tbuckley/cabot-search huggingface dataset:
Correlation between circulating cell-free RNA biomarkers and response during combination immunotherapy in previously refractory metastatic TNBC patients.
Authors: Chad Garner, Tara Elisabeth Seery, Chaitali Singh Nangia, John H. Lee, Liyang Huang, Leonard S. Sender, Shahrooz Rabizadeh, Patrick Soon-Shiong
Journal: Journal of Clinical Oncology (2019)

e14027 Background: A commercial liquid biopsy test was included as an exploratory component of an integrated immunotherapy clinical trial in previously refractory metastatic TNBC patients, combining innate, high-affinity natural killer cell (haNK) therapy with adenoviral and yeast-based vaccines and an IL-15 superagonist (NCT 03387085). The purpose of the study was to assess the utility of cell-free circulating RNA (cfRNA) as a predictor of treatment response. Methods: Blood was drawn from trial participants at baseline and at 2-6 week intervals throughout the treatment protocol. cfRNA and cfDNA were extracted from plasma and tested for analytes by quantitative PCR (qPCR) in a CLIA and CAP certified laboratory. This study is based on the analysis of 18 the cfRNA analytes (AR, PD-L1, CTLA-4, LAG-3, EGFR, HER2, ERCC1, TIM-3, MGMT, RRM1, SLC29A1, TOP1, TOP2A, TOP2B, TUBB3, TYMP, TYMS, XRCC1) in six patients that had at least three testing time points; new patient recruitment and serial testing are ongoing. The relative expression of each RNA analyte was normalized by beta-actin. Tumor size was evaluated by imaging using the RECIST criteria. Results: The amount and variability of cfRNA was positively correlated with the tumor size. As cfRNA quantity and variability increased or decreased, a corresponding increase or decrease in tumor size was observed, respectively. Not all 18 genes showed consistent patterns of change across the six patients, however the average expression and variability of the 18 genes showed evidence of a correlation with tumor size change from baseline (p-values = 0.08 and 0.03, respectively). Only trace levels of PD-L1 expression were observed in all 6 patients at baseline, prior to the initiation of the combination immunotherapy. Among the 5 patients that showed a reduction in tumor size of at least 10%, 4 also showed an associated increase in cfRNA PD-L1 expression from nearly 0 to normalized values between 2.1 and 6.8. Conclusions: Exploratory analysis in an ongoing combination immunotherapy clinical trial for TNBC showed that increasing and decreasing cfRNA levels are correlated with increasing and decreasing tumor size, respectively. Increased PD-L1 cfRNA levels are correlated with beneficial treatment response. Liquid biopsy of cfRNA could provide an effective biomarker of treatment response. Clinical trial information: NCT03387085.
Case 44-1983
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Charles M. Poser, Raymond A. Sobel, John J. Halperin
Journal: New England Journal of Medicine (1983)

Presentation of CaseA 41-year-old woman was admitted to the hospital because of spastic tetraparesis.The patient was the firstborn child of three siblings. She was considered normal at birth but was clumsy during childhood and frequently dropped objects held in either hand. She was left-handed. At the age of 12 years linear growth ceased. X-ray films of the bones taken two years later showed arrested growth. She performed well in school, graduated from college, and became an elementary-school teacher. Eighteen years before admission her first child was delivered by cesarean section because her pelvis was too small. During her . . .
The missed potential of CD4 and viral load testing to improve clinical outcomes for people living with HIV in lower-resource settings
Authors: Peter D. Ehrenkranz, Solange L. Baptiste, Helen Bygrave, Tom Ellman, Naoko Doi, Anna Grimsrud, Andreas Jahn, Thokozani Kalua, Rose Kolola Nyirenda, Michael O. Odo, Pascale Ondoa, Lara Vojnov, Charles B. Holmes
Journal: PLoS Medicine (2019)

The combination of CD4 and viral load (VL) testing has long been recognized as integral to the management of HIV disease.However, recent shifts in the global HIV response have driven rapid changes in the prioritization and use of these tests.• CD4 remains the gold standard for assessing disease progression and the need for the World Health Organization's advanced disease package of screening, prophylaxis, or treatment for major opportunistic infections, which decreases mortality among eligible individuals.Yet, support for site-level provision of CD4 testing capacity is declining.• Access to routine VL testing, which is the focus of most laboratory resources in low-or middle-income countries (LMICs), is required to assess an individual's response to treatment.Results should lead to VL-informed differentiated service delivery and better clinical decision-making, including referral to intensified or less frequent clinical care.• However, available evidence suggests that the majority of CD4 and VL tests currently performed in LMICs do not lead to changes in clinical management, drawing urgent attention to the need to rethink the approach to testing and use of results along with continued efforts to improve access to the tests.• Frontline access to CD4 and VL remain essential.Yet, a laboratory system is only as good as its ability to return a result to patients and their providers.HIV programs and funders could improve clinical outcomes by measuring the success of their laboratory investments not just by the numbers of tests performed but by the ability of those test results to lead to better outcomes among people living with HIV.
HSD3B1 and overall survival (OS) in men with low-volume (LV) metastatic prostate cancer (PCa) treated with androgen deprivation therapy (ADT) or chemohormonal therapy in the CHAARTED Randomized trial.
Authors: Jason W.D. Hearn, Christopher Sweeney, Nima Almassi, Chad A. Reichard, Chandana A. Reddy, Brian Hobbs, David Frazier Jarrard, Yu-Hui Chen, Robert Dreicer, Jorge A. Garcia, Michael Anthony Carducci, Robert S. DiPaola, Nima Sharifi
Journal: Journal of Clinical Oncology (2019)

5020 Background: The HSD3B1(1245A &gt; C) variant allele, whose frequency varies by race, encodes a missense sequence that stabilizes the rate-limiting enzyme responsible for extragonadal androgen synthesis, thus enhancing intratumoral dihydrotestosterone (DHT) synthesis. Multiple retrospective studies have found that men inheriting the HSD3B1(1245C) variant allele exhibit early resistance to ADT. We sought to validate these findings with prospective data from the Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED). Methods: Men with newly metastatic PCa were randomized to receive either ADT plus docetaxel at a dose of 75 mg/m 2 every 3 weeks for 6 cycles (arm A) or ADT alone (arm B). We determined germline HSD3B1 genotype in the subset of men with LV disease ( &lt; 4 bone metastases, no visceral metastases). We analyzed freedom from castration-resistant prostate cancer (CRPC) and OS according to HSD3B1 genotype using Cox and Kaplan-Meier methods. Results: 197 patients with LV disease had blood samples available and were genotyped, including 97 in arm A and 100 in arm B. Docetaxel did not improve OS of LV men. Of the 197 men, 47% were homozygous wild-type (WT), 43% were heterozygous, and 10% were homozygous variant. When all 197 men were analyzed as one goup, the median time to CRPC was 39.7 mos. in homozygous WT men vs. 25.0 mos. in men with one or more copies of the variant allele (HR 1.27, 95% CI 0.89 to 1.82; p = 0.187). Although OS data are still maturing, at 52 months OS was 83% (95% CI 75% to 91%) in homozygous WT men vs. 64% (95% CI 55% to 74%) in men with one or more variant alleles. There was a suggestion that docetaxel delayed development of CRPC among men with at least 1 variant allele (20.3 vs. 40.7 mos.; HR 0.66, 95% CI 0.40 to 1.04; p = 0.08). Benefit for men with high-volume disease was not evident. Conclusions: Inheritance of the HSD3B1(1245C) allele that augments DHT synthesis may be associated with lower OS in men treated with ADT with or without docetaxel for LV newly metastatic PCa. Additional study is warranted in patients with LV disease. Clinical trial information: NCT00309985.
Characteristics of T-cell receptor repertoire between lung cancer patients and healthy people.
Authors: Naixin Liang, Si Chen, Yuting Yi, Yan-Fang Guan, Xuefeng Xia, Xin Yi
Journal: Journal of Clinical Oncology (2019)

e20728 Background: Deep sequencing studies on T cell receptor (TCR) repertoire have provided a wealth of information, such as immune status, virus infection history and so on. As we all known, the thymus begins to involute at the time of birth, so does the immune system. We can use TCR sequence to describe changes in human’s immune system with age, the difference between males and females and immune stat of cancers. Methods: We analyzed TCRβrepertoire in 334 healthy individuals without cancer, aged 2–83 years, and 207 lung cancers. In detail, genomic DNA was extracted from peripheral blood and used to amplified and sequenced the CDR3 region of rearranged TCRβ genes. Finally, we got the relative frequencies of individual T cell clones. Shannon’s entropy was calculated on the clonal abundance of all productive TCR sequences. The normalized Shannon’s entropy (Shannon index) was determined by dividing Shannon’s entropy by the natural logarithm of the number of unique productive TCR sequences. HEC was defined by a CDR3 aa clonotype clonal frequency exceeding 0.1%. Results: Analysis had been made to test the age relationship among a cluster of commonly used immune parameters, such as Shannon’s entropy, clonality and so on. Two outcomes, Shannon index and HEC, had showed a more closed correlation with age. Shannon indexs were significantly decreasing with age (p = 6.2×10 -11 ), while HECs increased with age (p = 5.3×10 -10 ) . Comparison of the peripheral blood T cell repertoire diversity between male and female, we found TCRβdiversity decreases more rapidly in 20 to 40 years for males than for females. No gender difference was observed in the youngest cohort and the oldest age cohort. Lung cancer patients has a lower T cell diversity compared with health people aged 40 years or more (6.43±1.30 vs 6.71±1.70, p = 6.3×10 -5 ). Conclusions: Our data suggest that the human peripheral blood TCR repertoire diversity decrease from young ( &lt; 20 years) to middle-aged ( 20 to 65 years ) to elderly adults ( &gt; 65 years). Moreover, TCR repertoire displays significant gender difference in the 20-40 years age group. Lung cancer patients suffer a poorer immune state than healthy people.
Randomized phase 2 trial of the combination of vincristine and irinotecan with or without temozolomide, in children and adults with refractory or relapsed rhabdomyosarcoma (RMS).
Authors: Anne Sophie Defachelles, Emilie Bogart, Michela Casanova, Hans Merks, Gianni Bisogno, Giuseppina Calareso, Soledad Gallego Melcon, Susanne Gatz, Marie-Cecile Le Deley, Kieran McHugh, Alicia Probst, Nathalie Rocourt, Rick R. van Rijn, Keith Wheatley, Veronique Minard-Colin, Julia Chisholm
Journal: Journal of Clinical Oncology (2019)

10000 Background: Vincristine with Irinotecan (VI) is effective in patients with relapsed RMS but outcomes remain poor. The addition of temozolomide to VI (VIT) is attractive owing to different resistance mechanisms and distinct toxicity profiles. Methods: The VIT-0910 trial, an EpSSG-ITCC randomized phase 2 trial, evaluated efficacy and safety of VI and VIT in patients (pts) aged 0.5-50 years with relapsed/refractory RMS. Pts received Vincristine 1.5 mg/m2 d1, d8, Irinotecan 50mg/m2 d1-d5 +/- Temozolomide 125 mg/m² d1-d5 (150 mg/m² from cycle 2 if no toxicity &gt; grade 2); 21-day cycles were given until progression/unacceptable toxicity. The primary endpoint was centrally reviewed objective response rate (ORR) after 2 cycles (primary lesion, WHO response criteria: metastatic sites, RECIST 1.1 ). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events (NCI-CTCAE v4). Initially a Simon 2-stage design was used to analyse separately 40 pts/arm. After amendment, the trial sample size was increased to 120, and a comparison between arms, adjusted for confounding factors, was added to the statistical plan. Results: 120 pts (60 VIT, 60 VI) were recruited in 37 European centers from 03/2012-04/2018. Median age was 11 years (0.75-46), 89% pts relapsed RMS. ORR was 24/55 (44%) for VIT vs 18/58 (31%) for VI; adjusted odds ratio =0.50, 95%CI, 0.22-1.12, p=0.09. The VIT arm achieved significantly better PFS (adjusted Hazard Ratio (HR)=0.65, 95%Cl, 0.43-0.97, p=0.036) and OS (HR=0.53, 95%CI, 0.33-0.83, p=0.005) compared to VI. PFS and OS results were similar when only relapsed patients were included. Adverse events ≥ grade 3 were more frequent in VIT compared to VI, but only hematological toxicity was significantly increased (81% for VIT, 59% for VI, odds ratio=1.36, 95%CI, 1.06-1.76, P=0.02). Conclusions: The addition of temozolomide to VI improves PFS and OS of pts with relapsed/refractory RMS. VIT is now standard treatment for relapsed RMS in Europe. Clinical trial information: NCT01355445.
Assessment of neurocognitive function in illiterate patients of high-grade glioma treated with chemoradiation.
Authors: Monica Malik, Deepthi Valiyaveettil, G Ashalatha, Prathyusha E, Deepa M. Joseph
Journal: Journal of Clinical Oncology (2019)

e13543 Background: Although the role of chemo-radiation (CRT) in gliomas has been studied extensively, its effects on neurocognitive function (NCF) remain elusive. Assessment of NCF in illiterate patients is a challenge. Methods: Illiterate adults with histopathologically proven high grade gliomas planned for CRT following maximal safe resection were included. Temozolomide based CRT using standard protocols was planned. Neurocognitive function was assessed using the Addenbrooke’s Cognitive Examination (ACE-III) questionnaire prior to the start of CRT and at 3 and 6 months post RT. The subventricular zones (SVZ) and hippocampus were contoured using standard guidelines. The NCF scores were compared using the paired t test. Results: 32 patients were recruited. The median age was 40 years. M:F ratio was 1:1.16. IMRT to a dose 60 Gy with concurrent and adjuvant temozolomide was planned. Overall there was no significant difference in scores at 3 months and a significant decline in visuospatial scores at 6 months (p &lt; 0.001). Mean doses to the ipsilateral and contralateral SVZ were 49.5 Gy and 35 Gy respectively. Based on mean ipsilateral SVZ dose, patients were divided into: Group I &lt; 50 Gy (n = 18), group II ≥ 50 Gy (n = 14). At 3 months there was significant improvement in scores in Group I whereas a decline in scores in Group II. At 3 months, memory (18.73 vs 21.93; p = 0.021) and fluency (10.20 vs 11.67; p = 0.042) showed improvement in group I patients. In group II there was decline in visuospatial scores (14.41 vs 13.71; p = 0.016) at 3 months. At six months, there was improvement in memory (17.94 vs 22.94; p = 0.002), attention (14.78 vs 16.39; p = 0.031), fluency (10.11 vs 11.67; p = 0.018) and total ACE scores (80.83 vs 89.94; p = 0.008) in group 1 patients and a significant decline in visuospatial function, attention, memory and language scores in group II patients. Higher contralateral SVZ doses (&gt; 35 Gy) correlated with a significant decline in visuospatial scores at 3 and 6 months. Lower mean dose to ipsilateral hippocampus (&lt; 40 Gy) correlated significantly with improved memory scores. Doses to contralateral hippocampus did not correlate with scores. Conclusions: The Addenbrooke’s Cognitive Examination (ACE-III) questionnaire can be used to assess NCF in patients with gliomas including illiterate patients. Lower mean doses to the ipsilateral and contralateral SVZ and hippocampus resulted in improvement/preservation of memory, attention and fluency whereas higher doses were associated with a decline in scores.
Cancer-testis gene-expression features in various tumors.
Authors: Kristina I. Soldatova, Oleg Ivanovich Kit, Roman E. Tolmakh, Liubov Yu Vladimirova, Denis S. Kutilin
Journal: Journal of Clinical Oncology (2019)

e14260 Background: Cancer-testis antigens (CTA) can be an effective target for immunotherapy. Immunotherapeutic approaches targeting CTA in breast cancer (BC), endometrial cancer (EC), ovarian cancer (OC), and colon cancer (CRC) are in the incipient stages of development. The purpose of our study was screening of CTA specific for BC, EC, OC and CRC, based on an analysis of transcriptional profiles of CT-genes. Methods: Tumor and intact tissues of the breast, uterus, ovaries and colon were studied in 35, 30, 20 and 60 patients, respectively. RNAs were isolated using the method described by Chomczynski and Sacchi (2006). The REVERTA-L reagent kit was used for the cDNA synthesis. Relative expression of 16 genes ( MAGEA1, MAGEA2, MAGEA3, MAGEA4, MAGEB1, MAGEB2, GAGE1, GAGE3, GAGE4, MAGEC1, BAGE, XAGE3, NYESO1, SSX2, SCP1, PRAME1) was determined by Real-Time qPCR (with GAPDH and GUSB as reference genes). Statistical analysis was performed using the Mann-Whitney test. Results: BC patients showed significantly (p &lt; 0.005) increased expression of MAGEA3, MAGEA4 and GAGE3 in tumor tissues compared to normal ones; EC patients - significantly (p &lt; 0.05) increased expression of MAGEA1, MAGEA2, MAGEA4, MAGEB2, GAGE3, NY-ESO1, SCP1 and PRAME1 in tumor tissues compared to normal ones; OC patients - significantly (p &lt; 0.05) increased expression of MAGEB1, MAGEB2, GAGE1, NY-ESO1 and decreased expression of MAGEA3, MAGEA4, GAGE3, GAGE4, XAGE3, SSX2, SCP1 and PRAME1; CRC patients - significantly (p &lt; 0.05) increased expression of SSX2 and PRAME1, together with decreased BAGE expression, in tumors compared to normal tissues. Conclusions: Analysis of the transcriptional activity of CT-genes revealed the most common diagnostic markers and immunotherapeutic targets for every malignancy: in BC - MAGEA3, MAGEA4 and GAGE3, in EC - MAGEA1, MAGEA2, MAGEA4, MAGEB2, GAGE3, NY-ESO1, SYCP1 and PRAME1, in OC - MAGEB1, MAGEB2, GAGE1 and NY-ESO, in CRC - SSX2 and PRAME1.
Association of frequent amplification of chromosome 11q13 in esophageal squamous cell cancer with clinical benefit to immune check point blockade.
Authors: Feng Wang, Chao Ren, Qi Zhao, Nong Xu, Lin Shen, Guanghai Dai, Xianglin Yuan, Ye Chen, Shujun Yang, Jianhua Shi, Xichun Hu, Xiaoyan Lin, Qingyuan Zhang, Jifeng Feng, Yi Ba, Yunpeng Liu, Wei Li, Yongqian Shu, Fenghua Wang, Rui-hua Xu
Journal: Journal of Clinical Oncology (2019)

4036 Background: Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer in South America and East Asian countries and remains an unmet medical need worldwide. Previous studies have shown the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic ESCC. However, robust predictive biomarkers to PD-1 antibody-based immunotherapy remain undefined. Methods: Patients included in this analysis were part of multi-center, phase Ib/II trial (NCT02915432) evaluating the safety and activity of toripalimab, a humanized PD-1 antibody in solid tumors. To identify molecular determinants of response, we performed whole exome sequencing (WES), messenger RNA sequencing and immunohistochemistry on patients’ samples and evaluated genomic and transcriptional biomarkers, PD-L1 expression and tumor mutational burden (TMB) for correlation with clinical efficacy. Results: Sixty advanced chemo-refractory ESCC patients were enrolled and 59 were treated with toripalimab. 94.9% (56/59) patients experienced at least one treatment related adverse event after 16 months; mostly grade 1 or grade 2. Treatment-related grade 3 or higher AEs occurred in 30.5% (18/59) of subjects. By the data cutoff date, 11 (18.6%; 95%CI 9.7 to 30.9) patients achieved an objective response, while the disease control rate was 47.5% (95%CI 34.3 to 60.9). Copy number analysis identified 24 out of 50 (48%) patients with amplifications of chromosome 11q13 region, which was consistent with elevated mRNA expression of amplified genes, including CCND1(Cyclin D1) and fibroblast growth factor family members ( FGF3/4/19). Patients without 11q13 amplification, had significantly better objective response rate (ORR 30.8% versus 4.2%, p= 0.024) and progression free survival (3.7 versus 2.0 months, HR = 0.47 [95%CI 0.24 to 0.91], p= 0.025) when compared with 11q13 amplified individuals. In contrast, patients with high TMB (≥12 Mutations/Mb; 11/47, 23.4%) or positive PD-L1 expression (TC or IC 1%; 19/57, 33.3%) showed no significant advantage in ORR or survival. Conclusions: Toripalimab has demonstrated a manageablesafety profile and promising anti-tumor activity in chemo-refractory ESSC patients. Genomic amplification of 11q13 region may serve as a negative predictive marker for advanced ESSC patients receiving anti-PD-1 based immunotherapy. Further interrogation of putative resistance genes that lie within this region is under study. Clinical trial information: NCT02915432.
Association of patient characteristics with real-world ROS1 NSCLC testing patterns among community practices in the United States.
Authors: William Bruce Wong, Ning Wu, Ravindra Gupta, Aaron Scott Mansfield
Journal: Journal of Clinical Oncology (2019)

e18321 Background: Despite the availability of targeted therapy for ROS1 NSCLC since 2016, there is limited information on real-world ROS1 testing practices to identify patients potentially eligible for targeted treatment among community practices. The objective of this study was to characterize ROS1 testing rates and identify potential barriers to ROS1 testing. Methods: The Flatiron Health EHR-derived database was used to identify patients diagnosed with advanced NSCLC between 7/1/2016 - 7/30/2018 and received systemic treatment in a community practice setting. Descriptive statistics were used to summarize the population, biomarker testing rates and timing of testing. Logistic and multinomial regressions including patient demographics and clinical characteristics were used to identify factors associated with the following outcomes: ROS1 testing, testing for biomarkers other than ROS1 (PDL1, ALK, EGFR) , longer times from advanced diagnosis (adv. dx) to ROS1 test results and initiation of therapy prior to ROS1 testing. Results: Of 9,275 eligible patients, ROS1 testing rates in squamous (SQ) and non-squamous histologies increased over the study period (30% to 52%, 62% to 75% respectively). Older age, males, poorer performance status, SQ histology, history of smoking and recurrent disease (RD) patients were significantly less likely to be tested. Among patients not tested for ROS1, 62% were tested for other biomarkers including &gt; 50% of non-squamous patients tested for PDL1, EGFR or ALK and 51% of squamous patients tested for PDL1. The median time from adv. dx to test result was 24 days, with patient characteristics (i.e. Hispanic ethnicity, history of smoking) as well as test type predicting longer times to test results ( &gt; 41 days vs. &lt; 24 days after adv. dx). Patients who had a delay in test results were more likely to receive other therapy prior to availability of their ROS1 test results (25+ days vs. &lt; 24 days OR [95% CI]: 9.18 [7.87, 10.70]). Conclusions: In real-world practice, patient characteristics were associated with ROS1 testing and testing delays which may result in some patient subgroups being less likely to be identified for potential targeted therapy.