tbuckley/cabot-search huggingface dataset:
Predictive and prognostic values of circulating tumor DNA (ctDNA) clearance in osimertinib treated advanced non-small cell lung cancer cohort.
Authors: Yong Song, Shenglin Ma, Meiqi Shi, Xingxiang Xu, Xueqin Chen, Yong Wang, Zhenhua Yang, Tengfei Zhang, Min Li, Haiyan Li, Lu Zhang, Xinru Mao
Journal: Journal of Clinical Oncology (2019)

3036 Background: Although growth advantage of certain clones would ultimately translate into a clinically visible disease progression, radiological imaging does not reflect clonal evolution at the molecular level. CtDNA, validated as a tool for mutation detection in lung cancer, reflects dynamic molecular changes. Here, we evaluated the potential of ctDNA in monitoring molecular changes and predicting clinical outcomes of EGFR T790M-positive osimertinib treated NSCLC pts. Methods: This prospective multicenter study, enrolled 72 T790M positive osimertinib-treated advanced NSCLC pts who progressed on prior EGFR-TKI to evaluate the potential of ctDNA in monitoring, is part of the ongoing ASTRIS study (NCT02474355). Longitudinal plasma samples, collected from 52 pts, were subjected to sequencing using a panel consisting of 168 lung cancer-related genes. Results: Genomic profile prior to the initiation of osimertinib revealed that mutations participating in cell cycle (14 pts, p = 0.004) and P53 pathways (43 pts, p = 0.032) were associated with shorter OS ( p53 was excluded from analysis due to high mutation frequency). Interestingly, pts with undetectable ctDNA at first follow-up (within 50 d, n = 41) were correlated with longer PFS (p = 0.009) and OS (p = 0.022). With a median follow-up of 168 d (ranged from 40 - 550 d), 32 pts experienced radiological disease progression. Among them, 11 (34%) experienced molecular progression reflected by emergency of new mutation or increased allelic frequency of existing mutation prior to radiological progression, with an average leading time of 74 days. Pts with molecular PD prior to radiological PD were more likely to harbor any gene copy number amplification (CNA, p = 0.035) and p53 (p = 0.023) mutations at radiological PD. In addition, pts with CNA at radiological PD had shorter PFS (p = 0.002) and OS (p = 0.052). Conclusions: This clinical trial study demonstrates that ctDNA clearance at first follow-up can serve as a predictive and a prognostic marker for pts undergoing osimertinib treatment. Furthermore, it revealed the potential of ctDNA in early detection of disease progression, preceding imaging modalities with an average lead time of 74 days.
Lung cancer diagnosed by an incidental lung nodule program or lung cancer screening.
Authors: Matthew Smeltzer, Walter Stevens, Nicholas Ryan Faris, Jennifer Kethireddy, Meghan Brooke Meadows, Meredith Ray, Amanda Epperson, Kim Adams, Angela Fulford, Ajay Wagh, Jim Machin, Keith Tokin, Rob Optican, Jeffrey Wright, Edward T Robbins, Raymond U. Osarogiagbon
Journal: Journal of Clinical Oncology (2019)

8546 Background: Early detection reduces lung cancer (LC) mortality. We prospectively evaluated LC patients diagnosed through Lung Cancer Screening (LCS) or an Incidental Lung Nodule Program (ILNP) (‘early detection’ programs) compared to routinely diagnosed LC patients in a multidisciplinary program (MDP). Methods: We compare demographics, tumor characteristics, and survival between the three groups diagnosed within the same healthcare system from 2015-2018. The ILNP prospectively tracks patients with suspicious lung lesions on routinely-performed studies flagged by radiologists using a standard macro text. LCS used Medicare eligibility criteria. Statistical methods include the chi-square test, Kruskal-Wallis test, and proportional hazards models with hazard ratios (HR) and 95% confidence intervals. Results: ILNP detected 201 lung cancers from 4713 scans (4.3%), LCS yielded 35 lung cancers from 1540 low-dose CT scans (2.3%), while MDC had 926 LC cases not detected by LCS or ILNP. Mean age at diagnosis for ILNP/LCS/MDC was 70/69/67 years (p = 0.0083); African Americans were under-represented in LCS (25%/11%/32%, p = 0.0104). LCS had the highest proportion with commercial insurance (46%/54%/43%, p = 0.3442). Early detection groups were more likely to have adenocarcinoma histology (ILNP/LCS/MDC: 61%/57%/49%, p = 0.0113). Smoking exposure was highest in LCS cohort (mean pack years: 48/64/52, p = 0.0500); 11% of ILNP, 8% MDC patients were never-smokers. Only 36% ILNP and 39% MDC patients were eligible for LCS by NLST criteria and 30%/40% by NELSON criteria. Reasons for ineligibility included smoking status in 73-90% and age in 7-27% of patients. Stage I/II distribution was (66%/58%/21%, p &lt; 0.0001), stage IV 15%/20%/36%; surgical resection rates were (56%/55%/31%, p &lt; 0.0001). Overall survival was longer in early detection groups (LCS HR: 0.31 [0.11,0.82]; ILNP HR: 0.51[0.33,0.81]) compared to MDC (p = 0.0011). Conclusions: The majority of LC patients were ineligible for LCS, but the ILNP identified LC in a high proportion of such patients, with similar stage re-distribution, curative-intent treatment, and survival rates. Structured ILNP complement LCS for early LC detection, such programs need to be built out.
Causes of patient ineligibility in clinical trials of metastatic urothelial cancer.
Authors: Gwynn Ison, Virginia Ellen Maher, Chana Weinstock, Sundeep Agrawal, Michael Holman Brave, Yang-Min Ning, Harpreet Singh, James Xu, Amna Ibrahim, Julia A. Beaver, Richard Pazdur
Journal: Journal of Clinical Oncology (2019)

4556 Background: Registrational trials of PD-1/PD-L1 inhibitor therapy help inform clinicians and patients about the expected outcomes of patients receiving these drugs. However, the clinical trial population does not reflect all patients with the underlying disease. There have been ongoing efforts to expand eligibility criteria for clinical trial enrollment that are expected to mitigate some of these factors. We reviewed four registrational trials of PD-1/PD-L1 inhibitor therapy to better understand why patients were deemed ineligible for trial enrollment and whether expanded eligibility criteria may have addressed the reasons for ineligibility. Methods: We reviewed four trials that led to approval of PD-1/PD-L1 inhibitor therapy. These trials screened 1931 and enrolled 1253 patients with metastatic or locally advanced urothelial cancer who had previously received platinum-based therapy. We examined the datasets to determine patient demographics and reasons for trial ineligibility. Results: There were no differences in the demographics characteristics of patients who were eligible or ineligible for study treatment. However, when compared to the SEER database the screened population was younger, and minorities were under-represented. Causes of patient ineligibility included: 1) Lack of Tumor Tissue/PD-L1 Low Tumor Staining (23%), 2) Underlying Disease characteristics were not met (19%), 3) Laboratory Abnormalities (18%), 4) Excluded Co-morbid Conditions (16%), 5) Poor Performance Status (15%), 6) Refused Consent (10%), 7) Other (7%), and 8) Incorrect Prior Therapy (5%). Conclusions: Clinical trial accrual should be representative of all patients with the underlying disease. Changes in trial eligibility criteria such as less stringent requirements concerning tumor tissue (when possible), co-morbid conditions, laboratory abnormalities, and performance status may improve patient accrual. These, when added together, formed the majority of the reasons for clinical trial ineligibility.
Colorectal cancer: Improving screening in rural clinic.
Authors: Thuy Thanh Thi Le, Lorraine Fleckenstein, Zhaozhi Jiang, Shellian Davis, Lakshmi Yarlagadda
Journal: Journal of Clinical Oncology (2020)

e19215 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. From 2010 to 2014, CRC was also the second leading cause of cancer deaths in North Carolina (NC). Between 2012-2016, the age adjusted mortality rate was 18-25 per 100,000 persons in Robeson County, NC. During this timeframe, it is estimated that if all people aged 50 and older in NC were routinely screened, 40 out of 100 deaths from late stage CRC can be prevented. A chart review in a rural primary care clinic identified patients not being appropriately screened for targeted intervention. Methods: Retrospective chart review at Lumberton Medical Clinic, a rural outpatient Internal Medicine Clinic, reviewed 1622 records from adults 50-75 years old during the timeframe September 2017 - August 2018 for phase I and 1588 records from September 2018-August 2019 for phase II. Patients with history of CRC or status-post colectomy for other reasons were excluded from this study. Patient records were assessed for compliance with USPTF CRC screening guidelines – adults aged 50 to 75 years receive screening as follows: 1) Fecal occult blood testing (FOBT) annually 2) Flexible sigmoidoscopy every 5 years 3) Colonoscopy every 10 years OR 4) Combined FOBT (every 3 years) + flexible sigmoidoscopy (every 5 years). Following data analysis in phase I, interventions to increase screening rates were initiated – provider education, posters hung in exam rooms, and individualized letters mailed to patients found deficient. The success of this effort was measured in phase II. Results: For phase I, the review showed 56% of patients received appropriate screening and 44% were found with no documentation of screening. Following interventions, 76% received appropriate screening and 24% with no documentation. Thus, there is ~35% improvement in screening rate. Conclusions: The mortality rate from CRC is higher in Robeson County compared to the NC state rate. Additionally, 40% of deaths from late-stage CRC may be prevented by doing a routine screening. It is the responsibility of providers to emphasize the importance of proper screening. This retrospective review showed ~ 35% improvement in screening rates following interventions. The result might not be as high as expected due to several factors: 1) new resident physicians and faculty 2) few posters were taking down due to disagreement with the guidelines by one of the 3 main providers 3) patients might not receive the letters. To further increase the screening rate, we are implementing the “Preventive Maintenance” tab in our electronic medical record system at the end of clinic visits.
Linking CRISPR-Cas9 interference in cassava to the evolution of editing-resistant geminiviruses
Authors: Devang Mehta, Alessandra Stürchler, Ravi B. Anjanappa, Syed Shan-e-Ali Zaidi, Matthias Hirsch-Hoffmann, Wilhelm Gruissem, Hervé Vanderschuren
Journal: Genome biology (2019)

Geminiviruses cause damaging diseases in several important crop species. However, limited progress has been made in developing crop varieties resistant to these highly diverse DNA viruses. Recently, the bacterial CRISPR/Cas9 system has been transferred to plants to target and confer immunity to geminiviruses. In this study, we use CRISPR-Cas9 interference in the staple food crop cassava with the aim of engineering resistance to African cassava mosaic virus, a member of a widespread and important family (Geminiviridae) of plant-pathogenic DNA viruses.Our results show that the CRISPR system fails to confer effective resistance to the virus during glasshouse inoculations. Further, we find that between 33 and 48% of edited virus genomes evolve a conserved single-nucleotide mutation that confers resistance to CRISPR-Cas9 cleavage. We also find that in the model plant Nicotiana benthamiana the replication of the novel, mutant virus is dependent on the presence of the wild-type virus.Our study highlights the risks associated with CRISPR-Cas9 virus immunity in eukaryotes given that the mutagenic nature of the system generates viral escapes in a short time period. Our in-depth analysis of virus populations also represents a template for future studies analyzing virus escape from anti-viral CRISPR transgenics. This is especially important for informing regulation of such actively mutagenic applications of CRISPR-Cas9 technology in agriculture.
The dynamic detection of drug area under curve (AUC) guides clinical usage of docetaxel in solid tumors.
Authors: Yan Zhang, Yuan Wu, Xiaomei Zhang, Deliang Yang, Bo Shen, Geyu Liang, Martin Qi
Journal: Journal of Clinical Oncology (2019)

3024 Background: The dosage of most chemotherapy drugs were performed based on the patients’ body surface area (BSA), including docetaxel (DTX). Previous studies showed that this conventional administration of DTX might cause adverse event, such as neutropenia, and neutropenia was proved to associate with DTX area under curve (AUC). This study was designed to evaluate the effect of dose-administration of DTX based on dynamic detection of DTX AUC on clinical outcomes. Methods: A total of 209 patients with DTX chemotherapy (one cycle every 3 weeks) were enrolled, and all patients received 2-6 cycles of treatment. In the first cycle, dosage of DTX based on BSA was administrated in all study population. From the second cycle, one group patients (control group) received DTX according to traditional BSA and the other group patients (experimental group) on the basis of dynamic detection of DTX AUC. The primary outcome was incidence rate of neutropenia and the second outcome was disease control rate (DCR). Results: Patients with grade 3 or higher neutropenia from the fourth to sixth cycle of DTX chemotherapy were significantly lower in the experimental group compared with the control group (P= 0.039, 0.012, and 0.001, respectively). In the experimental group, compared with the first cycle, and the number of patients falling within the therapeutic window increased by 27.19% in the sixth cycle after dose adjustment according to the AUC value of previous cycle. The DCR in the experimental and control group is 85.32% and 72.00%, respectively (P= 0.018). Conclusions: The administration method based on dynamic detection of AUC of DTX could significantly reduce incidence rate of neutropenia and received a higher DCR, but the result needed to be confirmed in further studies.
Sonographic and histopathologic characteristics of MMR-deficient endometrial cancer.
Authors: Daniel Arnold Smith, Raj M Paspulati, Nami R Azar, Kai Laukamp, Elias Kikano, Stefanie Avril, Nikhil H. Ramaiya
Journal: Journal of Clinical Oncology (2019)

e17111 Background: Mismatch repair (MMR) deficiency has emerged as a key biomarker in endometrial cancer with roles in prognosis and guiding therapy. However, the differences of sonographic features between MMR-deficient and MMR-proficient endometrial cancers at initial presentation have not been established. Methods: Transvaginal ultrasound studies of 103 endometrial cancers (60 MMR-deficient, 43 MMR-proficient) at initial presentation were retrospectively analyzed by two experienced radiologists. Histopathologic findings and sonographic features of endometrial morphology recorded according to IETA terminology were compared using Likelihood Ratio Chi-Square and Mann–Whitney U tests. Results: The MMR-deficient group comprised of 90% and the MMR-proficient group of 100% endometrioid subtypes. The following sonographic features were statistically different between MMR-deficient (age 45-95) and MMR-proficient (age 45-83) groups: uniform endometrial echogenicity/pattern, non-uniform endometrial echogenicity/pattern, endometrial midline morphology, presence of a bright edge, and endomyometrial junction morphology. Ultrasound findings of endometrial thickness, synechiae, intracavitary fluid, color Doppler score, and vascular pattern were not significantly different. Statistically significant differences in pathology features included FIGO grade, myometrial invasion, and lymphovascular invasion, while FIGO stage showed no difference. Conclusions: MMR-deficient endometrial cancer is characterized by several statistically different ultrasound and histopathologic features on initial presentation compared to MMR-proficient endometrial cancer.[Table: see text]
Rates of genotyping for <i>KRAS</i>, <i>NRAS</i>, <i>BRAF</i>, microsatellite instability (MSI), and mismatch repair (MMR) in metastatic colon cancer patients: Gaps and implications.
Authors: Martin Gutierrez, Kristin Sedgwick Price, Richard B. Lanman, Rebecca Nagy, Irfan Shah, Shivam Mathura, Andrew David Norden, Stuart L. Goldberg
Journal: Journal of Clinical Oncology (2019)

e15123 Background: Molecular genotyping is essential to optimal treatment selection in metastatic colon cancer (mCC) as mutations in exons 2,3,4 of KRAS and NRAS (expanded RAS) and BRAF V600E predict lack of response to anti-HER2 therapy, and microsatellite instability high (MSI-H) predicts positive response to immune checkpoint inhibitor (ICPI)s. The National Comprehensive Cancer Network (NCCN) first recommended molecular genotyping for mCC in 2009 and by 2016 recommended all pts with mCC have expanded RAS, BRAF, and mismatch repair deficiency (MMRd) testing. This study updates genotyping rates in metastatic colon cancer (mCC) in a real-world practice setting. Methods: We performed a retrospective review of genomic testing patterns from pts with mCC diagnosed between January 2013 and December 2017 from 22 academic and community health centers in the United States who contributed to COTA’s de-identified Real World Evidence database. Results: 563 pts with mCC were identified in the Cota database over the 5-year period. 341 (61%) pts with mCC had testing for KRAS, 130 (23%) for NRAS, 177 (31%) for BRAF, and 297 (53%) for MMRd. Testing rates for NRAS, BRAF and MMRd all increased from 2013 to 2017 but remained suboptimal with undergenotyping rates of 48%, 45% and 12% respectively by 2017. 33 (6%) pts received cetuximab and/or panitumumab without prior testing for both KRAS and NRAS, despite established lack of benefit. Between 2016 and 2017, when NCCN recommended testing for KRAS, NRAS, BRAF and MMRd, only 24% of mCC pts were tested for all biomarkers. Conclusions: Although molecular genotyping rates increased over the described 5-year period, since 2016, less than one quarter of all mCC pts in this cohort received guideline recommended genotyping. Approaches that may improve complete genotyping rates in mCC, such as plasma-based comprehensive genomic profiling, may improve optimal treatment selection and should be tested in prospective trials.
The combined treatment of 150 kHz tumor treating fields (TTFields) and cisplatin or pemetrexed inhibits mesothelioma cells in vitro and in vivo.
Authors: Uri Weinberg, Mijal Munster, Karnit Gotlib, Rosa S. Schneiderman, Yaara Porat, Tali Voloshin, Shiri Davidi, Anna Shteingauz, Noa Kaynan, Einav Zeevi, Moshe Giladi, Eilon David Kirson, Adrian Kinzel, Yoram Palti
Journal: Journal of Clinical Oncology (2019)

e20069 Background: Malignant pleural mesothelioma (MPM) is an aggressive thoracic cancer mostly linked to asbestos exposure. The standard of care (SOC) therapy for unresectable MPM is cisplatin plus pemetrexed. Treating Fields (TTFields) therapy is an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. We explored the potential use of TTFields alone and in combination with SOC as a treatment for MPM. Methods: NCI-H2052 and MSTO-211H cells were treated at various TTFields frequencies for 72 hours using the inovitro system. The combined treatment of TTFields and cisplatin or pemetrexed was tested by applying TTFields at the optimal frequency together with various drug concentrations. Cell counts, clonogenic potential and induction of apoptosis were determined. TTFields (1.2 V/cm) were applied for 8 days to rats injected to the intrapleural cavity with IL-45 cells, and overall survival was tested. Results: TTFields optimal frequency was 150 kHz for both human cell lines. TTFields application (1.1 V/cm, 72 hours) at 150 kHz led to 45%-51% reduction in cell counts and 46-64%% additional reduction in clonogenic potential. The combined treatment of TTFields and cisplatin or pemetrexed led to a significant reduction in cell count, induction of apoptosis and reduced clonogenic potential as compared to each modality alone (p &lt; 0.0001(. TTFields significantly prolonged the survival of rats compared to control group. Safety studies did not reveal any adverse events associated with 150 kHz TTFields application to the rat torso. Conclusions: These results demonstrate that TTFields can be an effective treatment against mesothelioma and the combination with cisplatin or pemetrexed may further enhance treatment efficacy. These results are in consistency with the recent phase 2 study (EF-23 trial) that showed improved overall survival for combined treatment as compared to historical control with no increase in systemic toxicity.
The effect of E2F7 expression in prostate cancer on apoptosis and cell cycle of prostate cancer cells.
Authors: Ying Wang
Journal: Journal of Clinical Oncology (2019)

e16568 Background: Prostate cancer (PCa) is a leading cause of illness and death among men in the United States and Western Europe. However, the molecular mechanisms by which PCa developed has not been fully illustrated. Methods: Here, the expression of E2F7 in PCa was examined using IHC method and western blotting assay, and the expression of miR-30c was measured using qRT-PCR method. The cell cycle and apoptosis was determined by FACS. Cell Counting Kit-8 was used to testify cell proliferation. miR-30c mimics, miR-30c inhibitors and E2F7 siRNA transfections were performed to study the loss- and gain-function. Duel-luciferase reporter assay was performed to verify that E2F7 was one of the potential targets of miR-30c. Results: It was found that E2F7 was overexpressed in PCa cells and tissues compared with normal ones. Inhibition of E2F7 in PCa cells led to significant decreased proliferation rates, increased G1 phase percentage, and higher apoptosis rates of PCa. Duel-luciferase reporter assay showed that E2F7 was one of the targets of miR-30c. Moreover, introduction of miR-30c resulted in decreased proliferation rates, increased G1 phase percentage, and higher apoptosis rates of PCa cells while miR-30c inhibitor led to lower apoptosis rates of PCa cells. Conclusions: In conclusion, our study demonstrated that E2F7 may play a tumorigenesis promoting role of PCa cells, and that E2F7 was regulated via miR-30c, indicating that E2F7 and miR-30c might be viable therapeutic targets for PCa.
The cross talk between the molecular alterations and tumor immunity in the microenvironment in non-small-cell lung carcinoma.
Authors: Chengzhi Zhou, Yanhui Chen, Ying Hu, Yang Liu, Henghui Zhang
Journal: Journal of Clinical Oncology (2019)

e20043 Background: The previous study indicated that the biomarkers of molecular alterations and tumor immunity in the microenvironment could predict the response of immunotherapy in NSCLC patients. However, the cross talk between the two factors is unclear. This study was designed to investigated the features of tumor immunity in the microenvironment of deferential molecular characterization in NSCLC patients. Methods: Tumor tissue and matched blood samples from 62 patients with NSCLC were collected. The mutation profiles were sequenced by a cancer gene-targeted NGS panel. The PD-L1 expression and immune cells infiltrated in tumor microenvironment were detected by multiplex immunofluorescence staining. Results: The distinct of molecular alterations showed the different tumor microenvironments in terms of immune cell composition and of PD-L1 expression by tumor cells in NSCLC. KRAS-mutated tumors were characterized by higher level of PD-L1 expression and lower NK cells infiltrated in tumor area than KRAS-wild type tumor. TP53-mutated tumors were characterized by higher CD8 + T cell and lower NK cells infiltrated in tumor area. In contrast, EGFR-mutated tumors were characterized by lower level of PD-L1 expression and higher NK cells. Moreover, we found that the PD-L1 expression increased in MET gene CNV gain tumors than MET wild type tumors. Conclusions: The features of tumor immunity in the microenvironment changed in deferential molecular characterization in NSCLC. it may help to explain the phenomenon that the efficacy of immunotherapy changed in deferential molecular characterization of NSCLC.