tbuckley/cabot-search huggingface dataset:
Trends and disparities in place of death for cancer patients in the United States, 1999-2015.
Authors: Fumiko Ladd Chino, Arif Kamal, Thomas William LeBlanc, Yousuf Zafar, Gita Suneja, Junzo P. Chino
Journal: Journal of Clinical Oncology (2018)

6522 Background: Dying in a preferred place is an essential component of high quality cancer care. Comprehensive national trends and disparities in place of death are unknown as prior research is limited in scope and to patients ≥65. Methods: CDC WONDER contains death certificate data for all US counties and is maintained by the National Center for Health Statistics. Place of death was obtained for all cancer deaths from 1999- 2015, as well as year of death, age, sex, race, ethnicity, marital status, and education. Place of death was dichotomized to death at home or hospice facility vs other location. Using data from the most recent year (2015), univariate (UVA) and multivariate (MVA) logistic regression were used to test for disparities in place of death associated with sociodemographic variables. Results: In the study period, 9,646,498 cancer deaths occurred, with 45.5% dying at home or hospice facility. 30.3% of deaths occurred in patients < 65. From 1999-2015, inpatient deaths decreased from 36.6% to 24.6%, while home deaths (38.4 to 42.6%) and hospice facility deaths (0 to 14.0%) increased (all p < 0.001). On UVA, older age, female sex, white race, Hispanic ethnicity, marriage, higher education, and pancreatic or colorectal cancer were associated with death at home or in a hospice facility. On MVA, all assessed factors were associated (p < 0.05) except education and ethnicity. In particular, being married (OR 2.04, 95% CI 1.98-2.10) and having pancreatic cancer (OR 1.36, 95% CI 1.33-1.40) were associated with death at home or hospice, while being black (OR 0.74, 95% 0.73-0.76) or Asian (OR 0.65, 95% CI 0.62-0.68) and having breast cancer (OR 0.90, 95% CI 0.88-0.92) had decreased odds of dying at home or hospice. Despite improvements over time, in 2015 black patients remained 42% more likely to die in hospital (32.8% black vs 23.1% white) and 21% less likely to die at home (34.6% black vs 43.7% white) (both p < 0.001). Conclusions: Inpatient cancer deaths decreased by one third with commensurate rise in home and hospice facility deaths over the study period. Multiple sociodemographic factors were associated with place of death; targeted efforts to increase utilization of palliative care and hospice services may decrease these disparities.
Distinct gene expression, mutational profile and clinical outcomes of V600E and V600K/R BRAF-mutant metastatic melanoma (MM).
Authors: Ines Esteves Domingues Pires Da Silva, Kevin Y. X. Wang, James S. Wilmott, Jeffrey Holst, John J Park, Camelia Quek, Matthew Wongchenko, Yibing Yan, Graham J Mann, Matteo S. Carlino, Richard Kefford, Richard A. Scolyer, Jean Yang, Georgina V. Long, Helen Rizos, Alexander M. Menzies
Journal: Journal of Clinical Oncology (2017)

9541 Background: BRAF V600E and V600K/R mm have distinct clinicopathologic features suggesting different etiology. V600K/R mm appears less responsive to MAPK inhibitors (MAPKi) compared to V600E MM. We investigated potential mechanisms for this by comparing the gene expression and mutation profiles of these two melanoma subgroups. Methods: BRAF V600 mutant mm patients (pts) treated with MAPKi (BRAFi +/- MEKi) between July/2009 and July/2013 were selected. Demographics, clinicopathologic features and clinical outcomes were examined. Pre-treatment FFPE tumors underwent RNA expression profiling (795-gene nanostring panel) and DNA sequencing (239 gene NGS panel). Molecular results were validated using an independent cohort from the The Cancer Genome Atlas (TCGA). Results: 95 mm pts were included (78 V600E, 17 V600K/R), with median (med) follow-up of 18.4 months (mo). 74 (78%) had BRAFi, 21 (22%) had BRAF/MEKi. At MAPKi start, there were no differences between subgroups regarding age, gender, ECOG, AJCC stage or LDH level. V600K/R pts had a trend to less tumour regression by RECIST (med 30% vs 51%, p = 0.08) and shorter PFS (med 5.1 vs 7.1mo, p = 0.08) than V600E, with no difference in OS (20.8mo vs 17.9mo, p = 0.64). V600K/R had lower expression of the MAPK-pathway feedback regulator DUSP6 and glycosyltransferase GCNT1, compared to V600E (p &lt; 0.05). Analysis of TCGA data (122 V600E, 21 V600K/R) confirmed these findings. There was a trend toward higher mutational load in V600K/R than V600E, confirmed with TCGA data (p &lt; 0.05). V600K/R had a higher proportion of mutations in PIK3CA and several tumour suppressor genes (FBXW7, NF2, RB1 and SMAD4), with only FBXW7 confirmed using TCGA data. Conclusions: V600K/R mm has inferior response and shorter survival with MAPKi than V600E, potentially due to less reliance on MAPK pathway activation (lower DUSP6 expression) and greater use of alternative drivers of oncogenesis (higher mutational load, particularly in tumor suppressor genes). Further analyses will be performed, including comparison of MAPK and additional pathway signalling in cell models. Response to immunotherapy will also be examined.
TCT-737 Very Late Stent Thrombosis after Revascularization with Biodegradable Polymer Drug-Eluting Stents. From the SORT OUT VII Trial
Authors: Lisette Okkels Jensen, Michael Maeng, Bent Raungaard, Knud Hansen, Johnny Kahlert, Svend Eggert Jensen, Julia Ellert, Christian Terkelsen, Hans Erik Botker, Steen Dalby Kristensen, Henrik Hansen, Jens Lassen, Karsten Veien, Evald Christiansen
Journal: Journal of the American College of Cardiology (2018)
Abstract B009: Amalgamated c-MYC activation and p53 loss drives rapid prostate tumorigenesis and lethal epididymis tumors in Ai-Myc model
Authors: Wei Wang, Yanling Meng, Bingning Dong, Feng Yang
Journal: Cancer Research (2018)

Abstract c-Myc is one of the most frequently amplified genes in human cancers, including prostate cancer (PCa). It is also frequently overexpressed in PCa as early as prostatic intraepithelial neoplasia (PIN). c-Myc overexpression has been shown to induce pathologic changes of mouse prostate, from mostly normal histology, hyperplasia, mPIN, to invasive prostate tumors. Here we describe an Ai-Myc model designed to ectopically express c-Myc and an enhanced luciferase (Luc2) in any tissue in a Cre-inducible manner. To study PCa, Ai-Myc mice were crossed with PB-Cre4 mice to turn on c-Myc expression in prostate epithelia. Once turned on, the expression of transgenes no longer depends on androgen, which allows studying castration of PCa. These mice developed early onset of mPIN along with enhanced apoptosis; only a small fraction of aged mice developed prostate tumors, indicating that c-Myc alone is not sufficient for effectively driving prostate tumorigenesis. Although mutation or loss of p53 is not common in early PCa, it is strongly correlated to PCa disease stages, metastasis, and castration resistance, and p53 is the most significantly altered gene in metastatic castration-resistant PCa. Therefore, we performed conditional ablation of p53 in the PB-Cre4/Ai-Myc mice to model a significant fraction of advanced PCa and to investigate whether loss of p53 inhibits c-Myc oncogene induced apoptosis for robust prostate tumorigenesis. Indeed, these mice rapidly developed prostate tumors; however, within 3-5 months, all mice also unexpectedly developed lethal epididymis tumors, a rare type of cancer in human. Early castration to fully remove epididymis followed by implantation of testosterone pellets allows these mice to develop advanced prostate tumors with metastasis. In summary, we have developed a novel c-Myc induced PCa model and demonstrated that amalgamated c-Myc activation and p53 loss drives rapid prostate tumorigenesis. Our study also unexpectedly revealed a potent tumorigenesis pathway for cancer of epididymis, a rare and poorly understood type of cancer accounting for at most 0.03% of male cancers. Citation Format: Wei Wang, Yanling Meng, Bingning Dong, Feng Yang. Amalgamated c-MYC activation and p53 loss drives rapid prostate tumorigenesis and lethal epididymis tumors in Ai-Myc model [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B009.
Phase I/II clinical trial of ibrutinib and buparlisib in relapsed/refractory diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma.
Authors: Connie Lee Batlevi, Stephanie De Frank, Caitlin Stewart, Paul A. Hamlin, Matthew J. Matasar, John F. Gerecitano, Alison J. Moskowitz, Audrey M. Hamilton, Andrew David Zelenetz, Pamela Drullinsky, David J. Straus, Anita Kumar, Craig H. Moskowitz, Joanna Dicostanzo, Devin Callan, Dana Tsui, Jurgen Rademaker, Heiko Schöder, Ai Ni, Anas Younes
Journal: Journal of Clinical Oncology (2018)

7520 Background: Bruton's tyrosine kinase (BTK) and PI3K inhibitors synergize effectively in both in vitro and in vivo models of B-cell non-Hodgkin lymphoma (Griner, et al, PNAS, 2014; Erdmann et al, Blood, 2017). We report on a phase I/II clinical trial of ibrutinib (BTK inhibitor) and buparlisib (pan-PI3K inhibitor) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). Methods: Patients (pts) were eligible if they had relapsed/refractory DLBCL, FL, or MCL, ECOG ≤2, and adequate organ function. Ibrutinib and buparlisib were given daily by mouth on a 28-day cycle with dose reductions permitted after cycle 1 unless a DLT was noted. Tumor response was based on a modified Lugano classification with CRs requiring FDG-PET resolution and ≥ PR by CT. Results: 37 pts were enrolled (DLBCL N = 14, FL N = 5, MCL N = 18) with median prior systemic therapies being 3 for DLBCL (range 1-7), 2 for FL (all had 2 prior regimens), and 1 for MCL (range 1-3). Ibrutinib 560 mg and buparlisib 80 mg was selected for dose expansion cohort based on rash and diarrhea requiring dose reductions. Thirty-six pts were evaluable for toxicity while 1 pt was not evaluable for progression within one week of therapy. Grade 3/4 adverse events related to therapy included rash (22%), hyperglycemia (16%), diarrhea (11%), hypertension (11%), anorexia (8%), mood changes (8%), ALT elevation (5%), lipase elevation (5%), anemia (5%), and hyponatremia (5%). Five pts discontinued buparlisib but continued ibrutinib for neurocognitive toxicities related to buparlisib. Thirty-five pts were evaluable for response with best overall response rate (ORR) as follows: DLBCL 31% (N = 13, 3 CR, 1 PR), FL 20% (N = 5, 1 CR), MCL 88% (N = 17, 11 CR, 4 PR). Conclusions: Combination of BTK and PI3K inhibition such as ibrutinib and buparlisib demonstrate a reasonable safety profile and promising clinical activity, especially in MCL. Long term follow-up and correlative analysis of tumor targeted sequencing and cell free DNA analysis is ongoing. Clinical trial information: NCT02756247.
The BRIGHTER trial: A phase 3 randomized double-blind study of napabucasin (NAPA) plus paclitaxel (PTX) versus placebo (PBO) plus PTX in patients (pts) with pretreated advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Manish A. Shah, Kohei Shitara, Florian Lordick, Yung-Jue Bang, Niall C. Tebbutt, Jean-Philippe Metges, Kei Muro, Lin Shen, Sergei Tjulandin, John L. Hays, Rui-hua Xu, Marilyn Fontaine, Emily Brooks, Bo Xu, Wei Li, Chiang Li, Laura Borodyansky, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2018)

4010 Background: NAPA is an oral investigational agent, hypothesized to inhibit cancer stemness pathways, including STAT3 pathway implicated in cancer stem-cell viability. Synergistic antitumor activity of NAPA + PTX was observed in preclinical and early clinical testing. Methods: BRIGHTER is a randomized, double-blind, placebo-controlled phase 3 trial (NCT02178956), assessing efficacy and safety of NAPA + PTX versus PBO + PTX in pts with pretreated, advanced gastric and GEJ adenocarcinoma. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival (PFS), objective response (ORR) and disease control (DCR) rates, and safety. Pts were randomized 1:1 to NAPA (960 mg total daily dose) + weekly PTX (80 mg/m2) or PBO + weekly PTX (80 mg/m2). Results: 714 pts were randomized from October 2, 2014, to December 12, 2016. At interim analysis of 380 events, the data safety monitoring board recommended trial unblinding when meeting the primary endpoint at final analyses appeared unlikely, though no safety concerns of clinical significance were identified. OS follow-up continued with median follow-up of 6.8 m (0.10-32.4) with final analysis performed at 565 events: 36.7%/63.2% (ECOG 0/1), 72.1%/27.9% (M/F), 74.6%/25.4% (gastric/GEJ). The mOS was 6.93 m vs 7.36 m in NAPA and PBO arms (HR 1.01 [95% CI, 0.86-1.20] p=0.8596), respectively. The mPFS was 3.55 m vs 3.65 m in NAPA and PBO arms (HR 1.00 [95% CI, 0.84-1.17] p= 0.9679), respectively. Among evaluable pts, DCR was 55 % vs 58% in NAPA and PBO arms Diff -3% (95% CI, -11%-5%, p= 0.6555), respectively, with an ORR of 16% vs 18% in NAPA and PBO arms Diff -2% (95% CI, -8%-4%, p=0.7358), respectively. The overall incidence of adverse events (AEs) was 98.6% vs 96.6% in NAPA and PBO arms without any additive toxicity. AEs ≥ Grade 3 occurred in 69.2% vs 59.7% in NAPA and PBO arms, with ≥Grade 3 diarrhea in 16.0% vs 1.4%, respectively. Conclusions: An international, placebo controlled phase 3 2nd line study of NAPA + PTX did not improve OS or PFS in pts with gastric and GEJ adenocarcinoma. Addition of NAPA to PTX was tolerable. Clinical trial information: NCT02178956.
Phase 1/2 study of in situ vaccination with tremelimumab + intravenous (IV) durvalumab + poly-ICLC in patients with select relapsed, advanced cancers with measurable, biopsy-accessible tumors.
Authors: Craig L. Slingluff, Daniel Dasilva, Paul Schwarzenberger, Toni Ricciardi, Mary J. Macri, Aileen Ryan, Ralph Rudolph Venhaus, Nina Bhardwaj
Journal: Journal of Clinical Oncology (2017)

TPS3106 Background: Immunotherapy has demonstrated promising antitumor activity in various advanced cancers. Combined tumor targeting from multiple drugs with unique mechanisms may provide further improved outcomes. Tremelimumab (TRE) is a CTLA-4 antibody and durvalumab (DUR) blocks PD-L1. Poly-ICLC is a toll-like receptor 3 agonist. Intratumoral (intra-T) injection of poly-ICLC directly alters the tumor microenvironment (TME), and by creating an in situ vaccination, may trigger a clinically effective systemic anti-tumor response when also combined with DUR and TRE. Methods: This is an ongoing Phase 1/2, open-label, multicenter study (NCT02643303). The study evaluates the use of intra-T administration of TRE and IV DUR + poly-ICLC (intra-T and intramuscular [IM]) to determine the safety, preliminary efficacy and immune activity of this regimen in patients with advanced, measurable, biopsy-accessible tumors: head and neck squamous cell carcinoma, breast cancer, sarcoma, merkel cell carcinoma, cutaneous T-cell lymphoma, melanoma, genitourinary cancer, and other solid tumors. Phase 1 determines the recommended combination dosing (RCD) for the regimen with dose de-escalation based on dose limiting toxicities (DLTs) and standard 3 + 3 rules. Starting doses are: DUR, 1500 mg IV; TRE, 75 mg IV; TRE, 10 mg intra-T; poly-ICLC, 1 mg intra-T/IM. Phase 1 starts with Cohort 1A (DUR + poly-ICLC). Upon demonstration of tolerability, enrollment proceeds with Cohort 1B (DUR + IV TRE + poly-ICLC) and Cohort 1C (DUR + intra-T TRE + poly-ICLC). The RCD is the highest dose at which &lt; 2/6 patients have DLTs. In Phase 2, up to 66 evaluable patients are treated using the RCD regimen, with enrollment of 6 patients per tumor type initially, and enrollment of 6 additional patients per 3 tumor types contingent upon at least 1 response among the initial 6 patients. Study endpoints are RCD and safety, objective response rate, progression-free survival, and overall survival. Exploratory endpoints are biological activity, including effects on the TME and immunological responses. Enrollment opened on 28 Dec 2016. Clinical trial information: NCT02643303.
Lymphocyte apoptosis as a predictive biomarker for radiotherapy de-intensification in EBV-associated nasopharynx cancer.
Authors: Kevin Lee Min Chua, Waseem Ahamed Shihabuddeen, Than Than Shwe, Sze Huey Tan, Joseph Wee, Terence Tan, Melvin Chua
Journal: Journal of Clinical Oncology (2017)

e17545 Background: Emerging evidence in viral-associated head and neck cancers supports the concept of dose de-intensification in these radiosensitive tumors, but different strategies exist in selecting patients for treatment de-intensification. We hypothesize that patients who develop severe late toxicities (LT) to radiation (RT) have better tumor control, due to a common radiosensitivity index. Here, we investigate the utility of a normal tissue radiosensitivity assay (RT-induced lymphocyte apoptosis, RILA) in predicting clinical outcomes (tumor control and normal tissue toxicity) of patients with EBV-associated nasopharynx cancer (NPC). Methods: RILA assay was assessed in a cohort of locally advanced NPC patients from a randomized controlled phase III trial (N = 172, NCC0901) of cisplatin-RT with or without induction gemcitabine, carboplatin and paclitaxel. LT was assessed by CTCAE v.2 at the following intervals (2 mo yr 1, 4 mo yr 2, 6 mo yr 3-5, annually thereafter). We performed the RILA assay (48 h post 8 Gy) in a subset of cases (N = 87). Results: At a median follow-up of 5.7y, DFS (3y 74.9% GCP vs 67.4% Control, p = 0.362) and incidence of severe Grade ≥3 LT did not differ between the treatment arms. In keeping with our hypothesis, onset of severe LT was associated with reduced risk of disease relapse; OR 0.19 (95% CI = 0.02 – 1.59, p = 0.168). High %RILA, stratified by top quartile, was associated with severe LT (OR 1.92 [95% CI = 0.67-5.5], p = 0.26); and lower rate of recurrence (4.5% (1/22), high %RILA vs19.7% (12/61), low %RILA, p = 0.086). Interestingly, subset analyses revealed that CD8+, but not CD4+ subpopulation of immune cells, was strongly associated with recurrence; OR 8.58 for low %CD8-RILA (p = 0.001). Conclusions: Herein, we showed that %RILA may be a useful biomarker for tumor and normal tissue radiosensitivity of EBV-associated NPC. If validated, this predictive assay will enable precision matching of RT-sensitive patients for de-intensification in EBV- and other viral-associated head and neck cancers. The association between tumor control and CD8-subset of immune cells suggests an immune dependency for RT.
Small cell carcinoma of the head and neck: Incidence and survival trends based on the Surveillance and Epidemiologic and End Results (SEER) analysis.
Authors: Marta Bean, Michael Goodman, Conor Ernst Steuer, Mihir Patel, Mark William McDonald, Kristin Ann Higgins, Taofeek Kunle Owonikoko, Jonathan Jay Beitler, Dong Moon Shin, Nabil F. Saba
Journal: Journal of Clinical Oncology (2017)

e17508 Background: Small cell carcinomas of the head and neck (SmCCHN) are rare neoplasms with an unfavorable prognosis. Population based data describing survival and prognostic factors for this malignancy are limited. Methods: Data was obtained from the US National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database for the period 1973-2013. Patient and tumor related characteristics for SmCCHN were compared with squamous cell carcinomas (SCC) of the same anatomic sites. Survival for the two groups was compared by constructing Kaplan-Meier curves and Cox proportional hazard models with and without propensity score matching. Cox models results were expressed as hazard ratios (HR) and the corresponding 95% confidence interval (CI). Results: The dataset included 609 SmCCHN and 227943 cases of SCCHN. SCCHN patients with SmCCHN included significantly greater proportions of females and whites. SmCCHN was more likely to originate in the salivary glands and present with more advanced stage and grade. The overall 5 year and 10 year survival estimates were 27% and 18%, respectively. Corresponding values for SCCHN were 46% and 31%. The multivariable analyses adjusting for age, sex, race, marital status, year of diagnosis, stage, grade and receipt of radiation, the HR comparing SmCCHN to SCCHN was 1.53 (95% CI: 1.39-1.68). Elderly, male, black and not married persons had worse prognosis compared to their respective reference groups. Other factors independently associated with lower survival included more advanced stage and tumor grade, and earlier decades of diagnosis. In the propensity score matched analyses the corresponding HR was 1.27 (95% CI: 1.15-1.40). Conclusions: Compared to SCCHN, SmCCHN in addition to carrying a worse survival, is more likely to originate in the salivary glands, present with more advanced stage, and affect females and whites.
Clinical utility of plasma-based digital next-generation sequencing (NGS) in patients with advance-stage lung adenocarcinomas with insufficient tumor samples for tissue genotyping.
Authors: Jon Zugazagoitia, Inmaculada Ramos Garcia, Jose Manuel Trigo Perez, Magda Palka, Ana Gómez Rueda, Eloisa Jantus-Lewintre, Carlos Camps, Dolores Isla, Santiago Ponce Aix, Rosario Garcia Campelo, Mariano Provencio-Pulla, Reyes Bernabe Caro, Oscar Juan Vidal, Enriqueta Felip, Javier De Castro, Jose Miguel Sanchez Torres, Iris Faull, Richard B. Lanman, Pilar Garrido Lopez, Luis G. Paz-Ares
Journal: Journal of Clinical Oncology (2018)

9101 Background: Approximately 20 % of tumor biopsies from patients with advanced-stage lung adenocarcinomas yield insufficient tissue for successful molecular subtyping. In this study, we have analyzed the clinical utility of NGS of cell-free circulating tumor DNA (ctDNA) in patients with inadequate tumor samples for tissue genotyping. Methods: We prospectively selected consecutive patients with advanced-stage lung adenocarcinomas with insufficient tissue for EGFR, ALK or ROS1 genotyping across 12 Spanish institutions (January-September 2017). Cases with known alterations in any of these genes were ineligible. ctDNA NGS was performed by Guardant Health (Guardant360, Redwood City, CA), using a hybrid-capture-based 73-gene panel. Variants were deemed actionable if they were part of the OncoKB precision oncology knowledge database, and classified in 4 levels based on their clinical or preclinical evidence for drug response. All patients provided informed consent. Results: We included 93 patients; 48 (52 %) were treatment naïve. Eighty-three patients (89 %) had detectable levels of ctDNA, and none of the clinical characteristics predicted ctDNA detection. Level 1-4 actionable drivers were detected in 53 patients (57 %) in the entire cohort and 29 patients (60 %) in the treatment naïve subgroup, of which 13 (14 %) and 7 (15 %) respectively had level 1-2A drivers (FDA-approved and standard-care biomarkers according to lung cancer guidelines). The majority of patients with actionable drivers had clinically relevant co-mutations (n = 46, 87 %), without significant differences across the 4 actionable subgroups. Thirteen patients (14 %) received genotype-matched therapies, the majority of which achieved clinical benefit. Seven treatment-naïve patients (15 %) received targeted drugs as their first-line therapy. Most patients with level 1-2A (85 %), but a minority with level 2B-4 drivers (5 %), received targeted therapies. Conclusions: ctDNA NGS (Guardant360) detects actionable drivers and allows timely initiation of genotype-matched therapies in lung adenocarcinoma patients with insufficient tumor for tissue genotyping.