tbuckley/cabot-search huggingface dataset:
Genomic alterations in 670 patients with diverse cancers analyzed by next-generation sequencing (NGS) of circulating tumor DNA (ctDNA).
Authors: Maria Clemence Schwaederle, Ranajoy Chattopadhyay, Shumei Kato, Paul T. Fanta, Kimberly Banks, David Eric Piccioni, Sadakatsu Ikeda, AmirAli Talasaz, Richard B. Lanman, Lyudmila Bazhenova, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2017)

11593 Background: NGS of blood-derived ctDNA allows non-invasive tumor profiling. Liquid biopsy studies with clinical correlation have so far been mainly limited to small size cohorts. Methods: We performed comprehensive plasma genomic testing of ctDNA (NGS) in 670 patients (pts) (54-70 genes); Guardant Health, Inc.; (Clinical Laboratory Improvement Amendment certified and College of American Pathologists accredited). Results: The most represented cancers were gastrointestinal (31.8%), brain (22.7%), and lung (20.7%) (Table). Sixty-three percent of pts (N = 423) had ≥1 alteration. The most frequent alterations (characterized and variants of unknown significance (VUSs)) were in TP53 (32.5% of pts), followed by EGFR (13%), KRAS (12.5%), and PIK3CA (9.1%); for characterized alterations, the breakdown was 30.7% ( TP53), 7.6% ( EGFR), 12.2% ( KRAS), and 7.7% ( PIK3CA). Interestingly, 32% of brain tumors had ≥1 ctDNA alteration. Head and neck tumors were independently associated with a higher number of alterations (P=0.019). Forty-eight percent of pts (320/670) had potentially actionable alterations; in 241, (75% of 320), by an FDA-approved drug (mostly off label). Illustrative examples of clinical utility will be presented such as a patient with gastric cancer and EGFRamplification in ctDNA who received anti-EGFR treatment (60% regression), as well a patient with aggressive gynecologic malignancy who received immunotherapy based on a hypermutated ctDNA profile. Conclusions: Most pts, including a subset of those with brain tumors, demonstrated ctDNA alterations. Pts with head and neck tumors harbored higher numbers of alterations. Overall, three quarters of pts with alteration(s) had ≥1 aberration that could potentially be pharmacologically tractable, suggesting the need to further assess the utility of ctDNA in a therapeutic setting. [Table: see text]
Microvessel density as a prognostic marker in high-risk renal cell carcinoma.
Authors: Sarah A. Weiss, Maneka Puligandla, Lucia Jilaveanu, Naomi B. Haas, Xin Victoria Wang, Christopher Zito, Marta Boeke, Veronique Neumeister, Judith Manola, Robert S. DiPaola, Harriet M. Kluger
Journal: Journal of Clinical Oncology (2017)

4565 Background: Increased vascularity is a hallmark of renal cell carcinomas (RCC), particularly clear cell RCC. The vascular endothelial growth factor (VEGF) pathway, implicated in tumor angiogenesis, is dysregulated in RCC. The phase 3 trial ECOG-ACRIN E2805 enrolled 1,943 patients (pts) with resected high-risk RCC (pT1b high grade to pT4 any grade or N any). Pts were randomized to adjuvant sunitinib, sorafenib, or placebo. Our aim was to determine the prognostic and predictive role of microvessel density (MVD), VEGF receptors, and ligands in nephrectomy specimens. Methods: We obtainedpre-treatment primary RCC tissue from 822 pts and built tissue microarrays using 3 cores from each sample. Using quantitative immunofluorescence we measured tumor MVD (area of CD34-expressing cells) and intensity of the VEGF/VEGF-R family (VEGF-R1, R2, R3 and VEGF-A, B, C, D) in tumor cells. We tested for association with disease-free survival (DFS) and overall survival (OS) by the stratified log-rank test. Associations with treatment arm and clinicopathologic variables were determined. Results: High MVD (above the median) was associated with prolonged OS for the entire cohort (p = 0.021, HR 0.63) and for pts treated in the placebo group (p = 0.014). The association between high MVD and OS was weaker in patients treated with sunitinib or sorafenib (p = 0.060). High VEGFD expression overall was associated with shorter OS (p = 0.027) but not for placebo (p = 0.16). Yet high MVD was not associated with improved DFS (p = 1.00). High MVD correlated with above-median age ( &gt; 56) (p = 0.032), Fuhrman grade I/II (p &lt; 0.001), clear cell histology (p &lt; 0.001), and absence of necrosis (p &lt; 0.001) but not with gender, sarcomatoid features, lymphovascular invasion, or tumor size. In multivariable analysis, MVD remained independently associated with improved OS for the entire cohort (p = 0.013). Conclusions: High MVD in nephrectomy specimens of high-risk RCC pts is associated with improved OS, regardless of treatment arm. MVD is thus an independent prognostic, rather than predictive, biomarker. Further studies should assess whether incorporating MVD into clinical models will predict outcome in resected high-risk RCC pts and if MVD can be used for pt selection for adjuvant therapy.
Prognostic factors associated with survival and recurrence in resectable gastric cancer: Retrospective analysis of 379 patients operated at Cremona Hospital from 2007 to 2016.
Authors: Michele Ghidini, Bianca Maria Donida, Luigi Totaro, Margherita Ratti, Claudio Pizzo, Ilaria Benzoni, Daniele Lomiento, Federico Aldighieri, Laura Toppo, Valerio Ranieri, Chiara Senti, Giulia Tanzi, Mario Martinotti, Rodolfo Passalacqua, Massimo Rovatti, Gianluca Tomasello
Journal: Journal of Clinical Oncology (2018)

e16079 Background: Surgical resection remains the only curative treatment option for non-metastatic gastric cancer (GC). A large cohort of GCs from a high-volume Italian center was analyzed to describe clinical outcomes and prognostic factors. Methods: 379 GC patients (pts) undergoing curative resection from 2007 to 2016 were considered. Variables analyzed were: age, sex, tumor location (cardia vs non-cardia), histology (intestinal vs diffuse), tumor invasion (T1-2 vs T3-4), nodal status (N0 vs N+), resection margins (R0 vs R1-2), grade (G1-2 vs 3-4), HER2, HP infection, (neo)adjCT, adj CTRT, NLR and lymphadenectomy (D1 vs D2-3). Results: Male to female ratio was 1.5:1. Median age at diagnosis was 75y (IQR 67-81, range 41-92). Histology was intestinal in 68.5% and 11.5% had cardia as primary. HER2 was amplified in 31.6% (available in 98 pts). HP was positive in 20.9%; 46.9% stage I-II, 36.3% stage III and 16.8% with oligometastatic disease. Grouping data by year of diagnosis (2007-2011 for 195 and 2012-2016 for 184 cases) there was a statistically significant difference in the rate of lymphadenectomy (p < 0.001) with D1 decreasing from 64% to 26% as compared to D2 lymphadenectomy. Type of surgery (partial vs total) did not change over the years; 6.9% of pts received neoadj CT, 37% adj CT and 16.7% adj CTRT. At 24.13 months median follow up, mOS was 29.7 months (IC95%, 23.4-36.0) with no significant difference between year groups. Variables significantly associated with OS were: N+ (HR = 2.31, p < 0.001), positive resection margins (HR = 2.54, p < 0.001) and adj CT (HR = 0.44, p < 0.001). Disease recurrence (info available in 56% pts) was registered in 32% of cases, with no significant differences between year groups; mTTP was 23.2 months (9.0-52.4). Age > 65y (HR = 2.85, IC95% 1.06-7.63, p = 0.038), T3-4 (HR = 4.91, IC95% 1.44-16.67, p = 0.011) and R+ (HR = 3.76, IC95% 1.72-8.18, p = 0.001) were shown to have an effect on DFS at multivariate analysis. Conclusions: Our analysis performed on a very large cohort of consecutive resected GC pts confirms the prognostic value of N and R status and adjCT on OS.
Risk of second primary cancers among patients with stomach cancer: A population-based study in South Korea.
Authors: Jaesung Heo, O Kyu Noh, Mison Chun, Young-Taek Oh, Oyeon Cho
Journal: Journal of Clinical Oncology (2018)

e16054 Background: The growing number of incident cases of gastric cancer along with improved survival results in a rising population of survivors at risk of second primary cancers (SPC). Aims: In this study, we analyzed SPC risk in stomach cancer survivors to compared the incidence of SPC with that expected in the general population. Methods: We selected adult ( > 19 years) patients with gastric cancer as first primary malignancy diagnosed from January 2010 to December 2014 using claims data from the Health Insurance Review and Assessment Service (HIRA) in South Korea. We analyzed the frequency and standardized incidence ratios (SIRs) to estimate the risk of SPC in gastric cancer survivors. Results: Among 115,914 patients with first primary gastric cancer, 3,165 (2.7%) developed SPC. The mean time to first SPM from the time of diagnosis of stomach cancer was 20.2 ± 12.5 months. The most common site was colorectal, which occurred in 529 patients (16.7%), and lung in 407 patients (12.9%), thyroid in 284 patients (9.0%), prostate in 270 patients (8.5%), liver in 260 patients (8.2%), and esophagus in 185 (5.8%). Among men, the most frequent were colorectal, lung, prostate and esophageal cancer; in women, colorectal cancer, thyroid and breast cancer were the most common. The SIR for all cancers was 1.24 in all patients, 1.30 in males, and 1.14 in females. Among both sexes, significantly higher SIRs were observed for cancers of the esophagus (6.94), small intestine (5.63) and Non-Hodgkin lymphoma (3.50). Interestingly, there was decreased risk of thyroid (SIR: 0.63), breast (SIR: 0.52) and skin cancer (SIR: 0.83). The risk of secondary cancer was found to be significantly higher within one year after primary cancer diagnosis (SIR: 2.42). Conclusions: Patients with gastric cancer were found to be at increased risk of developing SPC in compared to the general population. Close surveillance of these patients within one year after diagnosis was needed for early detection.
Effect of adding immunotherapy (IT) to treatment regimen of mantle cell lymphoma (MCL): Analysis of the National Cancer Data Base (NCDB).
Authors: Alaa Altahan, Eric Vick, Upama Giri, Eric Wiedower, Michael Gary Martin
Journal: Journal of Clinical Oncology (2017)

e19022 Background: There has been some improvement in overall survival (OS) for patients with MCL over the past years [Gordon 2014]. However, side effects of treatment remain a major concern. With introduction of novel therapies like IT, it is imperative to optimize treatment regimens to improve survival while minimizing toxicity. Methods: MCL patients (pts) who were diagnosed in 2013 or later with information available about chemotherapy (CT) and IT and did not receive transplant were extracted from NCDB. Pts were assigned to age categories and were sorted into six groups based on different combinations of CT (none, single agent (SA), and multi-agent (MA)) with or without IT. Cox regression analysis was used to perform multivariate analysis that included age category, sex, race, clinical stage, Charlson/Deyo score, CT, radiation, and IT for each group. Multivariate p values (p) were used to analyze statistical significance. Kaplan Meier method was utilized to analyze OS. T-test was used to compare means (t-p). Results: 1438 total pts were identified with a mean age of 70 (range 24-90); 71% male; 93% white, 4% black, 3% others; 42% with stage III/IV disease. 667 pts did not receive CT or IT, and 40 received IT alone and both of these groups were excluded from further analysis. 52 pts received SA- (without) IT, 206 received SA+(with) IT and 260 pts received MA-IT and 213 MA+IT. Mean age was 72 and 66 for SA and MA groups, respectively (t-p&lt;0.01). Mean OS for SA+IT was 27 months (m) vs SA-IT 16 m (p &lt; 0.01). MA+IT v MA-IT showed no difference in mean OS (25 vs 26 m, respectively, p =0.49). Although there was a significant difference in OS between SA and MA groups without IT (16 vs 25 months, p &lt; 0.01). SA + IT group showed comparable mean OS time to MA + IT (27 vs 26 m, p =0.145). Conclusions: For MCL pts, MA has superior OS to SA group. However, adding IT significantly improves OS for SA group and makes it comparable to MA. Adding IT to MA did not provide significant difference in OS. These results highlight the possibility of achieving same OS with less toxic regimens. Hence further evaluation in a prospective study to optimize treatment while reducing toxicity is warranted.
Genomic correlates of response to immune checkpoint blockade in microsatellite stable solid tumors.
Authors: Natalie Vokes, Diana Miao, Claire Margolis, David Liu, Stephanie Wankowicz, Bastian Schilling, Lynette M. Sholl, Gad Getz, Pasi A. Janne, Robert I. Haddad, Toni K. Choueiri, David Allen Barbie, Rizwan Haq, Mark M. Awad, Dirk Schadendorf, F. Stephen Hodi, Joaquim Bellmunt, Kwok-Kin Wong, Peter S. Hammerman, Eliezer Mendel Van Allen
Journal: Journal of Clinical Oncology (2018)

3036 Background: Immune checkpoint inhibitors have improved survival in multiple malignancies, but genomic biomarkers for efficacy in microsatellite stable tumors are incompletely characterized. Methods: Tumor and germline whole exome sequencing (WES) from pre-treatment tumors in immune checkpoint-treated patients were assembled from 7 published studies and from 78 newly sequenced tumors (total n = 249). Tumor types included were melanoma (n = 151), non-small cell lung cancer (n = 57), bladder cancer (n = 27), head and neck cancer (n = 12), sarcoma (n = 1), and anal cancer (n = 1). The sequencing data were processed through a uniform pipeline, and the results were correlated with clinical outcomes to immune checkpoint therapy to identify tumor genomic features that contribute to response. RECIST (v1.1) was used to define responders as those with complete or partial response, and those with progressive disease as non-responders. Results: Although tumor mutational burden was correlated with response, its univariate predictive power in this cohort was low (AUC = 0.66). Further analyses identified additional correlates of response, including individual driver genes in kinase signaling and chromatin regulators, global mutational signatures, and specific HLA-restricted neoantigens. Copy number analysis corroborated associations between specific pathways and absence of response to immunotherapy, including increased copy number events in the interferon-γ pathway in nonresponders (19/123 vs 3/70, p = 0.034). However, many of these molecular features were interrelated and potentially confounded with one-another. Power simulations showed that significantly larger sample sizes are necessary to disentangle these features, highlighting the complexity of identifying genetic driver events that generate an immunoresponsive tumor environment. Conclusions: This study represents the largest analysis to date of WES obtained from solid tumors in patients treated with immune checkpoint inhibitors. This work defines a path for gathering insights from multiple cohorts, and advances hypotheses of biological mechanisms and biomarkers of response to immune checkpoint therapy for further study.
Effects of strong cytochrome P450 (CYP)3A4 inducers/inhibitors on the pharmacokinetic (PK) profile of anamorelin in healthy volunteers.
Authors: Elizabeth Duus, Mark A. Matson, Alberto Bernareggi
Journal: Journal of Clinical Oncology (2018)

e22180 Background: Anamorelin is an oral selective ghrelin receptor agonist in development that showed benefits for patients with advanced non-small cell lung cancer and anorexia/cachexia (ROMANA studies; Temel J. Lancet Oncol. 2016; Currow D. Ann Oncol. 2017). Anamorelin is metabolized in the liver, primarily by the CYP3A4 isoenzyme. Strong inducers/inhibitors of CYP3A4 might change its PK profile. Methods: Two phase I clinical trials in healthy volunteers evaluated the effects of the CYP3A4 inhibitor ketoconazole and the CYP3A4 inducer rifampin on the PK profile of anamorelin. Volunteers received oral anamorelin, alone or combined with oral ketoconazole (anamorelin 25 mg; ketoconazole 200 mg every 12 hours [hr] for 3 doses) or rifampin (anamorelin 100 mg; rifampin 600 mg once daily for 7 days). To assess the PK profile of anamorelin, serial blood samples were collected in both studies. Results: Concomitant ketoconazole administration significantly increased anamorelin maximum plasma concentration (Cmax; mean ± standard deviation = 118 ± 114 ng/mL vs 368 ± 120 ng/mL; p≤0.001) and area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞; 261 ± 127 ng*hr/mL vs 840 ± 193 ng*hr/mL; p≤0.001), while significantly decreasing the time necessary to reach Cmax (tmax; 1.53 ± 0.704 hr vs 0.638 ± 0.221 hr; p≤0.01). Concomitant rifampin administration significantly decreased anamorelin Cmax (1005.9 ± 340.18 ng/mL vs 454.3 ± 209.29 ng/mL; p < 0.001) and AUC0-∞ (2390.70 ± 1019.241 ng*hr/mL vs 778.99 ± 434.572 ng*hr/mL; p < 0.001). Mean tmax of anamorelin did not significantly change following concomitant rifampin administration (1.02 ± 0.71 hr vs 0.86 ± 0.50 hr; p = 0.663). Conclusions: Concomitant administration of anamorelin should be approached with caution with strong CYP3A4 inhibitors and inducers because it may significantly affect its PK profile and, consequently, anamorelin safety or efficacy.
Differential sensitivity to cytotoxic chemotherapy according to histologic growth pattern of advanced lung adenocarcinoma.
Authors: Xiangyun He, Arpita Desai, Saraswati Pokharel, Sharmeen Mansoor, Shipra Gandhi, Chong Wang, Hongbin Chen, Alison Meagher, Grace K. Dy
Journal: Journal of Clinical Oncology (2016)

9098 Background: The purpose of this study was to examine the association between lung adenocarcinoma growth patterns and response to cytotoxic chemotherapy. Methods: Patients (pts) diagnosed with inoperable stage III/IV lung adenocarcinoma from 11/1/2011 to 6/30/2014 at our institute, who received cytotoxic chemotherapy as first line treatment were retrospectively analyzed. Pts were grouped into solid/papillary/micropapillary (SPM) versus (vs) acinar/lepidic (AL) groups. The primary end point was to determine the objective response (OR) using RECIST version 1.1, time to response (TTR) and duration of response (DOR). Secondary end points were to examine differences in overall survival (OS), estimated by Kaplan-Meier (KM) method and compared using the Log-rank method according to treatment regimen used for each histologic subtype. Results: Only 69 of 222 pts had sufficient diagnostic material for analysis: 41(59%) pts in the SPM, 28(41%) in the AL group. The demographic features were comparable. There were no ALK+ pts. Majority of patients (85%) received pemetrexed (pem). 16(41%) from SPM and 4(18%) from AL group had OR to pem-based therapy (p= 0.0503). The median TTR was 2.89 and 4.89 months (p= 0.8499), and median DOR was 3.77 and 6.84 months (p= 0.3208). In comparison, 2(40%) from SPM and 3(50%) from AL group had OR to taxane (tax)-based therapy. Median TTR was 5.02 and 5.67 months and median DOR was 4.36 and 4.75 months. KM curves showed better OS in AL vs SPM patients, regardless of chemotherapy regimen used (pem: p= 0.0902; tax: p= 0.0578). OS of patients with SPM subtype who received pem- vs tax-based regimens were 13.6 (95% CI 7.34-22.10) vs 9.57 months (95% CI 6.39-26.36) (p= 0.30). OS of patients with AL who received pem- vs tax-based regimens were 39.96 (95%CI 14.52 – 39.96) vs not yet achieved (95% CI 8.49 – not yet achieved) (p =0.91). Conclusions: AL subtypes have a trend towards better OS compared to SPM subtypes, regardless of chemotherapy regimen used. We also observed a trend that SPM subtypes were more likely to exhibit objective response and OS benefit to pem-based regimen compared to AL subtypes.
TCT-322 Agreement between coronary CTA and conventional angiography on the SYNTAX score tertiles stratified by anatomical complexity in the SYNTAX III Revolution trial
Authors: Carlos Collet, Daniele Andreini, Ulf Teichgräber, Torsten Doenst, Holger H. Sigusch, Jasmina Alibegovic, Robert Manka, André Plass, Ahmed Ouda, Dries Belsack, Jens Czapla, Stijn Lochy, Danny Schoors, Yoshinobu Onuma, Patrick Serruys, Antonio Bartorelli
Journal: Journal of the American College of Cardiology (2018)
Use of a chemotherapy toxicity prediction tool to decrease the risks for hospitalization in the elderly.
Authors: Mintcho Elinov Mintchev, Adrian Reyes Bersabe
Journal: Journal of Clinical Oncology (2018)

256 Background: Oncologists commonly use performance status scores such as ECOG and Karnofsky when making treatment decisions. However, there is limited data on the utility of these measures in selecting therapy and predicting treatment-related complications in the elderly. In July 2016, medical oncologists at our institution made it standard practice to use the Cancer and Aging Research Group toxicity prediction score (CARG) to identify elderly patients who are “fit” for conventional therapy versus those who are “frail” and may experience increased complications. Methods: We retrospectively reviewed referrals to our outpatient medical oncology clinic for patients 75 years of age and older. Referrals leading to systemic therapy (i.e. chemotherapy, targeted therapy, and immunotherapy) or changes to conventional therapy based on CARG were included in our study. We evaluated CARG utilization during the 6 months before and the 6 months after its institution. We also assessed how changes to therapy due to CARG impacted admissions and emergency department (ED) visits. Results: Thirty-eight patients with mean age of 81.2 years, 52.6% male, met inclusion criteria. Their diagnoses included GI (36.8%), lung (21.1%), hematologic (18.4%), breast (10.5%), GU (2.6%), and other (10.5%) malignancies. During 2016, CARG was assessed in 14 patients, 9 of whom received systemic therapy. CARG was assessed in 12.5% and 41.2% of patients receiving systemic therapy in the 6-month periods before and after its incorporation, respectively. Patients whose therapy was decreased in intensity or withheld based on CARG had fewer mean admissions (0.7 versus 2.25), days of admission (4.3 versus 8), and ED visits (1.1 versus 2.5) compared to those who received conventional therapy. However, the study lacked power to establish statistical significance. Conclusions: A CARG assessment occurred in less than 50% of elderly cancer patients who received systemic therapy and further inquiry may help formulate interventions to increase its adoption. Therapy modifications based on CARG may lead to fewer hospitalizations, admission days, and ED visits, but more consistent use of the score and further investigation are necessary.