tbuckley/cabot-search huggingface dataset:
Circulating tumor DNA in patients with metastatic urothelial cancer: concordance of genomic findings with matched tissue biopsies.
Authors: Jean-Michel Lavoie, Gillian Vandekerkhove, Matti Annala, Nora Sundahl, Takeshi Sano, Werner J. Struss, Tilman Todenhöfer, Piet Ost, Kim N. Chi, Peter C. Black, Bernhard J. Eigl, Alexander William Wyatt
Journal: Journal of Clinical Oncology (2019)

e16036 Background: Patients (pts) with metastatic urothelial cancer (mUC) now have access to many different treatment options. This creates an incentive for molecular profiling of their tumors, with the aim of developing biomarkers. Genomic profiling may leverage the presence of circulating tumor DNA (ctDNA), but it has not been shown whether this recapitulates the findings from tissue samples. Methods: Whole blood samples were collected for next-generation sequencing of leukocyte and cell-free DNA (cfDNA). Deep targeted sequencing was performed across a UC-specific custom 50-gene panel (median depth of 986x). Matched archival tissue was profiled using the same assay for 65 pts. Results: Between 11/2011 and 12/2017, 90 pts developed mUC (87 evaluable). Baseline characteristics: median age 67, 83% male, 14% upper-tract disease, 17% stage IV at initial presentation. Treatments delivered: 76% platinum-based chemotherapy, 47% PD-1/PD-L1 inhibitor. At a median follow-up of 12.8 mo., 45% remain alive. We found ctDNA fractions above 2% in at least one blood collection in 81% of cases. For 17 pts, matched metastatic biopsies and cfDNA collection were available; in those cases 82% of coding somatic mutations identified in tissue were independently detected in cfDNA. Half of discordant findings could be attributed to low ctDNA fraction. Most (89%) mutations detected in primary tissue (cystectomy or nephrectomy) were present in later cfDNA collections. ctDNA detected mutations in TP53 and ARID1A in 64% and 29% of pts, respectively. A tumor mutation burden ≥25 mutation per Mb was observed in 27% of cases. Conclusions: There is a high concordance between genomic findings from ctDNA and matched tissue of pts with mUC. This supports the use of liquid biopsies to study potential biomarkers in this disease.
A phase II, randomized, double-blind, placebo-controlled trial evaluating efficacy and safety of namodenoson (CF102), an A<sub>3</sub> adenosine receptor agonist (A<sub>3</sub>AR), as a second-line treatment in patients with Child-Pugh B (CPB) advanced hepatocellular carcinoma (HCC).
Authors: Salomon M. Stemmer, Nebojsa S. Manojlovic, Mihai Vasile Marinca, Petar Petrov, Nelly Cherciu, Doina Ganea, Tudor-Eliade Ciuleanu, Ioana Adriana Puscas, Muhammad Shaalan Beg, William T. Purcell, Adina-Emilia Croitoru, Rumyana Nedyalkova Ilieva, Sladjana Natošević, Amedeia Lavinir Nita, Dimitar Nikolaev Kalev, Zivit Harpaz, Motti Farbstein, Michael H. Silverman, Pnina Fishman, Josep M Llovet
Journal: Journal of Clinical Oncology (2019)

2503 Background: There is no established primary treatment for patients with advanced HCC and severe liver dysfunction (Child-Pugh B class; CPB), thus this representing a clear unmet need. Namodenoson, an A 3 AR agonist, showed promising preliminary results in this population in an open label phase 1/2 clinical study (NCT00790218), with median overall survival (OS) of 8.1 months. We present the results of a double blind, randomized phase 2, placebo-controlled study (NCT02128958), assessing the efficacy and safety of namodenoson as a second-line therapy of patients with advanced HCC and CPB class. Methods: Patients were randomized 2:1 to BID namodenoson (25 mg; n = 50) or placebo (n = 28) in 15 centers globally. Primary endpoint was OS and secondary endpoints were safety, progression-free survival (PFS), objective response (OR) and disease control rate (DCR). Assessment of OS and PFS was done by log rank test at a one final analysis when 75 deaths had occurred. Response was assessed by RECIST (local investigator) and mRECIST (central review). Results: The study did not meet the primary end point, with median OS 4.1 months (mo) for namodenoson vs. 4.3 mo for placebo (HR: 0.82). Pre-planned subgroup analysis of Child-Pugh 7 patients (n=56; namodenoson=34, placebo=21) showed median survival 6.8mo vs 4.3 mo [HR: 0.77 (95% CI 0.49-1.40)]. Similarly, for this subgroup of patients PFS was 3.5 mo vs 1.9 (HR=0.87). In terms of objective response, 3/34 patients assessed achieved OR (9%) with namodenoson vs 0% for placebo. Namodenoson was generally well-tolerated, with no treated patients being withdrawn for toxicity and no cases of treatment-related deaths. The most common adverse event (&gt;10%) were anemia, abdominal pain, ascites, nausea, asthenia, fatigue, peripheral edema, and increased AST. Treatment-related grade 3 toxicities accounted for anemia, fatigue and hyponatremia. Conclusions: Namodenoson has demonstrated favorable clinical safety profile in patients with advanced HCC and severe liver dysfunction. Although the primary end-point was not met, the subgroup analysis showed a positive signal of efficacy for OS in patients with Child-Pugh 7. Both safety and efficacy results warrant testing this drug in a phase III trial. Clinical trial information: NCT02128958.
Analysis of real-world data (RWD) on treatment (tx) sequencing in patients with advanced non-small cell lung cancer (aNSCLC).
Authors: Meng Ma, Xiang Zhou, Howard Goldsweig, Nicholas Hahner, Dianwei Han, Matthew Dietz, Scott Jones, Tommy Mullaney, Arielle Redfern, Whitney Jappe, Zongzhi Liu, Kamlesh Yadav, Michelle Zimmerman, Tony Prentice, Qi Pan, Fred R. Hirsch, William K. Oh, Eric E. Schadt, Dan Li, Rong Chen
Journal: Journal of Clinical Oncology (2019)

e20642 Background: While optimal sequencing of systemic therapy in aNSCLC is critical to achieve maximal clinical benefit, it is practically challenging to study tx sequencing through clinical trials. RWD allow retrospective, observational studies to examine tx patterns and associated clinical outcomes. Methods: 1,609 aNSCLC patients who received systemic therapies at Mount Sinai hospitals were analyzed for the number of line of therapy (LOT), therapeutic modalities (chemotherapy, targeted therapy and immunotherapy), and the sequence in which treatments were given when LOT &gt; 1. Time to tx discontinuation (TTD) was used as a surrogate clinical endpoint for outcomes. Results: 578 of the 1,609 (36%) patients received more than one LOT. 356 (22%) received tyrosine kinase inhibitors (TKIs), and 297 (16%) received immune checkpoint inhibitors (CPIs). Kaplan-Meier analysis revealed that among 297 patients who received CPIs, median TTD was longer in the 1 st line setting (295 days, 95% CI 169 to 523; n=132) than when LOT &gt; 1 (169 days, 95% CI 113 to 269; n=165), although the difference was not statistically significant (P=0.092, log-rank test). No difference of TTD on TKIs was observed between LOT = 1 and LOT &gt; 1 (P=0.51). With respect to tx sequencing, when patients (n=94) received TKIs as the 1 st LOT, 60%, 35%, and 5% of them received another TKI, chemotherapy, or a CPI-containing regimen, respectively, as the 2 nd LOT. Among patients (n=370) who progressed on 1 st line platinum-based chemotherapy, 52%, 32%, and 16% received another chemo regimen, a CPI-containing regimen, or a targeted therapy, respectively, as the 2 nd LOT; these percentages shifted significantly toward more CPIs (24%, 66%, 10% for chemo, CPI, targeted, respectively) when only 2016-2018 data were examined. In the 2 nd line setting after platinum therapy, TTD was significantly longer in the CPI group (332 days, 95% CI 169-484) compared to the chemo group (88 days, 95% CI 65-100; P&lt;0.0001), consistent with results from pivotal clinical trials. Conclusions: As the tx algorithm of aNSCLC has been evolving rapidly, we observed diverse tx patterns in RWD. Various tx sequences may impact patient outcomes, and therefore warrant further investigation.
The utility of proton MR spectroscopy in diagnosing B cell lymphoma.
Authors: Saif Faiek, Lauren McKay, David Zeidwerg, David Stidd, Ruifeng Zhou
Journal: Journal of Clinical Oncology (2019)

e13536 Background: Diffuse Large B Cell Lymphoma (DLBCL) is the most common and increasingly prevalent subtype of Non-Hodgkin lymphoma in both immunocompromised and immunocompetent patients. Its pathogenesis is thought to represent rearrangements, translocations, and transformations of both the immunoglobulin heavy and light chain genes along with somatic mutations of the variable regions of these same genes. A 66-year old Caucasian male with a past medical history of smoking presented to the hospital due to concerns of mental status change, flat affect, and fronto-orbital headache for one-week duration. The patient denied any drug or substance abuse. Physical exam was diffusely normal with the exception of flat affect. Methods: Magnetic resonance spectroscopy is a noninvasive, non-ionizing diagnostic analytical technique that has been used to measure metabolic changes in brain lesions. Results: Lhermitte’s sign was negative and NIH stroke scale was calculated to be 0. CT demonstrated a 17mm frontal lobe lesion. Follow up with MRI showed three bilateral enhancing brain lesions, but no metastasis or primary tumor was seen via CT of chest, abdomen, and pelvis. Initial differential diagnosis included: Tumefactive Multiple Sclerosis, Acute Demyelinating Encephalomyelitis or CNS lymphoma. EEG did not highlight any focal or epileptiform abnormalities and lumbar puncture was negative for Creutzfeld Jacob Disease and Multiple Sclerosis. The patient was discharged with a course of intravenous steroids only to present a few weeks later with no improvement of symptoms. The patient then had proton magnetic resonance spectroscopy (MRS). MRS pattern spikes and chemical profile suggested lymphoma, which was confirmed by a brain biopsy. The patient was subsequently transferred to the University of Pennsylvania for treatment and further management. Conclusions: This case illustrates the beneficial use of MRS, as data patterns it provides compliments the clinician’s knowledge to proceed with appropriate treatment.
Immune biomarker expression in the tumor microenvironment in Chinese patients with esophageal squamous cell carcinoma was explored.
Authors: Pengfei Li, Hongli Luo, Yanhui Chen, Yating Wang, Huan Chen, Lihong Wu, Yegang Ma, Henghui Zhang
Journal: Journal of Clinical Oncology (2019)

e15542 Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies in China, of which the standard treatment of advanced esophageal cancer is chemotherapy followed by surgery. Recently, immunotherapy has shown great potential in ESCC treatment. The aim of this study was to explore the landscape of immune-related gene expression in the tumor microenvironment (TIME) and further explore the relationship between immune biomarkers and therapeutic effect. Methods: We retrospectively analyzed PDL1(clone sp142)/PD1 expression in a cohort of Chinese patients (male = 92, female = 18; median age = 64, range from 36 to 84) with ESCC. Patient samples were detected in Genecast. Co. from February 2017 to November 2018. Another 6 patients (male = 4, female = 2) who accepted anti-PD1/PD-L1 antibody treatment were analyzed. PD-L1/PD-1 expression and the incidence of CD8, CD57, CD68, CD163 TILs were immunohistochemically. Results: In tumor cells, more than 32% (36/110) samples of ESCC patients was stained with PDL1 (≥1%), while52.8% (21/36) of these patients highly expressed PDL1 (≥10%, 10%-98%). In tumor infiltrating lymphocytes (TILs), 31.82% (35/110) patients expressed PDL1 (≥1%) and 1.82% (2/110) highly expressed PDL1 (≥10%, 10%-50%). For PD1 expression in TILs, 17.27% (19/110) samples were positively stained with PD1 antibody (≥1%). In a subset of ESCC patients who received immune checkpoint blockade therapy (including 2 responders and 4 non-responders), the median percentage of CD163, CD68, PDL1, CD8, PD1 and CD57 were 1.49% (0.44%-9.98%), 0.40% (0.16%-19.08%), 3.74% (0%-45%), 9.52% (4.20%-13.79%), 4.51% (1.37%-33.43%) and 0.68% (0.08%-1.74%), respectively in tumor area and 4.14% (1.85%-15.99%), 1.62% (0.21%-11.47%), 4.87% (0.33%-18.97%), 7.74% (5.88%-14.35%), 3.93% (1.92%-20.54%) and 0.92% (0.27%-2.18%), respectively in stroma area. When compared with non-responders, samples from the responders showed higher CD8 expression in tumor area. Conclusions: Percentage of PDL1/PD1 expression is relatively high in Chinese patients with ESCC. High levels of CD8 positive TILs might be beneficial to patients with ESCC. Clinical investigations with large sample sizes are warranted to prove our findings.
Impact of surgery type on survival in breast cancer patients.
Authors: Phuong Tuyet Ngo, Shruti Bhandari, Drew Murray, Sarah Mudra, Xiaoyong Wu, Rachana Shirish Lele, Sudhir Srivastava, Mounika Mandadi, Elizabeth Carloss Riley
Journal: Journal of Clinical Oncology (2019)

e12072 Background: Breast cancer is the most common malignancy affecting women, and treatment is multidisciplinary. Both patient and tumor related factors impact surgical decision making. Recently, rates of mastectomy, prophylactic mastectomy and reconstruction have increased. The impact of this on modern survival, the relationship to patient and tumor related factors is not well described. Methods: The National Cancer Database identified 1,042,057 patients who underwent surgery with lumpectomy or mastectomy with or without reconstruction for stages I-III breast cancer from 2004-2014. Variables collected included gender, race, age, stage, facility type, insurance status, and overall survival. Data was analyzed using univariable and multivariable logistic and Cox proportional hazards regression models. Results: Of all surgeries, 61.2% were lumpectomy (n = 638,088), 27.9% were mastectomy without reconstruction (n = 290,463) and 10.9% were mastectomy with reconstruction (n = 113,506). African American patients were more likely to get mastectomy without reconstruction than lumpectomy (OR 1.05; 95% CI 1.03-1.06, p &lt; 0.001) but less likely to get reconstruction than lumpectomy (OR 0.73; 95% CI 0.71-0.75). Patients 50-65 years were less likely to get mastectomy either with and without reconstruction compared to lumpectomy (OR 0.45; 95% CI 0.44-0.46; OR 0.87; 95% CI 0.86-0.88, p &lt; 0.001, respectively). Reconstruction was more likely in patients with private insurance compared to those with Medicare (OR 1.46; 95% CI 1.43-1.50, p &lt; 0.001) and was less likely to occur at a community center compared to an academic facility (OR 0.48; 95% CI 0.47-0.49, p &lt; 0.001). Mastectomy without reconstruction also had a higher likelihood of death when compared to lumpectomy patients (HR 1.28; 95% CI 1.26-1.29, p &lt; 0.00). Conclusions: The majority of women in this large dataset had breast conserving surgery. Of those patients who underwent mastectomy, only a minority had reconstruction. Age &gt; 50 years and treatment at a non-academic facility were associated with less reconstruction along with established risk factors for worse outcome including African American race and Medicaid/Uninsured. Despite adjusting for these risk factors, mastectomy without reconstruction was still associated with a lower survival. Further analysis including tumor biology is needed to better understand the impact of these findings.
Thick melanoma is associated with low melanoma knowledge and low perceived health competence, but not delays in care
Authors: Sophia H. Zhang, Rebecca Liu, Nalyn Siripong, John M. Kirkwood, Matthew P. Holtzman, Diwakar Davar, Yana Najjar, Keely Marshall, Stephanie R. Jackson Cullison, Neil A. Houston, Galen Switzer, Laura K. Ferris
Journal: Journal of the American Academy of Dermatology (2019)
Clinical and molecular characteristics of non-small cell lung cancer patients from rural Maine.
Authors: Antoine Harb, Adam Curtis, Laura Skacel, Michael Babcock, Marek Skacel
Journal: Journal of Clinical Oncology (2019)

e18237 Background: Non-Small Cell Lung Cancer (NSCLC) is the most common malignancy worldwide and the leading cause of malignancy-related mortality in the United States. The state of Maine in particular, has one of the highest rates of lung cancer in the country. Methods: We reviewed all NSCLC patients (adenocarcinoma (AC) and squamous cell (SC) histology) diagnosed between January 2017 and June 2018 at Northern Light Cancer Institute. 261 patients with clinical follow-up were identified. We correlated their clinical characteristics with molecular abnormalities identified by Next Generation Sequencing (NGS) and Fluorescence in situ hybridization, PD-L1 status by immunohistochemistry, disease-free and overall survival. Results: 210 patients had AC and 51 SC. They were evenly split between men and women. The median age at diagnosis was 68 years. 99% of patients were Caucasian. 15 patients were never smokers, the rest were equally divided between active and previous smokers. 44% had early stage disease (I/II) and 56% had late stage disease (III/IV) on presentation. 36.4% had a PD-L1 high status. The frequencies of the molecular aberrations identified in AC and SC are listed in the table below: Treatment differed by stage, including surgery/Radiation +/- adjuvant chemotherapy for early stage disease, definitive chemo-radiation followed by immunotherapy for stage III disease. Stage IV patients were treated with immunotherapy, combination chemo-immunotherapy, targeted therapy, palliative radiation and hospice referral. After a median follow-up of 10.6 months, overall survival (OS) was 66%. Disease free survival (DFS) was 33%. Using univariate (chi-square), multivariate (logistic regression) and Kaplan-Meier (log rank) analyses, we identified that in addition to a high clinical stage, which was associated with shorter OS and DFS, high PD-L1 status, and the presence of p53 mutation, were independent predictors of shorter OS, and p53 mutation of shorter DFS. Conclusions: NGS-based molecular testing deployed in real-time non-academic setting proved to be a valuable tool to identify therapeutic and prognostic targets in NSCLC. Besides those endorsed by the NCCN guidelines, p53 mutation is a common abnormality associated with adverse outcomes. While high PD-L1 expression is a desirable immunotherapy marker, its presence also predicted adverse overall outcomes in our patients.[Table: see text]
Impact of delaying initiation of adjuvant chemotherapy and trastuzumab in patients with early-stage HER2-positive breast cancer.
Authors: Georgeta Fried, Shlomit Strulov Shachar, Sapir Anani
Journal: Journal of Clinical Oncology (2019)

e12033 Background: About 20% of breast cancers harbor an amplification and/ or overexpression of human epidermal growth factor receptor 2 (HER2).The treatment of HER2-positive BC combined of chemotherapy and Trastuzumab, results in reduction of disease recurrence in half. However, the optimal timing for adjuvant chemotherapy initiation is unclear. Methods: Retrospective chart review of 226 HER2-positive early-stage BC patients diagnosed between November 2002-May 2014 treated with adjuvant chemotherapy and Trastuzumab was obtained. Patients' average age was 54 years. Bivariate and multivariate analyses were performed to assess optimal timing for treatment initiation from primary diagnosis (obtained by tissue biopsy) and surgery. Primary endpoint was disease recurrence (locoregional/distant metastases). Other analysis included disease free survival (DFS), breast cancer specific survival (BCSS) and overall survival (OS). Results: Among 226 patients, 28 patients (12% of all patients) started Trastuzumab more than 36 weeks from primary diagnosis. The influence of a delay in treatment initiation was more profound as risk factors' number (e.g. stage, histopathological grade, positive lymph node status) increased, particulary with positive lymph nodes or a higher stage. 5-year disease free survival rates (DFS) in patients who had started Trastuzumab within than 36 weeks from diagnosis were: 93% in patient with 0-1 risk factors; 75% in patients with 2 risk factors; 77% in patients with 3-4 risk factors, and DFS rate dropped to 50% when Herceptin was initiated more than 36 weeks from diagnosis in patients with 3-4 risk factors. A higher disease recurrence rate (HR = 3.2 , p= 0.005,) was found in this subgroup, with highest negative impact in patients with stage III BC. A delay of more than 12 weeks from primary diagnosis to chemotherapy initiation in specific subgroups was attributed to a worse prognosis. The influence of treatment delay was more profound in patients with higher number of risk factors (e.g. stage, grade, positive lymph node (LN) status), particularly with positive LN or a higher stage. Conclusions: Delay in Trastuzumab initiation has a crucial negative influence upon DFS and OS rates, especially in specific subgroups with more risk factors. Delay of more than 12 weeks from primary diagnosis obtained by tissue biopsy to chemotherapy initiation may be associated with a worse prognosis.
The concomitant EGFR T790M/C797S in trans and cis in three osimertinib-resistant lung adenocarcinoma patients.
Authors: Chunling Liu, Jidong Li, Hailong Liu, Rong Du, Nan Fang, Jingbo Zhang, Yu Tang, Jianwei Wang, Qixi Wu
Journal: Journal of Clinical Oncology (2019)

e20105 Background: EGFR C797S mutation is an important cause of Osimertinib resistance. Previous studies showed that patients harboring EGFR C797S in trans with T790M are sensitive to a combination of first- and third-generation EGFR tyrosine kinase inhibitors (TKI). However, patients harboring EGFR C797S in cis with T790M are resistant to combination therapy or each single reagent. Methods: We performed next-generation sequencing on peripheral blood samples from patients with advanced lung adenocarcinoma who had been undergoing targeted therapy. Total DNA was extracted from formalin-fixed, paraffin-embedded tissue sections and quantified. Targeted regions of 14 lung cancer-associated genes were amplified by PCR, barcoded and sequenced using an Illumina MiSeq 500 platform. Results: Among 6489 Lung adenocarcinoma patients sample, we identified concomitant trans and cis EGFR T790M/C797S in three patients with very poor prognosis. All three patients were sensitive to the first-generation EGFR TKI, and took Osimertinib when disease progressed. When resistant to Osimertinib, the patients went to genetic testing to find new target therapy. Patient No. 1 was a 66-year-old man with mutations of EGFR exon 19del (25.08%), EGFR T790M (10.08%) / C797S (5.37%) in trans and in cis, TP53 exon8 mutation (12.35%). This patient died 20 days after the genetic testing without any further treatment. Patient No. 2 was a 53-year-old woman who carried gene mutations including EGFR exon 19del (0.51%), EGFR T790M (0.57%) and C797S (0.47%) in trans and in cis. She was treated with the combination of first- and third-generation EGFR TKI, and disease progressed after 50 days. She died half months after the gene test. Patient No. 3 was a 63-year-old woman whose gene mutation included EGFR L858R (77.49%), EGFR T790M (40.94%) and EGFR C797S (5.46%) in trans and in cis, also combined with EGFR amplification. Treatment with vascular endothelial growth factor receptor (VEGFR) inhibitor Anlotinib was attempted, but the patient died within one month after the gene test. Conclusions: We firstly reported three cases with concomitant EGFR T790M/C797S in trans and EGFR T790M/C797S in cis mutation in the word. Physicians tried either the EGFR TKI inhibitor combination therapy or VEGFR inhibitor, but neither of them had an effect on these patients. All three patients had very poor prognosis and died within two months of the gene test, indicating that the concomitant of the cis and trans mutation could be a very important prognostic prediction factor.