tbuckley/cabot-search huggingface dataset:
Association between participation in religious activities and depression and anxiety in older patients with cancer.
Authors: Yu Cao, Daneng Li, Kemeberly Charles, Enrique Soto Perez De Celis, Can-Lan Sun, Leana Chien, Elsa Roberts, Daisy Rivera, Jeanine Moreno, William Dale, Marianna Koczywas, Vincent M. Chung, Marwan Fakih, Joseph Chao, Mihaela C. Cristea, Dean Lim, Sumanta K. Pal, Vani Katheria, Heidi Tan, Arti Hurria
Journal: Journal of Clinical Oncology (2018)

10044 Background: Older patients (pts) with cancer are at risk for depression and anxiety, which are often under-recognized. Participation in religious activities has been associated with better mental health in pts with cancer; however, data are conflicting and few studies focus on older pts. This study explores associations between participation in religious activities and depression and anxiety in older pts with cancer. Methods: This is a secondary analysis of a prospective study of pts age ≥ 65 with cancer. Prior to starting a new line of chemotherapy, pts self-reported if they felt depressed (yes/no on a 1-Question Yale Depression Screen) or anxious (score ≥ 6 on a 0-10 Likert Scale). Participation in public (e.g. church) and private (e.g. prayer) religious activities was measured via the Duke University Religion Index. High (≥ weekly public AND ≥ daily private), middle (≥ weekly public OR ≥ daily private), and low ( < weekly public AND < daily private) religious participation groups were defined. Univariate and multivariate logistic regression analyses were conducted evaluating associations between participation in religious activities and depression and anxiety. Results: Of 458 pts (mean age 72 [range 65-91]; 57% female, 55% non-Hispanic white), with 31% GI, 19% breast, and 18% GU cancers, the majority (75%) had stage IV disease. Twenty-four percent (N = 110) reported anxiety, and 21% (N = 97) depression. Thirty-five percent (N = 161) reported ≥ weekly public, and 45% (N = 208) ≥ daily private religious activity. Both groups tended to report less anxiety (OR 0.66, p = 0.08; OR 0.68, p = 0.08, respectively); neither group was less likely to report depression (OR 0.79, p = 0.33; OR 1.05, p = 0.83, respectively). Combined, the high religious participation group (27.5%; N = 126) reported less anxiety on univariate (OR 0.59, 95% CI 0.35-0.99, p = 0.04) and multivariate (OR 0.51, 95% CI 0.28-0.92, p = 0.03) analyses, adjusting for age, gender, race, education, number of comorbidities, physical function, and social support, but not less depression (p = 0.46). Conclusions: Among older pts with cancer, participation in both public and private religious activities is associated with less anxiety, but not less depression.
Real-world treatment patterns among newly diagnosed myelofibrosis patients.
Authors: Yoojung Yang, Mei Lu, Ellen Hooper, Joseph Feliciano, Abdalla Aly, Ruben A. Mesa
Journal: Journal of Clinical Oncology (2016)

e18556 Background: Pharmacologic and medical management of myelofibrosis (MF) in the real world is not well characterized. This retrospective study examined current MF treatment patterns in the United States. Methods: Adults ( ≥ 18 years) newly diagnosed with MF (ICD-9-CM: 289.83, 238.76) and continuously enrolled in a health plan for ≥ 6 months pre- and post-first MF diagnosis date were identified from the Truven Commercial Claims and Encounters and Medicare Supplemental Databases (01/2011 – 12/2014). Pharmacologic lines of therapy (hydroxyurea, ruxolitinib, erythropoietin stimulating agents [ESAs], steroids, etc) and medical procedures (stem cell transplant, splenectomy, spleen irradiation, and supportive care [RBC transfusion, platelet transfusion, and iron chelation therapy]) were examined from diagnosis to end of follow-up. The Kaplan Meier method was used to estimate time to initiation or discontinuation of therapy (defined as interruption of ≥ 90 consecutive days). Results: Among 1,658 newly diagnosed MF patients (median age: 66 years, 50% male, and 70% primary MF), 47% did not receive any pharmacologic or medical intervention during follow-up (median: 15 months, range: 6-38). Forty percent initiated 1st line (1L) therapy by 12 months after diagnosis. Among those receiving pharmacologic therapy (n = 693), 73.3%, 15.4 %, and 11.3% received 1, 2, and ≥ 3 lines of therapy, respectively. Hydroxyurea (34%) was the most common 1L therapy, followed by ruxolitinib (21%), ESAs (16%), and steroids (14%). Twenty-seven percent (n = 185) on 1L therapy progressed to 2L therapy, of which 42% (n = 38) progressed to 3L. Median time to discontinuation was shorter with advancing therapy lines (6.0, 4.4, and 2.9 months in 1L, 2L, and 3L, respectively). RBC transfusion was the most common supportive care with increasing prevalence in later lines of therapy (no therapy: 13%, 1L: 25%, 2L: 32% and 3L: 35%). Conclusions: This study revealed real-world heterogeneity of MF treatment patterns with limited pharmacologic options and high discontinuation rates in advanced lines of therapy. These findings suggest the unmet medical need for more safe and effective MF treatment options and a need for treatment guidelines to optimize individualized MF management.
Phase I/II study to evaluate the safety and efficacy of tenalisib, a novel PI3K δ/γ dual inhibitor in combination with pembrolizumab in patients with relapsed/refractory classical Hodgkin lymphoma.
Authors: Rod Ramchandren, Ryan C Lynch, Prajak J. Barde, Ajit Nair
Journal: Journal of Clinical Oncology (2018)

TPS7584 Background: Despite impressive activity of PD-1/PD-L1 therapy in HL, proportions of patients do not respond and eventually progress. Growing evidence suggests that high infiltrations of immune-suppressive myeloid cells are responsible for anti-PD-1/PD-L1 therapy resistance. These observations suggest a need for an immunotherapeutic combination to overcome such resistance mechanisms. PI3K δ/γ isoforms are known to play a role in modulating the tumor microenvironment. Tenalisib demonstrated marked reduction of Tumor Associated Macrophages (TAMs) and angiogenesis and showed synergy with checkpoint inhibition in syngeneic mouse models. Tenalisib has demonstrated single agent activity in relapsed refractory heavily pre-treated cHL (ORR 29% CR 7% PR 21%). The proposed study hypothesizes that Tenalisib in combination with Pembrolizumab improve the depth and durability of responses to anti-PD1 therapy. Methods: The primary objective of this phase I/II, open label, 3+3 dose-escalation study is to evaluate the safety, tolerability, and identify the maximum tolerated dose of tenalisib in combination with Pembrolizumab in relapsed/refractory cHL. Patients will be enrolled in two escalating cohorts (Tenalisib 400/ 800 mg BID and Pembrolizumab 200 mg, IV) to determine MTD/ optimal dose. In Expansion part, two groups will be initiated. The first expansion group will enroll 18 patients who are naïve to anti-PD-1 therapy to explore the additive/synergistic effect of the combination by measuring efficacy parameters (ORR, DoR, PFS). The second group will enroll 27 patients who have received treatment with pembrolizumab for at least 6 months and have not demonstrated a complete response. The objective is to understand whether combination therapy will overcome PD-1 resistance by augmenting conversion rates (i.e., improvement from progressive disease to CR or from SD to PR) upon combination. Disease response assessments will be determined per the Lugano classification (Cheson 2014). Eligible subjects will receive Tenalisib BID orally and Pembrolizumab 200 mg, IV every three weeks in a 21-day cycle.
Clinical utilization of precision oncology decision support for genomically-informed cancer therapy.
Authors: Amber Johnson, Yekaterina Khotskaya, Lauren Brusco, Jia Zeng, Vijaykumar Holla, Ann Marie Bailey, Beate Litzenburger, Nora Sanchez, Md Abu Shufean, Sarina Anne Piha-Paul, Vivek Subbiah, David S. Hong, Aung Naing, Mark Routbort, Kenna Rael Shaw, Gordon B. Mills, John Mendelsohn, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2016)

11605 Background: Precision oncology is hindered by the lack of decision support for determining whether patients’ genomic alterations are actionable. To bridge this knowledge gap, we established a Precision Oncology Decision Support (PODS) team that provides functional and therapeutic alteration-level annotations to providers at a major cancer center. Methods: Genomic alterations were annotated to determine actionability based on variant’s known or potential functional and/or therapeutic significance, as described (PMID:26148707). A web-based survey was implemented to capture clinical decisions made post-delivery of annotations provided for clinician-initiated requests, and results were manually validated. Results: From 2013-2015, the PODS team processed 1,669 requests for 4,084 alterations (2,260 unique) in 363 genes, detected in 47 tumor types, reported across 21 assays for 1,197 patients. 43% of requests were initiated by 56 patient care or clinical trial teams, and 54% were PODS-initiated for genomic testing programs. Annotations delivered evolved to include categorization based on actionability, and an actionable variant call was provided for 2,883 annotations: 35% were actionable, 11% potentially actionable, 31% unknown, and 23% not actionable. In 2015, clinical decision surveys were sent to requesting physicians for 314 patients, and 278 surveys were returned (response rate 88.6%). 71 patients (26%) enrolled on a genotype-matched trial, representing 20 trials matched to alterations in 27 genes. Trial enrollment varied by variant actionability (P = 0.002): 37% of patients with actionable, 30% with potentially actionable, 14% with unknown, and 5% with non-actionable variants were enrolled on genotype-matched trials. Conclusions: The demand for genomic testing interpretation has increased. The utility for a robust decision support approach, such as offered by PODS, is exhibited by a greater percentage of patients with actionable or potentially actionable alterations enrolled on genotype-matched clinical trials than those with unknown/non-actionable variants.
Non-invasive detection of crizotinib resistance in ALK-rearranged lung adenocarcinoma directs treatment with next-generation ALK inhibitors.
Authors: Nnamdi Ihuegbu, Kimberly C. Banks, Stephen R Fairclough, Oliver A. Zill, Darya Chudova, Richard Burnham Lanman, Collin M. Blakely
Journal: Journal of Clinical Oncology (2016)

e20643 Background: Somatic mutations (SNVs) in ALK are a common mechanism of resistance to crizotinib, and may respond to next-generation ALK inhibitors. Historically, identification of these ALK SNVs required repeat tissue biopsies because they are absent in pre-treated tissue samples. Circulating tumor DNA (ctDNA) next-generation sequencing (NGS) may provide a non-invasive way to identify these SNVs. Methods: Guardant360 is a ctDNA NGS test that sequences complete exons in the ALK gene and the intronic breakpoints needed to identify ALK fusions. It includes other guideline-recommended somatic genomic targets: SNVs in 70 genes, select fusions, indels and amplifications. Results: In the first 10,000 advanced-solid-cancer patients (pts) tested by Guardant360, ALK SNVs and fusions were detected in 6% of pts. EML4 was the most common ALK fusion partner (81%); STRN (9%), KIF5B (5%), VCL (2.5%), KCL (2.5%). Among 24 pts with ALK-fusion-driven lung adenocarcinoma (LUAD), mutant allele fraction (MAF) of ALK fusion ranged from 0.06% to 12.5%. We found several co-occurring SNVs, of which 10% were known resistance SNVs in ALK (detected in 4 pts): F1174C/V (3), G1202R (2), L1198F (1), I1171T (1), and L1196M (1). We also found co-occurring SNVs in other genes that are absent in treatment-naïve pts, suggesting possible novel crizotinib-resistance mechanisms. ALK L1198F, a rare alteration shown to re-sensitize to crizotinib, was detected in a patient who expired before re-treatment. In a case with serial draws, pre-treated ALK fusion MAF was 0.91%; at progression, ALK fusion MAF was 0.4% and F1174C was detected at 1.0%. Tissue results from both time points were concordant with ctDNA. The patient started alectinib in January 2016, and response scans are pending. Conclusions: We comprehensively cataloged mutations that likely arose at progression in ALK-fusion-positive LUAD pts treated with crizotinib, including five well-described crizotinib-resistance alterations. These results add to the growing body of literature demonstrating that comprehensive ctDNA assays provide a non-invasive means of detecting known and novel resistance mechanisms that inform treatment decisions.
Apatinib plus radiotherapy or not in chemotherapy-refractory recurrent or metastatic oral squamous cell carcinoma: A pilot study.
Authors: Hui Wu, Xiaoxu Lu, Jing Xu, Xueming Sun, Shujuan Wang, Wei Du, ShanTing Liu, DingJie Li
Journal: Journal of Clinical Oncology (2018)

e18101 Background: For patients (pts) with recurrent/metastatic oral squamous cell carcinoma (OSCC), treatment options are still unmet medical need. Apatinib, a new tyrosine kinase inhibitor targeting VEGFR-2, shows antitumor activity and manageable toxicities in multiple malignancies. This study aimed to explore apatinib alone or in combination with radiotherapy (RT) as second-line or beyond therapy in OSCC. Methods: Chemotherapy-refractory OSCC pts were recruited in this open-label exploratory study. Subjects were initially given 500 mg qd apatinib until disease progression or unacceptable toxicity. Dose reduction to 250 mg was allowed. Palliative local RT (GTV: 50-60 Gy/25-30 f; CTV: 40-50 Gy, 5 f/w) was given to Stage IVB pts who could tolerate concurrent RT. Herein, we reported the preliminary results at the cut-off date of Jan 10, 2018. Results: Ten pts were treated between Jun 2017 and Nov 2017. The median age was 70 yrs; 30.0% were male; ECOG PS 0-1/2 was 70.0/30.0%; 40.0% had ≥ 2 lines of chemotherapy. All pts were evaluated for radiographic response and safety analyses. One (10.0%) pt had complete response (CR), 5 (50.0%) had partial response (PR), 2 (20.0%) had stable disease and 2 (20.0%) had progressive disease. The ORR was 60.0% and DCR was 80.0%. Among the 5 pts who received apatinib combined with RT, 1 CR and 4 PR were achieved. Seven (70%) pts experienced treatment related adverse events (TRAEs). Most TRAEs were in grade 1/2 and could be well-controlled by symptomatic treatments. The grade 3/4 AEs were hypertension (4/10, 40%), fistula (1/10, 10%), hand-foot skin reaction (1/10, 10%) and heart failure (1/10, 10%). The cases experienced fistula and heart failure were combination therapy treated pts. Fortunately, the symptoms were alleviated by administration interruption and symptomatic therapy. No treatment-related death occurred. Conclusions: Apatinib alone or plus RT is efficacious in pretreated OSCC pts, with acceptable toxic effects. Pts might benefit more from the combination therapy, but with high risk of fistula that should be cautiously managed. This study gives rationale clinical evidence to conduct further larger confirmatory clinical trials. Clinical trial information: wuhui7008@126.com.
Mutation burden as a potential prognostic marker of melanoma progression and survival.
Authors: Danny Simpson, Robert Ferguson, Carlos N. Martinez, Esther Kazlow, Una Moran, Adriana Heguy, Douglas Hanniford, Eva Hernando, Iman Osman, Tomas Kirchhoff
Journal: Journal of Clinical Oncology (2017)

9567 Background: Recently, tumor mutation burden (TMB) has been shown to increase the presentation of neoantigens that stimulate immune tumor recognition, resulting in improved immunotherapy (IT) outcomes in melanoma and other cancers. As melanoma is highly immunogenic, here we tested whether TMB associates with immune recognition during tumor progression, hence impacting melanoma overall survival (OS), independently of IT treatment. Methods: We have generated somatic mutation data from 314 IT-naive metastatic melanomas from The Cancer Genome Atlas (TCGA). In the TCGA cohort, TMB has been calculated for 210 genes (200GS) previously established from TMB studies of anti-CTLA4 and anti-PD1/PD-L1 IT. For validation, we have sequenced exonic regions of 20 genes (20GS) with the highest TMB among 200GS in 89 IT-naive metastatic melanomas ascertained at New York University Langone Medical Center. The TMB was defined using total number of somatic, non-synonymous mutations in either 200GS (TCGA discovery) or 20GS (validation), respectively. For discovery and validation cohorts, OS from primary diagnosis of samples with high TMB was compared against low TMB, using thresholds established in previous studies. Results: We found that total TMB predicts better OS (p = 0.03, HR = 2.64) in TCGA melanomas. Restricting the analysis only to the established 200GS, this association became more significant in all patients (p = 0.01, HR = 2.67) as well as in patients without IT (p = 0.01, HR = 2.67). In the validation stage of 89 melanomas without prior IT treatment, a high TMB in a subset of 20GS accurately determined favorable OS (p = 0.02, HR = 2.69) and confirmed TCGA observations from the 200GS. Conclusions: Here we show, for the first time, that in addition to IT, high TMB predicts more favorable OS in patients that never received IT, potentially serving as a novel marker of prognosis of melanoma and likely other immunogenic tumors at early stages. In addition, our study suggests that TMB test can be robust when applied to only a small subset of genes that trigger significantly higher immunogenicity. This may also eventually assist with accurate sub-selection of early stage patients likely to respond to IT regimens.
Effects of ALK1Fc treatment on prostate cancer cells interacting with bone and bone cells in bone metastasis models.
Authors: Marianna Kruithof-de Julio, Letizia Astrologo, Eugenio Zoni, Sofia Karkampouna, Peter C Gray, Irena Klima, Joel Grosjean, Marie Jose Goumans, Lukas J.A.C. Hawinkels, Gabri Van der Pluijm, Peter ten Dijke, Martin Spahn, George N. Thalmann
Journal: Journal of Clinical Oncology (2017)

e16576 Background: Prostate cancer is the second most common cancer in men worldwide. Lethality is normally associated with the consequences of metastasis rather than the primary tumor. In particular, bone is the most frequent site of metastasis and once prostate tumor cells are engrafted in the skeleton, curative therapy is no longer possible. Bone morphogenetic proteins (BMPs) play a critical role in bone physiology and pathology. However, little is known about the role of BMP9 and its signaling receptors, ALK1 and ALK2, in prostate cancer and bone metastasis. In this context, we investigate the impact of BMP9 on primary prostate cancer and derived bone metastasis. Methods: The human ALK1 extracellular domain (ECD) binds BMP9 and BMP10 with high affinity. In order to study the effect of BMP9 in vitro and in vivo we use a soluble chimeric protein, consisting of ALK1 ECD fused to human Fc (ALK1Fc), for preventing the activation of endogenous signaling. ALK1Fc sequesters BMP9 and BMP10, preserving the activation of ALK1 through other ligands. Results: We show that ALK1Fc reduces BMP9-mediated signaling and decreases proliferation of highly metastatic and tumor initiating human prostate cancer cells in vitro. In line with these observations, we demonstrate that ALK1Fc reduces tumor growth in vivo in an orthotopic transplantation model. The propensity of the primary prostate cancer to metastasize to the bone is also investigated. In particular, we report how the ALK1Fc influences the prostate cancer cells in vitro and in vivo when these are probed in different bone settings (co-culture with bone cells and intraosseous transplantation in mice). Conclusions: Our study provides the first demonstration that ALK1Fc inhibits prostate cancer cells growth identifying BMP9 as a putative therapeutic target and ALK1Fc as a potential therapy. All together, these findings justify the ongoing clinical development of drugs blocking ALK1 and ALK2 receptor activity.
Development of TRIB3 as a novel preclinical and clinical pharmacodynamic biomarker for ABTL0812.
Authors: Héctor Pérez-Montoyo, Marc Yeste-Velasco, Sònia Solé-Sánchez, Paloma Bragado, Eva Colàs-Ortega, Nuria Eritja, Anna Lopez-Plana, Patricia Fernandez-Nogueira, Pau Muñoz-Guardiola, Elisabet Megías-Roda, Cristian Moiola, Isidre Felip, Ernest Nadal-Alforja, Marta Gil Martin, Margarita Romeo, Teresa Moran, Antonio Gil-Moreno, Xavier Matias-Guiu, Carles Domenech, Jose M Lizcano
Journal: Journal of Clinical Oncology (2018)

e14556 Background: ABTL0812 is a new chemical entity, currently in Phase I/II clinical trial for Non-Small-Cell Lung Carcinoma (NSCLC) and endometrial cancer in combination with paclitaxel and carboplatin (P/C). It has shown an excellent safety profile and signs of efficacy, as indicated by several long disease stabilizations, in a Phase I clinical trial. ABTL0812 inhibits PI3K/Akt/mTOR pathway by overexpressing TRIB3, an endogenous pseudokinase that impedes Akt activation. Given the central relevance of TRIB3 in ABTL0812 mechanism of action, we have investigated the potential use of TRIB3 as a pharmacodynamic biomarker to monitor ABTL0812 activity. Methods: TRIB3 mRNA and protein levels were measured by RT-qPCR and immunoblot in endometrial cancer and NSCLC cell lines (including adenocarcinoma and squamous), in NSCLC cell line-derived xenografts and endometrial cancer patient-derived xenografts (PDX) by RT-qPCR and immunohistochemistry. Finally, mRNA whole blood TRIB3 levels were evaluated in human patients from the Phase I/II clinical trial. Results: endometrial cancer and NSCLC cells incubated with ABTL01812 alone or in combination with chemotherapy showed an overexpression of TRIB3 at mRNA and protein level, indicative of ABTL0812 activity on human cancer cells. This overexpression is also detected in vivo, as shown by the increase of mRNA and protein levels in endometrial cancer PDX and in NSCLC cell line-derived xenografts treated with ABTL0812 alone or in combination with P/C. Finally, overexpression of TRIB3 mRNA levels in whole blood was detected as soon as 8 hours after the first administration of ABTL0812 to patients from Phase I/II clinical trial. This increase is maintained three weeks after starting the treatment with ABTL0812 and having received the first P/C cycle. Conclusions: here we present TRIB3 as a novel pharmacodynamic biomarker for ABTL0812 in NSCLC and endometrial cancer patients. This novel biomarker is central in ABTL0812 mechanism of action and it can be measured by a non-invasive method in blood, serving as a molecular indicator of its activity and allowing the monitoring of its pharmacological response.