tbuckley/cabot-search huggingface dataset:
Immune correlates of CD73 expression in patients with urothelial carcinoma (UC).
Authors: Edwin Lin, Roberto Nussenzveig, Andrew W Hahn, Mark Yandell, Lauren Christine Harshman, Neeraj Agarwal, Abhishek Tripathi
Journal: Journal of Clinical Oncology (2019)

4548 Background: Checkpoint inhibitors have improved outcomes in UC. However, response rates are low and additional mechanisms of immune evasion need to be ascertained. CD73 (encoded by NT5E) converts extracellular AMP to adenosine, which exerts an immunosuppressive effect in the tumor microenvironment by inhibiting infiltrating T and NK cells. Utilizing The Cancer Genome Atlas (TCGA) bladder cancer dataset, we evaluated correlations between NT5E expression and the immune milieu in UC. Methods: RNA-seq data from 411 primary UC tumor samples were obtained from the TCGA. Patients were split into low, intermediate, and high NT5E expression groups (≤ -1, -1 to 1 and ≥1 standard deviation from the overall mean). A tumor inflammation signature (TIS) reflecting an inflamed tumor phenotype was calculated based on the averaged expression of 18 previously validated genes (Ayers et al, 2017). NT5E expression was compared between tumors with high and low TIS scores and among the TCGA molecular subtypes. Abundance of infiltrating immune cell subsets was estimated based on expression of previously identified 782 immune metagenes and compared between NT5E expression groups (Charoentong et al, 2017). The Mann-Whitney U test assessed statistical significance, and the Bonferroni correction was used to control for false discovery rate. Results: NT5E expression was significantly higher in tumors with a high TIS score compared to those with low TIS score (P&lt;0.0001) and correlated with expression of other immune checkpoints such as PD-L1, IDO and LAG-3 (each P&lt;0.01). Patients with basal/squamous subtype had the highest NT5E expression compared to luminal or neuronal subtypes. High NT5E expression was associated with increased infiltrating NK cells, neutrophils, Tregs and decreased Type 2 T helper cells. Conclusions: High expression of NT5E in UC patients with an inflamed tumor phenotype was associated with an increase in infiltrating Tregs, and the basal/squamous subtype. Our findings highlight a potential role of CD73-adenosine pathway as a mechanism of immune evasion and a novel therapeutic target in UC. Further studies to assess the clinical impact of NT5E expression on outcomes in UC patients treated with immunotherapy are needed. AT and NA: equal contribution.
Prognostic value of tumor infiltrating lymphocytes in epithelioid malignant pleural mesothelioma.
Authors: Michael Adashek, Abigail Sy Chan, Johnathan Heath, Rachel Fanaroff, Michael E Kallen, Joseph S. Friedberg, Melissa Culligan, Tamara Khashab, Kenneth David Miller
Journal: Journal of Clinical Oncology (2019)

e20064 Background: Malignant Mesothelioma (MM) is an aggressive malignancy with survival of 4-12 mo. without treatment and 10% 5-year survival. The response of patients with MM to immunotherapy has increased interest in the tumor immune microenvironment. The purpose of this study was to determine if tumor infiltrating lymphocytes (TIL) are correlated with survival in epithelioid MM. Methods: Immunohistochemistry was performed on specimens from 27 patients with epithelioid mesothelioma using CD4, CD8, and CD68 antibodies. Infiltrate density was scored (0-3+) by pathologist estimate in intratumoral and adjacent tumoral tissue. ANOVA and regression analysis were performed. Overall survival (OS) for the entire group and time to progression (TTP) for nine patients with known time from surgery until tumor recurrence were also studied as a surgical resection subgroup (SRG). Results: For the small SRG the relationship between (TTP) and TIL score of CD8 at the edge of the tumor was significant (F[2,6]=5.64, P=.042) however TIL score of intratumoral CD8 cell infiltrates and TTP did not demonstrate statistical significance. The relationship between OS with CD8 infiltrate at the tumor edge, for the entire group, approached significance at (F [3,22]=2.93, P=0.056). TTP and OS and the TIL score of CD4, CD68 at both tumor center and tumor edge did not demonstrate statistical significance. Conclusions: CD8+ lymphocytes are an important component of host immune defense against cancer. We found that in epithelioid MM the cellular infiltrate of CD8 lymphocytes at the edge of the tumor (but not with intratumoral CD8) was associated with longer time to recurrence. TTP and OS were not associated with CD4 and CD68 within or at the tumor edge. The role of CD8 T-cells and the quantitative difference between CD8 at the edge of tumor and intratumoral CD8 should be further investigated in order to optimize immunotherapy.
Sponsorship of pediatric oncology interventional trials.
Authors: Dylan Neel, David Stephen Shulman, Steven G. DuBois
Journal: Journal of Clinical Oncology (2019)

10044 Background: The sponsor of a clinical trial is the single entity responsible for the overall conduct and oversight of the trial. Sponsors may be pharmaceutical/biotech companies (“industry”), government agencies (e.g. NIH), or other entities such as academic institutions. Trial sponsorship may have important regulatory and financial implications for the trial intervention under investigation. We sought to compare oncology trial sponsorship based upon age of eligibility. Methods: We used the clinicaltrials.gov database to evaluate all interventional trials from September 1, 2009 to December 1, 2018. We included all trials regardless of indication and then separately analyzed only oncology trials. We analyzed sponsor status as “industry”, “government”, or “other”. Results: Sponsorship data were available for 59,582 interventional trials across all disciplines (n = 15,564 oncology trials). Across all disciplines and ages of eligibility, lead trial sponsorship was 34% industry, 5% government, and 61% other. Across all oncology trials, sponsorship mix was similar: 31% industry; 6% government, and 62% other. Among adult oncology trials (age of eligibility starting at age 18 years), trial sponsorship was 33% industry, 6% government, and 61% other. Among pediatric-only oncology trials (age of eligibility capped &lt; 18 years), trial sponsorship was 25% industry, 1% government, and 74% other. 5% of industry sponsored trials across all indications were pediatric-only compared to 0.63% of industry-sponsored trials in oncology. 95% of industry sponsored pediatric-only oncology trials were phase 1 or 2 trials, compared to 90% in adults. Conclusions: Pediatric-only interventional oncology trials are less likely to be industry sponsored compared to adult oncology trials or trials across all disciplines. Less than 1% of industry sponsored interventional trials in oncology focus on children &lt; 18 years of age.
Patient’s insurance status impact on biomarker testing in the United States market.
Authors: Daniel F. Winkelman, Amir Forouzan, Mike Lavin, Tanuja Tangudu, Kristopher Custer, Anise Kachadourian
Journal: Journal of Clinical Oncology (2019)

e18114 Background: Precision medicine in cancer treatment is driven by biomarker testing. If a patient is not biomarker tested, he or she may not receive access to targeted therapies that often offer greater efficacy. The purpose of this research study is to examine the insurance type of patients that are untested for biomarkers in the United States. Methods: BrandImpact is a longitudinal panel of 450 Oncologists who continuously report cancer treatment decisions from the point-of-care. The BrandImpact data set includes 60,465 patient visits reported in 2018. This study followed market research best practices. This research included visits by patients diagnosed with metastatic: NSCLC, melanoma and ovarian cancer who were either tested or untested for the following biomarkers: EGFR, ALK, ROS1, PD-L1, BRAF and BRCA. Results: The baseline measure for this analysis is that 18% of the patient visits reported that were not biomarker tested. The table at the end of document outlines the untested patient visits by insurance type for comparison purposes. Conclusions: The rate of biomarker testing for metastatic cancer patients treated by Oncologists differs by insurance type. Patients with Medicare Only insurance (25%) are untested at a statistically significantly higher rate than the baseline All category. It should be noted that patients without insurance or who were cash-paying had the highest rates of being non-biomarker tested. It is recommended that further research be conducted into the reasons behind the significantly higher rate of non-testing for Medicare Only patients. It seems counter intuitive that this patient population is treated less than optimally due to limited access to targeted therapies. [Table: see text]
The impact of race and socioeconomic status on outcomes for HPV-associated squamous cell carcinoma of the head and neck.
Authors: Luke Roy George Pike, Trevor Joseph Royce, Amandeep R Mahal, Daniel W. Kim, William L. Hwang, Brandon Arvin Virgil Mahal, Nina Niu Sanford
Journal: Journal of Clinical Oncology (2019)

e18103 Background: The socioeconomic factors affecting outcomes of human papillomavirus (HPV)-associated squamous cell carcinoma of the head and neck (SCCHN) are poorly characterized. Methods: A custom Surveillance, Epidemiology, and End Results (SEER) database identified adult patients with primary non-metastatic SCCHN and known HPV status diagnosed between 2013-14. Multivariable logistic regression defined associations between patient characteristics and HPV status, with adjusted odds ratios (AORs) and 95% confidence intervals (CIs) reported. Fine-Gray competing risks regression estimated adjusted hazard ratios (AHRs) and 95% CIs for cancer-specific mortality (CSM), including a disease subsite*HPV status*race interaction term. Results: 4735 patients with non-metastatic SCCHN and known HPV status were identified. HPV-associated SCCHN was positively associated with oropharyngeal primary, male sex and higher education and negatively associated with uninsured status, single marital status, and non-white race (p≤0.001 for all). For HPV-positive oropharyngeal SCCHN, white race was associated with lower CSM (AHR 0.55, 95%CI 0.34-0.88, p = 0.01) and uninsured status was associated with higher CSM (AHR 3.12, 95%CI 1.19-8.13, p = 0.02). These associations were not observed in HPV-negative or non-oropharynx SCCHN. Accordingly, there was a statistically significant disease subsite*HPV status*race interaction (p int &lt; 0.001). Conclusions: Non-white race and uninsured status were associated with worse CSM in HPV-positive oropharyngeal SCCHN, while no such associations were observed in HPV-negative or non-oropharyngeal SCCHN. These results suggest that, despite having clinically favorable disease, non-white patients with HPV-positive oropharyngeal SCCHN have worse outcomes than their white peers. Further work is needed to understand and reduce socioeconomic disparities in SCCHN.
Use of surgery and stereotactic body radiotherapy (SBRT) in very elderly patients with early-stage non-small cell lung cancer (NSCLC): A national cancer database (NCDB) analysis.
Authors: Michael Kharouta, William Grubb, Tarun Kanti Podder, Tithi Biswas
Journal: Journal of Clinical Oncology (2019)

e20058 Background: SBRT treatment for very elderly ( &gt; 80 years) patients with early stage NSCLC has been reported to be well tolerated with good short term efficacy. Using a large hospital based registry, we report a comparison of patterns of practice, outcomes, and prognostic factors for very elderly patients undergoing any treatment for early-stage NSCLC. Methods: The NCDB was queried for patients with clinical Stage I-IIA NSCLC with age ≥ 80 years diagnosed from 2001-2015 treated with surgery or SBRT alone. Patients were excluded if they received chemotherapy /immunotherapy or non-standard SBRT doses (i.e. &gt; 5 fractions of RT, &lt; 30 Gy or &gt; 70 Gy total dose). Survival analyses were performed with propensity-matching, Kaplan-Meier estimates, Cox proportional hazards regression, and log rank testing. Results: 26039 patients met search criteria, median age 83 (80-90) years. 17141 (65.8%) patients underwent surgery, and 8898 (34.2%) underwent SBRT. Median follow up was 31 months. Median survival was 52 and 35 months for surgery and SBRT. Of patients receiving SBRT, 2044 (23%) had a contraindication to primary surgery due to patient risk factors. Age, clinical stage, tumor size, surgery type, CDCC score, BED, bronchial involvement, and type of treatment facility were predictive of median survival. BED &gt; 154 Gy was associated with greater median survival (p &lt; 0.01). Lobectomy was associated with greater median survival vs sub-lobar resection/pneumonectomy (p &lt; 0.0001). For stage I tumors, surgery was associated with better median survival (56 vs. 35 months, p &lt; 0.0001), but for stage IIA patients both modalities had similar median survival (30 vs 29 months, p = 0.04). Conclusions: Surgery remains the predominant treatment modality for early stage NSCLC in this very elderly population, and is associated with good outcomes for patients with stage I tumors. For elderly patients who are poor surgical candidates due to medical co-morbidities SBRT is associated with reasonable median survival. With limited information on patient comorbidities, more robust studies are needed to determine the effects of patient selection on treatment outcomes in this population.
Synchronous Detection of Circulating Tumor Cells in Blood and Disseminated Tumor Cells in Bone Marrow Predicts Adverse Outcome in Early Breast Cancer
Authors: Mark Jesus M. Magbanua, Christina Yau, Denise M. Wolf, Jin Sun Lee, Aheli Chattopadhyay, Janet H. Scott, Erin Bowlby-Yoder, E. Shelley Hwang, Michael Alvarado, Cheryl A. Ewing, Amy L. Delson, Laura J. van't Veer, Laura Esserman, John W. Park
Journal: Clinical Cancer Research (2019)

We examined the prognostic impact of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) detected at the time of surgery in 742 untreated patients with early breast cancer.DTCs in bone marrow were enumerated using the EPCAM-based immunomagnetic enrichment and flow cytometry (IE/FC) assay. CTCs in blood were enumerated either by IE/FC or CellSearch. Median follow-up was 7.1 years for distant recurrence-free survival (DRFS) and 9.1 years for breast cancer-specific survival (BCSS) and overall survival (OS). Cox regressions were used to estimate hazard ratios for DRFS, BCSS, and OS in all patients, as well as in hormone receptor-positive (HR-positive, 87%) and HR-negative (13%) subsets.In multivariate models, CTC positivity by IE/FC was significantly associated with reduced BCSS in both all (n = 288; P = 0.0138) and HR-positive patients (n = 249; P = 0.0454). CTC positivity by CellSearch was significantly associated with reduced DRFS in both all (n = 380; P = 0.0067) and HR-positive patients (n = 328; P = 0.0002). DTC status, by itself, was not prognostic; however, when combined with CTC status by IE/FC (n = 273), double positivity (CTC+/DTC+, 8%) was significantly associated with reduced DRFS (P = 0.0270), BCSS (P = 0.0205), and OS (P = 0.0168). In HR-positive patients, double positivity (9% of 235) was significantly associated with reduced DRFS (P = 0.0285), BCSS (P = 0.0357), and OS (P = 0.0092).Detection of CTCs in patients with HR-positive early breast cancer was an independent prognostic factor for DRFS (using CellSearch) and BCSS (using IE/FC). Simultaneous detection of DTCs provided additional prognostic power for outcome, including OS.
Cell-free DNA as a biomarker for taxane treatment in advanced prostate cancer.
Authors: Semini Sumanasuriya, George Seed, Niven Mehra, Rossitza Christova, Lorna Pope, Jane Goodall, Penelope Flohr, Gemma Fowler, Diletta Bianchini, Pasquale Rescigno, Suzanne Carreira, Wei Yuan, Sandrine Macé, Mustapha Chadjaa, Johann S. De Bono
Journal: Journal of Clinical Oncology (2019)

5070 Background: Antitumor efficacy of chemotherapeutic drugs docetaxel and cabazitaxel against hormone-sensitive and castration-resistant prostate cancer (CRPC) is well recognized. The identification and validation of minimally invasive biomarkers of taxane response remain of paramount importance. Methods: Serial pre-, during and post-treatment plasma samples were collected prospectively from two large Phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Chemotherapy-naïve patients (pts) were treated with docetaxel (75 mg/m 2 ) or cabazitaxel (20 or 25 mg/m 2 ) in FIRSTANA, and pts previously treated with docetaxel received cabazitaxel (20 or 25 mg/m 2 ) as second-line chemotherapy in PROSELICA. Plasma cell-free DNA (cfDNA) was extracted, low-pass whole genome sequencing (lp-WGS) libraries were prepared using the QIAGEN QiaSeq FX DNA library kit, and samples sequenced on the Illumina NovaSeq 6000. Targeted next-generation sequencing (NGS) on a custom-made AmpliSeq panel of 30 genes, pre-selected for putative roles in taxane resistance, was also performed. lp-WGS copy number (CN) profiles were generated using ichorCNA (v0.1.0) and targeted NGS variant calls derived using IonReporter software. Results: Overall, lp-WGS data was generated from 265 samples (99 pts; 51 treated on the FIRSTANA study, 48 treated on the PROSELICA study), acquired at three time-points (pre-, during and at progression). Average cfDNA input was 10 ng and mean coverage achieved was ~ 2X (SD 1.2X). We observed changes in lp-WGS tumor purity over time as a result of therapy; samples from non-responding pts exhibited significantly higher tumor purity values post-treatment compared with samples from responding pts (p = 0.02). Targeted NGS results were available from 294 pts (153 from FIRSTANA, 141 from PROSELICA), and changes in tumor purity were also associated with treatment response (p = 0.04). CN frequency of key CRPC genes was similar to previously reported datasets; several aberrant loci associated with response to taxane therapy. Conclusions: cfDNA lp-WGS may have clinical utility in the management of lethal prostate cancer. Funding: Sanofi. Clinical trial information: NCT01308580, NCT01308567.
A donor-dependent in vivo model for single agent and drug combination cytokine release syndrome safety evaluation.
Authors: James G. Keck, Mingshan Cheng, Michael Brehm, Dale Greiner, Lenny J. Shultz, Jens Rueter, Chunting Ye
Journal: Journal of Clinical Oncology (2019)

2612 Background: Although antibodies and CART cells therapies have been successfully used for cancer therapy, they can have lethal adverse effects such as cytokine release syndrome (CRS). The animal models and in vitro human PBMC assays presently in use can’t reliably predict the CRS in patients. A predictive marker for identifying patients at risk for developing CRS upfront would improve the safety of immune-oncology drug development. Methods: We have developed a rapid, sensitive and reproducible in vivo humanized mouse model for quantitating CRS. The NSG mouse and its derivatives are engrafted with human PBMCs. On day 6 we induced cytokines release with pembrolizumab, avelumab, atezolizumab, ipilimumab, anti-CD28, ATG and OKT3 in single dose; as well as combination treatments involving pembrolizumab, lenalidomide, ATG and anti-CD28. Furthermore, we compared our method versus the in vitro PBMC assay. The cytokine levels were also compared to the dose response. Results: There are about 10-15% CD45+ human cells on day 5 of engraftment; and among of them, there were approximately 70% CD3 T cells and 25% CD56 NK cells. All tested cytokines, human IFN-γ, IL-2, IL-4, IL-6, IL-10 and TNF were upregulated after 2 and 6 hours of OKT3, ATG, anti-CD28, pembrolizumab, avelumab and atezolizumab drug treatment. Mouse’s rectal temperatures dropped from 37-38 °C to about 36 °C at 6 hours’ time point in the treated groups. There is various cytokines release levels, low to high response in different donors with anti-CD28 treatment. All donors showed high response to OKT3. The cytokine release levels were consistent with a dose response or variable PBMC engraftment. The cytokine levels were also higher in some drug combination studies such as pembrolizumab combined with lenalidomide or ATG; anti-CD28 combined with ATG. Our in vivo method was able to determine CRS missed in the in vitro testing method. Conclusions: We have developed a rapid, sensitive and reproducible novel in vivo PBMC humanized mouse model that is able to differentiate human PBMC donors based on individual safety response to single agent and combination therapeutics of immune checkpoint inhibitors and possibly CAR-T therapy. This assay could be employed in future drug development.
Occupational health risk of pressurized intra-peritoneal aerosol chemotherapy (PIPAC) via endoscopical microcatheter system.
Authors: Tanja Khosrawipour, Alessio Pigazzi, Haris Chaudhry, Agata Mikolajczyk, Justyna Schubert, Veria Khosrawipour
Journal: Journal of Clinical Oncology (2019)

e14231 Background: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is becoming an increasingly widespread approach for delivering intra-peritoneal chemotherapy (IPC) by means of a chemoaerosol. In current studies, a flexible and easy-to-handle endoscopic microcatheter (MC) approach has been introduced to replace the conventional micropump used in PIPAC. While this new method has many advantages such as wide availability, cost effectiveness and improved drug distribution, its possible occupational health risks remain unknown. Methods: PIPAC was performed on three post mortem swine using the MC device. According to standard protocol in patients, solutions of doxorubicin and oxaliplatin were aerosolized in a standardized procedure room with laminar flow. Multiple probes of all surgical material including instruments and sutures, surrounding area surfaces and the operating personals’ items such as gloves and gowns were collected. Moreover, the air filter of the operating room was examined for doxorubicin and oxaliplatin concentrations. Results: The majority of probes showed no measurable doxorubicin or oxaliplatin concentrations. No exposure was detected on the operating personals’ gowns as well as the surrounding area surfaces. While a few of the surgical materials as well as the personals’ gloves and the main part of the application system showed low drug exposure, no drug exposure was measurable in the room filter. Conclusions: Our ex-vivo data suggest that PIPAC delivered via MC is safe and does not exhibit any major occupational hazards if the safety protocol is followed. MC offers an improved, easy-to-handle and cost-effective alternative to the micropump used in conventional PIPAC. Furthermore, the MC offers the great advantage of flexibility which allows access even in anatomically difficult situations and reduces the surgical point of entry to only one abdominal trocar placement.