tbuckley/cabot-search huggingface dataset:
High-intermediate risk endometrial cancer: Can gene expression predict recurrence?
Authors: Cindy Tawfik, Beomjy Kim, Angelina Londono, Ashwini A. Katre, Deborah L Della Manna, Warner King Huh, Eddy Shih-Hsin Yang, Kerri S. Bevis, John Michael Straughn, Charles A. Leath, Rebecca Christian Arend
Journal: Journal of Clinical Oncology (2017)

5591 Background: Studies have shown that adjuvant therapy increases progression free survival, but does not affect overall survival in patients with high-intermediate risk (H-IR) endometrial cancer (EMCA). Our objective was to develop a gene expression signature that may help identify H-IR EMCA patients with the highest risk of recurrence to help guide treatment strategies. Methods: Data was collected on all patients that met H-IR EMCA criteria diagnosed between 2000-2010 at UAB (n = 292). Of the patients that did not receive adjuvant treatment, 13 patients that recurred were matched to 13 patients that did not recur and original tumor was compared. Of those that recurred, 5 patients had original and recurrent tumor available for analysis. Gene expression data was collected using the Nanostring nCounter PanCancer Pathway 770 gene panel. Data was analyzed using nSolver Advanced Analysis Software. A fold change (FC) of ≥ ± 2 (p &lt; 0.05) was used to identify genes with a significant expression difference. Results: Comparing the 13 patients that recurred to the 13 that did not, there were 5 genes with FC ≥ +2: BAIAP3, PLCB1, IL1R1, NOS3 and RAD50. There were 29 genes with FC ≥ -2; the top 3 genes with decreased expression (FC ≥ -10) were: BMP7, FGF18, WNT7A. Genes in the Cell Cycle (CC) pathway were significantly different in the patients that recurred (p = 0.02). There were 61 genes with FC ≥ +2 when comparing the original tumor to recurrent tumor; the top 3 genes with increased expression (FC ≥ 10) were: FGF18, CCND1, HIST1H3H (p &lt; 0.05). There were 50 genes with FC ≥ -2; the top 3 genes with decreased expression (FC ≥ -1000) were: HOXA11, LEFTY2 and SFRP4. Wnt, Hedgehog, Chromatin Modification, DNA repair, TGF-β, MAPK, and CC pathways were significantly different in the recurrent samples compared to the original tumor (p &lt; 0.05). Conclusions: Our data suggests that gene expression panels could better identify patients that warrant adjuvant treatment. The CC pathway, which is significantly different in the original tumor from those that recurred and those that did not, was further altered in the recurrent tumor samples. Additional studies are on-going to validate these findings and to further investigate DNA mutation differences in larger cohort of patients.
Systematic review of pediatric oncology phase I trials: Toxicity and outcomes in the era of targeted therapies.
Authors: Julia Wanda Cohen, Srivandana Akshintala, Eli Kane, Seth M. Steinberg, Brigitte C. Widemann, Nirali N. Shah
Journal: Journal of Clinical Oncology (2018)

2536 Background: Historically, objective response rates (ORR) (CR/CRi + PR) in pediatric phase I oncology trials have been < 10%. With an increased emphasis on targeted treatment approaches, safety profiles and response rates may have changed. We analyzed outcomes of recent phase I pediatric oncology trials. Methods: Peer-reviewed phase I pediatric oncology trials published from 2012 through 2017 were identified through a PubMed search. Selection criteria included a pediatric population (median age ≤ 25 years), diagnosis of cancer (including CNS tumors), and a clear dose-escalation schema. Each publication was evaluated for therapy type (cytotoxic versus targeted, combination vs. single agent), trial design, patient characteristics, toxicity, and response. Results: Of 242 publications identified, 89 articles met the inclusion criteria. 46 (52%) incorporated targeted therapies. Total enrollment was 2187 patients; median age at enrollment/trial was 10 years (range 3-25 years). 1990 patients (91%) were evaluable for toxicity, of whom 256 (12.9%) experienced dose-limiting toxicity (DLT) with 3 study-related deaths (0.15%). Of 1708 patients evaluable for response in 78 trials, 287 (16.8%) demonstrated a response (188 CR, 15 CRi, 84 PR). 31 (40%) of trials had no objective responses. Sixteen trials (21%) had an ORR ≥ 25% (leukemia trials = 9, solid tumor trials = 7), of which 8 were combination cytotoxic trials and 8 were targeted trials, the majority enrolling patients with the relevant target (e.g. CD19-directed therapy for CD19+ disease). Comparison between the 46 targeted trials and the 43 cytotoxic trials demonstrated similar pooled rates of DLT (11.1% vs. 15.4%) and ORR (16.9% vs. 16.7%). Conclusions: Our systematic review of recent pediatric oncology phase I trials demonstrated a higher pooled ORR than rates previously reported without increased toxicity. A subset of trials with substantially higher ORR included combination cytotoxic trials and targeted trials with target specific enrollment, supporting earlier introduction of combinatorial approaches and inclusion of pediatric patients with the relevant target in early phase targeted trials.
Valaciclovir: a culprit drug for drug reaction with eosinophilia and systemic symptoms not to be neglected. Three cases
Authors: S. Ingen‐Housz‐Oro, C. Bernier, G. Gener, F. Fichel, A. Barbaud, B. Lebrun‐Vignes, H. Assier
Journal: British Journal of Dermatology (2018)
Use of intermediate clinical endpoints (ICE) as a primary efficacy endpoint in malignant melanoma.
Authors: Siva Narayanan, Dong Shao, Anshul Shah, Vidya Ramesh
Journal: Journal of Clinical Oncology (2017)

e21075 Background: Melanoma incidence in the US has seen a considerable increase, from 17.8 (1997) to 24.0 (2013) per 100,000, with localized melanoma accounting for 84% of all cases. Early detection and treatment can improve outcomes considerably, resulting in a 99% survival rate. The FDA, within its accelerated approval program, accepts ICE as a primary endpoint, shortening time for patient access to life saving medications. Our objective was to study use of ICE as a primary endpoint for therapies targeting non-metastatic/early-stage malignant melanoma. Methods: A systematic review was conducted in PubMed to identify clinical trials using ICE as a primary endpoint in early stage (non-metastatic, stage I or II) malignant melanoma. An additional search was conducted in clinicaltrials.gov to identify ICE as a primary endpoint in on-going malignant melanoma trials (assess evidence body being built). Searches were limited to the English language, between November 2011 and October 2016. Studies reporting only overall survival (OS) as the primary endpoint were excluded. Results: Of the 226 titles and abstracts screened from PubMed, seven trials were included in the analysis. Of 440 records screened from www.clinicaltrials.gov, one was included, resulting in eight studies of randomized phase 3 trials. Relapse-free survival (RFS) and disease-free survival (DFS) were reported in 3 trials each, and represent the most frequently reported primary ICE (38% each). RFS/DFS is defined as the time from randomization to recurrence of disease or death, and combined, encompass 75% of reported ICE. Other ICE reported were distant metastasis free interval (DMFI, 1 trial) and lymphnode field relapse (1 trial). One trial reported OS as a co-primary endpoint. Conclusions: Definitions of the most observed ICE in malignant melanoma, namely, RFS and DFS, appear to overlap, warranting further investigation into consolidation of outcomes to better assess the value of intermediate endpoints in early stage malignant melanoma. Findings indicate a slow, but growing body of evidence supporting ICE as a primary endpoint in malignant melanoma, bringing focus to prevention or delay of disease progression to alleviate patient burden.
The population-based impact of new therapeutic eras on outcomes in advanced melanoma.
Authors: Jordan Doherty, Shiying Kong, Winson Y. Cheung, Jose Gerard Monzon
Journal: Journal of Clinical Oncology (2018)

e21553 Background: The systemic therapy landscape for advanced melanoma has changed significantly over the past decade. While clinical trials show that targeted/immune checkpoint inhibitors improve survival, the magnitude of realized benefit in an unselected population is unclear. We examined the effect of new systemic therapies on survival outcomes for advanced melanoma in a large Canadian province Methods: All stage IV and IIIC-unresectable patients who were diagnosed in Alberta, Canada from 2007 to 2017 were categorized into 1 of 4 mutually exclusive cohorts based on availability of novel therapy; 2007-2009 (DTIC era), 2010-2012(CTLA-4 era), 2013-2014(BRAF/MEK era), and 2015-2017(PD-1 era). We assessed era impact on outcomes using Kaplan-Meier and Cox regression analyses, stratified by receipt of treatment, and BRAF status, if relevant. Results: Total sample size 339 patients (Table). Median age 61.2yr, 65.8% male, 58.7% stage IV. Compared to the DTIC era, there were significant improvements in median overall survival (mOS), particularly for treated patients in CTLA-4 and PD-1 eras (Table). Though improvement is seen in the BRAF era, it is limited to those with unknown BRAF status who may have received immunotherapy. Controlling for confounders, survival differences persisted and favored patients in the CTLA-4 (HR 0.703: 0.29-1.70) and PD-1 eras (HR = 0.758, 0.30-1.91) (p = 0.028). Importantly, no survival differences were observed across eras among patients who did not receive treatment. Conclusions: The introduction of new systemic therapies for advanced melanoma resulted in a population-based improvement in outcomes, but this was mainly limited to those who received treatment with immunotherapy. Table: Era (n) Treated mOS in months p = 0.028 Untreated mOS in months p = 0.75 DTIC(124) 21.1 11.1 CTLA-4 (60) 48.7 13.4 BRAF mt (20) 13.9 24.1 BRAF unknown (46) 41.8 7.5 BRAF wt (43) 6.5 14.8 PD-1 (48) 28.5 14.6
Factors impacting disease-free survival in adult B cell B-ALL patients achieving MRD-negative CR after CD19 CAR-T cells.
Authors: Kevin Anthony Hay, Jordan Gauthier, Alexandre V. Hirayama, Daniel Li, Alyssa Sheih, Vicky Wu, Jenna M. Voutsinas, Sindhu Cherian, Xueyan Chen, Barbara S. Pender, Reed M. Hawkins, Aesha Vakil, Rachel N. Steinmetz, Tinh-Doan Phi, Stanley R. Riddell, David G. Maloney, Cameron John Turtle
Journal: Journal of Clinical Oncology (2018)

7005 Background: Autologous T cells engineered to express a CD19-targeting 4-1BB-costimulated CAR (CAR-T cells) have produced high complete remission (CR) rates in adult B-ALL patients (pts; NCT 01865617), but factors associated with durable remission have not been determined. Methods: Pts who received CD19 CAR-T cells at or below the maximum tolerated dose with ≥ 6 months (mos) follow-up were included. Factors impacting disease-free survival (DFS) and overall survival (OS) were determined. Results: 56 pts (median age 40 yrs, range 20-76) with a median follow-up of 27.4 mos were studied. 50 (89%) achieved morphologic CR and 45 (80%) achieved CR without minimal residual disease (MRD- CR) by flow cytometry. Pts who achieved MRD- CR had better median OS compared to those with morphologic disease after CAR-T cells (16.8 vs 2.7 mos, p = .0301). In pts achieving MRD- CR, univariate analyses showed longer DFS with lower LDH (p = .0007), no extramedullary disease (p = .005), lower marrow blasts (p = .013), cyclophosphamide/fludarabine (Cy/Flu) lymphodepletion (p = .004), higher CAR-T cell dose (p = .033); and higher in vivo AUC d0-28 of CD4+ (p = .074) and CD8+ (p = .039) CAR-T cell counts. In a stepwise multivariable model, Cy/Flu lymphodepletion (HR 4.3, p = .001), low LDH (HR 1.4 for each 100 U/L increment, p = 0.003), and absence of extramedullary disease (HR 0.34, p = .001) before CAR-T cell infusion were associated with more durable DFS. In pts with normal LDH and no extramedullary disease who received Cy/Flu before CAR-T cells, the probabilities of 2 year OS and DFS were 62% and 62%, respectively. 18 pts underwent allogeneic HSCT after achieving MRD- CR (median 2.3 mos after infusion). Those with ≥5% marrow blasts before CAR-T cells who underwent HSCT had longer DFS and OS compared to those who did not receive HSCT (median EFS 20.0 vs 4.0 mos, p = .0006; OS 26.9 vs 6.7 mos, p = .035). In contrast, those with < 5% blasts before CAR-T cells may not benefit from HSCT after achieving MRD- CR (p = .14). Conclusions: More durable DFS after achieving MRD- CR was found in pts with low LDH, no extramedullary disease, and Cy/Flu before CAR-T cells. Those with morphologic disease before CAR-T cells who achieve MRD- CR may benefit from allogeneic HSCT. Clinical trial information: NCT 01865617.
Phase 1 dose escalation and expansion safety study of BLZ-100 in pediatric subjects with primary central nervous system tumors.
Authors: Dennis Michael Miller, Amy Lee, Jeff Ojemann, Bonnie Cole, Sandra Poliachik, Laura Ishak, Stacey Hansen, Julie Novak, Sarah Leary
Journal: Journal of Clinical Oncology (2016)

TPS10584 Background: BLZ-100 is an intraoperative, fluorescent imaging agent designed to specifically label malignant tissue and enable more precise surgical resection of tumor tissue. BLZ-100 achieves tumor targeting through the peptide portion of the molecule, a modified chlorotoxin (CTX) peptide, and its imaging properties from the coupled near-infrared fluorescent dye, indocyanine green. Tumor-specific uptake of BLZ-100 has been shown in multiple mouse tumor models, including the SMOA1 medulloblastoma model, which has an intact blood brain barrier. Methods: This study is the first clinical study in a pediatric population to characterize the safety and tumor uptake of BLZ-100 in central nervous system tumors. BLZ-100 is administered as an IV bolus to subjects at least 2 hours prior to the surgical procedure. Subjects with a MRI documented lesion consistent with central nervous system tumor for which maximum safe resection is planned are eligible. Subjects must have adequate bone marrow, liver and kidney function. Dose escalation is being conducted according to a traditional “3+3” design. Dose limiting toxicity is defined as any related adverse event (AE) of ≥ Grade 3 severity occurring within 7 days of BLZ-100 administration. Measures of safety include adverse events, laboratory measures of hematology, liver and kidney function, and coagulation parameters and changes in vital signs and electrocardiograms (ECG). Blood samples for pharmacokinetics are collected up to 48 hours post dose and will be measured using a validated LC/MS method. Fluorescence imaging in situ is assessed prior to and at the completion of the tumor excision using either the Fluobeam 800 or SIRIS fluorescent imaging device. To correlate fluorescence with the presence of tumor, portions of the excised specimens are frozen and subjected to fluorescent image analysis using an Odyssey scanner and histopathology. Two of five dose cohorts (1.7 and 3.5 mg/m2) are complete with the third cohort (6.9mg/m2) enrolling. No dose limiting toxicity has been observed in the 8 pediatric subjects treated as of January 22, 2016. Clinical trial information: NCT02462629.
Racial differences in the incidence and survival of patients with neuroendocrine tumors (NETs).
Authors: Amir Mehrvarz Sarshekeh, Dian Gu, Shouhao Zhou, Zhao Bo, Chan Shen, A. Dasari
Journal: Journal of Clinical Oncology (2018)

e16175 Background: NETs are the second most prevalent of all gastrointestinal (GI) malignancies. Racial disparities still persist in spite of rapid advances leading to the reduction in morbidity and mortality of NETs. We conducted a large-scale, population-based study to evaluate racial disparities in NET incidence and NET-specific survival. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) program to evaluate the incidence and survival of patients (pts) diagnosed with NETs between 2000 and 2014. The associated population data were used to determine age-adjusted incidence rates. Given excellent prognosis for non-metastatic NET, survival analyses were limited to distant stage NET and were calculated using Cox proportional hazards model for pts with metastatic pancreatic and gastrointestinal, separately to determine the effect of race. Results: Of the 69,372 pts, 54,959 (79.2%) and 9,981 (14.4%) were white and black, respectively with the rest being American Indian/Alaska Native (AI) or Asian/Pacific Islander (API). Blacks had the highest overall incidence of NET per 100,000 individuals (8.37) as compared to other races including whites (5.8), AI (3.24) or API (3.8). The most common site of NET in all races was rectum except in whites in whom it was lung. The disparities in incidence rate (black vs white) were more pronounced for NETs of the small intestine (1.83 versus 1.08) and rectum (2.35 versus 0.76). Survival continued to be worse for blacks with metastatic GI (HR 1.22, 95% CI 1.06-1.40; p= 0.005) and metastatic pancreatic NET (HR 1.20, 95% CI 0.93-1.55; p= 0.14). Conclusions: Significant racial differences were noted in the incidence and survival according to race. Blacks have higher incidence rates of NETs compared to other races with the most common site being rectum. Whites in contrast to other races develop lung NETs more often. In metastatic GI-NET, black pts show an inferior outcome compared with whites and other races. Future studies are warranted to identify the underlying causes of the disparity and to develop therapeutic strategies to eliminate them.
Comparative molecular analyses of colon versus rectal tumors.
Authors: John Marshall, Joanne Xiu, Wafik S. El-Deiry, Jimmy J. Hwang, Zoran Gatalica, Michael J. Pishvaian, Philip Agop Philip, Sandeep K. Reddy, Anthony Frank Shields, Mohamed E. Salem
Journal: Journal of Clinical Oncology (2016)

3552 Background: Colorectal cancer (CRC) is a heterogeneous disease. There is limited data on colon and rectal tumor molecular differences. Methods: A total of 8174 CRC tumors submitted to Caris Life Sciences for IHC (protein expression), ISH (gene amplification), and NGS sequencing between 2009 and 2015 were studied. Only tumors with origins that were clearly defined as ascending, transverse, or descending colon or rectum were included in this study. We excluded any cases without clear designation. Chi-square tests determined molecular differences between colon and rectal tumors. Results: A total of 2,010 tumors met our inclusion criteria and were examined. We compared primary (1o) colon (n = 502) with 1o rectal (n = 872) tumors; the colon 1os had higher rates of ATM (7.5% vs. 3.2%, p = 0.01), BRAF (24% vs. 3.4%, p < 0.01), CTNNB1 (4% vs. 0.3%, p = 0.003), IDH1 (2% vs. 0%, p = 0.01), GNAS (3.3% vs. 1%, p = 0.04), HNF1A (15% vs. 9%, p = 0.01), JAK3 (8% vs. 2.2%, p = 0.002), PIK3CA (24% vs. 12%, p = < 0.01), RB1 (1.7% vs. 0%, p = 0.02), and SMAD4 (17% vs. 12%, p = 0.05) mutations. However, mutations in APC and TP53, and amplification of HER2, were higher in rectaltumors (67% vs. 54% and 72% vs. 60% [both p < 0.01] and 5.4 % vs. 1.5% [p < 0.01]). Colon 1o tumors had higher MSI (17% vs. 0.7%, p < 0.01), EGFR (64% vs. 42%, p < 0.01), PD-1 (55% vs. 44%, p = 0.01), and TS (36% vs. 28%, p < 0.01) expression. In contrast, rectal 1o tumors had higher expression of MGMT (64% vs. 52%, p = 0.002), TLE3 (33% vs. 26%, p = 0.03), TOPO1 (52% vs. 36%, p < 0.01), and TUBB3 (41% vs. 30%, p < 0.01). When we excluded MSI+ tumors and analyzed only the MSI- tumor differences, colon tumors still had a greater frequency of BRAF (13% vs. 4.5%, p = 0.003) and PIK3CA (22% vs. 12%, p = 0.009) mutations, and higher EGFR expression (63% vs. 51%, p = 0.047) than rectal tumors, whereas, PTEN (56% vs. 41%, p = 0.004), TLE3 (43% vs. 29%, p = 0.004) and TOPO1 (50% vs. 38%, p = 0.03) were overexpressed in rectal tumors. Conclusions: Molecular profile differences between colon and rectal tumors suggest different carcinogenic pathways and biology. Low frequency mutations in several druggable genes, or protein overexpression (e.g., HER-2, PIK3CA, TOPO1) provide therapeutic targets. Our findings are consistent with the consensus molecular subtyping of CRC.
Genomic characterization of ductal adenocarcinoma of the prostate.
Authors: Michael Thomas Schweizer, Emmanuel S. Antonarakis, Tarek A. Bismar, Liana Guedes, Heather H. Cheng, Maria S. Tretiakova, Funda Vakar-Lopez, MD, Nola Klemfuss, Eric Quentin Konnick, Elahe A. Mostaghel, Andrew Caleb Hsieh, Peter S Nelson, Evan Y. Yu, Robert B. Montgomery, Lawrence D. True, Jonathan I. Epstein, Tamara L. Lotan, Colin Pritchard
Journal: Journal of Clinical Oncology (2018)

5030 Background: Ductal prostate cancer (dPC) is a rare prostate cancer variant associated with poor outcomes. Prior small case series have documented that dPCs may be enriched for alterations in DNA damage repair (DDR) pathway genes and activation of WNT- and PI3K-pathways. To expand these findings, we formed a multicenter collaboration with the goal to provide a comprehensive overview of the spectrum of mutations associated with dPC. Methods: We assembled three case series across multiple institutions in the United States and Canada. All patients carried a diagnosis of dPC, and histopathologic classification was confirmed by an expert genitourinary pathologist at each respective institution. All tumor tissue was sequenced on a targeted next-generation sequencing (NGS) assay, UW-OncoPlex, according to previously published methods. Tumor samples were acquired from men with dPC treated at the University of Washington/Seattle Cancer Care Alliance (N = 21), Johns Hopkins Hospital (N = 21) and University of Calgary (N = 8). Only pathogenic/likely pathogenic mutations are reported. Results: Tumors from 50 patients with known dPC were sequenced. Overall, 26 (52%) individuals had at least one alteration in a DDR gene, including 7 (14%) with a mismatch repair (MMR) gene mutation. Twenty (40%) cases had mutations predicted to result in PI3k-pathway activation, 15 (30%) patients had mutations that were predicted to result in activation of the WNT-signaling pathway (N = 11 inactivating APC mutations; N = 4 activating CTNNB1 mutations), and 12 (24%) had mutations in genes involved in MAPK-signaling. Other frequently altered genes included: FOXA1 (N = 17, 34%), TP53 (N = 9, 18%) and SPOP (N = 6, 12%). Alterations in AR were relatively infrequent (N = 4, 8%). Conclusions: This study confirmed that dPCs are enriched for actionable mutations. Over 50% of cases demonstrated at least one alteration in a DDR pathway gene, including a high percentage of cases with MMR deficiency. Patients with dPC should be offered NGS to guide standard of care treatment (e.g. anti-PD1 therapy, platinum-based chemotherapy) or to triage toward an appropriate clinical trial (e.g. PARP inhibitor trials).