tbuckley/cabot-search huggingface dataset:
The Immune Contexture Associates with the Genomic Landscape in Lung Adenomatous Premalignancy
Authors: Kostyantyn Krysan, Linh M. Tran, Brandon S. Grimes, Gregory A. Fishbein, Atsuko Seki, Brian K. Gardner, Tonya C. Walser, Ramin Salehi-Rad, Jane Yanagawa, Jay M. Lee, Sherven Sharma, Denise R. Aberle, Arum E. Spira, David A. Elashoff, William D. Wallace, Michael C. Fishbein, Steven M. Dubinett
Journal: Cancer Research (2019)

Abstract Epithelial cells in the field of lung injury can give rise to distinct premalignant lesions that may bear unique genetic aberrations. A subset of these lesions may escape immune surveillance and progress to invasive cancer; however, the mutational landscape that may predict progression has not been determined. Knowledge of premalignant lesion composition and the associated microenvironment is critical for understanding tumorigenesis and the development of effective preventive and interception strategies. To identify somatic mutations and the extent of immune cell infiltration in adenomatous premalignancy and associated lung adenocarcinomas, we sequenced exomes from 41 lung cancer resection specimens, including 89 premalignant atypical adenomatous hyperplasia lesions, 15 adenocarcinomas in situ, and 55 invasive adenocarcinomas and their adjacent normal lung tissues. We defined nonsynonymous somatic mutations occurring in both premalignancy and the associated tumor as progression-associated mutations whose predicted neoantigens were highly correlated with infiltration of CD8+ and CD4+ T cells as well as upregulation of PD-L1 in premalignant lesions, suggesting the presence of an adaptive immune response to these neoantigens. Each patient had a unique repertoire of somatic mutations and associated neoantigens. Collectively, these results provide evidence for mutational heterogeneity, pathway dysregulation, and immune recognition in pulmonary premalignancy. Significance: These findings identify progression-associated somatic mutations, oncogenic pathways, and association between the mutational landscape and adaptive immune responses in adenomatous premalignancy. See related commentary by Merrick, p. 4811
Clinical efficacy of abiraterone and enzalutamide metastatic castration sensitive prostate cancer patients who progressed rapidly on docetaxel with a genomic analysis.
Authors: Gang Chen, David James VanderWeele, Fatima Karzai, Marijo Bilusic, Munjid Al Harthy, Philip M. Arlen, Marc Robert Theoret, Inger L. Rosner, Guinevere Chun, Helen Owens, Anna Couvillon, Amy Hankin, Monique Williams, James L. Gulley, William L. Dahut, Ravi Amrit Madan
Journal: Journal of Clinical Oncology (2019)

e16536 Background: Docetaxel has become a standard of care for mCSPC. Enzalutamide and abiraterone have been proven to improve survival in metastatic castration-resistant prostate cancer (mCRPC) patients. Little is known about patients who have been treated with docetaxel for mCSPC and subsequent therapeutic responses. This retrospective analysis is to evaluate the response duration of abiraterone and enzalutamide in patients who previously received docetaxel for mCSPC but developed mCRPC within 12 months. Methods: Clinical Trial NCT02649855 enrolled patients with newly diagnosed mCSPC who were treated with standard androgen deprivation therapy (ADT) and docetaxel (75 mg/m2 every 3 weeks for 6 cycles) sequenced with immunotherapy (PROSTVAC) from February 2016 to present. Patients who had progression (based on consecutive PSA rises or imaging) within 1 year of completing docetaxel and went on to subsequent abiraterone/enzalutamide were evaluated. (Note these are different PSA progression criteria than used in CHAARTED, Sweeney, NEJM, 2015). A PCR-based NGS panel (OncoMine Comprehensive Assay v3) will evaluate available tissue from these patients. Results: Of the 46 patients evaluated regardless of immunotherapy sequence, 15 (33%) went on subsequent therapy after progression on docetaxel for mCSPC, with 12 patients starting abiraterone/enzalutamide (7 with high volume disease and 5 with low volume disease). The median age was 62 (41-83) years. 6/12 patients (50%) initiated enzalutamide and 6/12 patients (50%) initiated abiraterone. The median duration of treatment for both was 7.43 (1.53 – 16.0) months, the median time to prostate-specific antigen (PSA) progression was 2 (0 – 11) months; the median duration of PSA decline was 2 months in patients with both high and low volume disease. Of note, 3/12 (25%) of patients did not have PSA response, all of them had high volume disease. Conclusions: These data from a small cohort suggest that patients who have progression within 12 months of completing docetaxel for mCSPC have limited subsequent benefit from enzalutamide or abiraterone. Additional studies are required to determine optimal timing and treatment sequence for patients with mCSPC who rapidly develop mCRPC. Clinical trial information: NCT02649855.
Adjuvant endocrine monotherapy (ET) versus adjuvant breast radiation (RT) alone in healthy older women with stage I, estrogen receptor-positive (ER+) breast cancer: An analysis of the National Cancer Database (NCDB).
Authors: Anthony H. Bui, Manjeet Chadha, Theresa H. Shao, Naamit K. Gerber, Sarah P. Cate, Susan K. Boolbol, Nicole J. Zubizarreta
Journal: Journal of Clinical Oncology (2019)

519 Background: The NCCN guidelines state that breast RT may be omitted in patients &gt; 70 years of age with ER+, clinically node-negative, T1 breast cancer (BC) who receive adjuvant ET. Available data on older patients notes that local relapses are the most frequent site of failure, and distant relapse rates are low. The side effects of ET are not inconsequential and negatively affect QOL. The objectives of this study are to examine clinical outcomes including overall survival (OS) in women ≥70 years of age treated by lumpectomy(L)+ET and L+RT in the NCDB. Methods: The 2004-2013 NCDB includes 76,431 women ≥70 years with ER+ stage I BC who underwent L, and had a minimum one year follow up. Women who received no adjuvant therapy, both ET+RT, or any chemotherapy were excluded. To limit the analysis to healthy women, we excluded subjects with a Charlson comorbidity index &gt; 0. We identified 24,572 patients who received either adjuvant ET monotherapy or adjuvant RT alone. Among these, 46% (11,313) received ET and 54% (13,259) breast RT. Overall median follow up was 57 months (range: 12-143 months). Analysis of OS between the 2 treatment groups was performed using Kaplan-Meier statistics and Cox proportional hazards regression; propensity weighting was used to balance covariates across the 2 treatment groups. Results: After propensity weighting, demographic covariates including age, race, insurance, and facility type were balanced between the 2 treatment groups. The median OS for ET was 125.9 months (95% CI 120.1-131.8), and 127.2 months for RT (95% CI 124.5-131.7) (p &lt; 0.0001). The weighted hazard of death was 11.7% less in women receiving RT compared to ET (HR 0.883, 95% CI 0.834-0.936, p &lt; 0.0001). Conclusions: To our knowledge, this is the first large study comparing RT and ET monotherapy in healthy older women with stage I, ER+ BC. The OS with RT alone is not inferior to ET alone, and in this study population is noted to be better. While this analysis has various limitations not dissimilar from other NCDB database studies, our observations are encouraging and warrant further research with prospective studies.
Contemporary use of inpatient antineoplastic (IP) treatment (Rx): Who is getting care and why?
Authors: Hilal Hachem, David Levitz, Danai Dima, Joshua R. Dower, Rabiah B. Fresco, Ruth Ann Weidner, Rachel J. Buchsbaum, John Kalil Erban, Susan K. Parsons
Journal: Journal of Clinical Oncology (2019)

e18015 Background: The steady trend towards outpatient antineoplastic medication delivery has been spurred by improvements in supportive care, innovations in drug delivery, and financial considerations. Despite these trends, a significant number of patients (pts) continue to receive IP Rx for both hematological (HM) and solid cancers (ST). The purpose of this study is to describe a single center’s experience with IP Rx between 01/01/2015 and 12/31/2017. Methods: All pts ( &gt; 18yo) who received IP Rx for a cancer diagnosis, exclusive of stem cell transplantation, were identified from hospital pharmacy records. Patient and disease characteristics were collected at the index (initial) admission. All pts were followed for 1 year after index admission for 30-day readmission and subsequent admissions for IP Rx. Reasons for IP Rx included: urgent/emergent initiation of Rx; high acuity inpatient management for ST (e.g., intraperitoneal, intra-arterial, intravesical therapy) or complex HM regimen; ongoing Rx; palliation. Results: A total of 266 index admissions were identified with 66.2% of pts having a HM (n = 176) and 33.8% having a ST (n = 90). IP Rx was classified as urgent for 48.1% of pts (n = 128); 70.3% (n = 90) of these admissions were new diagnoses of which 91.4% (n = 86) were HM. High acuity IP management was required for 37.5% of pts (n = 100) (47% for ST (n = 47) and 53% for HM (n = 53)). The remaining index admissions were classified as ongoing Rx for 4.5% of pts (n = 12) and palliation for 9.8% (n = 26). Pts with ST required intensive care significantly more often than pts with HM (57.8% vs. 15.9%, p &lt; 0.001) but with no difference in inpatient mortality (4.4% vs. 5.7%, p = 0.891). The 30-day readmission rate was 32.2% for ST and 25.6% for HM (p = 0.515). After the index admission, 10% of ST pts and 60.2% of HM pts had at least 1 subsequent admission for IP Rx (p &lt; 0.001). Conclusions: In this 3-year retrospective review, the vast majority of pts receiving IP Rx required either urgent initiation of care or high acuity care, currently only available in the inpatient setting. While there is little evidence of routine IP Rx or opportunity, at present, to transition further care to the outpatient setting, the high rates of 30-day readmission warrant further evaluation.
The role of neurofilament aggregation in neurodegeneration: lessons from rare inherited neurological disorders
Authors: Alessandro Didonna, Puneet Opal
Journal: Molecular Neurodegeneration (2019)

Many neurodegenerative disorders, including Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis, are well known to involve the accumulation of disease-specific proteins. Less well known are the accumulations of another set of proteins, neuronal intermediate filaments (NFs), which have been observed in these diseases for decades. NFs belong to the family of cytoskeletal intermediate filament proteins (IFs) that give cells their shape; they determine axonal caliber, which controls signal conduction; and they regulate the transport of synaptic vesicles and modulate synaptic plasticity by binding to neurotransmitter receptors. In the last two decades, a number of rare disorders caused by mutations in genes that encode NFs or regulate their metabolism have been discovered. These less prevalent disorders are providing novel insights into the role of NF aggregation in the more common neurological disorders.
Phenotypic and functional characteristics of patient derived murine xenograft models.
Authors: Verena Imke Isabel Kiver, Annika Wulf-Goldenberg, Caroline Schweiger, Philipp Jurmeister, Bernadette Brzezicha, Olga Gorea, Susen Burock, Cornelia Kolberg-Liedtke, Jens Hoffmann, Jens Uwe Blohmer, Ulrich Keilholz, Carsten Denkert
Journal: Journal of Clinical Oncology (2019)

e14694 Background: Generation of patient-derived models for breast cancer has been difficult. In other histologies, success was higher in refractory disease. With the goal to develop a protean resource for testing novel compounds and combinations for treatment refractory breast cancer, we establish patient-derived murine xenograft models (PDX) from tumors clinically unresponsive to at least anthracyclin, platin and taxane. Here we report phenotypic and drug testing data of our established breast cancer models. Methods: On immunodeficient NOG mice, PDX were engrafted from breast cancer tissue samples. The tissues were obtained from patients with disease progression after chemotherapy with three to four drugs. The established PDX were characterized by immunohistochemistry and the PDX and primary tumor are currently undergoing exome and transcriptome sequencing. The PDX were tested for response to all standard chemotherapy agents. The drug testing included platin, taxane, anthracycline, 5-FU, Everolimus, Eribulin and depending on the subtype tamoxifen, olaparib, and a CDK4/6 Inhibitor. Results: Since May 2017 30 breast cancer samples have been processed under rapid and stringent conditions. Currently five models, three TNBC and two hormone receptor positive PDX, have been fully engrafted, phenotypically compared and drug tested. The immunohistochemistry (estrogen/progesterone/androgen/Her2 receptor, Ki-67, CK5/6) of original tumor and PDX were correlative. All patients had shown clinical resistance to platin, anthracyclines, and taxanes in the neoadjuvant or palliative setting. Concordant with the clinical resistance, the PDX models showed only limited or transient sensitivity to single agents. Six more PDX, three TNBC, two HR+ and one Her2+, are currently in various states of engraftment and testing. Conclusions: With our stringent approach, we successfully generated PDX models in 15%, which may rise to 30% with the ongoing models. Phenotype between patient tumors and PDX was consistent. The minor differences in responsiveness to chemotherapy may be due to differences in stromal factors. In summary, the PDX of refractory tumors are a versatile resource for preclinical studies of novel treatment approaches.
Hypoxia signaling and immune infiltration in a presurgical trial of sunitinib in patients with clear cell renal cell carcinoma (RCC).
Authors: Elshad Hasanov, Christine B Peterson, Surena F. Matin, Christopher G. Wood, Kanishka Sircar, Nizar M. Tannir, Eric Jonasch
Journal: Journal of Clinical Oncology (2019)

e16115 Background: Presurgical clinical trial design allow for pharmacodynamically relevant tissue collection that can inform regarding drivers of tumor biology. An unmet need is the ability to identify tumors that may respond to immunotherapy and the underlying mechanism of immune infiltration. Methods: This single arm phase II study was designed to test efficacy and safety of presurgical sunitinib treatment in metastatic RCC, and to identify drivers of tumor biology. Patients (pts) with metastatic RCC and a resectable primary received sunitinib 50mg PO daily for four weeks, and underwent restaging. If deemed a candidate, pts underwent cytoreductive nephrectomy (CN) during their second cycle of sunitinib, with last dose administered the day before surgery. Pts were restaged postoperatively and continued on sunitinib if no progressive disease was seen. Genomic and histological characteristics of RCC were evaluated for correlations between response and biological features. Results: Between June 2008 and October 2011, 50 pts were enrolled. 41 underwent CN. Seven pts showed refractory disease and were not considered surgical candidates. No sunitinib related perioperative toxicities were observed. Six pts progressed on first postoperative imaging studies, with three patients developing new brain metastases. Median progression free survival (PFS) was 8.6 months, and overall survival was 38 months. Objective response rate was 30 percent with 2 pts demonstrating a complete response. Analysis on 39 pts showed HIF1a staining was significantly associated with PFS (p = 0.023*, univariate Cox model), with a hazard ratio (HR) of 1.028 (95% CI, 1.004-1.053). This association remained significant in a multivariate Cox model adjusting for age and gender (p = 0.019*). In addition, HIF1a correlated with multiple immune markers (CD8, CD45RO, PD1, Treg, CD68, and LAG3). Analysis of genomic correlates is ongoing. Conclusions: Presurgical sunitinib therapy in RCC is safe and efficacious. HIF1a staining is associated with shorter PFS, and with increased immune infiltration. Tissue HIF1a should be explored as a marker, and studied mechanistically as a driver of the immune microenvironment in RCC. Clinical trial information: NCT00715442.
Longitudinal tumor size and NLR as predictive factors of individual survival compared to their baseline values in patients with non-small cell lung cancer treated with durvalumab.
Authors: Kirill Zhudenkov, Sergey Gavrilov, Kirill Peskov, Gabriel Helmlinger, Sergey Aksenov
Journal: Journal of Clinical Oncology (2019)

e20047 Background: Our ability to accurately predict survival of patients with non-small cell lung cancer (NSCLC) while on treatment is limited. Prognostic markers such as stage and tumor size are well established, while neutrophil-to-lymphocytes ratio (NLR) and other hemogram measurements have recently been studied. Gain in prognostic accuracy of these markers when measured longitudinally has not been established. Methods: There were 679 NSCLC patients (Stage 3 or 4, ECOG PS 0 or 1) from clinical studies of durvalumab 10 mg/kg every two weeks (NCT02087423 and NCT01693562). We developed three models of overall survival (OS) all with ECOG as covariate: a Cox proportional hazards model with baseline tumor sum-of-longest-diameters (SLD) and NLR as covariates (COX); a joint model of OS and longitudinal SLD and baseline NLR (JM SLD); and a joint model of OS and longitudinal SLD and NLR (JM SLD&amp;NLR). We compared prognostic accuracy of these markers measured longitudinally vs. at baseline, using predicted probability of OS at 12 months after start of durvalumab as a prognostic score. We evaluated predictive performance of the models using area under the receiver-operating characteristic curve (ROC AUC) describing trade-off between true and false positives (i.e., survival past 12 months). The AUCs were calculated for patients in the dataset using longitudinal data up to different cut-offs. Results: The AUC for all patients starting durvalumab using baseline ECOG, SLD and NLR was 0.73, while it decreased to 0.64 for patients surviving to 6 months, compared to 0.50 for noninformative models. The AUC using longitudinal information for SLD and NLR was larger the more longitudinal data was used for prediction and was 0.81 using 6 months’ worth of data. Conclusions: Using longitudinal information for SLD and NLR increased individual predictive performance of these markers compared to only baseline information in NSCLC patients. [Table: see text]
Racial differences in intravenous bisphosphonate utilization among older patients with multiple myeloma.
Authors: Jifang Zhou, Karen Sweiss, Pritesh Rajni Patel, Edith Nutescu, Naomi Ko, Brian C-H Chiu, Gregory Sampang Calip
Journal: Journal of Clinical Oncology (2019)

e18165 Background: Intravenous bisphosphonates (IV BP) reduce the risk of skeletal-related events in patients with multiple myeloma (MM). However, data describing racial differences in utilization of IV BP in non-clinical trial settings is limited. In this study, we evaluated population-level IV BP utilization and factors associated with initiation and discontinuation of IV BP therapy. Methods: We conducted a retrospective cohort study of patients aged 65 years or older diagnosed with first primary MM between 2001 and 2011. Patients were identified using the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database and followed through December 2013. Patients were required to have Medicare Parts A and B coverage and patients with end-stage renal disease were excluded. Treatment with anti-MM therapy (chemotherapy and/or proteasome inhibitors) were treated as time-dependent variables. We analyzed cumulative incidences of IV BP initiation from the diagnosis of MM for all patients and separately time to discontinuation from IV BP initiation. In multivariable Fine and Grey models accounting for competing risks, we estimated subdistribution hazard ratios (SHR) and 95% confidence intervals (CI) for initiation and discontinuation. Results: 14,231 eligible patients had a mean [median] age of 76.8 [76] years and 51.8% were male. During a median follow-up of 23.1 months, 53.7% of patients received at least one intravenous bisphosphonate (IV BP) administration. IV BP initiation, duration and treatment frequency differed between racial groups. Among white patients, 64.4% of IV BP were administered every 4 weeks, compared to 59.3% in African Americans, 62.7% in Hispanic, and 64% in Asians. In multivariable models, Black patients experienced a significant delay in IV BP initiation (SHR 0.75, 95%CI 0.70-0.80) and were more likely to have early discontinuation (SHR 1.08, 95%CI 1.00-1.17). Conclusions: Despite recommended therapy with IV BP for MM patients, approximately half of older patients did not receive the therapy, with a significant lag experienced among racial minority groups. Efforts to improve uptake of IV BP and continued management of therapy in minority groups are needed. [Table: see text]
Health-related quality of life (HRQoL) in patients with advanced melanoma receiving immunotherapies across real-world clinical practice settings.
Authors: Richard Wayne Joseph, Frank Xiaoqing Liu, Alicia C. Shillington, Cynthia Macahilig, Scott J. Diede, Vaidehi Dave, Qing Harshaw, Todd L Saretsky, Alan S Pickard
Journal: Journal of Clinical Oncology (2019)

e21004 Background: Pembrolizumab (PEMBRO) and combination ipilimumab + nivolumab (IPI+NIVO) are FDA-approved immunotherapies for advanced melanoma (AM). HRQoL was better maintained with PEMBRO vs IPI in KEYNOTE-006. CheckMate-067 reported no clinically meaningful HRQoL differences with IPI+NIVO vs IPI. As randomized trial data are lacking, we compared HRQoL outcomes in AM between PEMBRO and IPI+NIVO in real-world clinical settings. Methods: A prospective, observational study was conducted with sponsor blinded to sites, and sites blinded to sponsor; nine oncologists from 9 US academic centers and affiliated satellite clinics enrolled AM patients (pts) age ≥18 years initiating first-line PEMBRO or IPI+NIVO between June 2017 – March 2018. The European Organization for the Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ C30) and EQ-5D-5L were administered at baseline and weeks 6, 12, 18, and 24 following therapy. Least squared (LS) mean changes in HRQoL scores from baseline were compared using mixed-effects models for repeated measures, adjusting for baseline covariates. Results: A total of 225 PEMBRO and 187 IPI+NIVO pts were enrolled, with &gt; 95% questionnaire completion rates through week 24. At baseline, PEMBRO pts were more likely &gt; age 65 (49% vs 37%, p = .011), stage IV disease (92% vs 85%; p = .002), and higher comorbidity index (1.0 vs 0.6; p &lt; .001) compared with IPI+NIVO pts. Adjusted EORTC global health status/quality of life (GHS) LS mean changes from baseline showed greater improvement with PEMBRO vs. IPI+NIVO at 12, 18 and 24 weeks. At week 24, PEMBRO pts achieved a 3.3-point improvement (95% CI = 0.8, 5.7) and IPI+NIVO pts had no significant change (1.0, 95% CI = -1.6, 3.5), with a LS mean difference of 2.3 points (p = .037; 95% CI = 0.14, 4.51). At week 24, the EQ-5D visual analogue scale increased 1.0 (95% CI, -1.2, 3.2) for PEMBRO vs IPI+NIVO which decreased 0.9 (95% CI = -3.2, 1.3), with a statistically significant LS mean difference of 2.0 (95% CI = 0.4, 3.9; p = .045). Conclusions: Results from 2 measures suggest HRQoL was maintained vs. baseline in both PEMBRO and IPI+NIVO pts, with a significant between-group difference favoring PEMBRO in GHS over 24 weeks.