tbuckley/cabot-search huggingface dataset:
Investigating the feasibility of targeted next-generation sequencing to guide the treatment of head and neck squamous cell carcinoma.
Authors: Bhumsuk Keam, Sun Min Lim, Sang-Hee Cho, In Gyu Hwang, Myung-Ju Ahn, Keon Uk Park, Ji-Won Kim, Yoon Ho Ko, Hee Kyung Ahn, Sang Hoon Chun, Ji Hyung Hong, Jonggwon Choi, Eun Joo Kang, Tak Yun, Keun Wook Lee, Jin-Soo Kim, Hyun Woo Lee, Min Kyoung Kim, Hwan Jung Yun, HyeRyun Kim
Journal: Journal of Clinical Oncology (2018)

e18017 Background: Head and neck squamous cell carcinoma (HNSCC) is a deadly disease in which precision medicine needs to be incorporated. We aimed to implement next-generation sequencing (NGS) in determining actionable targets to guide appropriate molecular targeted therapy in HNSCC patients. Methods: Ninety-three tumors and matched blood samples underwent targeted sequencing of 244 genes using the Illumina HiSeq 2500 platform with an average depth of coverage of greater than 1000×. Tumor RNA was isolated and used to screen for the expression of 55 immune-related genes using Nanostring assay. Clinicopathological data were analyzed in correlation with NGS data. Results: TP53 was the most common mutation, occurring in 47 (51%) patients, followed by CDKN2A (n = 23, 25%), CCND1 (n = 22, 24%) and PIK3CA (n = 19, 21%). The total mutational burden was similar between human papillomavirus (HPV) positivity. Inactivating mutations such as CDKN2A and CDKN2B deletions (n = 6), and CCND1 amplification (n = 17) were exclusively identified in HPV-negative tumors. HPV-negative specific genetic alterations in receptor tyrosine kinases (RTKs) including EGFR, FGFR1/3 and PDGFRA were noted. Mutations of NOTCH1 (P= 0.027), CDKN2A (P < 0.001) and TP53 (P= 0.038) were significantly associated with poorer overall survival. FAT1 mutations were highly enriched in cisplatin responders, and potentially targetable alterations such as PIK3CA E545K and CDKN2A R58X were noted in 14 (15%) patients. Overall pathway analysis revealed that alterations in genes involved in cell death and PIK3CA/AKT/MTOR pathway were predominant. HPV (+) tumors were significantly associated with immune signature-related genes compared to HPV (-) tumors. HPV (-) tumors harbored higher levels of immune activation: specifically, CD3 (P= 6.0 x 10-6), CECAM1 (P= 4.9 x 10-5) and IL2R (P= 6.9x10-5) expression. Conclusions: We found several targetable genetic alterations, and our findings suggest that implementation of precision medicine in HNSCC is feasible. The predictive value of each targetable alteration should be assessed in a future umbrella trial using matched molecular targeted agents. Clinical trial information: NCT03292250.
TCT-38 Impact of FFRCT on decision making and outcomes in stable coronary artery disease in North America: results of the International ADVANCE Registry
Authors: Koen Nieman, Manesh Patel, Hitoshi Matsuo, Jeroen Bax, Bjarne Norgaard, Daniel Berman, Gilbert Raff, Niels Peter Rønnow Sand, Jeroen Sonck, Mark Rabbat, Lynne Koweek, Gianluca Pontone, Kristian Ovrehus, Fay Nous, Takahiko Suzuki, Takashi Akasaka, Campbell Rogers, Jonathon Leipsic
Journal: Journal of the American College of Cardiology (2018)
First-line panitumumab plus docetaxel and cisplatin in advanced gastric or gastroesophageal junction adenocarcinoma: Results of a phase II trial (SPIGA).
Authors: Guillermo Alfonso Quintero Aldana, Sonia Candamio Folgar, Jose Carlos Méndez Méndez, Margarita Reboredo, Mónica Jorge Fernández, Manuel Constenla, Carlos Romero Reinoso, Mercedes Salgado Fernández
Journal: Journal of Clinical Oncology (2016)

e15507 Background: Panitumumab (Pmab) is the first fully human IgG2 monoclonal antibody that is directed against the human EGFR which is over-expressed in around 35-80% of gastric cancers. We tested if the addition of Pmab to the first-line treatment combination of docetaxel (DOC) plus cisplatin (CIS) provided benefit to pts with advanced gastric or gastroesophageal junction adenocarcinoma. Methods: This was a phase II, open-label, single-arm, multicenter study which included pts ≥ 18 years with histologically or cytologically confirmed adenocarcinoma of the stomach or gastroesophageal junction with advanced unresectable or metastatic disease, measurable disease (revised RECIST guideline) and ECOG ≤ 2. All pts received Pmab 6 mg/kg, DOC 50 mg/m2 and CIS 50 mg/m2every 2 weeks for 6 months or until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate. EGFR expression and RAS mutation status were not determined. Results: 44 pts were included: median age 67.8 years (range 43-83), 68% men. Confirmed response rate was noted in 25.0% of pts (95% CI 13.2-40.3), 6.8% were complete radiological responses (median duration: 6.0 months). Stable disease was obtained in 45.5% of pts. Median progression-free survival was 5.0 months (95% CI 3.6-6.9) and median overall survival was 7.2 months (95% CI 5.5-9.0). There was one death reported as related to any of the three treatments (general state deterioration). The incidence of grade 3/4 treatment-related toxicities was 45.5%, 75.0% and 75.0% for Pmab, DOC and CIS, respectively. Toxicities that led to treatment discontinuation were reported in 47.7% of pts for Pmab, 70.5% for DOC and 68.2% for CIS. Most common grade 3/4 toxicities related to Pmab were asthenia (11.4%) and skin rash (11.4%). Grade 3/4 neutropenia (40.9%) and grade 3/4 asthenia (29.5%) were the most common toxicities related to DOC and CIS, respectively. Conclusions: Combination of DOC plus CIS with Pmab shows potential benefits for some pts with advanced gastric or gastroesophageal junction adenocarcinoma with an acceptable safety profile. The effect of RAS status as a predictive factor of response in our cohort is unknown. Clinical trial information: NCT01379807.
Cardiovascular disease risks among head and neck cancer survivors in a large, population-based cohort study.
Authors: Mei Wei, Mia Hashibe, Sarah Abdelaziz, Jason Hunt, Luke Buchmann, Kerry G. Rowe, John Synder, Yuan Wan, Vikrant Deshmukh, Michael Newman, Alison M Fraser, Kim Herget, Marcus Monroe
Journal: Journal of Clinical Oncology (2018)

6051 Background: Over 63,000 Americans develop head and neck cancer (HNC) yearly. The 5-year survival rate for HNC patients is 40-90%. HNC shares risk factors to cardiovascular disease (CVD), such as age > 60 years, male sex, low fruit and vegetable intake, tobacco and alcohol use. Our study was to investigate cardiovascular complications and risk factors for CVD among HNC survivors. Methods: A total of 1,901 HNC patients diagnosed between 1997 and 2012, and 7,796 age and sex matched individuals from the general population were identified. CVD diagnoses were identified in electronic medical records: statewide ambulatory surgery and inpatient visit databases linked to the Utah Population Database. Multivariate Cox proportional hazard models were used to calculate hazard ratios (HR) for cardiovascular outcomes at 0-2 years, 2-5 years and 5+ years after HNC diagnosis. Results: Within the first 2 years after cancer diagnosis, HNC survivors had higher risks of developing CVD than matched comparison individuals, such as heart valve disease (HR 3.33, 95% 2.60-4.28), cardiomyopathy(HR3.21, 95% 2.04-5.03), systolic heart failure (HR 3.90, 95% 3.10-4.89), conduction disorders (HR 5.73, 95% 4.02-8.16), acute myocardial infarction (HR 3.11, 95% 2.08-4.65), coronary atherosclerosis (HR 3.42, 95% 2.90-4.03) and cardiac dysrhythmias (HR 4.26, 95% 3.68-4.93). The risks persisted even 5 years after cancer diagnosis. More baseline comorbidities(HR 1.27, 95%1.01-1.58), late stage of disease (HR 2.20, 95% 1.64-2.96), age > = 65 years old (HR 1.56, 95% 1.27-1.92), radiation therapy (HR 1.33, 95% 1.07-1.65) and chemotherapy (HR 1.72, 95% 1.39-2.13) were associated with increased CVD risk. Baseline comorbidities such as diabetes (HR 3.68, 95% 2.82-4.80), hyperlipidemia (HR 4.59, 95% 3.62-5.82), hypertension (HR 2.90, 95% 1.60-2.52) and chronic kidney disease (HR 5.14, 95% 4.19-6.30) were associated with increased CVD risk. Conclusions: Compared to the general population, HNC survivors have higher risk of developing CVD. Older age, late stage of cancer, comorbidities, radiation therapy and chemotherapy were risk factors. Close CVD monitoring and preventive treatments should be considered in this population.
Immune checkpoint inhibition (ICI) in advanced cutaneous squamous cell carcinoma (cSCC): Clinical response and correlative biomarker analysis.
Authors: Jong Chul Park, Lori J. Wirth, Keith Flaherty, Donald P. Lawrence, Shadmehr Demehri, Stefan Kraft, Ruth Foreman, John R Clark, Justine Vanessa Cohen, Yuhree Kim, Genevieve Marie Boland, Dennie Tompers Frederick, Ryan J. Sullivan
Journal: Journal of Clinical Oncology (2018)

9564 Background: ICI has shown major benefit in cutaneous malignancies including melanoma and Merkel cell carcinoma. Efficacy data in cSCC is, however, limited. Here we report our institutional experience of anti-PD-1 therapy in patients (pts) with advanced cSCC, and biomarker analysis. Methods: We conducted a retrospective analysis of cSCC pts treated with nivolumab or pembrolizumab at Massachusetts General Hospital. NGS and IHC for PD-L1 expression and immune cell composition were performed, and correlation with response was analyzed. Results: 13 cSCC pts treated with ICI were identified, 7 of whom had predisposing conditions: CLL or other lymphoma (n = 3), xeroderma pigmentosum (n = 2), and Marjolin’s ulcer (n = 2). 8 pts were treated with pembrolizumab and 5 with nivolumab. 9 pts (69%) had prior cytotoxic chemotherapy or cetuximab. At median follow-up of 16.5 months, 7 pts (62%) achieved objective responses with 2 complete responses. 4 pts had stable disease over 6 months and 2 had primary resistance. 12-month progression-free survival (PFS) and overall survival (OS) was 68.4 % and 83.3%, respectively. Median PFS and OS were not reached. Grade ≥ 3 adverse events were observed in 3 pts (23%), including 1 treatment-related death (myocarditis). Pre-treatment tissues were available for 11 pts. CD4, CD8 T cells and Tregs were present in variable frequencies and showed no association with response. PD-L1 expression in either tumor (TC) or immune cells (IC) was observed in most pts (78%). Mean TC and IC PD-L1 expression in responders vs nonresponders was 11.5 vs 0% and 5 vs 5%, respectively. TC but not IC PD-L1 expression correlated with response (cut-off 1%, p = 0.04). TP53, PIK3CA, DKN2A, and TERT promoter alterations were common. Tumor mutation burden analysis is underway, and its correlation to response will be analyzed. Conclusions: Our single institution “real-world” experience with anti-PD-1 therapy in advanced cSCC shows promising activity, including in pts who would not be eligible for clinical trial enrollment. PD-L1 expression was common and TC expression correlated with response. Further molecular analysis to identify potential predictive biomarkers is ongoing.
NAMPT inhibition is a novel synthetic lethal therapeutic approach exploiting nuclear-mitochondrial crosstalk in ERCC1-deficient populations.
Authors: Mehdi Touat, Tony Sourisseau, Luc Friboulet, Nicolas Dorvault, Roman Chabanon, Daphné Morel, Julien Adam, Sylvie Sauvaigo, David Enot, Ludovic Bigot, Clément Pontoizeau, Frédéric Bouillaud, Ken Olaussen, Gérard Pierron, Alain Sarasin, Anne Lombès, Alan Ashworth, Christopher J. Lord, Jean-Charles Soria, Sophie Postel-Vinay
Journal: Journal of Clinical Oncology (2017)

e23159 Background: ERCC1 (Excision Repair Cross-Complementation group 1) deficiency is the most frequent DNA repair defect in non-small cell lung cancers (NSCLC), making this enzyme an attractive therapeutic target for synthetic lethal (SL) approaches. Previous data support that DNA damage response is involved in regulation of metabolic homeostasis. We hypothesized that ERCC1 deficiency resulted in metabolic reprogramming of cancer cells that in turn generated specific vulnerabilities. Methods: High-throughput proteomic SILAC (stable isotope labeling by aminoacids in cell culture) and metabolomic (LC-MS, GC-MS, LC-QTOF) profiling were performed on a in-house generated NSCLC model of ERCC1 deficiency. Nicotinamide phosphoribosyltransferase (NAMPT) was selected as main hit and revalidated in low-throughput. Sensitivity to NAMPT inhibition was assessed in several NSCLC models. Potential SL interactions were investigated using functional DNA repair and metabolic assays, and transmission electronic microscopy (TEM). Results: We found marked metabolic rewiring in ERCC1-deficient populations, including decreased NAMPT and NAD+ levels and defects in the tricarboxylic acid cycle. These caused exquisite selective sensitivity to NAMPT inhibition in several in vitro and in vivoNSCLC models; these effects were reversed by the restoration of a functional ERCC1 isoform, establishing a causal link with the ERCC1 defective state. TEM, functional DNA repair and metabolic studies revealed structural and functional defects in the mitochondria of ERCC1-deficient cells, and allowed us to propose a model for this nuclear-mitochondrial SL link. A correlation between NAMPT expression and ERCC1 expression was observed in NSCLC patient samples. Conclusions: These findings open novel therapeutic opportunities that exploit a previously undescribed nuclear/mitochondrial SL link between ERCC1 deficiency and NAMPT inhibition in NSCLC. This highlights the potential for targeting DNA repair / metabolic crosstalk for cancer therapy, and support the evaluation of NAMPT inhibitors in ERCC1-deficient tumors.
Sixty seconds on . . . neonatal herpes
Authors: Nigel Hawkes
Journal: BMJ (2018)

Yes, if you are infected with herpes. Transferred to a newborn, the infection can have serious consequences, including long term neurological damage and, in some cases, death. That’s why the tabloids, with their instinct for the jugular, call it “the kiss of death.”

Estimates vary. The figure usually cited for the UK is 1.6 infections per 100 000 …
A phase 1b/2 study combining MM-151 + nal-IRI + 5-FU + leucovorin in RAS-wildtype metastatic colorectal cancer (mCRC).
Authors: Emily Chan, Wael A. Harb, Kabir Mody, Xiaoy Jiang, Ty McClure, Jeffrey D. Kearns, Andrea Valencia, Jonathan Fitzgerald, J. Marc Pipas, Rachel Nering, Lionel D Lewis
Journal: Journal of Clinical Oncology (2016)

TPS3633 Background: Colorectal cancer is a leading cause of cancer death worldwide and the third most common cancer in men and women. Despite recent approvals of new agents in refractory disease, there has been little change in the composition of first-line therapies in recent years, which generally include chemotherapy in combination with a biologic, either an EGFR-targeted antibody or a VEGF inhibitor. Investigational agents currently in development represent attempts to improve anti-neoplastic efficacy within these established drug classes. MM-151 is a oligoclonal mixture of three IgG1, anti-EGFR antibodies designed to bind distinct non-overlapping EGFR epitopes and inhibit ligand-mediated signal amplification. MM-151’s molecular composition enables antagonism of clinically relevant EGFR ligand mixtures, EGFR down-regulation and immune effector function (ADCC, CDC). Nal-IRI is a nanoliposomal formulation of irinotecan. In a randomized phase-III study (NAPOLI-1) of patients with metastatic pancreatic cancer previously treated with gemcitabine-based therapy, nal-IRI + 5-FU/LV demonstrated its safety and significant clinical activity, increasing overall survival (OS) and progression-free survival (PFS) relative to 5-FU/LV. The current study will characterize preliminary safety, initial efficacy and biomarker / pharmacodynamic profile of MM-151 + nal-IRI + 5-FU/LV in mCRC patients who are treatment naïve to an EGFR inhibitor or irinotecan-based chemotherapy. Methods: In the dose finding cohorts of this Phase 1b/2 study, a modified toxicity probability interval approach (mTPI) will be utilized to determine the maximum tolerated dose (MTD) of MM-151 in combination with nal-IRI, 5FU and leucovorin. Enrollment will be determined by the safety profile observed, with approximately 8-12 pts anticipated. In the Phase 2 portion of the study, approximately 20-30 pts will receive the combination at the defined MTD. The primary objectives of this phase of the study is to characterize initial efficacy, obtain additional safety data, and complete pharmacodynamic and biomarker evaluation through the collection of pre-treatment and on-study samples.
Development of a comprehensive cell-free DNA (cfDNA) assay for early detection of multiple tumor types: The Circulating Cell-free Genome Atlas (CCGA) study.
Authors: Eric A. Klein, Earl Hubbell, Tara Maddala, Alex Aravanis, John F. Beausang, Darya Filippova, Samuel Gross, Arash Jamshidi, Kathryn Kurtzman, Ling Shen, Anton Valouev, Oliver Venn, Nan Zhang, David A. Smith, Timothy Joseph Yeatman, Robert Tibshirani, Richard Thomas Williams, Anne-Renee Hartman, Michael Seiden, Minetta C. Liu
Journal: Journal of Clinical Oncology (2018)

12021 Background: Globally most cancers are detected at advanced stages with high treatment burden and low cure rates. A noninvasive cfDNA blood test detecting multiple cancers at early stages when curative treatment is more likely to succeed is desirable. CCGA (NCT02889978) is a prospective multi-center observational study for development of a noninvasive cfDNA-based multi-cancer detection assay. Methods: Prospectively collected samples (N = 1627) from 749 controls (no cancer diagnosis, C) and 878 participants (pts) with newly diagnosed untreated cancer (20 tumor types, all stages) were analyzed in a preplanned substudy. 3 prototype sequencing assays were performed: paired cfDNA and white blood cell (WBC, 60,000X) targeted sequencing (507 genes) for single nucleotide variants/indels; paired cfDNA and WBC whole genome sequencing (WGS, 30X) for copy number variation; cfDNA whole genome bisulfite sequencing (WGBS, 30X) for methylation. For each assay a detection model was developed for all cancer pts; sensitivity was estimated at 95% specificity. Results: Pts w/cancer and C had similar age, smoking status and gender. WGBS had the highest sensitivity and is reported here; results were consistent across assays. Detected (sensitivity [95% CI]) cancers (stage I-III) included 28 colorectal (66% [48-84]), 19 esophageal (63% [38-84]), 5 head and neck (56% [21-86]), 5 hepatobiliary (80% [28-99]), 73 lung (59% [47-70]), 17 lymphoma (77% [50-93]), 11 multiple myeloma (73% [39-94]), 10 ovarian (90% [56-99]), and 10 pancreatic (80% [44-98]). Breast cancer-specific assay results are reported separately. Cancers with low signal ( < 10% sensitivity) include low gleason score prostate cancer, thyroid, uterine, melanoma, and renal. Comparison to tumor WGS and multi-assay classification will be reported. Conclusions: A cfDNA-based blood test detected multiple cancers at various stages with high specificity, indicating this approach is promising as a multi-cancer screening test, including for lethal unscreened cancers where stage shift can impact mortality. Further assay and clinical development of a multi-cancer cfDNA test in an asymptomatic population is ongoing. Clinical trial information: NCT02889978.
Molecular profiling-based prognostic prediction of patients with advanced small-cell lung cancer.
Authors: Hibiki Udagawa, Shigeki Umemura, Sachiyo Mimaki, Genichiro Ishii, Keisuke Kirita, Shingo Matsumoto, Kiyotaka Yoh, Seiji Niho, Hironobu Ohmatsu, Katsuya Tsuchihara, Koichi Goto
Journal: Journal of Clinical Oncology (2016)

8560 Background: Genetic alterations such as inactivating mutations in TP53 and RB1, gene amplifications of the MYC family members and genetic alterations in the PI3K/AKT/mTOR pathway were observed in small-cell lung cancer (SCLC). However, their prognostic impact on the outcome of patients with advanced SCLC has not been well investigated. Methods: We collected 124 biopsy samples obtained from advanced SCLC patients before cancer treatment. Genomic DNA extracted from biopsy samples was subjected to a 1.499 Mb-sized custom panel capturing all exons of 244 cancer-related genes and the captured DNA was analyzed by a next generation sequencing (HiSeq system, Illumina). The medical records of the patients were retrospectively reviewed and associations between genetic alterations and overall survival (OS) of the patients were evaluated. Results: The demographics of the 124 patients were as follows: median age, 68 years (range: 37-85); male, 101cases (81%); history of smoking, 122 (98%); ECOG performance states 0-1, 102 (82%) and extensive disease, 88 (71%). We identified high prevalence of inactivating mutations in TP53 (105cases, 85%) and RB1(51 cases, 41%). Gene amplifications of the MYC family were detected in 10 (8%) and genetic alterations in the PI3K/AKT/mTOR pathway were detected in 16 (13%) of the tumors In addition, genetic alterations in the MAPK pathway were detected in 10 (8%) of the tumors. The median OS of the patients harboring genetic alterations in PI3K/AKT/mTOR pathway, MYC family, MAPK pathway and others were 8.0, 3.0, 23.0 and 11.1 months, respectively. In the multivariate analysis, the presence of genetic alterations in the PI3K/AKT/mTOR pathway was significantly associated with an unfavorable survival [p = 0.03, HR 1.86 (95%CI, 1.05-3.11)]. In the subset analysis with extensive disease, the presence of genetic alterations in the PI3K/AKT/mTOR pathway was also significantly associated with an unfavorable survival [p = 0.02, HR 2.27 (95%CI, 1.17-4.07)]. Conclusions: Genetic alterations in the PI3K/AKT/mTOR pathway were associated with worse prognosis of patients with advanced SCLC. Sequencing-based genetic profiling gives useful information to predict the prognosis in advanced SCLC.