tbuckley/cabot-search huggingface dataset:
Interleukin-6 is potential target to de-couple checkpoint inhibitor-induced colitis from antitumor immunity.
Authors: Daniel H. Johnson, Yared Hailemichael, Wai Chin Foo, Kenneth R. Hess, Cara L. Haymaker, Khalida M Wani, Alexander J. Lazar, Chantal M Saberian, Salah E Bentebibel, Elizabeth M. Burton, Hamzah Abu-Sbeih, Yinghong Wang, Patrick Hwu, Adi Diab
Journal: Journal of Clinical Oncology (2019)

2616 Background: A deep understanding of the immunobiology of checkpoint inhibitor (CPI) induced immune related toxicities, such as immune related enterocolitis (irEC), and how these compare to the immune signatures in tumors could lead to the development of strategies that de-couple autoimmunity from anti-tumor immunity. Methods: Total RNA from patient-matched irEC and normal colon FFPE tissue from patients [n = 12] receiving CPIs were profiled with the 770 gene NanoString nCounter PanCancer Immune Profiling Panel (NanoPCIP). The mean fold change in gene expression from normal vs. irEC inflamed colonic tissue and baseline vs. on-treatment tumor samples from patients responding or non-responding to ipilimumab based therapy were analyzed. C57BL/6 mice with B16.BL6 melanoma tumors were treated with systemic anti-IL-6 + anti-CTLA-4 vs. anti-CTLA4 alone vs. placebo and tumor size was measured. Results: In patients with irEC, the highest significantly upregulated differentially expressed gene (DEG) in inflamed colon tissue encoded for IL-6 (Fold change +24.1). None of the significant and highest upregulated DEGs in the colitis, including IL-6, were significantly upregulated in responding tumors. Interestingly, IL-6 was also the highest upregulated DEG in non-responding tumors numerically. When comparing mean fold changes across these analyses, the gene with the largest difference in upregulatation between colitis and responding tumors was IL-6; the other highest upregulated genes in colitis encoded for neutrophil and monocyte chemotactic molecules. In our mouse models, the addition of IL-6 blockade to anti-CTLA-4 therapy significantly improved tumor shrinkage compared to anti-CTLA-4 alone. Conclusions: Our data demonstrates that IL-6-mediated inflammation may be more prevalent in irEC and tumors not responding to CPIs than in tumors responding, and blocking IL-6 enhances CPI anti-melanoma activity. Targeting IL-6 may ameliorate irEC without hindering anti-tumor immunity.
Discussions of Dense Breasts, Breast Cancer Risk, and Screening Choices in 2019
Authors: Karla Kerlikowske, Diana L. Miglioretti, Celine M. Vachon
Journal: JAMA (2019)

This JAMA Insights Clinical Update reviews uncertainties about incorporation of measures of breast density into breast cancer risk prediction models and the need for appropriate screening intervals for women with dense breasts on digital mammography or breast tomosynthesis.
Identification of MET Exon 14 skipping by targeted RNA-based next-generation sequencing in Chinese Patients with NSCLC.
Authors: Nanying Che, Ziguang Xu, Yujie Dong, Peng Cheng, Yun Gao, Yang Yu, Shijun Fu, Min Gao, Lingfei Kong
Journal: Journal of Clinical Oncology (2019)

e20018 Background: MET (mesenchymal-epithelial transition) exon14 skipping mutations have been reported to represent a clinically unique molecular subtype of NSCLC. The prevalence rates of MET exon 14 skipping in lung adenocarcinoma are quite different, from 0.9% to 4.0% in Asian populations. Since some somatic variants not covering the MET exon 14 splice sites might also induce MET exon 14 skipping, we believed that RNA-based sequencing is the most accurate method to detected exon 14 skipping. Methods: A total of 951 NSCLC patients from two hospitals were enrolled in this study. We detected MET exon14 skipping using both targeted DNA- and RNA-based next generation sequencing and elucidated the driver gene mutation profile of Chinese NSCLC patients. Results: The overall estimated prevalence of MET exon 14 skipping was approximately 1.8% (14 of 772) in adenocarcinomas and 1.7 % (16/951) in NSCLCs. Furthermore, we compared the detection rate of MET exon 14 skipping from different specimen source, including surgical resection, percutaneous transthoracic needle biopsy (PTNB) and transbronchial lung biopsy (TBLB). Notably, the detection rate of MET exon 14 skipping from surgical resection specimen is 2.3% in NSCLCs and 2.0% in adenocarcinomas, respectively. MET exon 14 skipping was identified in 7.1% of EGFR/KRAS/ALK/ROS1/RET negative adenocarcinomas (13 of 196). In addition, PD-L1 trended to be highly expressed in NSCLC patients harboring MET exon 14 skipping (55.6% vs 17.3%, p = 0.022). Conclusions: In this study, the prevalence of MET exon14 skipping in lung adenocarcinomas in East Asian population was very close to that of West population using RNA-based NGS. The NSCLC patients with Met exon 14 skipping tended to be older than patients with other oncogenic driver mutations, such as EGFR, ALK, ROS1. In addition, PD-L1 trended to be highly expressed in NSCLC patients with MET exon 14 skipping.
Weight change after (neo)adjuvant chemotherapy in a cohort of breast cancer survivors: Trends by race, hormone positivity, and chemotherapy regimen.
Authors: Bradley S Colton, Samuel Kareff, Shaw Li, Princess Alintah, Chiranjeev Dash, Asma Ali Dilawari
Journal: Journal of Clinical Oncology (2019)

e12018 Background: It is estimated that over 50% of breast cancer survivors gain weight during treatment; patients receiving chemotherapy are at higher risk for weight gain. Previous studies have reported limited information about weight gain with current chemotherapy regimens. Methods: Individual data were collected from a cohort of 98 breast cancer patients treated with neoadjuvant or adjuvant chemotherapy between 2015 and 2017 at Lombardi Comprehensive Cancer Center. Weight was recorded from baseline visits and ≥ 1 visit following completion of chemotherapy. Regimens were grouped into anthracycline- (AC) and non-anthracycline-based (NAC) chemotherapy. Results: Overall, 49% ( n = 48) of patients gained weight after chemotherapy, though African-American patients demonstrated higher baseline BMI. Patients with ER-positive cancers displayed greater weight gain than hormone-negative counterparts ( p = 0.04); PR- or HER2-status was not associated statistically significant changes in weight ( p = 0.12 and 0.82, respectively). Among patients who did gain weight, NAC was associated with greater weight gain (4.47kg) than AC-based regimens (2.54kg) ( p = 0.03). Conclusions: ER positivity and NAC may serve as independent predictors of weight gain during chemotherapy. Further studies might consider further analyzing these trends to demonstrate additional long-term patterns. Baseline and After Chemotherapy BMI (kg/m2) and Weight Change (kilograms and percentage change) (P* derived from ANOVA). [Table: see text]
Changes in critically ill cancer patients’ short-term outcome over the last decades: results of systematic review with meta-analysis on individual data
Authors: Michaël Darmon, Aurélie Bourmaud, Quentin Georges, Marcio Soares, Kyeongman Jeon, Sandra Oeyen, Chin Kook Rhee, Pascale Gruber, Marlies Ostermann, Quentin A. Hill, Pieter Depuydt, Christelle Ferra, Anne-Claire Toffart, Peter Schellongowski, Alice Müller, Virginie Lemiale, Djamel Mokart, Elie Azoulay
Journal: Intensive Care Medicine (2019)
Immunotherapy disparities in metastatic melanoma.
Authors: Thomas Oliver, Todd A. Pezzi, Ashley E. Pezzi, Amanda Shreders, Henry Dao, Jennifer A. Crozier, Christopher Pezzi
Journal: Journal of Clinical Oncology (2019)

9525 Background: Historically, patients with advanced malignant melanoma had a dismal prognosis with an estimated median overall survival of nine months. Therapy response rates and long-term survival have significantly improved with the advent of immunotherapies and targeted chemotherapies. First approved in 2011, there has been subsequent development of more advanced immunotherapeutic agents and targeted chemotherapies, with continued improvement in median overall survival. We examined patterns in the use of immunotherapy and other systemic therapies for metastatic melanoma, as well as the demographic and socioeconomic predictors for the use of these therapies, in order to identify and understand potential barriers to access in the United States. Methods: We used the NCDB for all patients aged 18-years and older who were diagnosed with metastatic melanoma of cutaneous origin from 2004-2014. Patients were included if they had distant metastases or American Joint Committee on Cancer (AJCC) Stage IV. Sociodemographic data, including race, age, insurance status, facility providing care, Charlson/Deyo comorbidity score11, and education by patient’s zip code, were collected. Results: In patients under age 65 with a Charlson-Deyo score of zero, immunotherapy utilization ranged between 8.5–13.4% during 2004 to 2010. In 2011, the usage increased to 16.5% and rose every subsequent year to 29.6% in 2014. Patients were less likely to receive immunotherapy if they had no insurance, were of older age, or received care at a community practice rather than an academic center. Those who received immunotherapy had greater overall survival compared with those who did not. Conclusions: Immunotherapy and targeted agents have become standard of care in those with metastatic melanoma. Adoption of immunotherapy use for metastatic melanoma has been relatively slow despite evidence showing an overall survival benefit; our analysis suggests this is explained in part by socioeconomic barriers.
Differences in MSI phenotype between cancer types using a new PCR-based pan-cancer biomarker panel.
Authors: Jeff Bacher, Eshwar Udho, Doug Storts, Richard Halberg, Steven Galllinger, Mark A. Jenkins, Noralane M. Lindor
Journal: Journal of Clinical Oncology (2019)

e13145 Background: A multiplexed biomarker panel was developed for detection of MSI that is more sensitive than currently available systems. Preliminary data showed an increased MSI sensitivity for colon polyps, endometrial (EC) and skin cancers. This study expands that finding to 14 different types of cancer. Methods: Selection of the best microsatellite markers was done using a cohort of 160 patients ≤55 years with ≥1 colon polyp and 100 EC patients ≤ 50 years. To validate the new panel, a cohort of 100 Lynch syndrome CRC, 100 sporadic MSI-High CRC, 100 sporadic MSI stable CRC and 219 extra-colonic cancers from the Colon Cancer Family Registry were tested for MSI. Samples were screened using a new 8-marker panel and Promega’s MSI Analysis System. Mismatch repair (MMR) gene mutation status and expression were determined. To compare the relative sensitivity of the 8-marker panel across all cancer types we developed a quantitative “MSI-score” for each cancer type. Results: Considerable differences in MSI phenotypes were observed between cancer types and a new approach to scoring MSI in extra-colonic cancers is proposed. Relative intensity of the MSI phenotype was characterized by MSI-Scores ranging from high of 66 (small intestine) to 6 (brain). The mutations in MSI samples were significantly more common and allele size shifts larger with the new biomarkers, making MSI classification more accurate and robost. MSI, IHC and MMR gene mutation status were highly correlated. Conclusions: The MSI sensitivity of the new biomarker panel for most cancer types was significantly higher than currently available PCR-based MSI systems. Development of the new pan-cancer PCR-based MSI system allows laboratories to leverage established equipment and known analysis techniques to keep turnaround time and costs, quick and affordable compared with emerging NGS-based technologies.
MET kinase domain rearrangements across 10 cancer types.
Authors: Jun Zhao, Jin Chen, Haitao Ma, Ke Ye, Yue Shi, Yuting Yi, Xiaoling Zeng, Yan-Fang Guan, Jiayin Wang, Xin Yi, Xuefeng Xia
Journal: Journal of Clinical Oncology (2019)

3078 Background: MET is a transmembrane receptor tyrosine kinase and deregulated in many kinds of tumors by mutation, rearrangement and amplification. Since the first c onstitutively active MET rearrangement ( TPR-MET) was discovered, many other MET rearrangements have been identified in various tumor types. However, the frequency and characteristic of MET rearrangement in Chinese cancer patients is still unclear. Methods: Targeted sequencing using 1021-gene panel or 59-gene panel was performed on 3952 tissue samples and 5100 blood-based ctDNA samples from 9052 unique patients across 10 cancer types. All MET exons were sequenced, but MET intronic breakpoints were not specifically baited. Results: 24 (0.27%) MET kinase domain rearrangements (KDRE) were identified in 9052 patients. Specifically, 0.25% (16/6284) in non-small cell lung cancer (NSCLC), 0.69% (2/290) in gastric adenocarcinoma, 0.32% (2/897) in colorectal cancer, 0.33% (2/610) in breast cancer, 0.3% (1/330) in hepatocellular carcinoma and 0.69% (1/145) in ovarian cancer, none in 139 pancreatic cancer, 136 thyroid cancer, 111 renal cell carcinoma and 110 esophageal squamous cell carcinoma. Among all of the MET KDRE, 17 were fusions with 5’ identified partner, 3 were kinase domain duplication (KDD) and 4 were probable fusions with unidentified partner. The most common 5 ’partner gene was CAPZA2, followed by CD47 and TES. In the MET KDRE cases in NSCLC, 56.25% (9/16) did not found any clinical actionable variants referring to the NCCN guideline. In addition, MET amplification, EGFR L858R or exon 19 deletion and KRAS mutation co-occurred in 25% (4/16), 18.75% (3/16) and 12.5% (2/16) of NSCLC MET KDRE cases respectively. Conclusions: Our results, for the first time, illustrate the MET KDRE across 10 cancer types among Chinese population and might provide some novel targets to develop new therapies for patients with MET KDRE. MET KDRE across different tumor types. [Table: see text]
Germline DNA damage repair gene alterations in Chinese prostate patients: More than HRR and MMR.
Authors: Junlong Wu, Yu Wei, Changbin Zhu, Bo Dai, Xiaojian Qin, Fangzhu Gao, Dingwei Ye, Yao Zhu
Journal: Journal of Clinical Oncology (2019)

e13041 Background: Prostate cancer is a worldwide most occurred malignancy in male population. Genetic aberrations of homologous recombination repair (HRR) pathway were proved to be associated with aggressive disease and poorer outcome but may also lead cancer cells more vulnerable to PARP inhibitors. Other than HRR, germline variants in mismatch repair (MMR), nucleotide excision repair (NER) were also identified. Thus, it is important to clarify the distribution of germline alterations of DDR pathways in Chinese prostate cancer patients. Methods: Sixty-five prostate cancer patients unselected for family history, stage of disease, or age at diagnosis were collected. DNA from peripheral blood was extracted. Whole-exon was captured and sequenced subsequently using MGI-SEQ 2000 platform. A total of 229 DDR genes were selected for further analysis. Germline variants were determined to be deleterious according to the ACMG 2015 guidelines. Results: Ten of 65 patients (15.38%) had 7 pathogenic/likely pathogenic germline variants involving 5 different genes: FANCD2 (n = 5), BRCA2 (n = 3), CHEK2 (n = 1), ATM (n = 1) and RECQL (n = 1). Nine patients (13.84%) carried variants predicated to be deleterious via in silico predicators. Taken together, deleterious/potential deleterious germline variants were categorized into 5 DDR pathways which were Fanconi Anemia (9.2%), HRR (9.2%), MMR (4.6%), BER (4.6%) and NER (1.5%). Patients with pathogenic/likely pathogenic germline variants had tendency to be early-onset (mean age [range] at diagnosis, 52[43-67] versus 64[37-80] years, P = 0.001). PSA level at initial diagnosis and self-reported family history did not have significant difference between deleterious mutation carriers and non-carriers (P = 0.396 for PSA level, P = 0.753 for family history). Moreover, metastasis and Gleason score were not associated with deleterious germline variants. Conclusions: Our data showed approximately 52% DDR mutation occurred in other DNA repair pathways besides HRR and MMR, which was a unique spectrum of germline variants in Chinese prostate cancer patients. This indicated distinct genetic etiology and potential therapeutic targets of prostate cancer in Chinese population. Moreover, early-onset in patients with deleterious germline variants is an important clinical character. Whole DDR pathway genes’ testing and counseling should be considered for application for young individuals.
Pilot study to enhance FDG-PET imaging of prostate cancers with the metabolic inhibitor ranolazine.
Authors: Isabel R. Schlaepfer, Elizabeth R Kessler, Jennifer J Kwak, Lauren Liebman, Paul Maroni, Ramesh Karki, Dan Lopez Paniagua, Phillip Koo, Francisco G. La Rosa, Dexiang Gao, L. Michael Glode, Thomas W. Flaig, Elaine Tat Lam
Journal: Journal of Clinical Oncology (2019)

e16551 Background: 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) is a widely-used imaging modality for many cancers; however, its utility in prostate cancer is limited. Fatty acid oxidation (FAO) is a primary source of energy for early prostate cancer. We previously demonstrated that FAO inhibition in prostate cancer mouse models resulted in increased glucose metabolism and enhanced tumor FDG uptake, with peak uptake at 24 hours. To validate these preclinical findings, we conducted a pilot study to evaluate whether a partial FAO inhibitor, ranolazine, increases tumor FDG uptake on PET imaging for prostate cancer. Methods: Prostate cancer patients with untreated localized cancer (arm 1) and with metastatic disease on hormonal or other therapy (arm 2) were enrolled and underwent baseline and post-treatment FDG-PET/CT scans (standard dose of 10 mCi FDG). Ranolazine 1000mg PO BID x 2 doses was given within 24-48 hours of the second scan. The primary objective was to evaluate the rate of successful enhancement of FDG uptake on PET imaging, based on one or more of the following criteria: 30% increase in maximum SUV with an absolute change of 2 units; 30% increase in mean SUV with an absolute change of 0.75 units; or 20% increase in mean SUV with an absolute change of 1 unit. Results: Eleven patients (four in arm 1, seven in arm 2) were enrolled. Ranolazine was well tolerated by all participants, with no adverse effects observed. Both increases and decreases in SUV uptake were observed on the post-ranolazine scans. No patient met the predefined criteria for successful enhancement of FDG uptake. There was an incidental finding of thyroid cancer seen in one patient that was discovered on PET imaging. The study was closed early due to the emerging clinical availability of alternative and effective PET imaging modalities such as [ 11 C] choline, [ 18 F] fluciclovine, [ 68 Ga] PSMA, and [ 18 F] sodium fluoride. Conclusions: Given the small sample size, we were not able to make any firm conclusions. In this limited study, ranolazine treatment did not result in enhanced FDG-PET-tumor detection. ClinicalTrials.gov identifier: NCT01992016. Supported by the William Meyn Foundation; NIH/NCI P30CA46934, 5K12CA086913, CA168934; ACS RSG-16-256-01-TBE; Colorado Translational Research Imaging Center Pilot Award; Paul Sandoval Cancer Research Summer Fellowship. Clinical trial information: NCT01992016.
Clinical significance of ZHX2 in colitis and colorectal carcinogenesis.
Authors: Yonghua Bao, Yongchen Guo, Wancai Yang
Journal: Journal of Clinical Oncology (2019)

e15010 Background: Colorectal cancer (CRC) is one of the most common malignancies. Mechanistic studies have revealed that the malignant transformation of chronic colitis is one of the major causes besides the activation of Wnt/beta-catenin signaling. Our preliminary data have shown that ZHX2 is a common target of the miRNAs and is associated with colitis malignant transformation. This study aimed to explore the changes of ZHX2 in colitis-CRC tissues and their clinical significance, and to reveal the underlying mechanism. Methods: ZHX2 protein expression levels were analyzed by immunohistochemical staining in a CRC tissue microarray containing 400 cases of CRC and matched normal mucosa; mRNA levels were analyzed in fresh tissues by qRT-PCR. ZHX2 functional studies were conducted in ZHX2 transgenic mouse model and in vitro; Protein regulation was assayed by proteomic analysis using iTRAQ and RNA changes were assayed by RNA-sequence. Results: Protein and mRNA levels of ZHX2 were significantly increased in CRC and was associated with poor outcomes and recurrence, the copy numbers were also elevated in CRC. Intestine-specific transgenic Zhx2 mouse model showed chronic inflammation in the intestine at early age and intestinal carcinogenesis at late ages. Intestinal epithelial cell RNA sequence assay showed differential expression of genes and signaling pathways, compared to the wild-type mice. Biological functional studied showed that increasing ZHX2 in CRC cells enhanced cell proliferation, motility and migration, and suppressed cell apoptosis. Proteomic analysis showed that ZHX2 and HMGA1 were synergistic during tumorigenesis; mi-RNA regulatory study showed that miR-150 targeted ZHX2 and suppressed ZHX2 expression, but ZHX2 could regulate Wnt/beta-catenin and Serine family member PRSS8. Conclusions: This study has revealed the critical roles of ZHX2 in chronic colitis and its malignant transformation and underlying molecular mechanism, identifying a novel target for CRC prevention and therapy.
Efficacy of bone resorption inhibitors (BRI) + abiraterone acetate + prednisone (AA) vs. AA alone as first-line therapy for men with castration-resistant prostate cancer (CRPC) and bone metastases (BM) in an international multicenter hospital-based registry.
Authors: Edoardo Francini, Francesco Montagnani, Nuzzo Pier Vitale, Nimira S. Alimohamed, Irene Moreno Candilejo, Pietro Rosellini, Miguel Gonzalez-Velez, Jaime Rubio, Li Zhang, Grace Shaw, Francesca Crivelli, Roberto Petrioli, Carmelo Bengala, Guido Francini, Jesus Garcia Foncillas, Alan Haruo Bryce, Christopher Sweeney, Lauren Christine Harshman, Richard Lee-Ying, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2019)

e16508 Background: BM in patients (pts) with CRPC correlate with higher mortality and costs. BRI zoledronic acid and denosumab are frequently used for the prevention of skeletal-related events (SRE) in pts with CRPC and BM. AA is the most common 1 st line treatment for men with metastatic CRPC. We sought to evaluate the impact of BRI on time to first SRE (ttSRE) and OS of pts receiving 1 st line therapy AA for CRPC with BM. Methods: We identified a cohort of men starting AA as 1 st line therapy for CRPC with BM between 2013-2015 from 7 hospitals’ IRB approved registries. Pts were grouped by use of concomitant BRI and subgrouped by volume of disease (per E3805 definition) at AA start. The endpoints were OS, defined as time from AA start to death or last follow-up visit, and ttSRE. Results: Of the 338 pts included, 256 (76%) received AA alone and 82 (24%) AA+BRI. ECOG PS (PS) was ≥1 for 178 pts (52.7%). No statistically significant difference in ttSRE was found between the 2 cohorts [see Table]. Median follow-up for OS was 25.6 months. Pts receiving concomitant BRI showed a significantly longer OS and a 36% decreased risk of death compared to AA alone (HR = 0.64; 95% CI, 0.64 0.46-0.91; p = 0.012). Notably, OS in the AA alone group was shorter than commonly described. The OS benefit with BRI was greater for men with high volume disease (HV) (HR = 0.42; 95% CI, 0.25-0.71; p = 0.001). On MVA, BRI vs. no BRI, low volume of disease vs. HV, PS 0 vs. ≥1, baseline VAS pain ≤3 vs. &gt; 5, and baseline PSA are independently associated with longer OS. Conclusions: Using a multicenter database, the addition of BRI to 1 st line AA for CRPC men with BM and poor prognostic factors did not improve prevention of SRE. However, concomitant use of BRI and AA was associated with a significantly improved OS, particularly in HV. Further research to determine the driving factors is needed. [Table: see text]