tbuckley/cabot-search huggingface dataset:
Clinical characteristics of patients with no evidence of disease (NED) versus residual disease (RES) to anti-HER2 therapy in metastatic breast cancer (MBC): A multi-institutional analysis.
Authors: Zachary William Neil Veitch, Philippe L. Bedard, Patricia A. Tang, Jessica L. Conway, Domen Ribnikar, Hamzeh Albaba, Karen M. King, Sasha M. Lupichuk, David W. Cescon
Journal: Journal of Clinical Oncology (2019)

1034 Background: Anti-HER2 therapy has improved survival in HER2+ MBC. Yet, large patient cohorts with no evidence of disease (NED) with long-term follow up are incompletely described in the literature. We evaluated the clinical characteristics of patients with HER2+ MBC and prolonged response to anti-HER2 therapy, exhibiting NED vs Residual disease (RES). Methods: Patients treated with chemotherapy plus trastuzumab (CT) from 2005-2013, or taxane plus trastuzumab-pertuzumab (TTP), or trastuzumab-emtansine (TDM1) from 2012-2016 for HER2+ MBC at Princess Margaret Cancer Centre in Toronto, Ontario or in Alberta, Canada were included. Duration on anti-HER2 therapy (without switch) was collected. Patients with median duration of response (MDR; months) 2x higher than phase II/III trials for each regimen (CT = 18.2; TTP = 40.4; TDM1 = 25.2) were included to select for prolonged response. Clinical features (ie: stage at diagnosis, survival, etc) and oncologist/radiologist reported best response were collected. Responses were grouped as NED (including sclerotic bone metastases) or RES. Clinical variables were evaluated by Chi-square and survival by Kaplan-Meier (log-rank). Results: 2403 patients (CT = 1830; TTP = 394; TDM1 = 179) were evaluated. After cut-off, 119 patients (5%) were included, with NED in 41% (49/119) and RES in 59% (70/119). More women aged &lt; 50 vs ≥50 (p = 0.015) had NED (61%) than RES (39%). No breast surgery (curative or metastatic) showed higher (p = 0.015) rates of NED (49%) relative to RES (27%). More women having NED (92%) than RES (37%) were still alive (p &lt; 0.0001) at data cut-off, with improved mPFS (years; p &lt; 0.0001) for NED (11.2, 95%CI: 11.2-NR) vs RES (3.0, 2.7-3.6), and mOS (years; p &lt; 0.0001) for NED (NR) vs RES (3.4, 95%CI: 2.8-4.2). Significance persisted with TDM1 patients excluded. Treatment type (p = 0.053) and number of organs with metastases (p = 0.067) were of borderline significance. Conclusions: Patients with NED have improved survival compared to RES. Younger age and avoiding breast surgery correlates with NED. Evaluation of genomic factors influencing NED are planned.
Long-term sexual impairment in relationship with metabolic health in testicular germ-cell tumor survivors.
Authors: Michal Chovanec, Lucia Vasilkova, Lucia Petrikova, Jana Obertova, Patrik Palacka, Katarina Rejlekova, Zuzana Sycova-Mila, Nikola Hapakova, Valentina De Angelis, Katarina Kalavska, Daniela Svetlovska, Beata Mladosievicova, Jozef Mardiak, Michal Mego
Journal: Journal of Clinical Oncology (2019)

e16060 Background: Treatment for germ-cell tumors (GCT) results in long-term sexual difficulties in GCT survivors, as we have shown previously. This study aimed to correlate the long-term sexual difficulties with serum parameters of metabolic functioning. Methods: GCT survivors (N = 155) from a national cancer center completed a Sexual Function Questionnaire that was modified from PROMIS Sexual Function and Satisfaction Questionnaire at a median 10 years of follow up (range 5-32). Twenty-nine (18%), 30 (19%) and 20 (13%) survivors have suffered from severe difficulty to achieve erection, maintain erection and achieve orgasm, respectively. Severe difficulty was characterized as a score of 0-2 (scale 0-5) in respective questions from the questionnaire. Sexual impairment was then correlated with parameters of metabolic functioning assessed from peripheral blood of all survivors drawn at the day of the clinical visit. Results: Survivors with difficulty to achieve erection had significantly higher levels of alanine-aminotransferase (ALT), aspartate-aminotransferase (AST) and lactate-dehydrogenase (all P &lt; 0.05). Impaired ability to achieve an orgasm also correlated with significantly higher levels of ALT, AST and LDH (all P &lt; 0.05). Survivors with difficulty to maintain erection had higher levels of LDH (P = 0.02) and AST (trend for P = 0.06), but not ALT ( P = 0.5) and their cholesterol levels were significantly higher ( P = 0.04). Furthermore, survivors with higher levels of glucose ( P = 0.04), thyroid stimulating hormone ( P = 0.04), but not of free-thyroxin ( P = 0.3) suffered from difficulty to achieve orgasm. Conclusions: Our prospective study shows that an impairment in sexual function resulting from curative treatment of GCTs may be related to metabolic health. Higher liver enzymes may be indicative of endothelial dysfunction and cardiovascular disorder. Long-term sexual impairment in GCT survivors should be a subject of further translational research to uncover the underlying molecular mechanisms.
Nab-paclitaxel/S-1(AS) versus nab-paclitaxel/gemcitabine(AG) for first-line chemotherapy in advanced pancreatic ductal adenocarcinoma (aPDAC): A retrospective analysis of efficacy and safety.
Authors: Yuan Zong, Zhi Peng, Ming Lu, Xicheng Wang, Jun Zhou, Lin Shen
Journal: Journal of Clinical Oncology (2019)

e15743 Background: AG significantly improved PFS and OS compared with gemcitabine monotherapy in patients (pts) with metastatic PDAC, but the confirmed ORR was limited to 23% with increased grade 3 or 4 myelosuppression. In GEST and JASPAC01 studies, S-1 showed non-inferior or superior activity to gemcitabine in advanced and postoperative PDAC. S-1 also developed less hematologic adverse events especially in neutropenia and was a convenient oral alternative. Two single-arm phase II trials in China demonstrated high ORR of 50.0-53.1% with AS. We investigated the efficacy and safety of first-line chemotherapy with AS versus AG in pts with aPDAC. Methods: A retrospective review was conducted of aPDAC pts treated with first-line AS and AG in GI dpt. Of PUCH between 11/2013 and 12/2018. Pts received 125mg/m2 nab-paclitaxel intravenously (IV) on day1, and 80-100mg S-1 orally per day on day1-7 every two weeks in AS cohort, while pts received 125mg/m2 nab-paclitaxel IV on day1,8, and 1000mg/m2 gemcitabine IV on day1,8 every three weeks in AG cohort. ORR, ORR of primary lesion, DCR, PFS, OS and safety were analysed between two cohorts. Survival outcomes were evaluated by Kaplan-Meier method and compared with the log-rank test. A Cox proportional hazard model was made to determine independent predictors of survival. Results: A total of 70 pts (45 in AS cohort, 25 in AG cohort) with locally advanced (4%) and metastatic (96%) PDACs were identified. 75% were male and the median age was 65(range 36-72). Among intention-to-treat population, the ORR and DCR were 40.0% vs 32.0% (p = 0.70) and 75.6% vs 64.0% (p = 0.57) in AS and AG cohort, respectively. The ORR of primary lesion was 31.1% with AS vs 20.0% with AG (p = 0.73). With the median follow-up of 9.8 months(range 2.3-22.2), the median PFS and OS were 4.7m vs 6.7m (HR, 1.2; 95% CI, 0.6 to 2.4; p = 0.62) and 10.3m vs 11.3m (HR, 0.9; 95% CI, 0.5 to 1.8; p = 0.78) in AS and AG cohort, respectively. Grade 3/4 toxicities occurred in 31.1% AS vs 36.0% AG (p = 0.59). Most G3/4 toxicities were: leukopenia/neutropenia (26.7% vs 20.0%), febrile neutropenia (2.2% vs 8.0%), thrombocytopenia (0 vs 12%), fatigue (4.4% vs 12%), peripheral neuropathy (0 vs 8.0%). In multivariate analysis, liver metastasis was the only independent predictor of poor OS (HR 0.3, 95%CI 0.1-0.8, p = 0.014). Conclusions: AS was a comparable and convenient alternative with manageable toxicities in aPDAC. There was a trend towards improved ORR of primary lesion compared with AG.
Lack of Gdf11 does not improve anemia or prevent the activity of RAP-536 in a mouse model of β-thalassemia
Authors: Amaliris Guerra, Paraskevi Rea Oikonomidou, Sayantani Sinha, Jianbing Zhang, Vania Lo Presti, Callum R. Hamilton, Laura Breda, Carla Casu, Ping La, Ana C. Martins, Anoop K. Sendamarai, Mark Fleming, Stefano Rivella
Journal: Blood (2019)
Relative risks of prostate cancer associated with different family cancer histories.
Authors: Jennifer Lynn Beebe-Dimmer, Ashley Kapron, Alison M Fraser, Ken R Smith, Kathleen A. Cooney
Journal: Journal of Clinical Oncology (2019)

1505 Background: Recently developed clinical guidelines have suggested that men in families with Hereditary Prostate Cancer (HPC), Hereditary Breast and Ovarian Cancer (HBOC), and Lynch Syndrome (LS) be referred for consideration of genetic testing, especially in the setting of aggressive disease. However, while a family history (FH) of the same disease among close relatives is an established risk factor for prostate cancer (PC), a direct comparison of risk associated with specific FH, and particularly with respect to known familial cancer syndromes, in a single population is needed. Methods: The Utah Population Database was used to identify 569,320 men, 40+ years with a pedigree that included at least three consecutive generations. Each man was evaluated for FH of FPC, HPC, HBOC and LS, as well as their own PC status. PC cases (N=34,889) were identified from both the SEER Utah Cancer Registry and death certificates and classified into one or more subtypes: early-onset (EO [age of diagnosis &lt;60 years]), lethal, and/or aggressive (Gleason Grade ≥7, metastatic, or lethal). Relative risks (RR) associated with each PC subtype, adjusted for important covariates, were calculated in STATA using a modified Poisson regression with robust error variances to obtain corresponding confidence intervals (CIs) for each FH definition. Results: A FH of HPC conveyed the greatest relative risk for all PC subtypes (RR=2.30; 95% CI 2.21-2.39), followed by HBOC and LS. Furthermore, the strongest risks associated with FH were generally observed for EO disease. No differences in risk by degree of FH were observed for either lethal or aggressive disease. Conclusions: In this large population-based family database, the risk of PC was shown to vary by cancer FH and was most strongly associated with EO disease. These results are critically valuable in understanding and targeting high-risk populations that would benefit from genetic screening and enhanced surveillance. [Table: see text]
Dynamic monitoring of circulating tumor DNA next-generation gene sequencing as a predictive biomarker of response and progression-free survival after pembrolizumab monotherapy in patients with advanced NSCLC.
Authors: Charu Aggarwal, Jeffrey C. Thompson, Austin Chien, Katie Quinn, Martina Lefterova, Rebecca Nagy, Stephanie Yee, Christine Agnes Ciunci, Evan W. Alley, Joshua Bauml, Roger B. Cohen, Corey J. Langer, Erica L. Carpenter
Journal: Journal of Clinical Oncology (2019)

3040 Background: Circulating tumor DNA next generation sequencing (ctDNA NGS) is increasingly being used to detect mutations (MT) in patients (pts) with metastatic (m) NSCLC. Limited data exist on the correlation of baseline ctDNA NGS profile and serial ctDNA NGS monitoring to response to immunotherapy. Methods: We conducted a prospective study in pts with mNSCLC receiving pembrolizumab monotherapy. Plasma was collected at weeks 0 (T0), 9 (T1), and 18 (T2). ctDNA NGS was performed using a 73 gene panel. Number of MTs and variant allelic fraction (VAF) were determined at baseline, and serially; change in mean VAF was calculated between T1-T0, and T2-T0. Response rate (RR) was assessed using RECIST 1.1. Correlations were made for pt characteristics, RR, progression free survival (PFS), and overall survival (OS). Results: We analyzed 95 samples from 33 pts, 21 female, median age 69 (range 51-89 years), smokers (n = 29), adenocarcinoma (n = 23), 25 pts enrolled at initial diagnosis, majority had high PD-L1 ≥50% (n = 29, 88%). At T0, 32 pts had detectable MT, median number of MTs was 4 (range 0-21), (non-synonymous MT = 3), most common MT was TP53 (n = 21). Confirmed PR was 27% (n = 9), clinical benefit rate (SD+PR) was 64% (n = 21), and 2 pts were not evaluable for response. Smokers were more likely to have higher number of MT at T0 (4 vs. 1 p = 0.003); there was no correlation with smoking and overall RR (p = 0.17). RR was not related to number of MT at T0, p = 0.37. A decrease in ctDNA VAF was seen in 6/9 pts with PR (mean VAF change range -0.11 to -0.001); 2/5 pts with PD showed an increase in mean VAF while 3 showed decrease. At median follow up of 9.26 months (mos), median PFS and OS were 7.4 and 10.5 mos, respectively. Median PFS was longer for pts with a decrease in ctDNA VAF at both T1-T0 (8.9 vs. 5 mos, p = 0.02) and T2-T0 (9.1 vs. 5.5 mos, p = 0.006). OS and additional biomarker analyses including correlation of response to a 2mb ctDNA plasma-based NGS panel will be reported at the meeting. Conclusions: Our results demonstrate that it is feasible to serially monitor plasma NGS, decline in mean ctDNA VAF correlates with radiographic response and PFS on immunotherapy with pembrolizumab.
2D and 3D thermally bioprinted human MCF-7 breast cancer cells: A promising model for drug discovery.
Authors: Aleli Campbell, Alexander Philipovskiy, Rosalinda Heydarian, Armando Varela-Ramirez, Denisse A. Gutierrez, Luis H. Solis, Michael E. Furth, Thomas Boland
Journal: Journal of Clinical Oncology (2019)

2605 Background: Breast cancer (BC) is the second leading cause of cancer death following lung cancer. Bioprinting, the use of computer aided process to print biological living and non-living material to create patterns in 2D or 3D structures, is a novel technique that has been proposed to be used to develop tissue engineered solutions for a wide array of clinical applications, e.g., skin grafting. We investigate here if bioprinted breast cancer cells show some of the hallmarks of cancer tissues, and thus may represent good in vitro models for drug discovery. Methods: For this study, MCF-7 BC cells were cultured, stained, counted and turned into a bioink solution by suspending in phosphate buffered saline solution. The cells were bioprinted over a 96-well plate and pre-incubated for 18 hours in DMEM and RPMI media with 10% Fetal Bovine Serum and Charcoal Stripped Serum, respectively. After 18 hours of incubation the media was supplemented with Tamoxifen at 5µM, 10µM, 50µM, 90µM and 110µM concentrations. Cytotoxicity was measured 24 hours post-treatment using a differential nuclear staining assay and an INCell 2000 bioimager system. Results: Bioprinted cells exposed to high concentrations of Tamoxifen (90 µM and 110µM) exhibited a viability of 8.2% and 10.8%, respectively. Whereas viability of manually seeded cells at those concentrations was 0.11% and 0.05%. Viability of negative and positive controls was at 7.6% and 97.0% for the bioprinted samples and for the normally seeded cells was 4.9% and 98.8% respectively. Conclusions: In our study, we have established a novel 2D/3D breast tumor model applying bioprinting technology for drug discovery. The higher cell viability of MCF-7’s at high concentrations of Tamoxifen could be attributed to the hormesis effect and activation of chaperone proteins, e.g., HSP70 and HSP90, possibly caused by bioprinting. We hypothesize that bioprinted MCF-7 cells also show increased levels of chaperone proteins, which may in a way mimic their in vivo behavior. In this novel in vitro 2D/3D model, the bioprinted cells show a more biological relevant behavior than normally cultured cells. Insights into the cell behavior after bioprinting may elucidate how to build improved in vitro models for BC research.
A randomized phase II trial of veliparib (V), radiotherapy (RT) and temozolomide (TMZ) in patients (pts) with unmethylated MGMT (uMGMT) glioblastoma (GBM).
Authors: Mustafa Khasraw, Kerrie Leanne McDonald, Mark Rosenthal, Zarnie Lwin, David M. Ashley, Helen Wheeler, Elizabeth Barnes, Matthew C. Foote, Eng-Siew Koh, Erik P. Sulman, Michael Back, Michael Buckland, Hao-Wen Sim, Lauren Fisher, Robyn Leonard, Merryn Hall, Sonia Yip, John Simes
Journal: Journal of Clinical Oncology (2019)

2011 Background: TMZ offers minimal benefit in uMGMT GBM pts. V is synergistic with both RT and TMZ in preclinical models, safe when combined with either RT or TMZ clinically, but the triplet (V+RT+TMZ) is poorly tolerated. This study examined a novel approach to patients with uMGMT GBM. Methods: VERTU is a randomized Phase 2 trial comparing Arm A (Standard of care) = RT (60Gy/30 fractions) + TMZ (75mg/m2 daily) followed by TMZ (150–200mg/m2D 1–5) every 28 days for 6 cycles vs Arm B (experimental arm) = RT (60Gy/30 fractions) + V (200mg PO BID) followed by TMZ (150–200mg/m2D 1–5) + V (40mg bid, D 1–7) every 28 days for 6 cycles in pts with newly diagnosed centrally determined uMGMT GBM. The study aims to randomize 120 pts (2:1 to the experimental arm). The primary endpoint was 6 months progression free survival (6mPFS) with multiple secondary and tertiary endpoints. Evaluation of feasibility and safety was planned after completion of RT in the first 60 pts (Stage 1). (ANZCTR #ACTRN12615000407594). Tumor tissue and serial bloods were collected for translational research. Results: 125 pts were randomized (41 Arm A, 84 Arm B). Mean (range) age 58 (22–78) years, 70% male, 61% ECOG 0, 86% macroscopic resection, 14% biopsy. At the time of analysis (cut-off date: 04/Feb/2019), median follow up was 16.5 months, 76 pts had died. 6mPFS (95% CI, Kaplan-Meier estimate) was 37% (22–52) in Arm A and 53% (41–63) in Arm B, and median PFS was 4.4m (95% CI 4.0–6.0) for Arm A and 6.2m (95% CI 4.9–7.1) for Arm B (HR = 0.81, 95%CI 0.54–1.21). 50% of pts in Arm A and 53% in Arm B experienced ≥ G3 adverse events (AEs). The most common G 3/4 AEs were decreased platelets, seizures, hyperglycemia and diarrhea (each 5%) in Arm A and decreased platelets (13%) and seizures (11%) in Arm B. Conclusions: In this multicenter, randomized study, the experimental therapy was feasible and well tolerated. The observed 6mPFS appeared longer in Arm B, but at the time of submitting the abstract, this result did not meet the prespecified primary endpoint. More mature results will be presented at the annual meeting. QoL in VERTU is reported separately. Central MR review, biomarker analyses, including DNA repair and methylation signature analyses are ongoing. Clinical trial information: ACTRN12615000407594.
Clonal evolution and osimertinib resistance mechanisms identified by whole exome and transcriptome sequencing in EGFR mutant NSCLC.
Authors: Nitin Roper, Anna-Leigh Brown, Sivasish Sindiri, Constance M. Cultraro, Shaojian Gao, Chul Kim, Chuong D. Hoang, Tapan K Maity, Elizabeth Akoth, Arun Rajan, Abhilash Karavattu Venugopalan, Christopher Trindade, Jun S. Wei, Anna Panchenko, Stephen M. Hewitt, Javed Khan, Udayan Guha
Journal: Journal of Clinical Oncology (2019)

9049 Background: Osimertinib, a 3rd generation EGFR TKI, has been approved for treatment naïve patients (pts) with metastatic EGFR mutant NSCLC. Mechanisms of resistance to osimertinib are emerging from limited studies using targeted sequencing platforms. Methods: We performed whole exome (WES) and RNA-sequencing of osimertinib resistant tumors of EGFR-mutant NSCLC pts treated in a prospective clinical trial (NCT02759835). Treatment naïve EGFR mutant pts or pts with T790M-positive NSCLC after EGFR-TKI treatment receive osimertinib. Upon progression, pts with ≤5 progressing sites undergo local ablative therapy (LAT; surgery, radiation, RFA) and resume osimertinib. We analyzed paired pre-treatment and post-progression tumors in 10 patients and post-progression tumors in 3 additional patients and investigated intra- and inter-metastatic tumor heterogeneity using tumors procured from LAT surgeries and autopsies. Results: Acquired, focal copy number amplifications (CNA) of oncogenes occurred in the majority of patients (54%, n = 7/13) whereas acquired osimertinib resistance mutation EGFR C797S was less common (15%, n = 2/13). Early progression on osimertinib ( &lt; 12 months PFS) in treatment naïve pts was associated with acquired, focal CNA. Despite pre-existing EGFR amplification, further amplification of the mutant allele of EGFR was the most common focal CNA (33%, n = 3/9). Other oncogenes amplified in resistant tumors include MET, KRAS, ERBB2 and YES1. CD274 (PD-L1) amplification occurred as the only putative mechanism of resistance in a pt without prior EGFR-TKI treatment. Using RNA-seq, we identified a pt who retained NSCLC histology, but upregulated genes associated with neuroendocrine differentiation upon osimertinib resistance. Clonal evolutionary analysis using WES of prospectively collected sensitive and resistant tumor tissue, including at autopsy is underway. Conclusions: Unbiased WES and transcriptome sequencing revealed heterogeneity, clonal evolution and novel osimertinib resistance mechanisms. Majority of pts had two or more resistance mechanisms suggesting the requirement of combination therapies to overcome resistance. Clinical trial information: NCT02759835.
Darier disease is associated with type 1 diabetes: Findings from a population-based cohort study
Authors: Martin Cederlöf, Philip Curman, Tara Ahanian, Ivone U.S. Leong, Kerstin Brismar, Etty Bachar-Wikstrom, Jakob D. Wikstrom
Journal: Journal of the American Academy of Dermatology (2019)
The consensus Immunoscore adapted to biopsies in patients with locally advanced rectal cancer: Potential clinical significance for a “Watch and Wait” strategy.
Authors: Carine El Sissy, Amos Kirilovsky, Marc Van Den Eynde, Alfredo Romero, Florence Marliot, Christine Lagorce, Frédéric Bibeau, Ilma Soledad Iseas, Enrique Luis Roca, Carlos Alberto Vaccaro, David Tougeron, Carlos Torres Carvalho, Nuno Figueiredo, Rodrigo O Perez, Angelita Habr Gama, Viorel Scripcariu, Jean-Pierre Gerard, Jerome Galon, Guy Zeitoun, Franck Pages
Journal: Journal of Clinical Oncology (2019)

2628 Background: We investigated whether an adaptation to rectal biopsies of the recently validated consensus Immunoscore, could predict the response to neoadjuvant treatment and delineate clinical responders that could benefit from a “Watch and Wait” (W&amp;W) strategy with acceptable outcomes. Methods: Initial biopsies from 273 patients with locally advanced rectal cancer (LARC) treated by neoadjuvant chemoradiotherapy (nCRT) followed by Total Mesorectal Excision (TME), were immunostained for CD3+ and cytotoxic CD8+ T cells and quantified by digital pathology to determine the Immunoscore within pre-treatment Biopsy (IS B ). Expression level of 44 immune related genes post-neoadjuvant treatment was investigated by Nanostring technology (n = 64 patients). Results were correlated with response to neoadjuvant treatment, disease free survival (DFS) and time to recurrence (TTR). Prognostic performance of IS B was finally assessed in 73 LARC treated by W&amp;W strategy. Results: IS B Low, Intermediate and High were respectively observed in 23.3, 50.4 and 26.3 % of the cohort. IS B was positively and significantly correlated with the response to nCRT, as evaluated by Dworak classification (P = .0034), ypTNM (P = .0003), down-staging (P = .0014), and neoadjuvant rectal (NAR) score, (P &lt; .0001). IS B status was also positively associated with the degree of local immune activation post-neoadjuvant treatment. IS B High patients were at low risk of relapse, with 5-year DFS rates of 81.1 % (CI, 71.3-92.1 %) as compared to 57.8 % (CI, 45.9-72.9 %) in IS B low patients. In multivariate analysis, IS B was the only significant parameter at presentation associated with DFS (High vs Low: P = .001). Among W&amp;W patients, significant difference was observed for TTR according to IS B status (High vs Low: P = .025). Conclusions: IS B could provide a reliable estimate of the response to nCRT and risk of recurrence in LARC patients' treated by TME or W&amp;W strategy.