tbuckley/cabot-search huggingface dataset:
Analysis of circulating tumor DNA (ctDNA) in pseudoprogression in anti-PD1 treated metastatic melanoma (MM).
Authors: Jenny HJ Lee, Georgina V. Long, Alexander M. Menzies, Alexander David Guminski, Richard Kefford, Helen Rizos, Matteo S. Carlino
Journal: Journal of Clinical Oncology (2017)

9546 Background: We have previously shown that undetectable ctDNA either at baseline or during therapy predicted response in mm patients (pts) treated with anti-PD1 antibodies (aPD1). Pseudoprogression, defined as radiological progression prior to response, occurs in 8% of pts treated with aPD1. We sought to determine if ctDNA could differentiate pseudoprogression from true progression, defined as continued clinical or radiological disease progression. Methods: Between July 2014 and May 2016, pts receiving aPD1 had serial bloods for ctDNA. Included pts either had RECIST PD at first restaging or early clinical progression. Those with untreated brain metastases were excluded from the analysis. ctDNA was quantified using digital droplet PCR for mutations (BRAF/NRAS) at baseline and during the first 12 wks of treatment. Based on our prior studies, ctDNA results were grouped in to ‘favorable’ and ‘unfavorable’ ctDNA profiles (see Table), and these were compared in pts with true and pseudoprogression. Results: 29 pts were included, 28 with RECIST PD at first restaging and one with early clinical progression. 9 (31%) pts had a subsequent RECIST PR or SD and were considered pseudoprogression and 20 (69%) had true progression. Of the pseudoprogressors, 7/9 pts remained in response with a median follow-up of 20 months (mths). 2/9 pts had disease progression at 7 and 18 mths, with ctDNA that remained detectable with a &gt; 10-fold decrease during treatment in both patients. Of those with true progression and a favourable profile, 1 had a &gt; 10-fold decrease in ctDNA by wk 12 and was switched to MAPK therapy prior to further imaging, and the other had an undetectable ctDNA at wk 6 which increased again at wk 12. The latter pt had a new lesion on first restaging CT scan despite PR in all existing lesions with true PD on second restaging at wk 24. Conclusions: ctDNA in patients with mm at baseline and early on aPD1 treatment differentiates pseudo from true progression. [Table: see text]
Multiregion whole exome seuquencing of pre- and early neoplastic lung lesions.
Authors: Jianjun Zhang, Dan Su, Junya Fujimoto, Lisa Ying, Chi-Wan Chow, Wenyong Sun, Jianhua Zhang, Jinlin Hu, Carmen Behrens, Mara Antonoff, Edwin Justin Ostrin, Myrna Godoy, William N. William, Stephen Swisher, J. Jack Lee, Ignacio Ivan Wistuba, Waun Ki Hong, Phillip Andrew Futreal
Journal: Journal of Clinical Oncology (2017)

e20042 Background: The widespread use of CT for lung cancer screening and other reasons has resulted in a dramatic increase in the number of indeterminate ground glass opacities (GGOs). While many of GGOs can be resected with minimal morbidity, the cost has been called into question. Furthermore, multifocality is a relatively common, which makes decisions on extent of surgical resection and potential benefit less clear. Chemoprevention is a theoretically appealing approach to reduce lung cancer incidence and mortality. However, randomized trials have been disappointing to date. This may be due to the constellation of many factors including lack of reliable biomarkers to identify high-risk patients, lack of appropriate molecular targets and appropriate drugs because of our rudimentary knowledge on early carcinogenesis of lung cancers. It has been postulated that atypical adenomatous hyperplasia (AAH) represents preneoplastic lesion that can progress to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and further to frankly invasive adenocarcinoma (ADC). However, the biology of these lesions is poorly understood and the definition and management of these lesions remain controversial. Methods: Study on early carcinogenesis is hampered by the small size of lesions and challenge of obtaining longitudinal samples at different stages of disease progression. Multiregion sequencing can depict genomic events relative to molecular time with early events ubiquitously present in all regions and late mutations confined to spatially separated regions of lesions. Using this approach, our recent work has reported that 20/21 canonical cancer gene mutations were early genetic events. Results: With intent to delineate the pivotal molecular events driving early carcinogenesis of lung cancer, we have collected 154 resected GGOs with including AAH (N = 40), AIS (N = 39), MIA (N = 55) and ADC (N = 20) based on the IASLC/ATS/ERS classification from 89 patients including 38 patients presenting with multifocal GGOs and 18 patients carry more than one type of pathology. Two to five spatially separated regions from each of the 154 lesions are subjected to whole exome sequencing. Conclusions: The data will be ready to present at the meeting.
Targeted-sequencing and comprehensive molecular profiling of gastric signet ring cell carcinoma.
Authors: Jia Wei, Nandie Wu, Yue Wang, Bo Xu, Yang Yang, Juan Du, Lixia Yu, Zhengyun Zou, Yang Shao, Shida Zhu, Baorui Liu
Journal: Journal of Clinical Oncology (2018)

e16065 Background: Gastric cancer is a heterogeneous disease with various molecular subtypes. Signet ring cell carcinoma is characterized by a highly malignant phenotype of gastric cancer with few known effective molecularly targeted therapies. The limited knowledge of the molecular mechanisms underlying signet ring cell carcinoma hinders the development of therapeutic strategies. Methods: We performed a targeted sequencing panel focusing on 416 genes in 70 gastric signet ring cell carcinoma (SRCC) tumor-normal pairs, for integrative genomic analysis. This gene panel is composed of 416 cancer-related genes which can test a wide range of genetic abnormalities including point mutations, fusions, insertions, deletions and amplifications. Furthermore, this panel covers all currently available molecular-targeted and chemotherapy drugs, and ongoing clinical trials. Results: We identified previously well-known oncogenes and tumor suppressor genes mutation, including chromatin remodeling genes CDH1(17%), ARID1A(9%), BRCA1 (6%), CHD4(6%), SMARCA4(4%), TP53(27%)dysregulation, activation of receptor tyrosine kinases genes ERBB3(9%), PIK3CA(7%), PTEN (6%), MTOR(4%), ERBB2(4%), ERBB4(3%), FGFR2(3%), FGFR4(3%), stem cell pathways genes TGFBR2(6%), APC(3%), and others. Meanwhile, we observed new significantly mutated genes in SRCC. Specifically, gene PKHD1(16%), MED12(16%), STAG2(10%), KDR (10% ), ATRX(9%) were frequently mutated in SRCC tumor samples. However, RHOA mutation was detected only in 4% tumor samples. For DNA copy number profiling, genes including NOTCH1(16%), FLT4(9%), CCND1 (7%), HNF1A(6%), CDKN2A(6%), CDKN2B(6%) and RECQL4(6%), were frequently altered in SRCC. Conclusions: Our genomic landscape revealed SRCC was a distinct entity which harboring different mutational profile to other gastric cancers. Our results may provide potential target for genome-guided personalized therapy in SRCC.
Effect of 2<sup>nd</sup> line pazopanib (PZN) on the number and phenotype of CTCs in patients with small cell lung cancer.
Authors: Ippokratis Messaritakis, Eleni Politaki, Stella Apostolaki, Maria Plataki, Filippos Koinis, Nikolaos Vovolinis, Eleftheria- Kleio Dermitzaki, Vassilis Georgoulias, Athanasios Kotsakis
Journal: Journal of Clinical Oncology (2016)

8562 Background: To investigate the effect of 2nd line PZN on the number and phenotype of CTCs in patients with SCLC. Methods: CTCs were detected in58 pts using the CelleSearch assay (CS) and double immunofluorescece (IF) staining with anti-CK, anti-CD56 and anti-TTF1 antibodies, before, after 1 cycle of PZN and at the time of disease progression (PD). Results: Using the CS and IF, CTCs were detected in 50% and 51.8% of pts, respectively. Patients with < 5 CTCs/7.5 ml of blood had a significantly higher probability to respond to PZN compared to patients with > 5 CTCs/7.5 ml of blood (p= 0.006). After 1 cycle of PZN, the decrease of the median number of CTCs was associated with the probability to achieve an objective response (p= 0.006). In 48.1% of the pts with < 5 CTCs/7.5ml of blood at the time of PD, CTCs could be detected using IF. The detection of > 5 CTCs/7.5 ml of blood at baseline was associated with a decreased PFS (p< 0.001) and OS (p= 0.001) and multivariate analysis revealed that the number of CTCs after 1 cycle of PZN was an independent factor associated with OS (p= 0.005). Conclusions: The enumeration and phenotypic characterization of CTCs in patients with SCLC treated with PZN are of clinical relevance and could be considered as a dynamic biomarker for the monitoring of treatment efficacy.
Persistent postmastectomy pain syndrome and posttraumatic stress disorder among breast cancer survivors (ORTHUS study): A study of the palliative care working committee of the Turkish Oncology Group (TOG).
Authors: Ali Alkan, Zeynep Gulsum Guc, Filiz Cay Senler, Tugba Yavuzsen, Handan Onur, Mutlu Dogan, Ebru Karcı, Arzu Yasar, Elif Berna Koksoy, Ozgur Tanriverdi, Nazim S. Turhal, Yuksel Urun, Dilsa Mizrak, Asiye Ozkan, Hakan Akbulut
Journal: Journal of Clinical Oncology (2016)

e21702 Background: Persistent postmastectomy pain syndrome (PMPS) is one of the most important disturbing symptoms. Posttraumatic stress disorder (PTSD) is an anxiety disorder which is characterized by reactions to reminders of the trauma that has been experienced. The purpose of this study is to evaluate the predictors of PMPS and PTSD in Turkish breast cancer survivors and the correlation between PMPS and PTSD. Methods: The study is designed as a multicenter survey study. Breast cancer patients in remission were evaluated. Patients were evaluated with structured questionnaires to assess the PMPS and clinical parameters associated with it. Turkish version of posttraumatic stress disorder checklist- civilian version (PCL-C) was used. Results: Between February 2015 and October 2015, 614 breast cancer survivors in outpatient clinics were evaluated. The incidence of PMPS documented is 45.1%. In the multivariate analysis low income, presence of PTSD and <46 months after surgery were associated with increased risk of PMPS(Table). PTSD was documented in 75%, and the mean PCL-C score was 32.4±11.1. PMPS and being married at the time of the evaluation were linked with PTSD. Conclusions: It’s the first data about the association between PMPS and PTSD. The clinicians should be aware of PMPS and PTSD in breast cancer survivors. PMPS OR CI(%95) p Low income* 1.89 1.08- 3.38 0.03 PTSD 3.14 2.05- 4.81 <0.001 Short interval after surgery** 1.71 1.18- 2.49 0.004 PTSD Married 1.57 1.0-2.41 0.03 PMPS 3.02 2.01- 4.55 <0.001 * Low income was assigned as <1000tl, which is the minimum wage in Turkey. **<46 months.
Circulating tumor DNA detection in stage I non-small cell lung cancer patients by targeted sequencing.
Authors: Kezhong Chen, Feng Lou, Fan Yang, Jingbo Zhang, Tian Guan, Jun Wang
Journal: Journal of Clinical Oncology (2016)

8514 Background: Circulating tumor DNA (ctDNA) isolated from peripheral blood has recently been shown to be an alternative source to detect gene mutations in primary tumors; however, most previous studies have focused on advanced stage cancers, few have evaluated ctDNA detection in early-stage lung cancer. Methods: We conducted a prospective study (NCT02645318) to assess the blood test sensitivity, specificity, and concordance of tissue tumor DNA (tDNA) and plasma ctDNA with clinical features in surgical non-small lung cancer (NSCLC) patients. Preoperative plasma samples and fresh tissue tumors were collected and detected by targeted sequencing with the Ion Personal Genome Machine (PGM) and AmpliSeq Cancer Panel. Results: Comparison of mutations in tDNA with those in ctDNA were conducted in 46 paired samples from stage I NSCLC patients. A panel of genes including frequent driver mutations like EGFR, KRAS, PIK3CA and other less frequent mutations were identified with an overall study concordance of 69.36% and sensitivity and specificity of 78.57% % and 55.56%, respectively. For the stage Ia sample pairs, the concordance was 66.67% with a sensitivity of 76.74% (95% CI: 49.76%-92.18%), specificity of 53.85% (95% CI: 26.12%-79.6%), and positive (plasma) predictive value of 68.42% (95% CI: 43.5%-86.44%). In comparison, stage Ib samples had 75% concordance with 81.82% sensitivity (95% CI: 47.76%-96.79%), 60.0% specificity (95% CI: 17.04%-92.74%), and 81.82% positive predictive value (95% CI: 47.76%-96.79%). Plasma ctDNA had a higher positive predictive value than currently used tumor biomarkers in early stage NSCLC(CA125, CA19-9, CEA, CYFRA21-1, NSE). CtDNA concentrations were found to be significantly associated with tumor-aggressiveness. Conclusions: This prospective study demonstrates the feasibility of identifying plasma ctDNA in the stage I lung cancer patients via targeted sequencing, demonstrating a potential utility of targeted sequencing of ctDNA in the management of early-stage NSCLC. Clinical trial information: NCT02645318.
Progastrin: A new specific early cancer screening biomarker.
Authors: Alexandre Prieur, Thibault Mazard, Eric Assenat, Marc Ychou, Sophie Gourgou, Odette Mariani, Thierry Bronzini, Anne Vincent- Salomon, Dominique Joubert
Journal: Journal of Clinical Oncology (2017)

11545 Background: One in two people will be diagnosed with cancer during his/her lifetime. Because we are lacking effective screening tests, most cancers are detected in late stages, when survival rates are very low. Here, we show the development of the first early cancer screening test for multiple cancers using progastrin (PG) as biomarker. The gene coding for PG is a target gene of the Wnt oncogenic pathway that is activated in almost all type of cancers, at the earliest stages of development. We showed that the neutralization of PG by a specific humanized antibody could be used for colorectal cancer treatment. Moreover, as PG is secreted by cancer cells, we can specifically detect it in the blood of persons having a cancer at early stage. Methods: Antibodies directed against PG were produced and selected for target specificity and affinity. ELISA is the most reliable assay to detect biomarker on the blood. Hence, selected antibodies were used to set up an ELISA sandwich to detect PG in the blood of patients with various types of cancers and at various stages. Results: We first set up a prototype ELISA using polyclonal antibodies. We validated our test using 223 blood samples from patients with polyps and colorectal cancers at various stages for which we observed an increased levels of PG. Then, we showed the presence of PG in the blood of 212 patients with other types of cancer, including liver, pancreatic and breast cancers, confirming that PG could be used as a biomarker for multiple types of cancers. Next, we set up our industrial ELISA using polyclonal and monoclonal antibodies called DECODE Lab and tested 245 new blood samples from patients with various types of cancer including early stages. Strikingly, using our test we were able to detect breast (AUC = 0.9638; sensitivity 70%), colorectal (AUC = 0.9635; sensitivity 73%), melanoma (AUC = 0.9882; sensitivity 87%) and cervix utery (AUC = 0.9827; sensitivity 84%) all stages combined with a high specificity of 97.5%. Finally, for early stage patients with melanoma and breast cancer, we had a sensitivity of 68% and 81% respectively. Conclusions: Taken together, the results presented here show that PG is a reliable biomarker for early cancer screening. The ELISA test that we developed is very efficient and now available for the clinic.
A correlative analysis of PDL-1, PD-1, and EGFR, HER2, HER3 expression in oropharyngeal squamous cell carcinoma (OPSCC).
Authors: Conor Ernst Steuer, Christopher C Griffith, Yuan Liu, Kelly R. Magliocca, Mihir Patel, Cynthia Cohen, Taofeek Kunle Owonikoko, Dong Moon Shin, Zhuo Georgia Chen, Nabil F. Saba
Journal: Journal of Clinical Oncology (2016)

6043 Background: Agents targeting the PD1/PDL1 pathway are currently under investigation for squamous cell cancer of the head and neck (SCCHN). We sought to explore the potential association of the PD1/PDL1 pathway with clinical characteristics, outcome and other biologically relevant alterations (EGFR, HER3, HER3) in SCCHN using an institutional patient and tissue database. Methods: Protein expression was assessed by IHC on tissue microarray sections (EGFR, HER2, HER3) and or whole tissue sections (PD1/PDL1) using monoclonal antibodies. Expression of EGFR, HER2, HER3 was quantified in tumor cells while PD1/PDL1 was quantified on tumor cells, peritumoral stroma and stroma lymphocytes using intensity, percentage of positively staining cells and H-Score (product of intensity and percentage). Maximum PD1 lymphocyte density was measured on a scale of 0 to 4 (none, rare, moderate, high, very high). Significant associations (p < 0.05) between biomarkers and patient outcome were tested using descriptive and inferential statistics, logistic regression and Cox proportional hazards models in SAS 9.3. Results: We employed 100 OPSCC tissue samples for the analysis. Median age was 59 years, p16 positive (71%), male (81%), never smokers (18%), and 77% with stage 3 or 4. 25% of all cases were PDL1 positive. PD1 lymphocyte score of 2-4 was recorded in 65% of cases. There was a higher proportion of PDL1 (+) tumors in p16(+) OPSCC (87%) than PDL1 negative tumors (65%, p = 0.047). PDL1 status highly correlated with advanced nodal disease on multivariate analysis (5.53 (CI 1.06-28.77), p = 0.042). There was no correlation between PDL1, PD1 and EGFR, HER2, or HER3 expression. There was no association of PDL1 status with disease free or overall survival. Lower density of PD1+ lymphocytes in peritumoral stroma was associated with increased risk of death on multivariate analysis (HR = 3.17(1.03-9.78), p = 0.045). Conclusions: There was no association between PD1/PDL1 and expression of EGFR, HER2, or HER3 in OPSCC. PDL1 expression on tumor cells correlates with p16 positivity in OPSCC and advanced nodal status while low density of PD1 on peritumoral stromal lymphocyte density correlates with increased mortality.
Differences in mortality among patients with acute leukemia admitted on weekends as compared to weekdays.
Authors: Kaushal Parikh, Mahek Shah, Dhruv Mehta, Delong Liu
Journal: Journal of Clinical Oncology (2017)

6576 Background: The association between weekend admissions and patient outcomes has been widely reported for several acute illnesses. However, this is the first study using a nationwide database to focus on outcomes of weekend admissions for acute leukemia. Methods: We used the 2002-2012 Nationwide Inpatient Sample Databases to identify patients admitted with a diagnosis of acute leukemia. Admissions were identified as weekend or weekday admissions and rates of mortality, in-hospital complications, existing comorbidities, and demographic differences were assessed. Adjusted logistic regression models were used to analyze mortality and complication outcomes. Results: Out of a total of 71,392 patients included in the analysis, 12,234 (17.1%) patients were admitted over the weekend. While there has been a general decline in admissions and mortality in acute leukemia from 2002-2012, mortality was 18.8% for weekend admissions and 16.3% for weekday admissions (p &lt; 0.001). Weekend admissions independently predicted higher mortality (adjusted odds ratio 1.128, 95% confidence interval, 1.06 to 1.20; p &lt; 0.001). These patients were also less likely to receive an early bone marrow biopsy than their weekday counterparts (45% vs 26.5%; p &lt; 0.001). Bone marrow biopsy was independently associated with a reduced in-hospital mortality (aOR 0.395, 95% CI 0.373 to 0.417; p &lt; 0.001). Admissions to teaching hospital were also associated with a lower mortality (aOR 0.890, 95% CI 0.845 to 0.936; p &lt; 0.001). Weekend admissions were also more likely to have in-hospital complications than weekday admissions (52.4% vs 50.5%; p &lt; 0.001). Conclusions: There was a significantly increased mortality among acute leukemia patients admitted on a weekend. Our study suggests that patients admitted over the weekend may be clinically sicker or receive inferior care than weekday admissions. We also conclude that patients admitted to teaching hospitals have a better outcome and emphasize the importance of availability of resources and early presentation to tertiary care centers.
Characteristics of esophageal carcinoma in a veteran population.
Authors: Theresa Ratajczak, Heidar Albandar, Parker Redlien, Sara Yacyshyn, Roland Markert, Geetika Kumar
Journal: Journal of Clinical Oncology (2016)

e15505 Background: Esophageal cancer is projected to increase by approximately 35% through 2025 in the U.S. We investigated the characteristics of esophageal carcinoma in a veteran population. Methods: Records of patients diagnosed with esophageal carcinoma between 1996-2014 were reviewed. Information on demographics, social and environmental factors, hereditary associations, location, grade, stage of tumor, treatment, and survival was collected. IBM SPSS Statistics 22.0 and proper data-dependent statistical testing was used. Results: 81 patients were classified as adenocarcinoma (EAC) and 37 as squamous cell carcinoma (SCC). Age at diagnosis for EAC and SCC was 67.1±9.7 vs. 67.0±10.8 years, (p = 0.83). Compared to SCC, patients with EAC were more likely to be white than African American (98.8% vs. 59.5%, p < 0.001). Veterans with EAC were more likely to have a ≥ 60-pack year history of smoking than with SCC (46% vs. 24% (p = 0.027). They did not differ in regards to heavy alcohol user (69% vs. 56%, p = 0.23). The two groups did not differ regarding family history of malignancy of any kind (62.2% SCC vs. 65.4% EAC, p = 0.73) or of solid tumors (35.1% SCC vs. 35.8% EAC, p = 0.94), GI cancer (13.5% SCC vs. 18.5% EAC, p = 0.50) or head and neck cancer (24.3% SCC vs. 22.2% EAC, p = 0.80). SCC was distributed nearly equally in the upper (33.3%), middle (36.1%) and lower third (30.6%) of the esophagus while EAC almost always occurred in the lower third (93.7%) [p < 0.001]. Approximately 75% of tumor grades were moderately or poorly differentiated (79.5% SCC vs. 71.6%). The mean length of tumors was 62.9±37.0 mm. Stage II was the most frequent classification (42.4% for SCC vs. 48.1% for EAC). Only 6.1% of SCC and 2.5% of EAC were stage 0 or I. Combination of chemotherapy and radiation was the most common therapy (46.1%). SCC and EAC patients did not differ in months of survival (SCC median = 7.0, interquartile range [IQR] = 13.5 vs. EAC median = 8.6, IQR = 11.9, p = 0.72). Conclusions: Patients did not differ on age, alcohol use, family history of malignancy and were similar in grade, length, stage, treatment, and survival. The changing epidemiology of esophageal carcinoma (EAC increasing and SCC decreasing), suggests that the relationships between the two cancers should be reassessed periodically.