). b) We ignore the reasons for these approval methods but they raise suspicion and unnecessary discomfort. c) From an ethical point of view, patients’ Informed Consent must specify that expected results for the new drug or NDI are based exclusively on trials sponsored by the selling pharmaceutical company, unless other ICS are published. d) The current state of affairs can only be reverted if regulatory agencies and the scientific community demand ICS as part of the drug approval process or post-marketing duties.
Moving away from the boilerplate: Real-world evidence for clinical trial laboratory criteria.
Authors: Hadley David , Edenfield William Jeffery , Kientop Debra A. 
Published: May 2019

e14581 Background: There is a need to enable as many suitable patients onto clinical trials in oncology, that are also representative of patients seen in clinical practice. Currently, oncology trials often require patients to have minimum laboratory tests for hematology and liver function amongst others. We compared the real-world laboratory results and clinical information in TransMed’s patient repository against the requirements of a set of clinical trials to assess patient eligibility retrospectively. Methods: Industry-sponsored clinical trials for follicular lymphoma which started in 2018 were retrieved from the U.S. National Library of Medicine’s clinical trials website. We aimed to find the most common set of diagnosis inclusion criteria and the range of platelet requirements to those observed from real-world data. TransMed’s patient data was collected from its consortium of 205 clinical sites, which includes a variety of source systems at each site, such as electronic medical record systems and laboratory information management systems among others. Results: There were 16 trials which matched our criteria. The most common trial inclusion criteria were for grades 1-3a, progression after at least one line of therapy, and a platelet count > 75 x10-9/L. We found 53 retrospectively-eligible patients who would have met the trial’s main criteria when the patient was between therapies in 2018. At some point within 90 days before starting another therapy, 9% (5/53) of patients failed the requirement for platelet count. Among those, 40% (2/5) were within a 10% drop in the required threshold. Conclusions: We have presented an exemplar combination of cancer diagnosis with a single laboratory test and found patients who could be considered for trials though are deemed ineligible due to a narrowly-missed requirement. Many such tests vary over time, by cancer type, prior treatment, comorbidities and should be considered in the context of other test results. By using real-world evidence at the time of trial design, clinical trials can be optimized to allow improved patient recruitment and expanded availability to patients while ensuring clinical suitability.
Trends in case-control allocation in phase III randomized cancer clinical trials.
Authors: Gupta Shruti , Gopishetty Swathi , Malhotra Srishti , Kota Vamsi , Jillella Anand P. , Guddati Achuta Kumar 
Published: May 2019

e14582 Background: Patients enrollment in cancer clinical trials has traditionally been limited to an equal distribution between cases and controls. Some clinical trials have an unequal distribution between the case and control arm. Although such unequal allocation is uncommon it has certain advantages and disadvantages to it. The trend and proportion of cancer clinical trials that have an unequal allocation has not been studied. Methods: Data about cancer clinical trials was extracted from clinical trials.gov. The query included phase 3 trials which included adults and were conducted between 2010 to 2017. Only clinical trials that were either completed or active – but not recruiting were included. T test was used to determine statistical difference between different subgroups. Results: 601 clinical trials were identified of which 356 trials with two arms and 47 trials with 3+ arms were identified. Amongst the eligible 298 trials with two arms, there were 216 trials with equal allocation (1:1) and 82 trials with unequal allocation. Amongst the eligible 29 trials with 3+ arms; there were 21 trials with equal allocation (1:1:1) and 8 trials with unequal allocation. There was no significant difference in the proportion of trials with unequal allocation over the time period from 2010 to 2017. The categories of cancer which had the highest number of two arm clinical trials with unequal allotment were: genitourinary, breast and hematological malignancies (Table). Conclusions: Cancer clinical trials with unequal allocation between case and control arms have been common in the past decade. This may represent a new trend in clinical trial design to help enhance closer monitoring of adverse events despite higher costs attached to this method.[Table: see text]
The relationship between response and dose in published, contemporary phase 1 oncology trials.
Authors: Hazim Antonious Ziad , Chen Emerson Yu-sheng , Mills Gordon B. , Prasad Vinay 
Published: May 2019

e14583 Background: Traditional dose-escalation trial designs have changed little even as diverse classes of oncology drugs have been developed. We aimed to examine whether the association of drug dose to preliminary clinical efficacy previously established in cytotoxic chemotherapies remains true in contemporary phase I dose-escalation oncology trials. Methods: We conducted a systematic review of recent early-phase, dose-finding clinical trials of oncology drugs from November 15, 2015 to November 15, 2018 to examine the relationship between the dose of the investigational drug and objective response rate. We searched PubMed using “cancer” or “oncology” search terms and selected studies that enrolled adults with advanced cancer, determined maximum tolerated dose (MTD) and/or recommended phase II dose, and reported efficacy results by drug dose level. Trials testing combination therapies, single dose level, and non-pharmacologic therapies were excluded. Information related to the study drug, study design, cancer type, dose levels, MTD, and recommended phase II dose were all collected. Treatment response for every dose level was categorized into: complete response, partial response, stable disease, and progressive disease. Dose level was categorized into four categories: < = 40%, 41-80%, 81-120%, and > 120% of the recommended phase II dose. Results: We identified 93 trials with 2506 participants having both dose and treatment response data. Of these trials, 71 (76%) were testing targeted agents, 7 (8%) were immunotherapy, and 6 (7%) were cytotoxic chemotherapy. Median response rate across trials was 5% (range 0-83%). Among the dose range of < = 40%, the response rate was 12% (57 of 491), 41-80% was 17% (95 of 562), 81-120% was 23% (272 of 1206), and > 120% was 29% (71 of 247). Conclusions: Observed treatment response across dose levels in recent phase I trials should cause us to re-examine the toxicity-benefit ratio and influence how we design phase I trials testing novel classes of oncology drugs.
Feasibility of a platform trial based on molecular analysis in rare gynecologic cancers.
Authors: Brown Jubilee , Farley John H. , Herzog Thomas J. , Crane Erin , Covens Al , Arguello David , Ramos Pilar , Chen Wangjuh , ElNaggar Adam 
Published: May 2019

e14585 Background: Challenges in patient accrual limit successful conduct of clinical trials in rare gynecologic malignancies. A platform trial using molecular analysis to guide therapy choice would optimize enrollment but would require actionable mutations (AM) to be feasible. Therefore, we sought to determine if enough AMs exist in rare gynecologic cancers (CA) to justify the design of a platform trial. Methods: We compiled all molecular profiling data performed at Caris Life Sciences through February 2019. Non-epithelial ovarian cancer (OC), rare epithelial OC, non-endometrioid uterine, neuroendocrine gynecologic, and vulvar CA were compiled. AMs were identified. Results: Among 280 cases of non-epithelial OC, 228 malignant stromal tumors and 52 germ cell tumors were identified. AMs in stromal tumors included KMT2D (9.8%), PIK3CA (7.8%), and 16 other AMs ( < 1% each). AMs in germ cell tumors included PIK3CA (20%), KIT (10%), PTEN (10%), TMB (8.2%), CDKN2A (8%), ARID1A (6%), and 16 other AMs ( < 6% each). Among 702 rare epithelial OCs, 132 mucinous CAs, 91 low-grade serous/endometrioid, 367 clear cell, and 112 carcinosarcoma (CS) cases were identified. AMs in mucinous CAs included KRAS (61.8%), CDKN2A (15.3%), PIK3CA (12.7%), ARID1A (9.9%), GNAS (6.9%), and 20 other AMs ( < 5% each). AMs in low-grade serous/endometrioid included KRAS (28.9%), ARID1A (13.3%), PTEN (8.9%), PIK3CA (7.8%), MSI (6.2%), and 15 other AMs ( < 6% each). AMs in clear cell OCs included ARID1A (53.4%), PIK3CA (47.5%), KRAS (11.6%), PTEN (6.8%), and 36 other AMs ( < 6% each). AMs in ovarian CSs included PIK3CA (7.2%), ARID1A (6.2%), and 22 other AMs ( < 5% each). Among 4864 rare uterine CA, 4670 sarcomas, 173 serous CAs, and 21 clear cell CAs were identified. AMs in uterine sarcomas included PTEN (40.1%), PIK3CA (37.1%), ARID1A (31.6%), MSI (20.7%), KRAS (16.8%), TMB (14%), PIK3R1 (10%), and 41 other AMs ( < 10% each). Among 102 gynecologic neuroendocrine tumors, AMs included ARID1A (29.2%), PIK3CA (18%), PTEN (18%), MSI (6.5%), TMB (6%), and 4 other AMs ( < 6% each). Among 59 vulvar CAs, AMs included CDKN2A (28.7%), PIK3CA (17.8%), NOTCH1 (9.6%), TMB (6.8%), and 24 other AMs ( < 5% each). Conclusions: A variety of actionable mutations are present in every type of rare gynecologic cancer evaluated, but mutations specific to individual histologies are not reliably present. This supports the use of molecular profiling to identify potential targets and supports a platform trial strategy to study rare gynecologic cancers.
Efficacy and toxicity of CDK 4/6 inhibitors in breast cancer: Systematic review and meta-analysis of the phase III clinical trials.
Authors: Farooq Faheem , Cohen Jules A. 
Published: May 2019

e14591 Background: Selective CDK4/6 inhibitors such as palbociclib, abemaciclib, and ribociclib have demonstrated efficacy in advanced HR+/HER2- breast cancer. Drug-related toxicity has been manageable, but variable amongst the drugs. This meta-analysis was conducted to guide CDK inhibitor choice based on efficacy and toxicity. Methods: A systematic literature review of Pubmed, Cochrane Library, and EMBASE was performed in December 2018. Efficacy was evaluated via reported progression free survival (PFS) and pooled hazard ratios (HR). Overall response rate (ORR), treatment discontinuation, and treatment-related adverse events (AEs) were measured via pooled odds ratios (OR). Meta-analyses were performed using random effects modeling and 95% confidence intervals (CI). Results: A pooled analysis of 7 phase III clinical trials (n = 4415) demonstrated a HR of 0.55 (CI: 0.51-0.60) for PFS and an OR of 1.93 (CI: 1.54-2.42) for ORR. First-line treatment trials (n = 3020) pairing CDK 4/6 inhibitors with NSAI/tamoxifen had a HR of 0.56 (CI: 0.51-0.60) for prolonged PFS and an OR of 1.64 (CI: 1.39-1.95) for ORR. Second-line treatment trials (n = 1916) pairing CDK 4/6 inhibitors with fulvestrant had an HR of 0.54 (CI: 0.48-0.61) for prolonged PFS and an OR of 2.48 (CI: 1.57-3.90) for ORR. Palbociclib and ribociclib had similar rates of grade 3/4 AEs, neutropenia, and treatment discontinuation. Abemaciclib had lower rates of grade 3/4 AEs overall, but significantly increased rates of diarrhea and treatment discontinuation due to AEs. Conclusions: Each drug demonstrated a significant improvement in PFS. However, there is no statistical difference in efficacy among the three CDK inhibitors. Treatment decisions can be guided by the tolerability of AEs amongst the medications. Further patient follow-up will illuminate whether there is an OS advantage in this novel drug class. [Table: see text]
Muscle wasting, visceral and subcutaneous adiposity, inflammation, nutritional deficiencies, and metastatic esophageal cancer (MEC) prognosis.
Authors: Bajwa Jaspreet K , Fares Aline Fusco , Dong George , Araujo Daniel Vilarim , Hueniken Katrina , Patel Devalben , Taylor Kirsty , Darling Gail Elizabeth , Wong Rebecca , Chen Eric Xueyu , Knox Jennifer J. , Jang Raymond Woo-Jun , Elimova Elena , Xu Wei , Liu Geoffrey , Rozenberg Dmitry , McInnis Micheal 
Published: May 2019

e14595 Background: MEC, associated with fatigue and dysphagia, leads to loss of skeletal muscle mass, malnutrition, subcutaneous and visceral adiposity. Cancer inflammation mobilizes muscle and adipose tissue, potentially leading to cachexia and sarcopenia. Supportive management depends on understanding the cancer frailty determinants that lead to poor outcomes. Methods: We retrospectively identified de novo MEC patients pts treated in Toronto, Canada (2007-2014). Body composition including visceral (VA) and subcutaneous adiposity (SA) at L3 level were assessed with baseline CT scans using SliceOMatic software by two outcome-blinded radiologists (Intraclass correlation, 0.92-1.00). Sarcopenia was assessed using Skeletal Muscle Index (SMI) with cut-offs defined either by optimized-stratification (OpS) or gender-dependent consensus cutoffs (GdC). Cox proportional hazard models generated adjusted hazard ratios (aHR). Results: Of 101 patients, 82% were male; 96% Caucasian; median age at diagnosis 61y (29-88); mean body mass index (BMI) 25.4; 69%/31% adeno/squamous cell carcinoma; median overall and progression free survival were: 6.4 (OS) and 3.9 mos (PFS). Median follow-up time was 5.6 mos. SMI-OpS and SMI-GdC were correlated (Rho = 0.67). Nutritional risk index, BMI, neutrophil-to-lymphocyte and neutrophil-to-platelet ratios were not associated with outcome (p > 0.20, each comparison). However, univariable analyses identified serum albumin, LDH, and either SMI-OpS or SMI-GdC as being associated with OS. In multivariable models, sarcopenia was associated with worse OS (SMI-OpS aHR = 1.93 (1.0-3.7) p = 0.046; SMI-GdC aHR = 2.30 (1.3-4.1) p = 0.004), and worse PFS (SMI-OpS aHR = 2.16 (1.2-4.0) p = 0.01; SMI-GdC aHR = 1.66 (1.0-2.9) p = 0.07)). In 55 pts receiving chemotherapy at diagnosis, less VA (p = 0.01) and SA (p = 0.02), as continuous variables, were associated with worse OS. Conclusions: Though no associations were found between nutritional deficiencies or inflammatory markers and prognosis, there was approximately a two-fold worse prognosis in the presence of sarcopenia, and associations with loss of adiposity. (JB/AFF/DR/MM contributed equally).