tbuckley/cabot-search huggingface dataset:
ctDNA as a potential prognostic marker for locally advanced rectal cancer patients with ‘watch and wait’ approach.
Authors: Lifeng Yang, Yaqi Wang, Hua Bao, Juefeng Wan, Xiaojun Fan, Hairong Bao, Lijun Shen, Yun Guan, Xue Wu, Yang Shao, Ji Zhu, Zhen Zhang
Journal: Journal of Clinical Oncology (2019)

3544 Background: ‘Watch and Wait’ policy has currently led to growing interest for organ-preservation after neoadjuvant chemoradiation (nCRT) to improve quality of life. However, how to predict and select patients who may achieve clinical complete response is still an unsolved issue. We conducted a pilot study to evaluate the potential role of ctDNA as a biomarker to predict treatment outcome and improve risk stratification in locally advanced rectal cancer (LARC). Methods: In this study, we recruited 119 patients with LARC receiving nCRT. 595 serial plasma samples were collected at d0, d15, d25 of radiotherapy as well before and 7 days post surgery. The level of ctDNA was calculated by dynamic monitoring the mutant allele frequency of somatic mutations in plasma. Plasma and tissue samples were subjected to targeted-NGS using a 422 cancer-related genes panel. We followed up patients with concomitant CT until disease progression or death. Results: Detected mutation of TP53 and APC gene in pre-treatment samples was negatively correlated with patients’ response to nCRT. Alterations in homologous recombination and adherens junction pathways were associated with a better response (P &lt; 0.05). Detection of pre-treatment mutations in any time points during nCRT was significantly (P = 0.03) decreased from TRG3 to TRG0 group (33%, 29%, 22% and 4%, respectively); while detection of acquired mutations showed an opposite trend (P = 0.04). A predictive model based on support vector machine was developed for prediction of pCR achieving a mean AUC of 0.85 assessed by repeated cross validation. Further, detection of pre-treatment mutations after completion of nCRT was significantly associated with worse disease-free survival (DFS) (P &lt; 0.05). Through tracking clonal extinction, persistence and emergence, patients were grouped into four evolutionary subtypes with distinct TRG and DFS. Conclusions: Our data showed the prognostic value of ctDNA on DFS. Dynamic monitoring of ctDNA can be used to predict TRG and prognosis in LARC patients receiving nCRT. ctDNA sequencing depicts the evolutionary trajectories of sensitive and resistant clones during nCRT in LARC. CtDNA could potentially be used to guide patient selection for W&amp;W strategy.
Towards an External Quality Assessment for Next Generation Sequencing in the Diagnosis of Rare Inherited Anaemias
Authors: Noemi Roy, Melanie Proven, Irene Roberts, Hannah Tamary, Dorine W. Swinkels, Aguilar-Martinez Patricia, Paola Bianchi, Raffaella Colombatti, Roberta Russo, Barnaby Clark, Mayka Sanchez, Rafael Andres DEL Orbe Barreto, Elisa Fermo, Vip Viprakasit, Jiraporn Korchuenjit, Tabita Magalhães Maia, Frances Smith, Maria del Mar Manu, Lydie Da Costa, Antonio Marzollo, Anabelen Hozdelarastrollo, Beatriz Arrizabalaga, Delasalle Barbara, Achille Iolascon
Journal: Blood (2018)
New onset diabetes as a predictive factor of focal lesions in the pancreas in a high-risk screening program.
Authors: Maria Fernanda Montiel, Pompeyo Rafael Quesada, Margaret Dunseith, Irina Cazacu, Alexandra Luzuriaga, Wenli Dong, Sarah A. Bannon, Maureen E Mork, Lei Feng, Y. Nancy You, Eduardo Vilar Sanchez, Banu Arun, Powel Brown, Michael Paul Kim, Matthew H. G. Katz, Anirban Maitra, Manoop S. Bhutani, Florencia McAllister
Journal: Journal of Clinical Oncology (2019)

1512 Background: Genetic evolution studies have suggested the existence of a window of opportunity to improve clinical outcomes by intercepting pre-malignant lesions. This study reports the outcomes of Pancreatic Cancer (PC) surveillance in a high risk (HR) cohort followed at The University of Texas MD Anderson Cancer Center (MDA) between 2014 and 2018. Methods: The MDA PC High-Risk Clinic (MDA-PCHRC) performs surveillance based on risk stratification. This study reports 54 months of surveillance. The patients were stratified based on PC family history, personal history of other cancers, and germline mutations ( BRCA1/2, PALB2, STK11, CDKN2A, TP53) with high susceptibility to PC. Low risk patients were not offered surveillance while patients in the moderate or high-risk category were enrolled into a program which included annual screening with blood markers (CA 19-9, fasting glucose, HbA1C, amylase, and lipase) and magnetic resonance imaging/ cholangiopancreatography (MRI/MRCP). High risk patients also had a baseline endoscopic ultrasound (EUS). We evaluated the yield of premalignant lesions detection and our main goal was to detect predictive factors of focal pancreatic lesions and to validate our risk stratification strategy. Results: A total of 206 patients have been referred to our clinic during this time period. From this group, 126 (61%) patients completed at least one cycle of baseline surveillance, for the purposes of the analysis we only focus in the high risk (n=71) and moderate risk group (n=38). We have identified de novo pancreatic focal lesions in 22 patients, 20 from the high risk group (28%) and 2 from the moderate group (5%). Those lesions included 7 patients with simple cysts, 9 with side-branch IPMN, 3 with main duct IPMN, 1 with pseudocyst, 1 with mucinous cyst and 1 with a solid nodule (pancreatic neuroendocrine tumor). We compared demographic information (age, gender, and ethnicity) as well as family and personal medical history between patients with focal pancreatic lesions vs negative or diffuse findings. We found that new onset diabetes was significantly correlated with presence of focal pancreatic lesions 5 (22%) of patients with focal lesions versus patients without non focal lesion 2 (2%) ( P=0.003). Conclusions: Screening at the MDA-PCHRC detect pancreatic premalignant lesions in 20% of the patients in our cohort. We validated our risk stratification methodology and found that new-onset diabetes is predictive of pancreatic lesions, thus suggesting that this factor could be an important biomarker of focal lesions in a HR population.
BRCA 1/2 mutations in high-grade serous ovarian cancer (HGS-OC) patients of three Latin American countries: Report of 412 cases.
Authors: Juan Molina, Omar Orlando Castillo Fernandez, Maria Lim, Luis Mas, Ignacio Fernando Veliz, Carmen Vargas
Journal: Journal of Clinical Oncology (2019)

e14288 Background: Ovarian Cancer (OC) is the most common gynecologic cancer in women in the World and with elevated mortality. High Grade Serous Ovarian Cancer (HGS-OC) is a common histotype and closely related with the presence of BCRA abnormalities. This is to our knowledge the first report of a large series of patients with HGS-OC evaluated in Latin-American countries. The study aim was to present the data obtained from Perú, Costa Rica and Panamá from January 2016 to December 2018. Methods: A cross-sectional evaluation was performed in patients diagnosed between 2016 and 2018 with HGS-OC in three countries in Latin America. The patients were selected from Cancer National Reference Centers in Perú, Panamá and Costa Rica. Germline BRCA 1 / 2 mutations were evaluated through Next Generation Sequencing (NGS) in blood samples. Results: During the period 412 HGS-OC were studied. The mean age at diagnosis was 56.55(SD:12.21) years for all the evaluated patients and 55.42(SD:8.60) years in the mutated cases. Pathogenic HGS-OC mutations in germline BRCA 1 / 2 were diagnosed in 72 cases. Germline BRCA 2 mutations were the most frequent abnormality detected in Panama and in Costa Rica with 70.0 %(7/10) and 77.8%(14/18), respectively. However in Perú, germline mutations in BRCA 1 represents the majority of the mutations with 79.3%(35/44). Variants of uncertain significance (VUS) were detected in 3.64 %(15/412). Positive family history for breast or ovarian cancer were detected in 13.8% of patients with pathogenic mutations(10/72). Specific mutation distribution evidenced in Perú that 6 of 44(13.6%) mutated patients had the mutation in BRCA 1 c.2105dupT; 6 patients of 18(33.3%) had the mutation in BRCA 2 c.5303_5304delTT in Costa Rica and 2 cases had the mutation in BRCA1 c.5186C &gt; A in Panama. The rest of mutations were less common. Conclusions: The frequency of Germline mutations BRCA 1 and BRCA 2 in patients with HSG-OC is similar to the reported in developed nations. However, the different mutation profile between the studied countries could be explained by the Latin-American genetic diversity. Most of the mutations we report were not described in previous studies evaluating breast cancer susceptibility.
Aggressiveness of care and overall survival in young metastatic colorectal cancer patients.
Authors: Madeleine Fish, Katie Kanter, Gianluca Mauri, Nora Horick, Jill N Allen, Lawrence Scott Blaszkowsky, Jeffrey William Clark, David P. Ryan, Ryan David Nipp, Bruce J. Giantonio, Lipika Goyal, Janet E. Murphy, Eric Roeland, Colin D. Weekes, Jennifer Yon-Li Wo, Theodore S. Hong, Andrew X. Zhu, Emily E. Van Seventer, Ryan Bruce Corcoran, Aparna Raj Parikh
Journal: Journal of Clinical Oncology (2019)

3563 Background: Colorectal cancer (CRC) incidence in patients younger than 50 years of age is steadily rising by 2% annually. Early-onset CRC usually presents with more aggressive features; however, data on prognosis are widely conflicting. Clinicians may hold an age-related bias in treating younger patients, but this proclivity and its effects have not been quantified. Methods: Patients with a history of metastatic CRC who consented to a departmental chart review protocol were collected between 2014 and 2018 at Massachusetts General Hospital. The cohort was divided into two groups based on age at initial diagnosis: &lt; 50 and ≥50. Data were gathered on treatments and clinicopathological features. A log-rank test compared survival from the diagnosis of metastatic disease between age groups. The distributions of clinicopathological features were compared using Wilcoxon rank sum tests. Results: 464 metastatic CRC patients were identified. 155 patients (33%) were &lt; 50 (median age 43, 49% female) and 309 patients (67%) were ≥50 (median age 61, 45% female). Sex did not significantly differ between the two groups (p = 0.45). Patients &lt; 50 received more lines of therapy after metastatic diagnosis than patients ≥50 (mean 2.7 v. 2.2; p = 0.002). Younger patients also received more resections of distant metastases (mean 0.62 v. 0.48; p = 0.01). A higher rate of enrollment in clinical trials for patients &lt; 50 approached significance (p = 0.06). Even so, patients &lt; 50 did not see a significant survival benefit over older patients (2/5-year survival from metastatic diagnosis 77%/47% v. 73%/38%, p = 0.23). Patients &lt; 50 had a lower proportion of right-sided tumors (p = 0.0002) and BRAF mutations (p = 0.0009). There was no difference in MSI status (p = 0.28), RAS mutational status (p = 0.40), mucinous features (p = 0.53), or signet ring features (p = 0.26). Conclusions: Overall survival in patients &lt; 50 is similar to patients ≥50, despite patients &lt; 50 receiving more aggressive therapy. Further study is warranted to better understand these differences. Potential areas of interest include performance status, age-related treatment bias, and biological factors.
Targeting IGF-1/2 with xentuzumab (Xe) plus enzalutamide (En) in metastatic castration-resistant prostate cancer (mCRPC) after progression on docetaxel chemotherapy (DCt) and abiraterone (Abi): Randomized phase II trial results.
Authors: Syed A. Hussain, Pablo Maroto, Miguel Ángel Climent, Diletta Bianchini, Robert Hugh Jones, Chia-Chi Lin, Shian-Shiang Wang, Emma Dean, Kate Crossley, Laura Schlieker, Thomas Bogenrieder, Johann S. De Bono
Journal: Journal of Clinical Oncology (2019)

5030 Background: Insulin-like growth factor receptor-1 (IGF-1R) signaling activates the PI3K/AKT pathway and may lead to androgen receptor (AR) transactivation and progression to endocrine treatment resistance. Xe, an IGF-ligand-neutralizing antibody, binds to IGF-1 and IGF-2 and inhibits IGF-1R signaling. This multi-center randomized phase II trial (NCT02204072) evaluated anti-tumor activity of Xe plus En in mCRPC. Methods: Men with histologically/cytologically confirmed mCRPC and progression after DCt+Abi were randomized to receive Xe 1000mg IV QW + En 160mg/day oral, or En alone (28-day cycles until progression or intolerable adverse events [AEs]). Primary endpoint: progression-free survival by investigator assessment (PFS-IA); secondary: PFS by central review (PFS-CR), overall survival (OS), AEs. Results: Overall, 43 patients were randomized per arm; 70% Caucasian and 29% Asian (median age 70 y; range 46–88). At baseline (BL) the two arms were generally well balanced, although 33% v 47% were ECOG PS O, and 72% v 56% had a Gleason total score ≥8. By data cut-off (23 October 2017), 39/43 (Xe+En) and 38/43 patients (En) had discontinued, most due to disease progression. The median PFS-IA was 7.4 m for Xe+En (95% CI: 3.5–8.7) and 6.2 m for En (3.5–11.1) [HR = 0.99 (0.56–1.73); p = 0.96]. The results were similar after adjusting for BL ECOG PS and Gleason score. The median PFS-CR was 3.6 m for Xe+En (3.5–8.1) and 6.2 m for En (3.6–8.3) (HR = 1.22 [0.70–2.13]; p = 0.48). OS data are immature. For the two arms, prostate-specific antigen (PSA) response rates were 21% and 19%; maximum decline in PSA: -20 v -9 μg/L; PSA change at week 12: 19% v 18%; maximum decline in circulating tumor cells (CTC): -52% v -35%; and CTC response: 16% v 11%. The most frequently reported AEs were: fatigue 67% v 49%; decreased appetite 56% v 54%; weight reduction 37% v 12%; anemia 33% v 44%; back pain 30% v 37%. Nine patients discontinued Xe due to AEs. Conclusions: Addition of Xe to En did not prolong PFS in mCRPC compared with En alone. There were no notable differences in PSA-related endpoints and CTC between arms. Clinical trial information: NCT02204072.
Bone metastases as predictors of treatment response and rapidly progressive disease in NSCLC patients on PD-1/PD-L1 immune checkpoint inhibitors (ICI).
Authors: Sally CM Lau, Lisa W Le, Elliot Charles Smith, Sze Wah Samuel Chan, Malcolm Ryan, M. Catherine Brown, Katrina Hueniken, Lawson Eng, Devalben Patel, RuiQi Chen, Mike Ru Sung, Alona Zer, Penelope Ann Bradbury, Pamela S Ohashi, Frances A. Shepherd, Ming Sound Tsao, Geoffrey Liu, Natasha B. Leighl, Adrian G. Sacher
Journal: Journal of Clinical Oncology (2019)

e20667 Background: The tissue microenvironment associated with specific organ metastases potentially influences the efficacy of checkpoint inhibitors. The presence of liver metastases is a predictor of poor response and survival in melanoma and is correlated with reduced CD8+ T cell infiltration. Our study examined clinicopathologic characteristics, focusing on sites of metastatic disease, that are associated with poor outcomes. Methods: Advanced NSCLC patients treated with ≥1 cycle of ICI were reviewed. Baseline age, sex, histology, stage, smoking status, ethnicity, PD-L1 expression and sites of metastases were recorded. Best overall response (BOR) was determined by clinical imaging response and categorized ordinally as shrinkage, stable, or progression, adapted from RECIST for CR/PR, SD, PD. A rapidly progressive phenotype (RPP) was defined as BOR of progression and ICI use of ≤2 months. The association between sites of metastases and clinical outcomes were investigated using logistic and cox regression models. Results: Among 219 eligible patients, bone was the most common metastatic site (34.7%), followed by brain (21.5%), adrenals (14.2%), and liver (13.7%). Bone metastases (OR 0.45, p = 0.004) were associated with a worse BOR, while only a trend was observed for liver metastases (OR 0.47, p = 0.06). Adrenal metastases were associated with a better BOR (OR 2.08, p = 0.04). But thorax limited disease did not associate with BOR (OR 1.08, p = 0.76). In a multivariate model, bone was the only metastatic site associated with a worse BOR (OR 0.50, p = 0.01). Further, bone metastases were associated with RPP (adjusted OR 1.91, p = 0.04). Both bone (adjusted hazard ratio/aHR 1.61, p = 0.01) and liver metastases (aHR 1.80, p = 0.02) were associated with a shorter time-to-treatment-failure. The presence of liver (aHR 2.63, p &lt; 0.001) but not bone (aHR 1.04, p = 0.86) metastases was a significant predictor of poor OS. Conclusions: We report a novel finding that the presence of bone metastases was associated with a worse clinical overall response on ICI and a rapidly progressive phenotype. Further investigations into the mechanisms of RPP in the presence of bone metastases are needed.
Vitamin D deficiency in patients with newly diagnosed cancer.
Authors: Hira Shaikh, Veli Bakalov, Shifeng Mao
Journal: Journal of Clinical Oncology (2019)

e13117 Background: Vitamin D deficiency (VDD) is pandemic in modern society. There has been increasing interest in vitamin D and its impact on cancer. A number of studies have been published on a possible link between VDD and cancer. However, because of inconsistent results, controversy remains in various aspects of vitamin D. In this study, we assessed the association of VDD with various cancers. Methods: A retrospective study was conducted in a tertiary care hospital network in western Pennsylvania. Electronic health record database was used to extract the data from patients seen in outpatient office with newly diagnosed cancer who had a measured 25-hydroxy vitamin D level at diagnosis between 02/2016 and 02/2018. VDD was defined as level less than 30 ng/dl. Patient demographics, smoking, and vitamin D status were used for multivariate logistic regression analysis in order to determine odds ratio (OR) of certain cancer type in our cohort. We used SPSS version 23 for statistical analysis. Results: A total of 934 patients (59.2% female) with cancer were included. Most patients, 86.4%, were Caucasian, and 10.8% African American (AA). VDD was found in 433 patients (46.4%) and more prevalent in men (n = 203, 53.3%), and AA (n = 65, 64.4%) in our cohort. The most common cancer type was breast cancer (30.9%), followed by prostate cancer (11.3%), lymphoma (11.1%), and lung cancer (7.8%). After adjusting to demographic characteristics and smoking status, VDD was significantly associated with pancreatic cancer (OR = 2.28, p = 0.02), and reversely associated with breast cancer (OR = 0.56, p = 0.001). VDD was also prevalent in colorectal cancer, but not statistically significant, (OR = 1.71, p = 0.064). Conclusions: Our study demonstrated that VDD is prevalent among cancer patients, especially in men and AA patients. There is a strong association between VDD and the malignancies of digestive system, particularly pancreatic cancer. Further studies are needed to assess the effect of VDD on disease-specific risk and cancer mortality as well as the impact of vitamin D supplement.
Harmonization of clinical data across Gen3 data commons.
Authors: LaRon Hughes, Robert L. Grossman, Zachary Flamig, Andrew Prokhorenkov, Michael Lukowski, Michael Fitzsimons, Tara Lichtenberg, Yajing Tang
Journal: Journal of Clinical Oncology (2019)

e18094 Background: Gen3 is an open source software platform for developing and operating data commons. Gen3 systems are now used by a variety of institutions and agencies to share and analyze large biomedical datasets including clinical and genomic data. One of the challenges of working with these datasets is disparate clinical data standards used by researchers across different studies and fields. We have worked to address these hurdles in a variety of ways. Methods: Gen3 is an open source software platform for developing and operating data commons. Detailed specification and features can be found at https://gen3.org/ with code located on GitHub ( https://github.com/UC-cdis ). Results: The Gen3 data model is a graphical representation of the different nodes or classes of data that have been collected. Examples include diagnosis, demographic, exposure, and family history. The properties and values on each node are controlled by the data dictionary specified by the data commons creator. While each commons may have a unique data model and dictionary, specifying external standards allows for easier submission of new data and assists data consumers with interpretation of results. A variety of external references can be supported, but here we demonstrate the use of the National Cancer Institute Thesaurus (NCIt). NCIt provides reference terminologies and biomedical standards that contain a rich set of terms, codes, definitions, and concepts. Using the same reference standards across commons allows for the export of clinical data between commons. The Portable Format for Biomedical Data (PFB) was created to facilitate data export and to allow the data dictionary schema as well as the raw data to be compressed and exported. This new file format, which utilizes an Avro serialization, is small, fast, easy to modify, and enables simple data export and import. PFB also has the ability to house entire external reference ontologies and it is easy to update the PFB references as changes are introduced. Conclusions: We have shown here how the Gen3 data model, use of external reference standards for clinical data, and the export/import format of PFB enable the harmonization of clinical data across different data commons.
PD-L1 expression in soft tissue sarcomas and its prognostic implication.
Authors: Mohamed Reda Kelany, Thomas Barth, Dina Salem, Marwa Mosaad
Journal: Journal of Clinical Oncology (2019)

e14261 Background: The expression rate of PD-L1 in human malignant tumors paid a lot of attention and has been reported to vary from 19% to 92%, and the expression of PD-L1 was associated with poor prognosis of various human and may predicted the response to immune checkpoint inhibitors. The purpose of this study to investigate the expression of PD-L1 and its clinic-pathological feature in soft tissue sarcomas (STS). Methods: We collected Paraffin embedded tissue of 50 Patients with STS retrospectively from the archives of Pathology and oncology Department, Ain Shams University Hospitals from 2011-2017.then we correlated between PD-L1 expression and the clinico-pathological features. For PD-L1 expression we followed the Cologne 6-step proportional scoring system, using the rabbit monoclonal antibody (E1L3N 13684) and Tumors with &gt; /10% membranous stained cells were considered to be positive for expression. The differences among variables were calculated by chi-square test. Results: PD-L1 expression was found in 12 (24%) of cases. Of all sarcoma subtypes , desmoid tumors had the highest prevalence of PD-L1 expression noted in 2/3 (66%) of samples followed by GIST 2/4(50%), then liposarcoma 3/11(27%). In addition, there were 2 rhabdomyosarcoma cases with tumor positivity for PD-L1 expression. We found that STS patients with PD-L1 expression have shorter survival with a median OS 11 vs 19 months (p-value = 0.1) as well as a mean PFS 6 vs 11 months (p-value = 0.1) in PD-L1 positive and negative respectively; this finding considered as clinically significant, but not reached to statistical significant . Conclusions: We report here that PD-L1 expression is as prognostic factor for poorer outcome. This finding may be clinically significant but does not reach the statistically significant levels due to small number of samples included. Its role beyond that of a prognostic biomarker remains to be established in the context of larger clinical trials. Clinical trial information: 31/2017.