tbuckley/cabot-search huggingface dataset:
Evaluating the capacity of connectome analysis to predict survival in high-grade astrocytoma.
Authors: Rebecca A. Harrison, Rongjie Liu, Vikram Rao, Melissa Petersen, Hannah Dyson, Shiao-Pei S. Weathers, Kristin Alfaro-Munoz, John Frederick De Groot, Shelli Kesler
Journal: Journal of Clinical Oncology (2019)

2049 Background: While factors such as age, histology and tumor molecular variants (e.g. IDH status) contribute to prognosis in patients with high grade astrocytoma (HGA), there remains a wide variability in patient survival outcomes. The connectome, or brain network organization, incorporates biologic, molecular and environmental processes providing a uniquely parsimonious summary of key prognostic factors. This study compared the capacity of machine learning (ML) models based on baseline connectomics and clinical variables to predict patient survival in HGA. Methods: Patients with a new diagnosis of HGA and a presurgical 3D, T1-weighted MRI available were retrospectively identified. Individual patient connectomes were derived from MRI with 90 cortical/subcortical features. Presurgical clinical features included age, gender, histology, tumor grade and IDH status. Three ML algorithms were implemented: extreme learning machine with Buckley–James estimator (ELMBJ), random survival forest (RSF) with logrank splitting and RSF with concordance index (CI) splitting. For each algorithm, we used a 60/40 training/testing split with 50 iterations and CI as the performance metric. We tested three models: 1) connectome only, 2) clinical only, and 3) connectome plus clinical variables. Results: Of patients identified (n = 105), 66 had glioblastoma and 39 had anaplastic astrocytoma. Thirty-eight harbored IDH mutation. Median overall survival was 27.43 months (SD 39.57). Connectome-only models showed better prediction performance compared to clinical-only models across all algorithms. ELMBJ showed the best performance (connectome median CI = 0.522, clinical CI = 0.201). Connectome models also performed as well as combined models (e.g. median CI = 0.523 for ELMBJ). Conclusions: This study demonstrates the potential of a connectome model to predict survival of patients with HGA. Replication in a larger sample is required to validate these results and refine ML models including examination of additional clinical features. If successful, use of a simple T1 MRI could provide additional variables to augment existing prognostic prediction, especially in scenarios where tumor genotyping is not available.
Determination of eligibility criteria for salvage hysterectomy after definitive radiotherapy/concurrent chemoradiotherapy for residual cervical disease.
Authors: Munetaka Takekuma, Fumiaki Takahashi, Takahide Arimoto, Mitsuya Ishikawa, Yukinobu Ota, Masahiro Kagabu, Takahiro Kasamatsu, Hiroyuki Kanao, Naoki Kawamura, Ryo Kitagawa, Wataru Kudaka, Shiro Suzuki, Kazuhiro Takehara, Michihiro Tanikawa, Takafumi Toita, Yoko Hasumi, Satoe Fujiwara, Mika Mizuno, Hiroaki Kobayashi, Nobuo Yaegashi
Journal: Journal of Clinical Oncology (2019)

5524 Background: Patients with persistent cervical cancer after definitive radiotherapy/concurrent chemoradiotherapy (RT/CCRT) have a poor prognosis. Salvage hysterectomy (HT) is potentially curative, but eligibility criteria therefor have not been determined. Methods: Part 1) Retrospective review of patients with persistent cervical cancer treated with definitive RT/CCRT at 35 institutions of the Japanese Clinical Oncology Group (JCOG) from 2005–2014. Differences between a salvage HT group and a systemic chemotherapy (CT) group after definitive RT/CCRT for residual tumor were evaluated. Clinical variables influencing a salvage HT treatment decision were evaluated using logistic regression analysis. Part 2) Questionnaire-based survey conducted by JCOG gynecologic oncologists assessing treatment choice for patients with residual cervical disease after definitive RT/CCRT. Patients with residual cervical tumor before, during and after definitive RT/CCRT were surveyed for 86 conditions and appropriate candidates for salvage HT were evaluated using heat map analysis. Results: Part 1) We identified 298 patients who underwent salvage HT or systemic CT. Median overall survival was 3.8 and 0.9 year in the HT and CT groups, respectively (HR 0.4341, 95% CI 0.336-0.559, p &lt; 0.01). FIGO stage and lymph node metastasis at initial treatment, performance status (PS) at diagnosis of residual cervical tumor and parametrial invasion of residual cervical tumor significantly influenced a salvage HT treatment decision. Part 2) Heat map analysis showed that surveyed variables segregated into 3 groups: i) in favor of salvage HT, ii) in favor of systemic CT, and iii) either. Conditions such as FIGO stage IB-IIB, PS of 0-1, residual tumor &lt; 4 cm, no parametrial invasion and no residual lymph node metastasis were included in group i, in favor of salvage HT. Conclusions: Eligibility criteria could be determined based on the results of the current study, and a prospective clinical trial evaluating the survival benefit of salvage HT for residual cervical tumor after definitive RT/CCRT is being planned by JCOG.
Randomized phase II study on the influence of <i>BRAF</i> and <i>PIK3CA</i> mutations on the efficacy of FOLFIRI plus bevacizumab (Bev) or cetuximab (Cet), as first line therapy of patients (pts) with <i>RAS</i> wild-type metastatic colorectal carcinoma (mCRC) and &lt;3 baseline circulating tumor cells (bCTCs).
Authors: Enrique Aranda, Pilar Garcia-Alfonso, Jose María Vieitez, Maria Jose Ortiz, Carlos López-López, Juan José Reina-Zoilo, Antonieta Salud Salvia, Guillermo Alfonso Quintero Aldana, Luis Robles, Maria Jose Safont, Adelaida La Casta Munoa, Inmaculada Alés, Eduardo Polo Marques, Javier Gallego Plazas, Beatriz García de Paredes, Rafael Lopez, Guillot Mónica, Manuel Valladares-Ayerbes, Javier Sastre, Eduardo Díaz-Rubio
Journal: Journal of Clinical Oncology (2019)

3549 Background: The outcome for mCRC has changed since the introduction of new chemotherapy schedules and targeted therapies, however new predictive biomarkers are needed. bCTCs and BRAF / PIK3CA mutations have been studied as a potential predictive biomarkers. The primary endpoint was progression-free survival (PFS) in pts WT KRAS and &lt;3 bCTCs, according to BRAF/ PIK3CA status. Methods: This is an open, multicentric, randomized phase II trial and included wildtype KRAS mCRC pts (RAS after approval of protocol amendment), younger than ≤70 with &lt;3 bCTCs, ECOG 0-1 and available tissue for molecular analyses. Pts were stratified per number of metastatic organs involved (1 vs &gt;1) and mutation status of BRAF and/or PIK3CA (WT vs MUT) and randomized to group A (FOLFIRI+Bev) or group B (FOLFIRI+Cet). Results: 240 pts (196 WT and 44 MUT: 6 BRAF, 12 PIK3CA and 6 BRAF + PIK3CA) were included. General characteristics per mutation status (WT vs MUT): Mean age (59 vs 61 years), gender (Male/Female 68/32 vs 70/30%), ECOG 0/1 (57/43 vs 66/34%), primary tumor unresected (48 vs 64%), RAS MUT in 12 pts (11 and 1 pts, respectively), previous chemotherapy (12 vs 9%). Overall response rate (ORR) was 52 and 41% in the WT and MUT groups, respectively. PFS and overall survival (OS) are presented in the table. Conclusions: In the low risk mCRC pts according to bCTCs, BRAF and/or PIK3CA MUT have a negative impact in OS and a trend to worse PFS in the ITT population. The impact of treatment is under evaluation and will be provided during the meeting. Clinical trial information: 2012-000840-90. [Table: see text]
Development and validation of a deep learning model to assess tumor progression to immunotherapy.
Authors: Yi Yang, Jiancheng Yang, Yuxiang Ye, Tian Xia, Shun Lu
Journal: Journal of Clinical Oncology (2019)

e20601 Background: Manual application of length-based tumor response criteria is the standard-of-care for assessing metastatic tumor response. It is technically challenging, time-consuming and associated with low reproducibility. In this study, we presented a novel automatic Deep Neural Networks (DNNs) based segmentation method for assessing tumor progression to immunotherapy. Next stage, AI will assist Physicians assessing pseudo-progression. Methods: A data set of 39 lung cancer patients with 156 computed tomography (CT) scans was used for model training and validation. A 3D segmentation DNN DenseSharp, was trained with an input size of on CT scans of tumor with manual delineated volume of interest (VOI) as ground truth. The trained model was subsequently used to estimate the volumes of target lesions via 16 sliding windows. We referred the progression-free survival (PFS) only considering tumor size as PFS-T. PFS-Ts assessed by longest tumor diameter (PFS-T diam ), by tumor volume (PFS-T vol ), and by predicted tumor volume (PFS-T pred-vol ) were compared with standard PFS (as assessed by one junior and one senior clinician). Tumor progression was defined as &gt; 20% increase in the longest tumor diameter or &gt; 50% increase in tumor volume. Effective treatment was defined as a PFS of &gt; 60 days after immunotherapy. Results: In a 4-fold cross-validation test, the DenseSharp segmentation neural network achieved a mean per-class intersection over union (mIoU) of 80.1%. The effectiveness rates of immunotherapy assessed using PFS-T diam (32 / 39, 82.1%), PFS-T vol (33/39, 84.6%) and PFS-T pred-vol (32/39, 82.1%) were the same as standard PFS. The agreement between PFS-T vol , and PFS-T pred-vol was 97.4% (38/39). Evaluation time with deep learning model implemented with PyTorch 0.4.1 on GTX 1080 GPU was hundred-fold faster than manual evaluation (1.42s vs. 5-10 min per patient). Conclusions: In this study, DNN based model demonstrated fast and stable performance for tumor progression evaluation. Automatic volumetric measurement of tumor lesion enabled by deep learning provides the potential for a more efficient, objective and sensitive measurement than linear measurement by clinicians.
Esophageal cancer: Five years of experience in an oncological reference center.
Authors: José Carlos Cessa-Zanatta, Fernando Alcorta-Nuñez, Carlos Eduardo Salazar-Mejía, Juan Manuel Muñoz-Ayala, Celia Beatriz Gonzalez-Alcorta, David Hernandez Barajas, Juan Francisco Gonzalez-Guerrero, Oscar Vidal-Gutiérrez, Adelina Alcorta-Garza
Journal: Journal of Clinical Oncology (2019)

e15536 Background: Squamous cell carcinoma and adenocarcinoma represent approximately 95% of malignant tumors of the esophagus. For most cases of the 20th century, squamous cell carcinoma was the predominant lineage. In the 1960s, squamous cell carcinoma accounted for more than 90% of all esophageal tumors in the United States of America, and adenocarcinoma was considered so uncommon that some oncological associations questioned its existence. However over time the incidence of esophageal adenocarcinoma (predominantly in the distal esophagus and gastroesophageal junction) has increased dramatically in Western countries, with adenocarcinoma now causing more than 60% of all esophageal cancers in the United States of America, unlike the rest of the world, where squamous cell carcinoma continues to predominate. Squamous cell carcinoma and adenocarcinoma differ in a significant number of clinical features, including tumor location and predisposing factors. Smoking and alcoholism are major risk factors for the development of squamous cell carcinoma, while the Barrett's esophagus with intestinal metaplasia (a complication of gastroesophageal reflux disease), obesity, and smoking are the risk factors related to adenocarcinoma of the esophagus. Objectives: To determine the incidence of esophageal adenocarcinoma in Mexico and its main characteristics, such as epidemiology, histological type and main risk factors. Methods: A descriptive analysis was conducted in which the histological type, age of diagnosis, location, age of the patients and risk factors were compared. Results: Average age on the studied population was 67.4 years (minimum 37, maximum 91); 74.3% of the subjects were male and 20.4%, female. It was found that the predominant histological type was Adenocarcinoma in 40.7% against 28.3% of the Epidermoid. Average age of diagnosis was at 65.88 years (minimum 37, maximum 89). In frequency of localization, lower third in 22.1%, union GE in 20.4%, middle third in 15%, and upper third in 12.4%). The predominant risk factors in our study were smoking (31%), alcoholism (36.3%) and GERD (12.4%). Conclusions: Oesophageal adenocarcinoma continues to be the most prevalent presentation of esophageal cancer in our population, despite epidemiological changes over time.
MEDIPLEX: A phase 1 study of durvalumab (D) combined with pexidartinib (P) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC).
Authors: Philippe Alexandre Cassier, Gwenaelle Garin, Lauriane Eberst, Jean-Pierre Delord, Sylvie Chabaud, Catherine Terret, Laure Montane, Anne-Sophie Bidaux, Séverine Laurent, Lise Jaubert, Celine Ferlay, Mathilde Bernardin, Séverine Tabone-Eglinger, Laurence Gilles-Afchain, Christine Menetrier-Caux, Christophe Caux, Isabelle Treilleux, David Pérol, Carlos Alberto Gomez-Roca
Journal: Journal of Clinical Oncology (2019)

2579 Background: Targeting tumor associated macrophages is an emerging strategy to increase the responsiveness of PDAC and CRC to anti-PD(L)1. Pexidartinib (P) is an orally active, small-molecule kinase inhibitor that targets the colony-stimulating factor-1 receptor (CSF1R) on macrophages. Methods: Adult pts with advanced/ metastatic PDAC or CRC were treated with a fixed dose of D (1500mg q4w, IV) and ascending doses of P (400, 600, 800 and 1000mg/d, orally). Dose escalation was conducted according to a Likelihood Continual Reassessment Method with a 28-day window to evaluate dose-limiting toxicity (DLT), a stopping rule advised dose escalation termination in case of a high probability ( &gt; 90%) for the next 6 pts to be assigned to the same dose. Following the determination of RP2D, 14 pts with PDAC and 14 pts with CRC who consented to serial tumor biopsies were enrolled in expansion cohorts to assess preliminary anti-tumor activity and biomarkers. Results: 19 pts (12M, 7F, median age, 56 y [range, 43-76y]) were enrolled in 4 dose escalation cohorts (P 400, 600 and 800mg/d: 3 pts each and P 1000mg/d: 10 pts). Pharmacokinetic analysis showed dose-dependent increase in the exposure of P from 400 to 1000 mg. Two DLTs (AST/ALT elevations including one with bilirubin increase) were seen at dose level P 1000mg/d. The most frequent ( &gt; 2pts) related (to either D, P or both) AEs were: fatigue, maculopapular rash/pruritus/dry skin, hair color changes, anorexia, edema (periorbital, limbs or face), AST/ALT increases, bilirubin increases, nausea, vomiting and diarrhea. The most frequent (≥2pts) Grade ≥ 3 AEs related to P were: AST/ALT increase, ALP increase, neutrophil or white blood cell count decrease, and fatigue. Clinical benefit rate at 2 months was 21% (4 SD /19pts), 2 pts with MSI-H CRC had SD for more than 6 months including 1 pt still receiving single agent D after &gt; 18 months. The RP2D for the combination was P 800mg/d + D 1500mg q4w. Enrolment in the expansion cohorts was completed in January 2019. Conclusions: Toxicity was consistent with the expected profiles of the individual drugs and no unexpected events were seen with the combination. Updated data will be presented at the meeting. Clinical trial information: NCT02777710.
Blood-based genomic profiling of circulating tumor DNA from patients with advanced biliary tract cancer.
Authors: Junying Wang, Jia Song, Jing Zhao, Yuzi Zhang, Shangli Cai, Chen Chen
Journal: Journal of Clinical Oncology (2019)

1576 Background: Biliary tract cancer (BTC) is a highly lethal malignancy as diagnosis occurring at late stages and marginally sensitive to chemotherapy. Increasing evidence indicates targeted therapeutics may provide new hope for improving clinical response in BTC, hence better comprehending the genomic profile is particularly important. However, tissue of BTC is highly wide tumor heterogeneity and often inadequate for molecular characterization, a proper method is urgently needed. Circulating tumor DNA (ctDNA) is an emerging technology for detecting actionable alterations, and may be regarded as a reliable tool to reveal genomic signature. Methods: Next-generation sequencing (NGS) targeted 150 cancer-related genes was used to detect blood-based ctDNA from 154 Chinese patients with BTC. The mean sequencing depth was more than 3000×. Somatic genomic alternations (GA) including single nucleotide variation (SNV), copy number variation (CNV) and fusion were analyzed and compared with an internal tissue genomic database (545 Chinese patients with BTC) tested by NGS and TCGA database (n = 227) tested by the whole exome sequencing (WES). Allele frequency (AF) represented the percentage of mutant allele reads relative to total allele reads (mutant plus wild type). Maximum somatic allele frequency (MSAF) was defined as the maximum AF (0.1% &lt; AF &lt; 35%) of all the somatic alterations identified per sample. Results: Among ctDNA database, at least one GA was found in 95% (147/154) of samples (a median of 4 GA per patient). The median MSAF across all cases was 6.47% (range, 0%-34.8%). Pathologic type (P &lt; 0.001) and sex (P &lt; 0.001) were significantly related with MSAF, respectively. Frequencies of SNV in commonly mutated genes from ctDNA were similar to those observed among tissue samples, like TP53 (35.1% vs 40.4%) and KRAS (20.1% vs 22.6%), however, a little lower in TCGA database (TP53 24.2%; KRAS 10.1%). Besides, the consistency of CNV detected from ctDNA and tissue was relatively poor, and tumor heterogeneity might be in charge of this phenomenon. Among the highly frequent mutations (AF &gt; 5%) in ctDNA, 45% of genes was considered as druggable targets, such as EGFR/RAS/RAF pathway and AKT/mTOR/PI3K pathway. Conclusions: These findings demonstrated that ctDNA tested by NGS was feasible in revealing genomic profiles and identifying potential therapeutic targets. Noninvasive ctDNA could be used as a complementary approach to tissue testing in patients with metastatic BTC.
Outcomes with CDK4/6 inhibitors based on endocrine sensitivity in hormone receptor-positive metastatic breast cancer (HR+ MBC).
Authors: Amit L Jain, Janice Nhan Mullins, Kelsey Anne Poorman, Amina Chaudhry, Harsha Avinash Ranganath, Emily McCollum Miller, Poojitha Valasareddy, Justin R Smith, Julie Ryder, Michelle Winerip, Lee S. Schwartzberg, Gregory A. Vidal
Journal: Journal of Clinical Oncology (2019)

e12526 Background: PALOMA-3 results demonstrated that patients (pts) with sensitivity to previous endocrine therapy had a substantial benefit with Palbociclib compared to those with intrinsic endocrine resistance (Turner NC et al. NEJM 2018). ESR1 mutation has been associated with decreased response to endocrine therapy (Fribbens C et al. JCO 2016) and NSD3 amplification in breast cancer cells have been correlated with the overexpression of ESR1 (Irish JC et al. Mol Oncol 2016). Here we demonstrate a real-world response to CDK4/6i based on high-risk features and correlation to biomarkers of response. Methods: We retrospectively analyzed 115 HR+MBC pts at a single large community cancer center who received CDK4/6i + endocrine therapy and 40 matched controls treated with endocrine therapy and underwent NextGen Sequencing (NGS) profiling of 592 genes (Caris Life Sciences, Phoenix, AZ). The primary outcome was progression-free survival (PFS). Hazard ratios were calculated from Cox proportional hazards models built using the survival package[1] in R. Results: Among 115 pts in the CDK4/6i cohort, the median PFS for pts treated in the first-line (N=77) versus (vs.) second-line (N=38) was 9.7 and 4.6 months (mo) respectively (HR 2.04, p=0.001). Further, the median PFS in first-line cases who had a Disease-Free Survival (DFS) of &gt;2 years (endocrine sensitive) (N=27) was 11.9 mo, and in pts with DFS &lt; 2years (endocrine resistant) (N=24), it was 7.7 mo (HR 0.71, p= 0.397). Six pts with ESR1 mutations had worse PFS compared to ESR1 wild-type (N=40) when treated with CDK4/6i in 1st line, 6.4 vs. 18 mo (HR: 2.25, p=0.052) and 2 nd line 2.5 (N=9) vs. 5.6 mo (N=17) HR: 2.09, p=0.1). NSD3 amplification was the only other genomic alteration showing significance as a negative predictor of PFS (first-line: 6.1 vs. 14.7 mo, HR: 2.40, p=0.04; second-line: 2.8 vs. 6.5 mo, HR: 3.61, p=0.06). NSD3 amplification appeared to have no significant effect in the control cohort 6.5 vs. 4.4 mo, (HR 1.29, p=0.63). Conclusions: In this real-world cohort, CDK 4/6 combination therapy benefits HR+ MBC patients in the first and second-line setting. ESR1 mutation is a predictor of worse outcome. NSD3 gene amplification is a potential biomarker of resistance to CDK4/6i combination therapy. (Therneau T (2015). A Package for Survival Analysis in S version 2.38, https://CRAN.R-project.org/package=survival).
A novel association between <i>GSTM1</i> null variant and anthracycline-induced cardiac dysfunction (ACD) in childhood cancer survivors (CCS): A COG ALTE03N1 report.
Authors: Purnima Singh, Xuexia Wang, Lindsey Hageman, Yanjun Chen, Tarek Magdy, Wendy Landier, Jill P. Ginsberg, Joseph Philip Neglia, Charles A. Sklar, Sharon M. Castellino, ZoAnn Eckert Dreyer, Melissa M. Hudson, Leslie L. Robison, Javier G. Blanco, Mary V. Relling, Paul Burridge, Smita Bhatia
Journal: Journal of Clinical Oncology (2019)

10030 Background: ACD is a leading cause of mortality in CCS. Previous studies have identified genomic variants that moderate the ACD risk. An agnostic evaluation of differential gene expression between those with and without ACD has not been explored, and could provide insights into the mechanism of cardiotoxicity. Methods: Gene expression profiles in leukocyte RNA from anthracycline-exposed non-Hispanic white (NHW) CCS (20 with ACD [cases]; 20 without ACD [controls]) used Illumina HumanHT-12 v4.0 Expression Beadchips. Gene expression profiles in h uman iPSC-derived cardiomyocytes (hiPSC-CMs – Day 30) from 6 childhood cancer patients (3 each with and without CD) treated with 1μM doxorubicin or vehicle for 24 h, used RNA-seq. Genotyping in leukocyte DNA from anthracycline-exposed NHW CCS (65 cases; 76 controls) to determine if the differentially-expressed genes mapped to genetic variants that modified ACD risk, used conditional logistic regression analysis adjusted for sex, age at cancer diagnosis, chest radiation and anthracycline dose. Patient characteristics are in Table. Results: Gene-expression in survivors:Glutathione S transferase mu 1 ( GSTM1) was differentially-expressed; RT q-PCR showed significant downregulation of GSTM1 in cases (0.67±0.57 vs. 1.33±1.33, p=0.049). hiPSC-CMs gene expression: GSTM1 was downregulated in patients with ACD (logFC = -1.4). Genotyping: Using PCR for GSTM1 null, we observed a significant association between CD risk and GSTM1 null genotype (OR=3.0; 95%CI, 1.4-6.2, p=0.003). Conclusions: We report an association between GSTM1 null genotype and ACD, previously unreported likely because GWAS studies did not examined gene deletions. GSTM1 is involved in detoxification of anthracyclines. This finding could facilitate identification of childhood cancer survivors at increased risk of ACD. [Table: see text]