tbuckley/cabot-search huggingface dataset:
Racial disparities in biomarker testing and clinical trial enrollment in non-small cell lung cancer (NSCLC).
Authors: Debora S. Bruno, Lisa M. Hess, Xiaohong Li, Eric Wen Su, Yajun Emily Zhu, Monaliben Patel
Journal: Journal of Clinical Oncology (2021)

9005 Background: Cancer racial disparities may exist at many levels in the health care system, from screening to timely diagnosis and treatments received, as well as clinical trial enrollment. This study investigated differences in black versus white race among patients with NSCLC undergoing biomarker testing and clinical trial enrollment in the US. Methods: This retrospective observational study utilized the Flatiron Health database, which includes longitudinal data of patients with advanced/metastatic NSCLC. Patients were eligible if they had evidence of systemic therapy in the database from 1/1/2017 through 10/30/2020. Descriptive analyses summarized differences by race in biomarker testing and trial enrollment. Multivariable regression examined the relationship between these factors. Results: A total of 14,768 patients were eligible: 9,793 (66.3%) were white and 1,288 (8.7%) were black. 76.4% of white patients and 73.6% of black patients underwent at least one single molecular test or comprehensive genomic analysis (p = 0.03). Next-generation sequencing (NGS) was performed among 50.1% of white patients and 39.8% of black patients (p &lt; 0.0001. Trial participation was observed among 3.9% of white and 1.9% of black patients (p = 0.0002). There was a statistically significant association between race (white vs black) and both biomarker testing (ever vs never) and trial participation (yes vs no) (both p &lt; 0.001, unadjusted chi square). Differences in NGS testing, baseline biomarker testing, and race were retained as statistically significant (p &lt; 0.01) in adjusted regression analyses. The receipt of first-line targeted therapy was comparable between white and black patients (10.2% and 9.2%, respectively, p = 0.24); however, this summary did not consider biomarker test results. First line use of pembrolizumab+carboplatin+pemetrexed was observed among 19.8% of white and 22.6% of black patients; carboplatin+paclitaxel was observed among 16.5% and 18.6%, and single-agent pembrolizumab was observed among 14.8% and 11.5%, respectively. Conclusions: The use of NGS-based testing, which is recommended by the National Comprehensive Cancer Network Clinical Guidelines in Oncology for patients with advanced/metastatic NSCLC, is the most notable disparity among black patients, with more than a 10 percentage-point difference in receipt of this testing versus white counterparts. This may in part contribute to the more than double the rate of participation in clinical trials observed among white patients, as many second line and beyond trials utilize molecular targets as inclusion criteria. While multiple factors are known to impact health care disparities, access to and receipt of appropriate biomarker testing may be an attenable goal in order to ensure equal access to quality care.
Abstract AP18: PRO-INVASIVE TUMOUR-STROMA INTERACTIONS: ROLE OF THE SECRETED OXIDOREDUCTASE CLIC3
Authors: Juan R Hernandez-Fernaud, Elena Ruengeler, Lisa J Neilson, Shehab Ismail, Iain McNeish, Samuel Atkinson, Sergio Lilla, Alice Santi, Stella M Valenzuela, Karen Blyth, Huabing Yin, Massimiliano Mazzone, Jim C Norman, Sara Zanivan
Journal: Clinical Cancer Research (2019)

Abstract Cancer cells are embedded within a microenvironment populated with cancer associated fibroblasts (CAFs) with whom they establish two-way communications through paracrine factors and physical interactions. Through these interactions, CAFs play pivotal roles in cancer and have emerged as promising therapeutic target. To unravel key contributors of CAF-tumour/stroma cell interactions, we have developed mass spectrometry (MS)-based approaches to map proteins secreted in condition medium and extracellular matrix (ECM). Through an extensive MS-proteomic comparative analysis of CAFs with their normal fibroblasts (NFs) counterpart, we have identified the chloride intracellular channel protein 3 (CLIC3), a protein previously considered an intracellular chloride channel (regulator), as one of the most upregulated proteins in CAFs and deposited in the ECM. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive blood vessels growth and increases invasiveness of cancer cells, both in vivo and in 3D cell culture models, via activation of the tissue transglutaminase-2 (TGM2). We found that CLIC3 is a glutathione-dependent oxidoreductase that reduces TGM2 and regulates TGM2 binding to its cofactors. Finally, CLIC3 is also secreted by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers and its levels in primary tumours and omental metastases correlate with poor clinical outcome. Our work has unraveled an unprecedented mechanism of cell invasion to be explored for targeting in ovarian cancer. Citation Format: Juan R Hernandez-Fernaud, Elena Ruengeler, Lisa J Neilson, Shehab Ismail, Iain McNeish, Samuel Atkinson, Sergio Lilla, Alice Santi, Stella M Valenzuela, Karen Blyth, Huabing Yin, Massimiliano Mazzone, Jim C Norman and Sara Zanivan. PRO-INVASIVE TUMOUR-STROMA INTERACTIONS: ROLE OF THE SECRETED OXIDOREDUCTASE CLIC3 [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP18.
Palliative care as a predictor of healthcare resource use at end-of-life in adult Albertan lung cancer decedents between 2008-2015: A secondary data analysis.
Authors: Nureen Sumar, Madalene Earp, Desiree Hao, Aynharan Sinnarajah
Journal: Journal of Clinical Oncology (2021)

e24009 Background: Early utilization of specialist palliative care (SPC) in cancer patients may reduce healthcare resource use, aggressive interventions, and costs at end-of-life. We evaluated the impact of SPC on healthcare resource utilization and aggressive interventions at end-of-life in patients who have died from lung cancer. Methods: Descriptive and multivariable logistic regression analyses were conducted on lung cancer decedents in the Calgary Zone, Alberta Health Services from 2008 to 2015. The primary exposure was timing of SPC (Early: receipt of SPC &gt; = 90 days before death; Late: &lt; 90 days before death; No SPC). The primary outcome was end-of-life healthcare resource use (defined as any of: hospital death, &gt; 1 emergency department visit, &gt; 1 hospital admission, &gt; 14 days of hospitalization, ≥1 intensive care unit admission, ≥1 new chemotherapy program (or any chemotherapy in the last 14 days of life) in the 30 days prior to death. Results: There were 3300 patients of which the majority (51.6%) of decedents were male. More female versus male lung cancer decedents (36.4% vs 28.7%) received early SPC. After adjusting for confounders, a strong association was found between early, late or no SPC and end-of-life healthcare resource use (OR no exposure 3.25 (95% CI 2.41-4.40) vs OR late exposure 2.44 (95% CI 2.03-2.92) compared to those with early SPC; p &lt; 0.001). Males had 1.53 the odds of aggressive care at end-of-life compared to females (p &lt; 0.001). Stratified analysis by sex revealed a strong association between the absence of SPC utilization and end-of-life healthcare resource use. Young age ( &lt; 50 at death) was a strong driver of aggressive care at end-of-life in females versus males [OR 5.44 vs 2.53]. Conclusions: Early specialist palliative care was significantly associated with less end-of-life healthcare resource use in both male and female lung cancer decedents, with less early specialist palliative care use in males. Keywords: palliative care, early palliative care, cancer, end-of-life, healthcare resource use, lung cancer.
A first-in-human study of mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed/refractory solid tumors: Dose escalation results.
Authors: Anthony W. Tolcher, Benedito A. Carneiro, Afshin Dowlati, Albiruni Ryan Abdul Razak, Young Kwang Chae, Jeannine A. Villella, Sheryl Coppola, Stefan Englert, Andrew C. Phillips, Andrew J. Souers, Zeena Salman, Sudhir Penugonda, John D. Powderly, Patricia LoRusso
Journal: Journal of Clinical Oncology (2021)

3015 Background: Mirzotamab clezutoclax (ABBV-155) is a first-in-class antibody drug conjugate comprised of a BCL-X L (B-cell lymphoma - extra long) inhibitor, solubilizing linker, and a monoclonal anti-B7H3 antibody. Methods: Patients (pts) with relapsed and/or refractory (R/R) solid tumors were administered mirzotamab clezutoclax with or without paclitaxel. Dose escalation of mirzotamab clezutoclax was guided by Bayesian continual reassessment. Primary outcomes were to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). Secondary outcomes: safety, pharmacokinetics, and overall response rate per RECIST v1.1. Results: As of November 6, 2020, 31 pts received mirzotamab clezutoclax monotherapy (monoTx) and 28 pts received combination therapy with paclitaxel (comboTx). Overall demographics: median age 62 years (range 25–79); 61% female; 86% white; 24% ECOG 0, 76% ECOG 1; 51% had &gt; 3 prior systemic therapies. The median duration of mirzotamab clezutoclax exposure was 3 cycles (range 1–14) for monoTx and 5 cycles (range 1–14) for comboTx. There were no dose limiting toxicities (DLT) reported with monoTx. In comboTx, 2 pts experienced a DLT: Grade 4 neutrophil count decreased and Grade 3 lymphocyte count decreased considered related to paclitaxel. 97% of all pts had adverse events (AEs). The most common AEs (in ≥20% of pts) overall were fatigue (39%), nausea (25%), diarrhea and arthralgia (22% each), vomiting and hypokalemia (20% each). AEs in ≥5 pts related to mirzotamab cleuzutoclax were fatigue (27%), diarrhea (12%), and nausea (9%). Related Grade 3/4 AEs overall (in &gt; 1 patient) included anemia, lymphocyte count decreased, fatigue, and diarrhea (3% each). One patient on monoTx experienced a fatal cardiac arrest. No fatal AEs occurred on comboTx. Responses were observed with comboTx as shown in the Table. Conclusions: Mirzotamab clezutoclax as monotherapy and with paclitaxel demonstrates a tolerable safety profile (MTD not reached) with anti-tumor activity in R/R solid tumors. Further investigation in prospectively-selected B7H3 positive tumors as monoTx in pts with R/R small cell lung cancer and with paclitaxel in pts with R/R breast cancer and docetaxel in pts with R/R non-small cell lung cancer in the dose expansion phase is ongoing. Clinical trial information: NCT03595059. [Table: see text]
Out-of-proportion肺高血圧症患者における拡張期肺血管圧較差の臨床的意義
Authors: Takeuchi Toshiharu, Gotoh Masahide, Aita Makoto, Date Ayumi, Sugiyama Eitaro, Minoshima Akiho, Shimamura Kohei, Sakamoto Naka, Tanabe Yasuko, Satoh Nobuyuki, Hasebe Naoyuki
Journal: Circulation (2014)
Association of <i>KMT2C/D</i> loss-of-function mutations with tumor infiltrating lymphocytes and response to immune checkpoint inhibitors in solid tumors.
Authors: Ruiqi Liu, Yanling Niu, Xin Zhang, Tonghui Ma
Journal: Journal of Clinical Oncology (2021)

2587 Background: Dysregulation of HMTs plays an important role in tumorigenesis. KMT2C and KMT2D are enzymatically active scaffold proteins that form the core of mammalian COMPASS complexes, which methylate the histone 3 lysine 4. Both KMT2C and KMT2D are involved in the regulation of gene expression. Therefore, we explored the associations of KMT2C/D loss-of-function (LOF) mutations with the expression of immune-related genes, the levels of tumor infiltrating lymphocytes (TILs), and response to immune checkpoint inhibitors (ICIs). Methods: KMT2C/D LOF mutations were defined as nonsense, frameshift, splice site variants within consensus regions, start lost, and stop lost/gained variants. An ICIs treatment cohort from the MSKCC was used for exploring the associations between KMT2C/D LOF mutations and ICIs efficacy. The RNA-Seq data obtained from the TCGA cohort was used for analysis of gene expression and the levels of TILs using CIBERSORT. Results: In MSKCC pan-cancer dataset, patients with KMT2C/D LOF mutations had a relatively longer median overall survival (OS) compared to those with non-LOF mutations, although the result did not reach statistical significance (P = 0.0832). Then we analyzed the predictive roles of KMT2C/D LOF mutations for each cancer type. The results showed that the predictive role of KMT2C/D LOF mutations for the clinical efficacy of ICIs therapy was only observed in colorectal cancer (P = 0.045). However, we did not find the associations of KMT2C/D LOF mutations with ICIs efficacy in bladder cancer, breast cancer, melanoma, glioma, head and neck cancer, renal cell carcinoma, NSCLC, and esophagogastric cancer. Consistently, analysis of TILs in colorectal cancer revealed that KMT2C/D LOF was associated with increased infiltration of several types of immune cells, such as CD8+ T cells (P = 0.0001), activated NK cells (P = 0.0001), M1 macrophage (P = 0.0005), M2 macrophage (P = 0.0115), and neutrophils (P = 0.0209). Meanwhile, regulatory T cells (Tregs) (P = 0.0048) and M0 macrophage (P = 0.0043) were dramatically decreased in KMT2C/D LOF group for colorectal cancer. Moreover, there were no significant relationships between KMT2C/D LOF and the levels of TILs in other cancer types. Our data also demonstrated that KMT2C and KMT2D could regulate the expression of more than 30 immune-related genes in colorectal cancer. Conclusions: Our data indicated that KMT2C/D LOF mutations were significantly correlated with better outcomes of ICIs therapy in colorectal cancer, suggesting it can be as a useful predictor for response to ICIs in colorectal cancer. Meanwhile, we found the associations of KMT2C/D LOF with the levels of TILs in colorectal cancer, but not in other cancer types, indicating that the efficacy of ICIs was consistent with the levels of TILs.
Complementary Role of Circulating Tumor DNA Assessment and Tissue Genomic Profiling in Metastatic Renal Cell Carcinoma
Authors: Zeynep B. Zengin, Caroline Weipert, Nicholas J. Salgia, Nazli Dizman, Joann Hsu, Luis Meza, Alexander Chehrazi-Raffle, Ramya Muddasani, Sabrina Salgia, Jasnoor Malhotra, Neal Chawla, Errol J. Philip, Lesli Kiedrowski, Benjamin L. Maughan, Nityam Rathi, Divyam Goel, Toni K. Choueiri, Neeraj Agarwal, Sumanta K. Pal
Journal: Clinical Cancer Research (2021)

The role of circulating cell-free tumor DNA (ctDNA) as an adjunct to tissue genomic profiling is poorly defined in metastatic renal cell carcinoma (mRCC). In this study, we aim to validate previous findings related to genomic alteration (GA) frequency in ctDNA and determine the concordance between ctDNA and tissue-based profiling in patients with mRCC.Results of 839 patients with mRCC who had ctDNA assessment with a Clinical Laboratory Improvement Amendments (CLIA)-certified ctDNA assay between November 2016 and December 2019 were collected. Tissue-based genomic profiling was collected when available and concordance analysis between blood- and tissue-based testing was performed.ctDNA was assessed in 839 patients (comprising 920 samples) with mRCC. GAs were detected in 661 samples (71.8%). Tissue-based GAs were assessed in 112 patients. Limiting our analyses to a common 73-/74-gene set and excluding samples with no ctDNA detected, a total of 228 mutations were found in tissue and blood. Mutations identified in tissue (34.7%; 42/121) were also identified via ctDNA, whereas 28.2% (42/149) of the mutations identified in liquid were also identified via tissue. Concordance between ctDNA and tissue-based profiling was inversely related to the time elapsed between these assays.This study confirms the feasibility of ctDNA profiling in the largest mRCC cohort to date, with ctDNA identifying multiple actionable alterations. It also demonstrates that ctDNA and tissue-based genomic profiling are complementary, with both platforms identifying unique alterations, and confirms that the frequency of unique alterations increases with greater temporal separation between tests.
Personalized DNA neoantigen vaccine in combination with plasmid IL-12 and pembrolizumab for the treatment of patients with advanced hepatocellular carcinoma.
Authors: Mark Yarchoan, Edward Gane, Thomas Urban Marron, Sarah Rochestie, Neil Cooch, Joann Peters, Ildiko Csiki, Alfredo Perales-Puchalt, Niranjan Sardesai
Journal: Journal of Clinical Oncology (2021)

TPS2680 Background: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death. Immune checkpoint inhibitors targeting PD-1 have limited activity in HCC as monotherapy, with response rates ranging from 14-17%. Tumor neoantigens derived from tumor-specific mutations can be incorporated into personalized therapeutic cancer vaccines to prime T cell responses, potentially enhancing responses to anti-PD1 therapy. DNA vaccines have been shown to elicit strong CD8 and CD4 T cell responses in preclinical and clinical trials. In preclinical studies, DNA-encoded neoantigen vaccines have shown induction of CD8 T cells against 50% of predicted high affinity epitopes with the ability to impact tumor growth. GNOS-PV02 is a personalized DNA vaccine, encoding up to 40 patient-specific neoantigens. In the GT-30 trial, it is used in combination with INO-9012 (plasmid-encoded IL-12) and pembrolizumab for the treatment of advanced HCC. Methods: The GT-30 trial (NCT04251117) is a single-arm phase I/II clinical trial to assess the safety, immunogenicity, and preliminary efficacy of GNOS-PV02 in combination with INO-9012 and pembrolizumab in patients with advanced HCC. Twenty-four patients are anticipated to be enrolled. Patients are recruited upon diagnosis or during first-line treatment with tyrosine kinase inhibitors (TKI). Tumors are biopsied for exome and transcriptome sequencing. The tumor specific vaccine is designed, optimized and manufactured during first-line therapy. Each vaccine encodes up to 40 neoantigens, which includes all detected neoantigens for the majority of HCC patients. After progression or intolerance with first-line therapy, patients can commence trial therapy with concurrent personalized vaccine and pembrolizumab. GNOS-PV02 + INO-9012 are administered Q3w for the first 4 doses and Q9w thereafter until disease progression. Pembrolizumab is delivered Q3w until disease progression. Immunogenicity of each of the vaccine epitopes will be determined by ex vivo ELISpot and flow cytometry. Clinical activity is assessed by RECIST1.1 at baseline and every 9 weeks. Serial biopsies will be obtained at 9 weeks and upon disease progression to evaluate changes in the exome, transcriptome and changes to the tumor microenvironment. Clinical trial information: NCT04251117.
Is Universal Next-Generation Sequencing Testing of Patients With Advanced Cancer Ready for Prime Time?
Authors: Catherine Dunn, Lucy Gately, Peter Gibbs
Journal: JAMA Oncology (2021)

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Radiomics-based prediction of response to multikinase inhibitors in radioiodine-refractory differentiated thyroid cancer patients.
Authors: Valentina Corino, Elena Colombo, Marco Bologna, Giuseppina Calareso, Luca Mainardi, Stefano Cavalieri, Daria Maria Filippini, Carlo Resteghini, Cristiana Bergamini, Lisa F. Licitra, Laura Deborah Locati
Journal: Journal of Clinical Oncology (2021)

6077 Background: Antiangiogenic tyrosine kinase inhibitors (TKIs) represent the first-line treatment for radioiodine-refractory differentiated thyroid cancer (RR-DTC). Currently, no predictive factors for the activity of these drugs are available. We investigated whether radiomics may have a predictive role in this setting. Methods: We retrospectively identified patients (pts) affected by metastatic RR-DTC, treated with TKIs between July 2008 and January 2020 at our Institution, with availability of computed tomography (CT) scans at baseline and after at least 2 courses of TKI. Response to TKIs was evaluated according to RECIST v1.1. Pts with complete or partial response at the first radiological evaluation were considered responders (R), pts with stable or progressive disease non-responders (NR). A dedicated radiologist segmented the target lesions as regions of interest (ROIs). Radiomic features related to multiple categories (shape and size, first order statistics, textural features) were extracted from each ROI and computed using the PyRadiomics library v. 3.0. A semi-supervised form of principal component analysis estimated principal components that were then used for response classification through a k nearest neighbors (kNN) classifier. The quality of the model was assessed through train-validation-test split (55% of the data used as training set, 25% as validation set, 20% as test set), repeated 100 times. Performance of the predictive models was quantified with the mean Area Under the ROC Curve (AUC) obtained in the test set. Results: A total of 51 pts with metastatic RR-DTC who had received lenvatinib (n=37), sorafenib (n=4), axitinib (n=3), or vandetanib (n=7) were analyzed. Median age was 64.6 years, with a male prevalence (72.5%). Metastatic sites were lung (84.3%), bone (35.3%), brain (9.9%). Median time from TKI treatment start to the first radiological evaluation was 2.77 months, 24 pts (47%) were R (all partial responses) and 27 (52.9%) NR. In the radiomic analysis, 851 features were computed and 4-19 principal components were selected. Models’ performance of prediction of early response to TKIs is presented in Table. For each value of AUC, the corresponding 95% confidence interval is reported in brackets. Conclusions: Radiomics predicted the response to TKIs of RR-DTC pts with an accuracy of 71%. Radiomics technique has the potential to enable clinicians to anticipate the probability of response to TKIs at baseline, directing toward the most suitable patient-tailored therapeutic path. Prospective studies may further validate these preliminary findings.[Table: see text]