tbuckley/cabot-search huggingface dataset:
Clinical efficacy of vaccination with the autologous tumor lysate particle loaded dendritic cell (TLPLDC) vaccine in metastatic melanoma.
Authors: Annelies Hickerson, Guy T. Clifton, Tommy A Brown, Jessica Campf, John William Myers, Timothy J. Vreeland, Diane F. Hale, Kaitlin M. Peace, Doreen O Jackson, Xianzhong Yu, Thomas Wagner, George Earl Peoples
Journal: Journal of Clinical Oncology (2019)

e21025 Background: The treatment of melanoma has changed drastically with the advent of immunotherapy. The autologous tumor lysate, particle loaded, dendritic cell (TLPLDC) vaccine stimulates T-cells and may work synergistically with other immunotherapies. Here, we describe results in patients (pts) with metastatic melanoma (MM) treated with the TLPLDC vaccine together with other approved therapies. Methods: The TLPLDC vaccine is created using autologous tumor lysate loaded yeast cell wall particles to prime autologous dendritic cells ex-vivo. 1-1.5x10 6 TLPLDCs are given via intradermal injection monthly x 4 followed by boosters at six and nine months (mo). Pts who recurred while enrolled in our adjuvant phase IIb trial of the TLPLDC vaccine and pts with MM with measurable disease enrolled in a separate phase I/IIa trial were offered vaccination of TLPLDC vaccine in an open-label fashion in addition to other approved therapies as determined by their treating physician. Tumor response is measured by RECIST 1.1 criteria. Results: To date, 50 pts have been enrolled in the two trials (25 pts in each). Of the 42 pts with measureable disease, 30 pts received at least one dose of the vaccine, 11 progressed prior to vaccine administration, and 1 is pending. 2 pts withdrew at 2 and 7 mo. Of the remaining 28 evaluable pts, 13 pts had progressive disease with a median follow-up (f/u) of 3 (range 0-12) mo, 12 pts had stable disease with a median f/u of 7.5 (range 1-23) mo, 2 pts had a partial response with f/u of 7 and 13 mo, and one pt had a complete response with 18 mo of f/u. Overall, in pts with measureable disease, the disease control rate was 54% (15/28) and objective response rate was 11% (3/28). 8 pts were without measurable disease at enrollment, 3 recurred at a median f/u of 8 mo and 5 remain disease-free at a median of 26 mo f/u. No grade ≥ 3 toxicities were observed with combination TLPLDC vaccination and approved systemic therapies. Conclusions: Vaccination with the TLPLDC vaccine in combination with systemic approved therapies in MM pts is well tolerated and may provide clinical benefit in patients with and without measurable disease. Clinical trial information: NCT02678741.
Efficacy and a novel clinicopathologic-genomic nomogram of atezolizumab in advanced non-small cell lung cancer (POPLAR and OAK): A combined analysis of two multicenter, randomized, phase II/III trials.
Authors: Yunfang Yu, Yongjian Chen, Anlin Li, Qiyun Ou, Ying Wang, Wei Ren, Wenda Zhang, Yujie Tan, Herui Yao
Journal: Journal of Clinical Oncology (2019)

2573 Background: Atezolizumab, a programmed death ligand 1 (PD-L1) inhibitor, prolonged overall survival (OS) compared with docetaxel among patients with previously treated advanced non–small-cell lung cancer (NSCLC) in two independent multicentre, randomized trials (POPLAR and OAK). We conducted a combined analysis of the two trials to evaluate its efficacy and genomic biomarkers, and to further developed a novel predictive clinicopathologic-genomic nomogram of immunotherapy in NSCLC. Methods: Patients (N = 1,137) with stage IIIB/IV NSCLC and disease progression after previously platinum-based chemotherapy were randomly assigned (1:1) to receive atezolizumab (1200 mg/kg every 3 weeks) or docetaxel (75 mg/m 2 every 3 weeks). The primary endpoint was OS. We applied a two-stage meta-analysis of pooled individual patient data in the intention-to-treat population. In OAK trial, patients treated with atezolizumab were randomly assigned (1:1) to the training group or the validation group to develop a predictive clinicopathologic-genomic nomogram of immunotherapy. POPLAR and OAK were registered with ClinicalTrials.gov, numbers NCT02008227 and NCT01903993. Results: In the pooled analysis, the median overall survival was 13.49 months (95% confidence interval [CI], 11.95 to 15.22) with atezolizumab versus 9.66 months (95% CI, 8.73 to 10.70) with docetaxel. The risk of death was 28% lower with atezolizumab than with docetaxel (hazard ratio [HR], 0.72; 95% CI, 0.62 to 0.83; P &lt; 0.001). The race, sex, tumor histology, eastern cooperative oncology group performance status, PD-L1 expression, and especially pretreatment mutation (TP53, DNMT3A and KEAP1) were significantly associated with OS, and were used for the development of the predictive nomogram. The clinical use of the nomogram showed a closer association with 3-year OS than the blood-based tumor mutational burden (bTMB) or PD-L1 expression alone (nomogram, AUC = 0.818; bTMB, AUC = 0.701; PD-L1, AUC = 0.526) among NSCLC patients who had received atezolizumab. The superior predictability of the nomogram was further confirmed in the validation and entire OAK cohorts. Conclusions: Among patients with advanced, previously treated NSCLC, OS was significantly better with atezolizumab than with docetaxel. Furthermore, we constructed a novel and powerful clinicopathologic-genomic nomogram for personalized immunotherapy options.
A randomized trial of a healthy lifestyle intervention versus usual care on chemotherapy and endocrine therapy adherence rate in women with breast cancer: The Lifestyle Exercise and Nutrition Early After Diagnosis (LEANER) Study.
Authors: Tara B. Sanft, Maura Harrigan, Brenda Cartmel, Leah M. Ferrucci, Karen Basen-Engquist, Dawn L. Hershman, Jennifer A. Ligibel, Marian Neuhouser, Anees B. Chagpar, Beth A. Jones, M. Tish Knobf, Andrea Silber, Fangyong Li, Melinda L. Irwin
Journal: Journal of Clinical Oncology (2019)

TPS11633 Background: The World Cancer Research Fund and the American Cancer Society provide diet and exercise guidelines for cancer survivors. Many women with breast cancer do not follow these guidelines. Adoption of recommended lifestyle behaviors soon after diagnosis may prevent adverse changes in body composition, breast cancer biomarkers, and may improve adherence to treatment thereby improving breast cancer prognosis. The Lifestyle, Exercise, and Nutrition Early after Diagnosis (LEANER) study is testing the impact of a healthy lifestyle intervention on chemotherapy completion and endocrine therapy adherence. Secondary endpoints include changes in inflammatory and metabolic biomarkers, body composition, and patient reported outcomes. Methods: Eligible participants are women with stage I-III breast cancer undergoing chemotherapy. 250 participants are being recruited and randomized 1:1 to a yearlong, 16 session, healthy diet and exercise counseling intervention or usual care group. The intervention is delivered in person and/or via telephone by registered dietitians with training in exercise science. Materials include workbooks, videos, cookbooks, fit bits, and home-based exercise equipment. Intervention is focused on graduated goal setting to meet the recommended diet and exercise guidelines for cancer survivors. The primary endpoint, chemotherapy completion rate, is gathered from the Electronic Medical Record and the average Relative Dose Intensity for the originally planned regimen is calculated based on standard formulas. Assessments are completed at baseline, post chemotherapy, 1- and 2- year time points (to assess adherence to endocrine therapy). Body composition is measured using dual energy X-ray absorptiometry, blood samples and patient reported outcomes are collected. At time of submission, 39 women have been randomized. Discussion: If successful, this study has the potential to make healthy lifestyle interventions initiated shortly after diagnosis a standard component of breast cancer treatment. Clinical trial information: NCT03314688.
Performance comparison of the methylated <i>BCAT1</i>/<i>IKZF1</i> ctDNA test (COLVERA) with the CEA assay for detection of recurrent colorectal cancer.
Authors: Erin L. Symonds, Susanne Kartin Pedersen, David Murray, Susan E Byrne, Paul Hollington, Philippa Rabbitt, Frederick S. Jones, Eva Segelov, Tadd Scott Lazarus, Lawrence Charles Lapointe, Graeme P. Young
Journal: Journal of Clinical Oncology (2019)

3589 Background: Early detection of recurrent colorectal cancer (CRC) will improve treatment options, but the current standard blood test of carcinoembryonic-antigen (CEA) has suboptimal sensitivity for recurrence. This study compared performance of a quantitative circulating tumor DNA (ctDNA) assay for methylated BCAT1 and IKZF1 (COLVERA) with that of CEA. Methods: 301 patients were monitored for recurrence after clearance of primary CRC. Blood was collected at scheduled intervals and concentrations of CEA and ctDNA were measured using the LIAISON CEA test (Diasorin) and the COLVERA ctDNA test (Clinical Genomics). Surveillance for recurrent disease was examined using regular CT scans. Sensitivity of each blood test for recurrence was assessed in the sample collected closest to the time of imaging confirming recurrence status. Absence of recurrence was defined as at least two consecutive clear CT scans. Receiver operator characteristic (ROC) analyses were used to determine optimal positivity threshold for Colvera. Results: 131 patients underwent satisfactory assessment for recurrence and had blood testing performed within 12 months of determining recurrence status (61.8% male, mean age 62.6 ±.12.2(SD)y). Of the 47 recurrence cases, 37 (74%) were distant. The areas under the ROC curves were 0.7761 and 0.8188 for CEA and COLVERA, respectively (each p &lt; 0.001). An optimal cut-off of 12.8pg/sample was determined for COLVERA and the standard 5ng/mL cut-off was selected for CEA. COLVERA had a significantly higher sensitivity for detecting recurrence as compared to CEA (68.1% vs 31.9%, p &lt; 0.001) with a similar specificity (97.6% Vs 96.4%, p = 0.6547). A multivariate analysis determined COLVERA to be a predictor of recurrence independent of CEA with positive COLVERA samples being 66.4 times (95%CI 14.0-315.8) more likely to have recurrence confirmed within the study timeframe, whereas CEA was not a significant predictor of recurrence (p = 0.228). Conclusions: These findings indicate that COLVERA, reporting in quantitative mode, is a more sensitive test than CEA. It provides a viable alternative for sensitive and early detection of recurrent CRC. Clinical trial information: 12611000318987.
Genome-wide cell-free DNA (cfDNA) methylation signatures and effect on tissue of origin (TOO) performance.
Authors: Minetta C. Liu, Arash Jamshidi, Oliver Venn, Alexander P. Fields, M. Cyrus Maher, Gordon Cann, Hamed Amini, Samuel Gross, Joerg Bredno, Meredith Miller, Jan Schellenberger, Kathryn N. Kurtzman, Eric T. Fung, Tara Maddala, Geoffrey R. Oxnard, Eric A. Klein, David R. Spigel, Anne-Renee Hartman, Alex Aravanis, Michael Seiden
Journal: Journal of Clinical Oncology (2019)

3049 Background: For multi-cancer detection using cfDNA, TOO determination is critical to enable safe and efficient diagnostic follow-up. Previous array-based studies captured &lt; 2% of genomic CpGs. Here, we report genome-wide fragment-level methylation patterns across 811 cancer cell methylomes representing 21 tumor types (97% of SEER cancer incidence), and define effects of this methylation database on TOO prediction within a machine learning framework. Methods: Genomic DNA from 655 formalin-fixed paraffin-embedded (FFPE) tumor tissues and 156 isolated cells from tumors was subjected to a prototype 30x whole-genome bisulfite sequencing (WGBS) assay, as previously reported in the Circulating Cell-free Genome Atlas (CCGA) study (NCT02889978). Two independent TOO models, one with and one without the methylation database, were fitted on training samples; each was used to predict on the test set. A WGBS classifier was used to detect cancer at 98% specificity; reported TOO results reflect percent agreement between predicted and true TOO among those detected cancers (166 cases: 81 stage I-III, 69 stage IV, 16 non-informative). Results: Genome-wide methylation data generated from this database allowed fragment-level analysis and coverage of ~30 million CpGs across the genome (~60-fold greater than array-based approaches). Incorrect TOO assignments decreased by 35% (20% to 13%) after incorporating methylation database information into TOO classification. Improvement was observed across all cancer types and was consistent in early-stage cancers (stage I-III). Respective performances in breast cancer (n = 23) were 87% vs 96%; in lung cancer (n = 32) were 85% vs 88%; in hepatobiliary (n = 10) were 70% vs 90%; and in pancreatic cancer (n = 17) were 94% vs 100%. Results using an optimized approach informed by these results in a large cohort of CCGA participants will be reported. Conclusions: Incorporating data from a large methylation database improved TOO performance in multiple cancer types. This supports feasibility of this methylation-based approach as an early cancer detection test across cancer types. Clinical trial information: NCT02889978.
Validation of a panel of risk factors for predicting breast cancer reappearance.
Authors: Giovanni Corso, Paolo Veronesi, Patrick Maisonneuve, Aron Goldhirsch, Virgilio Sacchini, Pietro Caldarella, Alessandra Margherita De Scalzi, Viviana Galimberti
Journal: Journal of Clinical Oncology (2019)

e12004 Background: The aim of this clinical study was to assess a panel of risk factors for ipsilateral breast tumor recurrence (IBTR) and de novo contralateral breast cancer (BC) after primary BC treatment. Methods: Retrospectively, 15,168 consecutive patients with primary monolateral BC were enrolled in this monocentric study (1994-2006). Clinicopathological features, follow-up and survival at 15 years were considered for statistical analysis. Results: Significant increased risk for IBTR were verified with younger age ( &lt; 50 years) [HR = 1.31 (1.15-1.49), p &lt; 0.0001], lobular subtype [HR 1.40 (1.15-1.70), p = 0.0007)], pT3 [HR 1.90 (1.42-2.54), p &lt; 0.0001] or pT4 [HR 2.70 (1.47-4.97), p = 0.001], metastatic axillary lymph nodes [HR 1.50 (1.29-1.73), p &lt; 0.0001], peritumoral vascular invasion (PVI) [HR = 1.27 (1.10-1.46), p = 0.001], luminal B [HR 1.57 (1.33-1.87), p &lt; 0.0001], HER2-positivity [HR 1.85 (1.32-2.59), p = 0.0004] and triple-negative subtype [HR 1.76 (1.28-2.43), p = 0.0005]. Older age ( &gt; 70 years) [HR 1.50 (1.05-2.15), p = 0.03] and positive family history [HR 1.86 (1.48-2.34), p &lt; 0.0001] were risk factors for contralateral BC. Significant protective factors for IBTR were mucinous subtype [HR 0.45 (0.27-0.77), p = 0.003], total mastectomy [HR = 0.37 (0.30-0.46), p &lt; 0.0001], hormonotherapy [HR 0.56 (0.45-0.69), p &lt; 0.0001], chemotherapy [HR 0.77 (0.66-0.90), p = 0.001] and external radiotherapy [HR 0.39 (0.31-0.50), p &lt; 0.0001]. Hormonotherapy was also confirmed as a protective factor for contralateral second BC [HR 0.51 (0.38-0.69), p &lt; 0.0001]. Cumulative incidence for IBTR at 5, 10, and 15 years was higher than for than for contralateral BC. Conversely, overall survival for IBTR was lower than for contralateral BC. Conclusions: We classified factors influencing IBTR and contralateral BC into high- and low-risk groups. The high-risk group for IBTR included: age &lt; 50 years, positive axillary nodes, PVI positivity, luminal B, HER2-positive, lobular and triple-negative subtypes. The low-risk group included: adjuvant treatments (hormone-chemotherapy, external radiotherapy) and mucinous histotype. We hypothesize that in the low-risk group, adjuvant treatments exert a strong impact in the prevention of IBTR risk (HER2-positive and triple negative BC should be considered also for neo-adjuvant therapies); this was not confirmed in the high-risk group, in which a more aggressive surgery is still theoretically justified. The proposed panel represents the basis for a nomogram to predict BC reappearance.
Targeting the androgen receptor as a novel therapeutic strategy for high-grade gliomas by suppressing glioma cancer stem cells.
Authors: Nan Zhao, Shaheen Ahmed, Fei Wang, DiMaio J Dominick, Chi Lin, Chi Zhang
Journal: Journal of Clinical Oncology (2019)

e13504 Background: Glioblastoma (GBM) is the most aggressive and most common type of primary brain malignancies with median overall survival being only 20.9 months. The incidence of GBM is 50% greater in men than in women, and GBM transplanted into animals grow at a slower rate in females compared with males. Gender difference in GBM indicates that sex hormones such as androgen receptor (AR) may be involved in the tumorigenesis of GBM. A newer generation of AR antagonist, Enzalutamide, is available for prostate cancer treatment in clinic and can pass the blood-brain barrier, thus a good candidate for GBM treatment. Methods: Cell proliferation assay, cell cycle analysis, and cell apoptosis assay were performed on different GBM cell lines after Enzalutamide treatment. After treating GBM cells with or without Enzalutamide in mono-layer cell culturing or tumor spheres, cancer stem cell sub-population (CD133+ cells) in different groups was compared using flow cytometry. After enriching GBM cancer stem cells by sorting CD133+ U87MG cells out, cell proliferation assay was performed on CD133+ U87MG cells. Western blotting was performed comparing marker gene expression levels including CD133 and c-Myc with total protein isolated from GBM cells treated with Enzalutamide at different time points. A syngeneic orthotopic GBM mouse model was used for in vivo study. The size of tumors in the brain was monitored weekly with and without Enzalutamide treatment by in vivo imaging system for the luciferase activities. Results: Enzalutamide inhibited the proliferation of GBM cells both in vitro and in vivo. Enzalutamide induced apoptosis of GBM cells as well as arrested the cell cycle at G2/M phase in a cell cycle that has a potential of radio-sensitizing effect. Enzalutamide decreased the cancer stem cells population both in cultured mono-layer cells and in tumor spheres. Enzalutamide inhibited the proliferation of CD133+ U87MG cells after four days’ treatment. c-Myc is a proto-oncogene and required for maintenance of GBM cancer stem cells. Both CD133 and c-Myc expression levels decreased in GBM cell lines after Enzalutamide treatment in a time-dependent manner. Conclusions: Enzalutamide targets cancer stem cells and inhibits the proliferation of GBM.
Palbociclib plus cetuximab versus placebo plus cetuximab in platinum-resistant, cetuximab-naive, HPV-unrelated head and neck cancer: A double-blind randomized phase II trial (PALATINUS).
Authors: Douglas Adkins, Jin-Ching Lin, Assuntina Gesualda Sacco, Jessica C. Ley, Peter Oppelt, Qi Shen, Kenneth Alan Kern, Holger C. Thurm, Shaw-Ling Wang, Jean-Francois Martini, Justin Hoffman, Bohuslav Melichar, Makoto Tahara
Journal: Journal of Clinical Oncology (2019)

6013 Background: Cetuximab monotherapy results in a median overall survival (OS) of approximately 6 months (mo) in platinum-resistant recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). HNSCC unrelated to human papillomavirus (HPV) is driven by hyperactivation of the CDK4/6 and cyclin D1 (CD1) regulatory complex, resulting in cell cycle progression and tumor growth, suggesting that CDK4/6 inhibition can be a rational therapeutic strategy in this setting. Palbociclib (PAL) is a selective CDK4/6 inhibitor that may reverse cetuximab resistance by countering the actions of deregulated CD1. PAL plus an epidermal growth factor receptor inhibitor synergistically reduced cell viability of HPV-unrelated HNSCC cell lines. In a single-arm, multicenter trial of platinum-resistant, cetuximab-naive, HPV-unrelated HNSCC, PAL in combination with cetuximab resulted in a median OS of 9.5 mo. Methods: In a double-blind randomized phase II trial, patients (pts) with platinum-resistant, cetuximab-naïve, HPV-unrelated HNSCC were treated with cetuximab plus either PAL (arm A) or placebo (arm B). Pts were stratified by performance status (PS) and prior immunotherapy (IT). 120 pts were required for 1:1 randomization to have ≥ 80% power to detect a hazard ratio (HR) of 0.6 (corresponding to a median OS of 10 mo in arm A and 6 mo in arm B) using a 1-sided log-rank test P=0.10). Key secondary endpoints included progression-free survival (PFS), adverse events (AEs), and p16 status. Results: Pts (n=125) were randomized (arm A, 65; arm B, 60). PS and prior IT were balanced between the arms. Median (95% CI) follow-up for OS was 15.9 (15.0–19.4) mo. Median OS was 9.7 (7.3–13.9) mo in arm A and 7.8 (6.7–10.6) mo in Arm B (stratified by PS: HR=0.82 [95% CI, 0.54–1.25], P=0.18). Median PFS was 3.9 mo in arm A and 4.6 mo in arm B (stratified by PS: HR=1.00 [0.7–1.5], P=0.5). Hematologic AEs were more common in arm A. Only 11 pts (9%) received IT after being treated on the trial. Conclusions: Among pts with platinum-resistant, HPV-unrelated HNSCC, PAL plus cetuximab resulted in a trend of prolongation of median OS compared with cetuximab. Clinical trial information: NCT02499120.
Randomized phase II trial of adjuvant hepatic arterial infusion (HAI) + systemic FOLFIRI +/- panitumumab (Pmab) in patients with resected RAS wild type colorectal cancer hepatic metastases (CRLM).
Authors: Nancy E. Kemeny, Haley Hauser, Marinela Capanu, T. Peter Kingham, William R. Jarnagin, Ronald P. DeMatteo, Andrea Cercek, Vinod P. Balachandran, Jeffery A. Drebin, Michael Ian D'Angelica
Journal: Journal of Clinical Oncology (2019)

3555 Background: HAI therapy has improved recurrence free (RF) survival in several randomized trials after resection of CRLM. The purpose of this trial was to determine whether systemic Pmab added to adjuvant HAI + FOLFIRI in RAS WT pts increases 15 months RF survival (RFS) after liver resection. Secondary endpoints are evaluation of overall survival, toxicity, and predictive biomarkers. Methods: RAS WT pts with resected liver mets were randomized to HAI + SYS (+/-) Pmab after stratification by clinical risk score (≥ 3 or &lt; 3) and previous chemotherapy (Y/N). For a particular arm, if 24 or more patients (pts) were alive and RF at 15 months, the regimen in that arm would be considered worthy of further investigation. The initial dose of HAI FUDR 0.12mg/Kg + dexamethasone was infused over the first 2 weeks of a 5-week cycle. Systemic chemotherapy was delivered on days 15 and 29 (irinotecan 125 mg/m 2 , LV 400 mg/ m 2 , 5FU 1000 mg/m 2 48-hour continuous infusion and +/- Pmab 6mg/kg). Patient characteristics were compared between arms using Fisher’s exact test and Wilcoxon rank-sum test. Survival curves were estimated using the Kaplan-Meier method and compared by the log-rank test. Results: After randomization of 75 pts, the arm receiving + Pmab met the decision rule of having ≥ 24 patients alive and RF at 15 months. The two arms had similar pt characteristics and toxicity, with the exception of Pmab related rash (Table). The 15-month RFS is 79% and 67% in +/- Pmab arms, respectively. With a median follow-up of 45 months, 3-year RFS is 65% [CL 0.45-0.78] and 42% [CL 0.24-0.57], and 3-year survival is 96% and 90% in +/-Pmab arms, respectively. Conclusions: In this trial, the addition of Pmab to HAI and SYS showed promising activity without increase in biliary toxicity and should be further investigated in a larger study. Predictive biomarkers will be presented. Clinical trial information: NCT01312857. [Table: see text]