tbuckley/cabot-search huggingface dataset:
Clinical outcomes following androgen receptor axis therapies (ARAT) among men with prostate cancer (PCa) having major cardiovascular diseases (CVDs) or extreme polypharmacy (EPP): A population based study.
Authors: Grace L. Lu-Yao, Ginah Nightingale, Nikita Nikita, Sheel A. Patel, Krupa Gandhi, Benjamin Leiby, Sarah Hegarty, Andrea Marie Barsevick, Norma Padron, Timothy Rebbeck, Andrew E. Chapman, Leonard G. Gomella, William Kevin Kelly
Journal: Journal of Clinical Oncology (2018)

5056 Background: The safety of ARAT (Abiraterone acetate (AA) and Enzalutamide (ENZ)) among men with existing CVDs or EPP (≥10 concurrent medications) is unknown since patients with these conditions are often excluded from the clinical trials. This study was undertaken to fill these knowledge gaps. Methods: This population-based study identified PCa patients from the linked Surveillance, Epidemiology and End Result-Medicare files diagnosed during 1/1/1991-12/31/2013. The primary endpoint was 6-month overall mortality after drug initiation. CVDs include acute myocardial infarction (AMI), atrial fibrillation (AFIB), congestive heart failure (CHF), stroke, and ischemic heart disease (IHD). Cox proportional hazard models were used to assess the risk of 6-month mortality. Results: Our study included 3,116 patients treated with AA only or AA as first ARAT and 1,162 patients treated with ENZ only or ENZ as first ARAT. The characteristics of the patients treated with AA and ENZ were similar. The majority of patients (67%) treated with ARAT had existing CVDs and the prevalence of EPP before drug initiation was high (46% for AA and 44% for ENZ). Six-month mortality was elevated among men with existing CVDs treated with ARAT (Table 1). EPP with ARAT was associated with an increase in 6-month mortality (AA: HR 3.22, 95% CI 2.16-4.81; ENZ: HR 1.63, 95% 1.03-2.58). To our knowledge, this is the largest population-based study to provide outcomes data among patients with existing CVDs or EPP, who were under-represented in the pivotal trials. The elevated 6-month mortality of men with CVDs or EPP treated with ARAT suggested that these patients represent a vulnerable patient population. Further studies are needed to determine the clinical benefits and risks of ARAT in men with advanced PCa and existing CVDs or EPP. Hazard ratios for 6-month mortality among men with cvds conclusions. AMI/no CVD CHF/no CVD AFIB/no CVD Stroke/no CVD IHD/no CVD AA 1.89 (1.27-2.80) 1.54 (1.20-1.97) 1.61 (1.22-2.12) 1.61 (1.18-2.20) 1.14 (1.13-1.77) ENZ 1.46 (0.73-2.92) 1.20 (0.79-1.81) 1.80 (1.14-2.82) 1.50 (0.90-2.50) 1.40 (0.99-1.99)
Defective homologous recombination in platinum based chemotherapy for gastric cancer.
Authors: Hiroshi Ichikawa, Masayuki Nagahashi, Yoshifumi Shimada, Takaaki Hanyu, Takashi Ishikawa, Yusuke Muneoka, Yosuke Kano, Tomohiro Katada, Kohei Miura, Yuki Hirose, Kizuki Yuza, Junko Tsuchida, Jun Sakata, Takashi Kobayashi, Hitoshi Kameyama, Hiroshi Yabusaki, Satoru Nakagawa, Shujiro Okuda, Kazuaki Takabe, Toshifumi Wakai
Journal: Journal of Clinical Oncology (2018)

e16068 Background: Defective homologous recombination (HR) due to genetic aberrations of HR genes contributes to a high response of platinum therapy in ovarian and breast cancers. The aim of this study is to clarify the clinical significance of defective HR in platinum based chemotherapy for gastric cancer (GC). Methods: A total of 26 patients (21 men and 5 women, with a median age of 66 years) who underwent platinum based chemotherapy for unresectable metastatic GC were enrolled in this retrospective study. Metastatic sites after gastrectomy were lymph node in 9 (35%), liver in 9 (33%), peritoneum in 8 (30%), others in 2 (7%) patients. Genetic aberrations of HR genes (BRCA1, BRCA2, RAD50, RAD51C, RAD51D, PALB2 and FANCD2) in the primary tumor were assessed by cancer gene-panel. We evaluated the association between defective HR and treatment response (RECIST ver. 1.1), progression free survival (PFS) and overall survival (OS). Results: BRCA1, BRCA2, RAD50, PALB2, and FANCD2 mutations were shown in 3 (11%), 1 (4%), 1 (4%), 1 (4%) and 1 patient (4%), respectively. Overall, 5 patients (19%) had genetic aberrations of HR genes (defective HR group). Objective response rate (complete or partial response) was 50% in the defective HR group and 25% in the proficient HR group (P = 0.55). Disease control rate (complete or partial response or stable disease) was 100% in the defective HR group and 50% in the proficient HR group (P = 0.12). Median PFS was 10 months (95% CI, 3.76–16.24) in the defective HR group and 3 months (1.73–4.27) in the proficient HR group (P = 0.042). Median OS was 17 months (15.04–18.96) in the defective HR group and 8 months (3.88–12.13) in the proficient HR group (P = 0.058). Conclusions: Genetic aberration ofHR genes was significantly associated with a high response of platinum based chemotherapy and favorable patient outcome in unresectable metastatic GC. Clinical utility of the assessment of defective HR as a predictive or prognostic indicator for unresectable metastatic GC is worth considering further large-scale studies.
Selective histone deacetylase inhibition augments melanoma immunotherapy.
Authors: Andressa Sodre Laino, David Michael Woods, Amod Sarnaik, Steven Quayle3, Simon S. Jones3, Eduardo M. Sotomayor, Jeffrey S. Weber
Journal: Journal of Clinical Oncology (2016)

e14521 Background: Histone deacetylases (HDACs) are epigenetic modulators and regulate gene expression. The impact of the HDAC6 selective inhibitor ACY1215 was explored on immune cell biology, with novel implications for the treatment of melanoma patient T cells ex vivo prior to adoptive transfer. Methods: T cells were obtained from peripheral blood mononuclear cells of healthy donors and melanoma patients. Tumor infiltrating lymphocytes (TILs) were isolated from surgical biopsies. Cells were treated ex vivo with ACY1215 or DMSO control. Viability was addressed by MTS colorimetric assay. Cytokine levels were evaluated by Luminex. Expression of T cell markers and IFNγ/CD107a production were assessed by flow cytometry. T cell cytotoxicity was determined by co-culture of TILs and melanoma and analysis of annexin V and propidium iodide. Affymetrix based microarray was performed on TILs for gene expression analysis. Statistical significance of DMSO vs ACY1215 treated T cells was based on paired, two-tailed, student’s t-test. Results: ACY1215 was unique among pan and selective HDAC inhibitors in modulating T cell function, with minimal impact on viability. Treatment of melanoma patient-derived T cells reduced Th2 cytokine production (IL-4, IL-6, IL-10; p < 0.01) and maintained Th1 effector cytokine levels (IFNγ, IL-2). ACY1215 increased expression of the activation/costimulatory markers CD69 and ICOS (p < 0.05), and enhanced a central memory phenotype expressed by healthy and melanoma patient CD4 and CD8 T cells during ex vivo expansion (p < 0.05), as determined by expression of CD45RO, CD45RA, CD62L and CCR7. In fact, ACY1215 increased central memory TILs derived from multiple cell preparations (e.g. pre and post rapid in vitro expansion; p < 0.05). ACY1215 treated TILs exhibited higher levels of IFNγ/CD107a expressing CD8 T cells (50% vs 35%, p < 0.05), and enhanced cytotoxicity (50% vs 70% killing of HLA matched targets with DMSO vs ACY1215 treated TILs). Microarray analysis revealed increased expression of genes associated with an inflammatory response and T cell memory in ACY1215 treated TILs. Conclusions: ACY1215 augmented T cell proliferation and function during ex vivo expansion, with possible translatable clinical implications.
Trial design of a first-in-human phase 1 evaluation of SY-1365, a first-in-class selective CDK7 inhibitor, with initial expansions in ovarian and breast cancer.
Authors: Geoffrey Shapiro, Kyriakos P. Papadopoulos, Khanh T Do, Dejan Juric, Rinath Jeseslsohn, Panagiotis A. Konstantinopoulos, Ursula A. Matulonis, Graeme Hodgson, Emmanuelle DiTomaso, Kristin Stephens, David A. Roth, Anthony W. Tolcher
Journal: Journal of Clinical Oncology (2018)

TPS2600 Background: SY-1365 is a selective and potent covalent CDK7 inhibitor. CDK7 activity has been implicated in various solid tumors with transcriptional dependencies. Recent preclinical studies have shown robust antitumor activity of SY-1365 in ovarian and breast cancer. In ovarian cancer, SY-1365 induced apoptosis in vitro and complete regressions in PDX models derived from heavily pre-treated patients (pts). In breast cancer, SY-1365 induced cell death in vitro across subtypes and displayed synergy when combined with fulvestrant in HR-positive models. These observations led to a change in the design of the expansion phase of this first-in-human study of SY-1365 to include a new focus on these tumors. The primary objectives of this study are to assess the safety and tolerability of SY-1365, and to determine dose-limiting toxicities, the MTD and the recommended Phase 2 dose. Secondary objectives include evaluation of pharmacokinetics and pharmacodynamic (PD) effects of SY-1365 in tumor and surrogate tissues, and assessment of preliminary antitumor activity. Methods: This is a multi-center, open-label Phase 1 trial expected to enroll approximately 117 pts. The dose escalation phase of the trial is open to solid tumor pts for whom standard curative or palliative measures do not exist or are no longer effective. SY-1365 is administered intravenously in two dose schedules, weekly and twice weekly for 3 weeks of each 4-week cycle. The expansion phase will evaluate preliminary antitumor activity in 3 ovarian cancer cohorts, either as a single agent or in combination with carboplatin, an HR+ breast cancer cohort in combination with fulvestrant in pts who failed treatment with a CDK4/6 inhibitor in combination with an AI, and a cohort in pts with tumors of any histology to evaluate PD endpoints in paired tumor biopsies. SY-1365 target engagement in PBMCs and available tumor biopsies will be assessed by measuring CDK7 occupancy over the course of treatment. Biological impact of SY-1365 will be assessed by quantifying gene expression and induction of tumor cell apoptosis when feasible. This trial opened in May 2017. Clinical trial information: NCT03134638.
Carcinosarcoma: A single centre experience and population based study.
Authors: Gaurav Bhattacharya, Ghufran Abdulghaffar Aljawi, Andrew Bang, Samy El Sayed
Journal: Journal of Clinical Oncology (2017)

e22526 Background: Carcinosarcomas, consisting of biphasic morphological patterns including both epithelial and sarcomatoid components, are rare malignant tumours. We highlight the incidence and outcomes of this unique disease at our large cancer referral centre. Methods: A retrospective review consisting of carcinosarcoma patients over a 10 years span from 1/1/2005 to 1/1/2015 with follow up data through to 2/2017 to ensure at least 2 years of post-treatment data collection by purveying Electronic Medical Records, paper charts and where required, communication with peripheral facilities, was conducted. Inclusion and exclusion criteria were histologic confirmation and age &lt; 18 years respectively. A comprehensive literature review was also conducted to identify current outcomes trends. Results: Seventy patients meeting selection criteria were identified out of a total of 968 entries involving all soft tissue tumors. Incidence was mainly of gynecological origin (88.5%), in female patients (92.9%) and chiefly Grade 3 disease. Commonest presenting symptom was vaginal bleeding (54.3%). A majority received surgery (90.0%) primarily with a curative intent. 54.3% of the patients received chemotherapy and 51.4% received radiation; both largely in an adjuvant setting. Commonest treatment regimen was Carboplatin/Paclitaxel (73.7%) with a median of 6 cycles provided. Overall, 11 patients had a component of local failure with the latest failure recorded at 13.3 months. Conclusions: Treatment outcomes for carcinosarcoma over the years remain comparable to published results although there remains room for improvement. More research is required to identify strategies for improvement in both locoregional and systemic control. [Table: see text]
Carfilzomib and dexamethasone (Kd56) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (RRMM): Updated overall survival (OS), safety, and subgroup analysis of ENDEAVOR.
Authors: Robert Z. Orlowski, Philippe Moreau, Heinz Ludwig, Albert Oriol Rocafiguera, Wee Joo Chng, Hartmut Goldschmidt, Zhao Yang, Amy Kimball, Meletios A. Dimopoulos
Journal: Journal of Clinical Oncology (2018)

8032 Background: The phase 3 ENDEAVOR trial demonstrated significantly improved PFS and OS with Kd56 vs Vd in RRMM patients (pts; Dimopoulos Lancet Oncol 2016 and 2017). We report updated data after additional follow-up. Methods: Hazard ratios (HRs) and 95% CIs were estimated using stratified or unstratified Cox proportional hazards models for primary and subgroup OS analyses, respectively. Results: 929 pts were randomized (Kd56, n = 464; Vd, n = 465). As of 19-Jul-17, median OS was 47.8 (Kd56) vs 38.8 (Vd) months (mos; HR, 0.76 [95% CI, 0.633–0.915]; median follow-up, 44.3 vs 43.7 mos). OS was longer with Kd56 vs Vd within age subgroups ( < 65 years [yrs]: median, 47.8 vs 42.2 mos; HR, 0.79 [95% CI, 0.598–1.031]; 65–74 yrs: median, 49.0 vs 36.2 mos; HR, 0.71 [95% CI, 0.520–0.958]; ≥75 yrs: median, 36.1 vs 23.9 mos; HR, 0.78 [95% CI, 0.506–1.199]). OS was longer with Kd56 vs Vd by prior lines of therapy (1 line: median, 51.3 vs 43.7 mos; HR, 0.77 [95% CI, 0.583–1.018]; 2–3 lines: median, 39.5 vs 28.4 mos; HR, 0.75 [95% CI, 0.589–0.959]) and prior bortezomib (btz) exposure (prior btz: median, 41.8 vs 32.7 mos; HR, 0.85 [95% CI, 0.669–1.082; no prior btz: median, not estimable [NE] vs 42.2 mos; HR, 0.66 [95% CI, 0.496–0.875]). OS was longer with Kd56 vs Vd for high-risk (median, 28.0 vs 22.7 mos; HR, 0.81 [95% CI, 0.580–1.136]) and standard-risk (median, NE vs 43.5 mos; HR, 0.79 [95% CI, 0.618–1.009]) cytogenetics pts. 457 (98.7%, Kd56) and 451 (98.9%, Vd) pts had an adverse event (AE); 379 (81.9%, Kd56) and 324 (71.1%, Vd) had a grade ≥3 AE. Exposure-adjusted pt incidences per 100 pt-yrs (95% CI) of AEs were 1352.07 (1233.62–1481.89) for Kd56 and 1754.86 (1600.15–1924.53) for Vd; for grade ≥3 AEs, these values were 162.31 (146.77–179.50) and 175.90 (157.75–196.13). The most common AEs in the Kd arm (≥ 30% of subjects) were anemia (43.6%), diarrhea (36.7%), pyrexia (32.6%), hypertension (32.4%), fatigue (32.2%) and dyspnea (32.2%). Conclusions: With median follow-up of ~44 mos, clinically meaningful OS improvements were observed with Kd56 vs Vd, including in all subgroups examined. The Kd56 safety profile was consistent with previous analyses. Clinical trial information: NCT01568866.
Effects of sonidegib dose reduction or delay in locally advanced basal cell carcinoma: 42-month data from BOLT.
Authors: Karl D. Lewis, Michael Robert Migden
Journal: Journal of Clinical Oncology (2018)

9573 Background: Sonidegib is a hedgehog pathway inhibitor (HPI) approved for the treatment of locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy. Patients treated with sonidegib may require dose reductions and/or interruptions to manage adverse events, and the impact of these adjustments on the long-term efficacy is unknown. Methods: BOLT was a randomized, double-blind, multicenter phase 2 study (NCT01327053). Patients with advanced BCC not amenable to curative surgery/radiotherapy and naive to HPI treatment were randomized 1:2 to sonidegib 200 mg or 800 mg QD, respectively. Data were analyzed at 6, 12, 18, 30, and 42 months. Patients receiving 800 mg were allowed two dose reductions (to 400 mg and 200 mg QD, respectively) for an adverse event (AE) related to sonidegib; among patients in the 200-mg arm, a delay was instituted until the AE resolved to ≤ grade 1. The primary endpoint was objective response rate (ORR) per central review; ORR by investigator review was analyzed as a secondary endpoint. We compared ORR in laBCC patients with (≥1) and without dose reduction/delay at the 42-month follow-up. Results: ORRs remained consistent with prior follow-up analyses. The frequency of dose reduction/delay was lower in the 200 mg (18%) vs. 800 mg (38%) arm (Table). Importantly, dose reduction/delay did not compromise efficacy. ORRs by investigator assessment were consistently higher than by central review. Conclusions: These data support long-term efficacy of sonidegib at the approved dose of 200 mg daily, and also suggest that dose reductions and/or treatment delays are possible without negatively impacting efficacy. Clinical trial information: NCT01327053.ORR in sonidegib-treated patients by dose reduction/delay (central and investigator review). ORR, % (95% CI) 200 mg QD 800 mg QD Central Investigator Central Investigator All patients n = 66 n = 128 56 (43, 68) 71 (59, 82) 46 (37, 55) 59 (50, 67) No dose reduction or delay n = 54 n = 80 57 (43, 71) 67 (53, 79) 34 (24, 45) 53 (41, 64) ≥1 dose reduction or delay n = 12 n = 48 50 (21, 79) 92 (62, 100) 67 (52, 80) 69 (54, 81)
Circulating tumor DNA as biomarker in mutant malignant melanoma.
Authors: Jan Braune, Dagmar von Bubnoff, Marie Follo, Ulrike Philipp, Erika Graf, Dietmar Pfeifer, Justus Duyster, Frank Meiss, Nikolas Von Bubnoff
Journal: Journal of Clinical Oncology (2018)

12042 Background: Available biomarkers LDH and S100B possess limited sensitivity and specificity to predict outcome in melanoma. In this pilot study we evaluated the use of circulating tumor (ct)DNA harboring BRAF and NRAS mutations as a predictive biomarker for treatment response and progression-free survival (PFS) in patients with locally advanced or metastatic melanoma. Methods: We analyzed 168 retrospective plasma samples from 40 unselected pts, and 311 samples from 33 pts included in a prospective trial (DRKS00009507). We included stage III disease with planned resection or stage IV disease before initiation or change of medical treatment. Blood samples were taken at baseline at d +8, d +28, and thereafter at 3 months intervals for up to two years. We developed hydrolysis probe based, Locked Nucleic Acid assays to detect BRAF, NRAS and wild type ctDNA by droplet digital PCR. Results were correlated with LDH, S100B and PFS. Results: Sensitivity of the specific assays was 0.01% with a limit of Blank of 0.28 copies/well. Of 37 stage IV pts with retrospective samples, 29 were positive for ctDNA at least once (78%). Out of eight negative pts, three were in CR, three had SD, and two were negative despite measurable disease. Positive pts had a mean of 9 (range: 1-17) and 283 (range: 0.1-16,388) ctDNA copies/mL for stage III and stage IV respectively. The presence of ctDNA one month after therapy initiation indicated poor PFS (hazard ratio [HR] 1.9, 95% CI 0.85-4.44). No measureable increase in ctDNA was a favorable prognostic factor for PFS for all therapies (hazard ratio [HR] 0.30, 95% CI 0.05-2.56) with a median PFS of 4.5 vs. 3.1 months (range 0.9-17.5 vs. 1.5-9.1) and particularly for those receiving Immunotherapy (hazard ratio [HR] 0.07, 95%CI 0.007-0.68) with a median PFS of 8.8 vs. 2.6 (range 1.8-17.5 vs 1.5-3.1). Based on 290 measurement pairs, ctDNA strongly correlated with S100 (r = 0.73) and LDH (r = 0.52). Conclusions: Residual ctDNA early after change or institution of treatment predicted tumor progression at first clinical response assessment. A positive to negative conversion or a decrease indicated a more favorable course especially for those receiving immunotherapy. These data support the use of ctDNA as an early predictive marker for treatment response. Clinical trial information: DRKS00009507.
Retrospective review of FOLFIRINOX in local advanced pancreatic cancer: Single institution experience.
Authors: Ashish Manne, Sushanth Reddy, Martin Heslin, Rojymon Jacob, Selwyn M. Vickers, Carlo M. Contreras, Anup Kasi, John Christein, Peng Li, James Posey, Ravi Kumar Paluri
Journal: Journal of Clinical Oncology (2017)

e15714 Background: Although combination of fluorouracil, irinotecan, Leucovorin and oxaliplatin [FOLFIRINOX] significantly increases survival in metastatic pancreatic cancer (MPC) compared to gemcitabine based on ACCORD trial, the efficacy and toxicities may be different in non-metastatic setting. We reviewed our institution’s experience with FOLFIRINOX in locally advanced pancreatic cancer (LAPC). Methods: We performed a retrospective review of clinical outcomes in patients diagnosed with LAPC and receiving between June 2010 and July 2015, with at least one year of follow up from diagnosis, at University of Alabama at Birmingham. Results: Total of 41 patients with ECOG performance scale of 0 or 1, who underwent neoadjuvant chemotherapy with FOLFIRINOX were assessed for clinical and pathological characteristics. Median age was 61 years (range 38-81) with 23 (56.1%) males, 28 (68.3%) Caucasians and 16 (39.0%) underwent surgery (whipple operation) post-neoadjuvant. Median OS (time of diagnosis to last follow up/death) is 83.5 months for whole cohort, survival rates are 94.9% at 1 year, 58.4% at 2 year, and 33.3% at 5 year.Median OS for those who underwent surgical resection following the chemotherapy is 38.6 months; 100% at one year, 85.1% at 2 year, 55.3% at 5 year; while median OS for those who did not undergo surgery is 21.8 months; 91.7% at one year, 41.5% at 2 year, 20.7% at 5 years. Among those who underwent surgery, the median recurrence free survival (time from surgery to relapse/progression) is 19.9 months with liver being common recurrence site (81%). There was no post-operative mortality in 30 days. Grade 3-4 toxicity occurred in 46% ( vomiting (12%), fatigue (28%) and neutropenia (54%), febrile neutropenia (9%)). There is a significant difference between surgery and non-surgery groups (p = 0.012) for improved OS by log-rank test. Conclusions: Neoadjuvant FOLFIRINOX treatment associated with high response rates leading to surgical resection in our cohort. Patients who underwent neoadjuvant chemotherapy followed by resection for LAPC have statistically significant improved OS compared to those who did not.