tbuckley/cabot-search huggingface dataset:
A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia
Authors: Haley E. Ramsey, Melissa A. Fischer, Taekyu Lee, Agnieszka E. Gorska, Maria Pia Arrate, Londa Fuller, Kelli L. Boyd, Stephen A. Strickland, John Sensintaffar, Leah J. Hogdal, Gregory D. Ayers, Edward T. Olejniczak, Stephen W. Fesik, Michael R. Savona
Journal: Cancer Discovery (2018)

Suppression of apoptosis by expression of antiapoptotic BCL2 family members is a hallmark of acute myeloblastic leukemia (AML). Induced myeloid leukemia cell differentiation protein (MCL1), an antiapoptotic BCL2 family member, is commonly upregulated in AML cells and is often a primary mode of resistance to treatment with the BCL2 inhibitor venetoclax. Here, we describe VU661013, a novel, potent, selective MCL1 inhibitor that destabilizes BIM/MCL1 association, leads to apoptosis in AML, and is active in venetoclax-resistant cells and patient-derived xenografts. In addition, VU661013 was safely combined with venetoclax for synergy in murine models of AML. Importantly, BH3 profiling of patient samples and drug-sensitivity testing ex vivo accurately predicted cellular responses to selective inhibitors of MCL1 or BCL2 and showed benefit of the combination. Taken together, these data suggest a strategy of rationally using BCL2 and MCL1 inhibitors in sequence or in combination in AML clinical trials. SIGNIFICANCE: Targeting antiapoptotic proteins in AML is a key therapeutic strategy, and MCL1 is a critical antiapoptotic oncoprotein. Armed with novel MCL1 inhibitors and the potent BCL2 inhibitor venetoclax, it may be possible to selectively induce apoptosis by combining or thoughtfully sequencing these inhibitors based on a rational evaluation of AML.See related commentary by Leber et al., p. 1511.This article is highlighted in the In This Issue feature, p. 1494.
Trends of new cancer drug approvals from the perspective of a publicly funded healthcare system: Analyses of the pan-Canadian Oncology Drug Review (pCODR) recommendations.
Authors: Saroj Niraula
Journal: Journal of Clinical Oncology (2018)

6516 Background: United States Food and Drug Administration (FDA) primarily takes into account the therapeutic index before approval of a new cancer drug whereas in countries with public funding of healthcare cost-effectiveness, utility, and adoption feasibility are also considered rigorously. Methods: Data from the pan-Canadian Oncology Drug Review (pCODR) – a national drug review system that makes evidence-based funding recommendations to Canada's provinces and territories - were collected. Analyses based on rationale of the pCODR recommendations and any conditions thereof, pCODR timelines compared to FDA approvals, published results of the pivotal clinical trials used to support the pCODR recommendations, cost/Quality Adjusted Life Years (QALY), and Incremental Cost Effectiveness Ratio (ICER)/QALY of the new drugs compared to controls were performed using established methods. Results: From inception to January 31, 2018, 60 new cancer drugs for 91 indications were reviewed by pCODR. There was a median of 15 months' time lag between FDA approval and final pCODR recommendation. Eighteen of the 91 pCODR reviews (approved previously by FDA for public use) received negative recommendation on the grounds of inadequate clinical benefits. Of the 73 that received positive pCODR recommendation, 90% were approved conditional on improvement in cost-effectiveness to an acceptable level. Surrogate outcomes were used as the primary basis for approval in 83% of the reviews, of which 4 drugs subsequently led to a compromise in overall survival compared to respective controls by a median of 1.5 months. Median ICER/QALY of new drugs, compared to the controls was $186,403 (range 7.2k to 4 millions). Conclusions: Close to a quarter of cancer drugs approved for public use by FDA do not meet Canadian standards for efficacy, and some may have detrimental effect on survival. A vast majority of the pCODR approved drugs are cost-ineffective at presented price. With finite resources to share among multiple societal priorities like education and preventative health, incremental cost of new cancer drugs is unsustainable even in the wealthiest of nations.
A machine-learning approach for the identification of highly predictive germline SNPs as biomarkers for response to bevacizumab in metastatic colorectal cancer using Elastic Net and Lasso.
Authors: Ana Barat, Dominiek Smeets, Bruce Moran, Sudipto Das, Johannes Betge, Verena Murphy, Elaine Kay, Nicole C.T. van Grieken, Henk M.W. Verheul, Timo Gaiser, Matthias Philip Ebert, Nadine Schulte, Bryan Hennessy, William M. Gallagher, Deborah A McNamara, Bauke Ylstra, Diether Lambrechts, Darran O'Connor, Annette T. Byrne, Jochen Prehn
Journal: Journal of Clinical Oncology (2018)

e15584 Background: Chemotherapy combined with the angiogenesis inhibitor bevacizumab (bvz) is approved as a first-line treatment in the setting of metastatic Colorectal Cancer (mCRC) since 2004, but low response rates underpin a need for predictive biomarkers to predict outcomes. Methods: Within the EU funded FP7 ANGIOPREDICT program (www.angiopredict.com) we employed exome sequencing to assess the single-nucleotide polymorphisms (SNPs) in a cohort of 180 retrospective mCRC patients treated with combined bvz + chemotherapy regimens (first, second and higher line; Betge et al 2016) and correlated the resulting germline SNPs to progression-free survival (PFS). Specifically, we employed a machine-learning approach based on repeated cross-validated Cox penalized regression (using both Elastic Net and Lasso) to select SNPs having potential as candidate biomarkers to predict outcome. Results: We identified two promising SNPs: rs12150220 on NLRP1 and rs13334970 on SRL. For rs12150220 on NLRP1, bearers of two copies of the rare allele T have significantly better PFS than bearers of any A (p-val= 1×10−4)*. For rs13334970 on SRL, bearers of homozygous rare allele A at this location have shorter PFS than bearers of at least one allele G (p-val= 1×10−4)*. NLRP1 (NLR Family Pyrin Domain Containing 1) encodes for a protein that is key for the caspase-1 activating inflammasome. SRL (Sarcolumenin) is a calcium-binding protein in the ER also linked with ER stress, caspase activation and inflammation. When looking at the interaction of these two SNPs, bearers of TT for rs12150220 on NLRP1 do significantly better regardless of their rs13334970 allele, but bearers of any A for rs12150220 on NLRP1 and AA for rs13334970 on SRL have significantly worse PFS, with all other combinations as baseline, (p-val= 2×10−10)*. Conclusions: These findings point to a role of inflammasome function in responses to bvz. * Wald test in the multivariable Cox proportional hazards regression model adjusting for age, gender, treatment line and grade of differentiation. Reference: Betge J, Barat A, Murphy V, Hielscher T, Van Grieken NC et al, Digestion. 2016; 94(3):129-137
A randomized phase II study of anti-PD1 antibody [MK-3475 (Pembrolizumab)] alone versus anti-PD1 antibody plus stereotactic body radiation therapy in advanced merkel cell carcinoma (Alliance A091605).
Authors: Jason J. Luke, Steven J. Chmura, Jacob B Allred, Joseph Kamel Salama, Hania A Al-Hallaq, Charles Hsu, Sue S. Yom, Mark Kozloff, Pamela N. Munster, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2018)

TPS9599 Background: Merkel cell carcinoma (MCC) is a rare cutaneous malignancy associated with ultraviolet light exposure, advanced age and infection with the Merkel cell polyomavirus (MCP). Historically, median survival in the metastatic setting was approximately 9.6 months with radiation and platinum- based chemotherapy as the foundations of treatment. More recently, outcomes have been markedly improved with the development of PD1/L1 antibodies. Durable response rates have been observed ranging from 30-50%, depending on line of therapy, that are independent of PDL1 or MCP status, mutation burden or tumor-infiltrating lymphocytes. A large preclinical literature and some clinical observations support the hypothesis that radiation may augment the systemic efficacy of immunotherapy (abscopal effect) through increased antigen presentation, T-cell priming, and interferon gamma associated signaling. No clinical studies to date have directly tested this hypothesis. Methods: This is an NCTN supported (Alliance for Clinical Trials in Oncology, SWOG and NRG Oncology) open-label phase II study comparing pembrolizumab with pembrolizumab plus stereotactic body radiation therapy to a single lesion in advanced MCC. The study randomizes patients 1:1 with eligibility including no prior therapy in the metastatic setting, ≥2 sites of RECIST measurable disease, ECOG performance status 0-2 and no autoimmunity or immunosuppression. The primary endpoint is progression-free survival in non-irradiated lesions (abscopal), with secondary endpoints evaluating response rate, overall survival and toxicity. Translational biospecimens, including archival tumor tissue (for PDL1, TMB, gene expression profiling and other analyses), serum and peripheral blood mononuclear cells and fecal microbiome samples, are being collected for analysis. The study is open to accrual via the Cancer Trials Support Unit (CTSU) of NCI to any NCTN group member site. Recruitment is on-going (target 96 patients). Clinical trial information: NCT03304639.
Prognostic sıgnificance of PD-L1 in stage II/III non-small cell lung cancer.
Authors: Deniz Tural, Mustafa Karaca, Emre Akar, Damla Okay, Ibrahim Cil, Nalan Akyurek, Aytug Uner, Ahmet Ozet
Journal: Journal of Clinical Oncology (2018)

e20532 Background: Prognostic significance of PD-1/PD-L1 axis expression in non-small cell lung cancer (NSCLC) remains uncertain despite being a predictive biomarker for novel immunotherapeutics. In this study, we have investigated PD-1/PD-L1 expression and its effect on disease prognosis and overall survival in stage II-III NSCLC patients. Methods: Clinic and pathologic features of stage II and stage III NSCLC patients were retrospectively analyzed from patients’ records in this study. PD-1 and PD-L1 immunohistochemistry staining were carried out to archived tumor specimens of the eligible patients. Percentages of PD-1 positive lymphocytes, PD-L1 positive tumor cells and PD-L1 positive tumor infiltrating immune cells were evaluated and considered as positive if ≥1% of the cells displayed staining. Results: Sixty-six male (89,2%) and 8 female (10,8%) of total 74 patients were eligible for the study. Thirty-three (44,6%) patients were diagnosed as stage II disease while 41 patients (55,6%) were diagnosed as stage III. PD-1 expression, PD-L1 expression in tumor cells and PD-L1 expression in tumor infiltrating immune cells were positive in 83,8% (n = 62), 45,9% (n = 34), 67,6% (n = 50) of total 74 patients, respectively.Three-year overall survival (OS) rate was calculated as 57,7%. Univariate analyses did not reveal any significant difference in 3-years OS between those with PD-1 and PD-L1 expression in tumor infiltrating immune cells and those without expression. (p = 0,413 and p = 0,099; respectively) However, 3-years OS was more favorable in those with PD-L1 expression in tumor cells than in those without PD-L1 expression (76,6% vs %41%, p = 0.031). In multivariate analyses, a positive trend was revealed in 3-years OS between those with PD-L1 expression in tumor cells and those without expression. (HR: 0,405; 95% CI: 0,153, 1,074; p = 0,069) Conclusions: In this study, better prognosis was obtained with positivity of PD-L1 in tumor cells. Therefore, it should be taking into consideration while designing adjuvant immunotherapy trials which are generally formed with stage I-III NSCLC patients, that expression of PD-1/PD-L1 pathway may have a positive prognostic effect.
Understanding of important chemotherapy terminology by underserved populations.
Authors: Rebecca D. Pentz, Candice A Jacson, Kristen Gillespy, Minisha Lohani, Margie D Dixon
Journal: Journal of Clinical Oncology (2017)

e18046 Background: Terminology used to describe chemotherapy can be difficult to understand, hindering shared decision making. Using a word bank of 42 misunderstood words we created previously (2016 ASCO abstract 164532), we identified the most misunderstood words and created 6 videos to describe six of them. Methods: An expert panel - three oncologists, two health literacy experts, an education specialist and a social worker - chose 20 words from the word bank to test. The number 20 was chosen to avoid participant fatigue. The 20 words were the 17 most frequently chosen by patients as hard to understand and 3 deemed crucial to understand by providers (curative, palliative, risk of infection) (Table). These words were tested for understanding with 50 underserved oncology patients, who were asked to provide definitions. Frequency of misunderstanding was calculated. Wrong definitions were tabulated to guide the expert panel in writing the script for the videos. Videos were created using VideoScribe software. Results: Eleven words were misunderstood by more than half of the participants (Table). After studying the wrong definitions, the expert panel provided definitions for six words (cancer, chemotherapy, curative, palliative, risk of infection, blood count) to create videos for a pilot study of the effectiveness of the videos. The video for ‘cancer’ can be found here https://www.youtube.com/watch?v=losI4fvESuU . Conclusions: Key words used to describe chemotherapy are not understood by patients. A simple intervention like a short video may aid in understanding. [Table: see text]
Defining tumor characteristics resulting in radiographic progression for better trial outcomes.
Authors: Manish Sharma, Anitha Singareddy, Michael O'Connor, Nicholas Enus, Sayali Karve, A. Kassel Fotinos-Hoyer, Daniel Clark
Journal: Journal of Clinical Oncology (2018)

e18594 Background: With PFS as a primary endpoint, the assessment of Progressive Disease (PD) is the single most important trial assessment. As such, in blinded independent central review (BICR) utilizing a double read with adjudication model, measures should be taken to ensure precision in the assessment of PD. This study seeks to categorize the causes of PD assessment by BICR and identify which have the highest rate of reader disagreement (RD). The outcome provides further insights into measures that may be taken to more effectively ensure precision in PD assessment. Methods: Per RECIST 1.1, an overall assessment of PD can be caused by progression of target lesions (TL) and/or non-target lesions (NTL) and/or the presence of new lesions (NL). A retrospective review of the causes of PD assessment within BICR data was performed for 10 arbitrarily selected trials in phases II or III with indications of breast, non-small cell lung, or ovarian cancer using RECIST 1.1. In total, 4723 subjects and 27214 visits were reviewed, of which 3351 were PD. The following variables for all visits with overall assessment of PD were reported: subject number, visit number, cause of PD, cause of PD category, and RD. Cause of PD was defined by category as: TL (1), NTL (2), NL (3), TL+NTL (4), TL+NL (5), TL+NTL+NL (6), NTL+NL (7) The cause of PD and rate of RD by category was calculated and the highest rates of RD by category were identified. Results: See Table 1. Conclusions: Though it is important to ensure overall precision in BICR data (i.e. assessment criteria training for readers, data/adjudication monitoring), special consideration on how overall assessment of PD based on TLs and/or NLs is determined may be warranted, as PD assessed based on these areas is a common cause of RD. The results suggest the difficult nature of suitable target lesion selection at baseline and the identification of unequivocal NLs. Additional investigation should be performed to identify appropriate measures to increase precision in these areas (i.e TL/NL definition, restriction of lesion type/locations of target lesions at baseline, and enhanced data monitoring). Table 1: Category 1 2 3 4 5 6 7 Visits Assessed as PD (n = 3351) 478 337 1514 323 176 217 306 RD Rate (%) 72 60 66 55 61 46 58
Phase I study of anti-PD1 in combination with low-dose decitabine in patients with advanced and untreated malignancies.
Authors: Chunmeng Wang, Yang Liu, Wenying Zhang, Meixia Chen, Lu Shi, Liang Dong, Xiang Li, Qingming Yang, Jing Nie, WeiDong Han
Journal: Journal of Clinical Oncology (2017)

e14555 Background: Anti-PD1 have produced significant antitumor activity in multiply malignancies, however, resistance to anti-PD1 is becoming increasingly apparent in recent years. Low-dose decitabine, a classical DNA hypomethylating agent, was shown to boost effector T cell function and trigger a T cell-mediated response. This phase I study was designed to assess the safety, immunological effects and antitumor activity of this novel combination in patients with advancedanduntreated lymphomas and solid tumors. Methods: Patients were treated with decitabine (10mg/d on day 1-5) and anti-PD1 (2-3mg/kg, day 8) per 3 weeks. Modified salvage regimens (lymphoma: COP; solid tumors: platinum-based chemotherapy) were allowed to be intermittently inserted for patients with aggressive progression. Treatment continued unless disease progression or severe toxicity. Safety was assessed by CTCAEv4.0, and response by standard international criteria. The phenotype and activity of T cells were periodically measured in peripheral blood by flow cytometry. Results: Todate, 11 patients with heavily treated history and refractory bulky lesions have been enrolled, including 8 with lymphomas (7 NHL, 1 HL resistant to anti-PD1) and 3 with metastatic solid tumors (2 gastric cancers, 1 esophageal cancer) failure to anti-PD1. 5 patients (45%) experienced Grade ≥ 3 toxicities, with 1 taken off due to toxicity, and 1 died of asystole during the term of severe cytokine release syndrome (CRS). The common events of leukocytopenia and CRS were prominent features of anti-PD1 plus decitabine. 9 patients were evaluable for response, 1 HL obtained complete response, 3 NHL and 3 solid tumors achieved partial response, and 2 NHL had stable disease with nearly 20% shrinkage. The frequency of interferon-γ-producing CD8+ T cells in the total CD3+ population was largely increased after anti-PD1 plus decitabine infusion. Conclusions: Decitabine augmented the pro-inflammatory effects of anti-PD1 characterized by systemic inflammation response, and further improved antitumor activity of anti-PD1. Clinical trial information: NCT02961101. Clinical trial information: NCT02961101.
FGFR1 protein overexpression as a prognosis marker for operated small cell lung cancer patients.
Authors: Xie Fa Jun, Hongyang Lu
Journal: Journal of Clinical Oncology (2016)

e20101 Background: This study was conducted to investigate whether mRNA or protein overexpression can predict the prognosis of patients with Small cell lung cancer (SCLC) after surgical resection. Methods: The expression of FGR1 was examined in 33 SCLC tissue samples by real-time quantitative PCR in mRNA level and immune-chemistry in protein level respectly. The association of the FGFR1 overexpression with overall survival (OS) and refractor-free survival (RFS) was analyzed. Results: FGFR1 was frequently overexpression in both mRNA level (17/33, 21.2%) and (15/33, 45.5%) in protein level. Interesting, negative correction was observed between mRNA and protein expression. Kappan-Melar analysis indicated that the FGFR1 protein overexpression was a significant negative prognostic factors for SCLC patient (HR = 2.76, 95%CI 1.09-18.2, p < 0.05). Patients with FGFR1 protein overexpression had both poor OS (63.0 vs. 22.0 months, p < 0.05) and RFS (48.0 vs. 9.0months, p < 0.05) compared to patients with normal expression of FGFR1. Conclusions: Our results suggest that elevated serum FGFR1 protein overexpression is a prognostic biomarker for poorer survival in small cell lung cancer patients.
TCT-601 Results of percutaneous coronary intervention with second-generation paclitaxel coated balloons in diabetic patients at a long-term follow-up.
Authors: José Abellán-Huerta, Ignacio Sanchez-Perez, Alfonso Jurado-Román, María López-Lluva, Juan Antonio Requena, Ramón Maseda Uriza, Fernando Lozano
Journal: Journal of the American College of Cardiology (2018)
Abstract 15481: The Vasoactive MicroRNA miR-487b-3p Undergoes A-to-I Editing of the Seed-Sequence During Post-Ischemic Neovascularization
Authors: Reginald van der Kwast, Paul Quax, Anne Yael Nossent
Journal: Circulation (2016)

Introduction: We have previously shown that miR-487b-3p plays an important role in cardiovascular pathology. MiR-487b-3p regulates arteriogenesis and angiogenesis in a murine hindlimb ischemia mode...
Variability of pelvic MRI performance in a prospective multicenter rectal cancer trial NCCTG N1048 (Alliance).
Authors: Marc Jeffrey Gollub, Qian Shi, Stephanie Nougaret, Preethi Subramanian, Jun Zhang, Michael V. Knopp, Jeffrey A. Meyerhardt, Eileen Mary O'Reilly, Charles Gregory Nyman, Lawrence Howard Schwartz, Deborah Schrag
Journal: Journal of Clinical Oncology (2018)

e18783 Background: To assess variation in technical performance and quality of tailored pelvic MRI for rectal cancer management in a prospective, multicenter, rectal cancer trial. Methods: An audit of cases submitted to the National Clinical Trials Network Imaging Core Lab (NCTN) (IROC) was performed on the Alliance for Clinical Trials in Oncology PROSPECT study, an NCI NCTN phase II/III trial for patients (pts) with locally advanced rectal cancer. Inclusion criteria were 1 rectal MRI per magnet type from any registered site which sent ≥ 2 patients’ MRIs to IROC in consideration for trial entry, and reviewed for eligibility by the radiologic PI (MJG). IROC extracted metadata from the Digital Imaging and Communications in Medicine headers of 131 exams from 78 sites using 21 different magnets. Major criteria (magnet strength, image plane, field of view [FOV], slice thickness, fat-saturation) and minor criteria (fast T2 imaging, bandwidth) were compared with the protocol-recommended - but non-mandated - imaging parameters. Image quality (optimal/suboptimal) was judged subjectively by the radiologic PI. Results: At the time of audit, 426 pts from 114 sites were enrolled, representing 31% (131/426) of pts and 68% (78/114) of sites. Major criteria (and compliance) with protocol recommendations were: 1.5/3.0 Tesla closed magnets (131/131; 100%); Axial-oblique plane perpendicular to the tumor (91/131; 69%); FOV < 26cm (109/128; 85%); Slice thickness < 5mm (102/130; 78%) and Non-fat-saturated-T2-images (126/131; 96%). Minor criteria were: Fast T2 sequences (130/131; 99%) and; Recommended bandwidth (50/131, 38%). Among the 131 exams, 13 (10%) were deemed of suboptimal quality. Conclusions: In this NCTN multicenter rectal cancer trial, compliance for major criteria was high and image quality optimal in 90%, but, two recommended techniques for optimal T-staging and margin assessment, i.e. axial oblique images and slice thickness < 5mm were inconsistently performed. Achievement of greater uniformity in image acquisition for optimal diagnostic capability is an important goal for implementation in multicenter trials in which imaging guides treatment.