tbuckley/cabot-search huggingface dataset:
VISION: An international, prospective, open-label, multicenter, randomized phase III study of 177Lu-PSMA-617 in the treatment of patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).
Authors: A. Oliver Sartor, Michael J. Morris, Richard Messman, Bernd J. Krause
Journal: Journal of Clinical Oncology (2020)

TPS259 Background: The novel therapeutic drug 177 Lu-PSMA-617 is a prostate-specific membrane antigen (PSMA) targeting agent that is used to deliver radionuclide therapy for the treatment of patients with mCRPC. Based on preclinical data that demonstrated high PSMA binding affinity and internalization, prolonged tumor uptake, rapid kidney clearance, and high tumor-to-background ratio, 177 Lu-PSMA-617 proceeded into clinical development. Preliminary clinical data indicates that 177 Lu-PSMA-617 may demonstrate clinical benefit in patients with mCRPC in a setting where patients had no clear standard of care. VISION (NCT03511664) is a phase 3 study designed to assess the efficacy of 177 Lu-PSMA-617 in patients with PSMA-positive mCRPC. Methods: Patients were randomized 2:1 to receive best standard of care with or without 177 Lu-PSMA-617. Eligibility criteria were: PSMA expressing tumor assessed by PSMA positron emission tomography imaging; prior exposure to a taxane and a novel androgen axis inhibitor (NAAI). The primary objective of this study is to compare the two alternative endpoints of progression-free survival (rPFS) and overall survival (OS). Stratification factors include lactate dehydrogenase, liver metastasis, ECOG PS, and use of an NAAI at time of randomization. On active treatment, median OS is assumed to be 13.7 months with a hazard ratio (HR) of 0.7306, and rPFS is assumed to be 6 months with an HR of 0.67. Enrollment began in June 2018 and the target of 814 patients has been reached. Clinical trial information: NCT03511664.
Patient-reported distress and symptoms predict post-esophagectomy outcomes.
Authors: Jonathan C. Salo, Patrick Leland Meadors, Sally J Trufan, Nicole Lee Gower, Michael David Watson, Lauren A Jeck, Joshua S. Hill, Declan Walsh
Journal: Journal of Clinical Oncology (2019)

e15567 Background: Esophagectomy is accompanied by significant morbidity, mortality and altered quality of life. Understanding the factors responsible for adverse post-operative outcomes is essential for risk stratification in the selection of patients for surgery. Patient-reported measures are important not only as treatment outcome metrics, but also in predicting tolerance to therapy. Postoperative length of stay is a convenient measurement of patient tolerance of surgery. Our study aim was to determine whether preoperative patient-reported measures could add additional predictive power to clinical variables in predicting postoperative length of stay. Methods: A tablet-based symptom screening tool measured Distress, Anxiety (GAD-2), and cancer-related symptoms preoperatively. A generalized linear model predicting postoperative length of stay was constructed using age, gender, insurance status, income, T stage, and sarcopenia (hand-grip strength &lt; 25kg). Patient-reported variables were then evaluated for their ability to predict length of stay in addition to these clinical factors. Factors found not significant (p &gt; 0.05) are indicated N.S. Results: Esophagectomy (n = 58): Median age 62 (IQR 54-70) and 46 men (79%). Adenocarcinoma in 52 (90%). Neoadjuvant chemoradiation administered in 37 (64%). Major complications occurred in 13 (22%). Median postoperative length of stay was 8 days (IQR 6-10). Distress, Pain, Nausea/Vomiting, Trouble Swallowing, and Insurance or Financial Concerns independently predicted postoperative longer length of stay on multivariable analysis, while accounting for preoperative clinical factors. Conclusions: Preoperative cancer patient symptom reporting adds additional information to traditional clinical factors in predicting length of stay post-esophagectomy. Patient-reported measures may identify patients who benefit from interventions for preoperative optimization.[Table: see text]
Assessment of the Fanconi anemia repair pathway as a predictor of clinical activity of pembrolizumab (PEM).
Authors: Miguel Angel Villalona-Calero, John Paul Diaz, Zuanel Diaz, Wenrui Duan, Eric Douglas Schroeder, Santiago Aparo, Troy Antony Gatcliffe, Alfredo Pedro Alonso, Sebastian Cuitiva, Federico Albrecht, Siddhartha A. Venkatappa, Victor Guardiola, Michael B. Troner, Sara M. Garrido, Gail Walker, Muni Rubens, Fernando I. De Zarraga, Hao Vuong
Journal: Journal of Clinical Oncology (2019)

2555 Background: Given the activity of immune checkpoint inhibitors (ICI) in mismatch repair deficient tumors, we evaluated if homologous recombination repair deficiency associates with solid tumor response to ICI. Methods: We conducted a phase 2 trial (NCT03274661) of PEM in metastatic solid tumor patients progressing on standard of care and for whom PEM had no FDA approved indication. We evaluated a triple stain (FANCD2foci/DAPI/Ki67) immunofluorescence functional assay of the Fanconi Anemia pathway (FATSI) in treated patients’ archived tumors as a correlative biomarker. Patients with microsatellite unstable tumors were not eligible. The primary objective was objective response rate (iORR, CR+PR) by Immune Response Criteria, with the hypothesis that patients with FATSI negative tumors will have better clinical outcome. Secondary objectives were progression free survival (PFS), 6 months PFS and survival. PEM was given every 3 weeks and computed tomography scans were performed every 6 weeks. We utilized a two-stage phase II trial design to detect an iORR ≥ 20% in the whole population tested vs. the null hypothesis that the true iORR ≤5%. If ≥ 2 of the first 20 evaluable patients had an objective response the trial proceeded to full accrual of 39 evaluable patients. Outcomes were evaluated according to FATSI staining. Results: 42 patients (40 evaluable) (35F,7M; median age 62[36-83]) enrolled. Median # of prior regimens was 2[1-7]. Primary Dx included ovarian/fallopian (13), endometrial (10), colorectal (3), cervix (2), pancreatic(2), vaginal (2) and 1 each of various others. No unexpected toxicities occurred. Response evaluation showed 2 CR, 5 PR, 11 SD, 22 PD and 2 NE (iORR 18%). FATSI tumor analyses results are available in 34 patients; 25 FATSI positive, 9 negative. 2 PR, 8 SD, 14 PD, 1 NE occurred among the FATSI (+) (iORR 8%) and 2 CR, 2 PR, 2 SD, 3 PD among the FATSI (-) patients (iORR 44%). mPFS and 6m-PFS were 54 days and 12% (3/25) in FATSI (+), versus 248 days and 56% (5/9) in FATSI (-) patients; p = 0.017. Conclusions: PEM has meaningful antitumor activity in non MSI-high malignancies with no current FDA approved indications. Evaluation of FATSI as a biomarker supports a biomarker selected population approach. Clinical trial information: NCT03274661.
Artificial intelligence and the future of endoscopy: should we be quietly excited?
Authors: Michael F. Byrne
Journal: Endoscopy (2019)

It is quite difficult these days to open a newspaper or webpage without reading about the advent, and possible threat, of artificial intelligence (AI) in our lives, whether that be self-driving cars, ever-improving facial recognition, automation of many hitherto manual jobs, and a litany of other applications. (In general literature, terms such as AI, deep learning, machine learning, and convolutional neural networks are used essentially synonymously.) Unsurprisingly, the field of medicine has not been immune from the "potential" that AI can bring, whether that be in image interpretation, drug discovery, "personalized medicine," genomics, or hospital-wide data analysis, to name just a few opportunities.
Lung cancer in African-Americans and analysis of estrogen plus progestin use.
Authors: Idoroenyi Usua Amanam, Rowan T. Chlebowski, Rebecca A. Nelson, Ravi Salgia
Journal: Journal of Clinical Oncology (2019)

e18258 Background: The 15-year Women’s Health Initiative (WHI) sponsored by the NIH has provided a robust dataset on health risks for post-menopausal black women (BW), including the impact of hormone therapy (HRT) on cancer risk. Women enrolled in the WHI randomized, placebo-controlled trial and taking HRT demonstrated no increase in lung cancer incidence, but a statistically significant increase in mortality. However, effects of estrogen plus progestin on non-small cell lung cancer (NSCLC) incidence and outcomes has not been extensively examined, especially in African Ancestry (AA) and smoking history. Methods: Study participants were identified who met WHI clinical trial entry criteria. Cox regression models and Kaplan-Meier method plots were utilized. Analyses adjusted for age, BMI, education, smoking status, alcohol use, health status, and physical activity. A secondary analysis was performed on BW based on AA via Affymetrix Human SNP Array. Results: 161, 808 pts were enrolled from October 1993 to December 1998 (after exclusions total analytic cohort = 142,503). 128,682 (90%) were white (WW) and 13,821 (10%) were BW. BW had lower incidence of NSCLC compared to WW (HR 0.68; P &lt; .0001). HRT participants had a 55% increase in incidence of NSCLC (p &lt; .0001). Former alcohol users had highest risk of NSCLC incidence (HR 2.72; p &lt; 0.0001). Age groups (55-59 years; 60-69 years; 70-79 years) were significantly less associated with BW compared to the youngest(50-54 years; P &lt; .0001). HRT participants were more likely BW (OR 1.17; p &lt; .0001). More current smokers were BW compared to WW (OR 1.75; p &lt; .0001). HRT participants had increased risk of death to NSCLC (HR 1.29; p &lt; .001). There was a trend for survival (p = 0.3667) in WW participants compared to BW (32 vs 28.0 months, respectively). BW who had &gt; 80% AA had a decreased incidence NSCLC trend compared to BW with &lt; 80% AA (HR 0.81; p = 0.2806). Conclusions: BW, especially those with high levels of AA had decreased incidence of NSCLC. Those patients who received HRT had higher incidence and death from NSCLC. Further investigations are required to understand the mechanisms that AA and HRT alter risks associated with NSCLC.
Long-term symptom burden and quality of life in metastatic melanoma patients treated with checkpoint inhibitors.
Authors: Maha Mamoor, Jessica A. Lavery, Robert Sidlow, Lauren J. Rogak, Bridgette Thom, Niloufer Khan, Shrujal S. Baxi, Jedd D. Wolchok, Michael A. Postow, Deborah Korenstein
Journal: Journal of Clinical Oncology (2019)

e23090 Background: Patients with metastatic melanoma (MMel) who achieve durable long-term responses to checkpoint inhibitors (CI) represent a new type of cancer survivor, but their long-term quality of life (QOL) is poorly described. We measured symptom burden and long-term QOL in MMel patients treated with CIs at Memorial Sloan Kettering Cancer Center (MSK). Methods: Between February and August 2018 we performed a cross-sectional survey of adult patients with MMel treated with CI at MSK beginning at least 12 months prior to this study. Surveys were self-administered online using RedCap. We assessed patient treatment experience and QOL using the PRO-CTCAE bank, EORTC, EQ-5D, and Fatigue Severity Scale. We performed chart abstraction to assess extent of cancer burden, ECOG status, Charlson Comorbidity Index (CCI), concurrent medical conditions, and immune-related adverse events (irAEs) developing during or after treatment. For analysis, we dichotomized age (&lt; 65 vs ≥65) and months from CI initiation (&lt; 25 vs ≥25). Results: We enrolled 107 patients (39% survey response rate); 106 completed surveys. Participants were 57.0% male and 93.5% white, with median age 60.5 years (IQR: 51.1, 67.5 years). 79.4% had a CCI of 0 at start of CI; preexisting autoimmune disorders were rare. Median time since CI initiation was 36.4 months (range: 14.2, 133.9 months). Median length of CI treatment was 7.3 months (IQR: 2.1, 24.3 months); 15 patients were on treatment at the time of survey completion. Among those off treatment at the time of survey completion, median time off treatment was 27.1 months (IQR: 16.7, 40.4 months). The most common irAEs were rash (34.6%), colitis (24.3%), thyroiditis (19.6%), hepatitis (18.7%), and hypophysitis (13.1%). irAEs did not differ by age. Few patients reported symptoms at time of survey, most commonly aching joints (18%), fatigue (14%), aching muscles (13%), and difficulty sleeping (11%). Few (&lt; 12%) had difficulty with physical, role, emotional, cognitive, or social functioning and almost none (1%) reported anxiety, depression or pain on the EQ-5D. QOL was excellent, with a median of 83.3% on the EQ-5D global health score and no differences based on toxicities or time from treatment. Conclusions: Long-term survivors of MMel patients report few burdensome symptoms after CI therapy and have excellent QOL.
Evaluation of TMB estimates for the prediction of response to immune checkpoint blockage.
Authors: Jan Budczies, Michael Allgäuer, Kevin Litchfield, Eugen Rempel, Petros Christopoulos, Daniel Kazdal, Volker Endris, Michael Thomas, Stefan Fröhling, Solange Peters, Charles Swanton, Peter Schirmacher, Albrecht Stenzinger
Journal: Journal of Clinical Oncology (2019)

2632 Background: Tumor mutational burden (TMB) is an emerging biomarker in immuno-oncology (IO). Panel sequencing (PS) is a promising approach for its implementation in clinical practice. Methods: We analyzed TMB as predictor of IO response in a multi-cancer cohort published by Miao et. al. The performance of three large panels (Illumina TSO500, Qiagen TMB [QIAseq] and Oncomine TMB [OTMB]) and two small panels (Illumina TST170 and Oncomine Comprehensive Assay [OCAv3]) was compared to WES by in silico simulations. Separation of responders (PR/CR) from non-responders (PD) was analyzed in the multi-cancer cohort (n = 193), in the lung cancer (n = 36) and in the melanoma (n = 125) subcohort. We also simulated PS in the TCGA pan-cancer cohort. Results: In lung cancer, TMB was strongly predictive for IO response (area under ROC curve [AUC] 0.78-0.94). WES performed (borderline)-significantly better than PS for all five panels (OCAv3: p = 0.011, TST170: p = 0.01, QIAseq: p = 0.048, OTMB: p = 0.063, TSO500: p = 0.11). For the cut-point of 199 mutations, misclassification rates compared to WES (16.7%) were borderline-significantly higher for the small panels OCAv3 (33.3%, p = 0.087) and TST170 (36.1%, p = 0.054), but not for the large panels. In melanoma, TMB was moderately predictive (AUC 0.58-0.63) and WES performed (borderline)-significantly better than the OCAv3, TST170, QIAseq and TSO500 panels. In the multi-cancer cohort, WES did not perform better than PS. TBM estimates from PS include an inherent fuzziness originating from restriction to a limited part of the coding sequence. Based on a random mutation model, we derived a mathematical formula for the coefficient of variation (CV) of TMB: The CV decreases inversely proportional with both the square root of the TMB level and with the square root of the panel size. We showed that the mathematical law is valid for real-word mutation data. Conclusions: Small panels (size &lt; 1 Mpb) performed imprecise in diagnostic TMB estimation. Even using the largest commercially available panels it can be challenging to capture the full predictive information of TMB. The detrimental effect of small panel size can be addressed by using larger panels, but halving the CV of TMB necessitates quadruplication of the panel size.
Impact of protein supplementation on lean muscle mass in adult survivors of childhood cancer engaged in resistance training.
Authors: Matthew R Krull, Carrie R. Howell, Robyn Partin, MS, Ginger Carney, Daniel A. Mulrooney, Leslie L. Robison, Melissa M. Hudson, Kirsten K. Ness
Journal: Journal of Clinical Oncology (2019)

10027 Background: Muscle weakness, low lean muscle mass and poor physical performance are prevalent among adult survivors of childhood cancer. We evaluated the effects of resistance training with and without protein supplementation on lean muscle mass, and muscle strength among childhood cancer survivors. Methods: This double-blind placebo-controlled trial enrolled survivors aged ≥18 to &lt; 45 years. Participants were randomized to resistance training with daily protein supplement (21g protein/day, 90kcal) (RT+S) or resistance training with placebo (sucrose, 90kcal) (RT+P). Both groups received educational materials, access to a local fitness center and a tailored resistance training program with tapered supervision. Lean muscle mass and muscle strength were assessed at baseline and 24 weeks, using dual x-ray absorptiometry and dynamometer testing respectively. Mean changes were compared within and between groups. Results: Of 93 participants randomized, 57 completed the 24-week intervention (24 in RT+S, 33 in RT+P). The mean age was 33.1 (SD 7.0), 67% were white and 47% female. The RT+S group had a significant increase in lean body mass (1.05 kg [SD 2.34], p = 0.04), while the RT+P group did not (0.13 kg [SD 2.19], p = 0.74). Mean change in handgrip strength also improved in the RT+S group (1.98 [SD 4.30], p = 0.03); change approached significance in the RT+P group (1.49 [SD 4.60], p = 0.07). All survivors significantly improved their strength over time (Table) as measured by one max repetition test at baseline and follow-up. Conclusions: Preliminary findings indicate that a supervised resistance training program among adult survivors of childhood cancer that includes protein supplementation is feasible and may increase total lean body mass and muscle strength. Clinical trial information: NCT02501460. [Table: see text]
Analysis of race and gender disparities in mortality trends from patients diagnosed with nasopharyngeal, oropharyngeal and hypopharyngeal cancer from 2000 to 2014.
Authors: Kristine Badin, Asha Nayak Kapoor, Achuta Kumar Guddati
Journal: Journal of Clinical Oncology (2019)

e17533 Background: Squamous cell carcinoma of the nasopharynx, oropharynx and hypopharynx constitutes a majority of head neck malignancies. The incidence-based mortality across different races has been noted to be divergent. This study analyzes the trend in incidence-based mortality from the years 2000 to 2014 amongst both the genders in Caucasian/White and African American/Black patients. Methods: The Surveillance, Epidemiology, and End Results (SEER) Database was queried to conduct a nation-wide analysis for the years 2000 to 2014. Incidence-based mortality for all stages of nasopharyngeal, oropharyngeal and hypopharyngeal cancer was queried and the results were grouped by race (Caucasian/White, African American/Black, American Indian/Alaskan native and Asian/Pacific Islander) and gender. All stages and ages were included in the analysis. T-test was used to determine statistically significance difference between various subgroups. Linearized trend lines were used to visualize the mortality trends of all sub groups. Results: Incidence-based mortality rates (per 1000) for nasopharyngeal, oropharyngeal and hypopharyngeal cancer all races and both the genders is shown in the table below. The male to female gender disparity in mortality is~ 1:3 in patients with nasopharynx across all races and becomes worse to ~1:4 and ~1:5 for patients with oropharyngeal and hypopharyngeal cancers respectively. Notably the highest incidence based mortality for nasopharyngeal cancers is seen in Asian/pacific Islander males and a similar peak is noted for hypopharyngeal cancers in African American/Black males. Conclusions: A significant gender disparity exists in all there pharyngeal cancers across all races. It is unclear if female gender is protective but further study is warranted in a stage- specific and age-specific manner to better understand this disparity.[Table: see text]
Next-generation sequencing (NGS) results among hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) patients treated with a CDK4 &amp; 6 inhibitor: A retrospective observational study based on real-world data.
Authors: Erika Paige Hamilton, Valerie Malyvanh Jansen, Emily Nash Nash Smyth, Daniel Schlauch, Gebra Cuyun Carter, Melinda D Willard, Amanda Misch, Lee Bowman, Yajun Emily Zhu, Samuel McNeely, Aimee Bence Lin, Shaita Picard, Kimberly Blackwell, Howard A. Burris, David R. Spigel
Journal: Journal of Clinical Oncology (2019)

1042 Background: Few real-world studies have characterized the frequency of genomic alterations of MBC tumors. Data characterizing alterations before and after treatment containing a CDK4 &amp; 6 inhibitor (CDK4 &amp; 6i) are similarly limited. We explore the genomic landscape of HR+/HER2- MBC tumors from patients (pts) treated with a CDK4 &amp; 6i in order to characterize potential mechanisms underlying sensitivity and resistance. Methods: NGS results of tumor and liquid biopsies obtained from 130 pts with estrogen receptor (ER+)/progesterone receptor (PR+)/HER2- MBC between Jan 2008 to Sept 2016 were analyzed. All pts received therapy containing a CDK4 &amp; 6i for MBC at a community cancer network and had NGS results available before and/or after exposure to CDK4 &amp; 6i. Samples were classified as sensitive (n = 69; duration of therapy ≥6 mo) or resistant (n = 61; duration of therapy &lt; 6 mo). The frequency of genomic alterations with likely or known significance including short variants, indels, copy number variants, and fusions were characterized. Results: Alterations in 215 unique genes were identified from the NGS results; PIK3CA, TP53, ESR1, CCND1, and FGFR1 were the most frequently altered genes. Select alterations in ESR1 (n = 21 vs 9) and RAD21 (n = 5 vs 0) were more frequent after exposure to CDK4 &amp; 6i. In NGS obtained before exposure to CDK4 &amp; 6i, alterations in select genes including RB1, MDM2, AURKA, and MYC were more frequent in the resistant samples, whereas ARID1A alterations were more frequent in sensitive samples. Of the 6 pts with paired NGS samples pre- and post-CDK4 &amp; 6i treatment, alterations in MYC, CDKN2A, PIK3CA, BRCA1, or RB1 were acquired in 3 pts. Conclusions: Based on real-world data, this study describes the genomic landscape of ER+/PR+/HER2- MBC tumors from pts treated with CDK4 &amp; 6i and identifies potential mechanisms underlying sensitivity and resistance to this new class of drugs. Further evaluation in larger datasets is warranted. Data inclusive of other ER/PR subtypes will be presented.