tbuckley/cabot-search huggingface dataset:
Outcome in congenital hepatoblastoma compared with previously reported data.
Authors: Angela D Trobaugh-Lotrario, Barbara H Chaiyachati, Rebecka Meyers, Beate Haberle, Gail Elizabeth Tomlinson, Howard M. Katzenstein, Marcio H. Malogolowkin, Dietrich von Schweinitz, Mark D. Krailo, James Henry Feusner
Journal: Journal of Clinical Oncology (2013)

10037 Background: Congenital hepatoblastoma, defined as diagnosis in the first month of life (Ammann RA, Plaschkes JLeibundgut K. Congenital hepatoblastoma: A distinct entity? Med Pediatr Oncol 1999:32:466-468.), has been reported to have a poor prognosis; however, a comprehensive evaluation of this entity is lacking. Methods: We performed a retrospective review including three patients from the senior authors’ personal series and 23 cases identified in the databases of several multicenter group studies (INT-0098, P9645, 881, P9346, HB 89, HB94 and HB 99). We then compared this series with the data of all cases of congenital hepatoblastoma previously published in the literature. Results: The overall 2-year survival in our case series was 86% (18/21) with a median followup of 85.5 months (range 44 to 230 months). Presentation and treatment were not substantially different from hepatoblastoma cohorts unselected for age. The infants in our study exhibited a comparable survival rate to the reported disease free survival for a similar cohort of hepatoblastoma patients unselected for age between 1986 and 2002 (82.5%) [Tiao GM, Bobey N, Allen S, et al. The current management of hepatoblastoma: A combination of chemotherapy, conventional resection, and liver transplantation. J Pediatr 2005:146:204-211.]. The overall 2-year survival rate of cases previously reported in the literature was 0% (0/11) for patients reported before 1992, and 47% (8/17) for those reported after 1992. The improved survival of our current series of patients, collected from the past 20 years of German and American multicenter trials and personal series, suggests that the outcome of HB at this young age is much better than has been historically reported. Conclusions: Congenital hepatoblastoma does not appear to confer a worse prognosis. The overall survival in our series does not appear to be worse than in older children; more rigorous analysis should be conducted in future multicenter trials. It is possible that congenital HB should be treated like all other patients with hepatoblastoma provided that the child is stable enough to proceed with surgery and chemotherapy and complete staging is performed.
A phase 2 study of temozolomide in patients affected by pretreated metastatic colorectal cancer with MGMT promoter methylation.
Authors: Maria Alessandra Calegari, Santa Monterisi, Alessandro Inno, Armando Orlandi, Michele Basso, Alessandra Cassano, Daniele Santini, Maurizio Martini, Tonia Cenci, Ivana de Pascalis, Brunella Barbaro, Floriana Camarda, Cesare Colosimo, Luigi Maria Larocca, Giuseppe Tonini, Stefania Gori, Carlo Antonio Barone
Journal: Journal of Clinical Oncology (2017)

629 Background: Presently few options are available for pts with mCRC who failed standard treatments and prognosis remains grim. MGMT promoter methylation is a frequent and early event in CRC tumorigenesis. This epigenetic silencing is a predictor of response to the alkylating drug TMZ in glioblastoma. Preclinical evidences and a couple of clinical cases showed TMZ activity in pts affected by mCRC with MGMT silencing. We designed a study to evaluate the efficacy and safety of TMZ in pts with refractory mCRC harboring MGMT promoter methylation. While the trial was ongoing three analogous studies, reporting discordant results, were published. Methods: This was a 3-institutional, single arm, phase 2 trial, planned according to a 2-stage Simon’s optimal design. The primary endpoint was ORR. Secondary outcomes included DCR, OS, PFS and safety. A first cohort of 21 pts was accrued: if more than 1 response was observed a second cohort of 20 pts would be enrolled; if 4 or fewer responses were observed by the end of stage two, then no further investigation would be warranted. MGMT promoter methylation was assessed on archival tissue samples by MS-PCR. Patients affected by MGMT methylated mCRC, who failed 2 or more prior treatments, received TMZ, provided by TEVA Pharmaceutical Industries, at a dose of 150-200 mg/mq/day once a day on days 1-5 every 28 days. Results: From July 2012 to June 2016, 225 pts were screened and 80 showed MGMT promoter methylation, among those 42 met the inclusion and exclusion criteria and were enrolled. ORR was 10% with no CR and 4 (10%) PR. SD was achieved in 9 (22%) pts, accounting for a DCR of 32%. At a median FU of 9 months all pts experienced PD and 88% died. Median PFS and OS were 2.6 months (95% CI 2.1-3.2) and 7.1 months (95% CI 5.1-9.2) respectively. Overall, any-grades AEs were reported in 75.6% pts, most of them were G1-2 (84%). The most frequent AE were nausea (56%) and platelet count decreased (39%). 4 pts discontinued study treatment due to AE. No SAE neither toxic death was recorded. Conclusions: The study did not meet its primary endpoint, however an interesting DCR (32%) and 4 PR were achieved. The role of TMZ in mCRC treatment remains still controversial and might warrant further analysis. Clinical trial information: 2012-002766-13.
A phase I study of EpCAM/CD3-bispecific antibody (MT110) in patients with advanced solid tumors.
Authors: Walter M. Fiedler, Martin Wolf, Maxim Kebenko, Marie-Elisabeth Goebeler, Barbara Ritter, Alexander Quaas, Eva Vieser, Youssef Hijazi, Ingrid Patzak, Matthias Friedrich, Peter Kufer, Stanley Frankel, Ruth Seggewiss-Bernhardt, Sabine Kaubitzsch
Journal: Journal of Clinical Oncology (2012)

2504 Background: MT110 is a bispecific T cell engaging antibody construct (BiTE ) that directs CD3 expressing T cells to kill target cells that express EpCAM, which is widely found on solid tumors. Methods: Safety, tolerability, pharmacokinetics and anti-tumor activity of MT110 in patients (pts) with advanced solid tumors were studied using a 3+3 design. Continuous IV infusions for at least 28 days of doses ranging from 1 to 48 µg/d have been tested. Stepwise intra-patient dose escalations within cycle 1 or at start of cycle 2 have been explored. Results: 51 pts (6 gastric cancers, 32 CRC, 2 SCLC, 5 NSCLC, 3 HRPC, 1 ovarian cancer) have been treated in 12 dose cohorts. The maximally administered dose includes day 1 dose of 3 µg/d escalated up to 48 µg/d. The maximum tolerable dose (MTD) has not yet been established. Diarrhea and elevations in liver function tests have been reported as dose limiting toxicity (DLT) for individual patients. Transaminase elevations were fully reversible and mitigated by dexamethasone at initiation or escalation of dose. Other adverse events of grade 3 or higher included transient lymphopenia, increase in lipase or amylase, nausea, vomiting, and hypoalbuminaemia. No CNS safety signal was observed. The mean serum half-life of MT110 was 4.5 hours. Mean steady state serum concentrations of MT110 were linear with dose across treatment cycles. At 48 µg/d, the mean Css was 3.2 ng/mL. This compares to preclinical EC90 of 1.35 – 3.85 ng/ml in CRC cell lines. Sixteen pts who received a dose of ≥ 24 µg/d were evaluable for anti-tumor response. Best response of SD was reported in 38%; median duration was 155 days (95% CI 92; 161). Anti-tumor activity was demonstrated on biopsy of liver metastases in one patient. Following at least 1 week of MT110 treatment at 48 µg/d, a decrease in circulating tumor cells was observed with a median nadir 74% below baseline. Conclusions: The use of stepwise dose escalation and concomitant dexamethasone resulted in improved tolerability. A dose of 48 µg/d appears tolerable. Tumor biopsy evaluation on treatment and pharmacodynamic evidence of anti-tumor activity are encouraging. Additional dose cohorts will seek to identify the recommended phase II dose and further evidence of anti-tumor activity.
Investigating <i>RUNX1</i> and <i>RUNX2</i> in prostate cancer.
Authors: Anne Jane McKillop, Joanne Edwards, Emma Johnson, Susan Mason, Ewan R Cameron, Karen Blyth
Journal: Journal of Clinical Oncology (2017)

232 Background: Prostate cancer is the most commonly diagnosed cancer in men and is increasing in incidence. Current treatment for metastatic disease is initially hormone treatment and chemotherapy. While this produces a response in the vast majority of patients, it is not curative. Novel therapeutic agents could provide a further treatment strategy and it is therefore important to understand the molecular pathways which contribute to this disease. The RUNX family of genes have been implicated as both oncogenes and tumor suppressors, with their role being context dependent. It has been reported that RUNX2 may have a tumor suppressor role in early stage prostate cancer but that this may switch to an oncogenic role in later stage disease. Methods: This project examines the expression of both RUNX1 and RUNX2 in a tissue microarray (TMA) of human prostate cancers. In parallel to the human studies both RUNX1 and RUNX2 were investigated in murine models of prostate cancer. Results: Analysis of the TMA showed that increasing levels of RUNX2 were associated with increasing Gleason grade, shorter time to relapse and poorer survival; the opposite effect was seen in RUNX1, where low levels of protein expression correlated with shorter survival. In concordance with the human results, reducing levels of RUNX2 in mouse models was associated with delayed tumor initiation, and smaller, less cystic tumors at endpoint. The opposite effect was seen with Runx1 where low levels resulted in more aggressive and invasive disease. Finally, when loss of both genes was combined in a model with loss of Pten and stimulation of WNT, survival was significantly reduced compared to controls. Conclusions: This study suggests that RUNX2 expression may correlate with a poorer prognosis in prostate cancer, while expression of RUNX1 is likely to be associated with an improved outcome.
Characterization of Lineage Vs. Context-Dependent Essential Genes in Multiple Myeloma Using Crispr/Cas9 Genome Editing
Authors: Geoffrey M. Matthews, Ricardo De Matos Simoes, Yiguo Hu, Michal Sheffer, Eugen Dhimolea, Paul J. Hengeveld, Megan A. Bariteau, Brian Glassner, Quinlan Sievers, Benjamin L. Ebert, Sara Gandolfi, Pallavi Awate, Huihui Tang, Franciska Vazquez, Aedin Culhane, Constantine S Mitsiades
Journal: Blood (2016)
Targeted NGS analysis including mRNA on FFPE tissue to assist oncology decision making.
Authors: Scott Morris, Eric James Thompson, Glen J. Weiss, Ramaswamy Iyer, Bryan Paul Schneider, Milan Radovich, Kenneth Groshart, David M. Loesch, Joseph Paulauskis, David Mallery, Robert James Penny
Journal: Journal of Clinical Oncology (2014)

e22098 Background: The value of examining neoplasms for DNA mutations via Next-Generation Sequencing (NGS) on formalin-fixed paraffin-embedded (FFPE) tumor tissue is widely recognized. However, similar clinical options for examining mRNA in FFPE samples are not widely available. The PCDx test generates data on a combination of somatic mutations, indels, chromosomal abnormalities, mRNA expression levels and DNA copy number changes. We sought to determine the results of adding mRNA analysis to DNA testing in tumor tissue from clinical samples using the PCDx test. Methods: FFPE blocks were submitted by various clinics, with no exclusionary criteria related to tumor origin, histology, and specimen age or specimen quality. Specimens varied in size from needle biopsies to tissue fragments >2 cm across. The age of specimens varied from less than a month to several years in age. RNA and DNA were extracted from submitted specimens, libraries were built and subjected to analysis on an Ion PGM sequencer. A biomarker was considered actionable if it has a published association with treatment response or a clinical trial listed in clinicaltrials.gov. Results: We report the results obtained from the first 62 patients examined from our test . The majority of these cases were from breast cancer, lung cancer, and colon cancer. 97% of cases (60/62) contained at least one actionable marker when both RNA and DNA were analyzed, which is substantially higher than the rate when only DNA is tested. The RNA findings contributed to identification of actionable biomarkers in 84% of cases. Conclusions: Sequencing RNA in addition to DNA is feasible in a clinical setting utilizing FFPE samples, and results in the discovery of more actionable markers than sequencing DNA only. This may result in treatment options that were not previously discoverable.
Obesity at diagnosis and breast cancer (BC) recurrence risk based on the 21-gene assay recurrence score (RS).
Authors: Kimberly Ridolfi, Chong Zhang, Adedayo A. Onitilo, Wendy M. Ledesma, Molly Andreason, Jessica Marie Engel, KyungMann Kim, Kari Braun Wisinski, Amye Tevaarwerk, John A. Charlson
Journal: Journal of Clinical Oncology (2012)

555 Background: Obesity at diagnosis has been associated with poorer overall survival in BC patients. The Oncotype Dx 21-gene assay RS has been shown to predict the risk of distant recurrence in estrogen receptor (ER) positive BC. This study aimed to evaluate if an association exists between body mass index (BMI) and RS. Methods: Retrospective chart review of patients (pts) with BC diagnosed 2005-2010 and a 21-gene assay was performed. Risk factors including BMI, hormone use, and menopausal status were collected as well as tumor characteristics such as ER/PR/HER2 status, stage, and grade. Univariate analysis of the association between BMI level (&lt;30 vs ≥30), and RS (≤18 vs &gt;18), stage (I vs II), and grade (1 vs 2 vs 3) was conducted using Chi square test. Correlation of BMI with RS (0-100) was also assessed via Spearman’s correlation. All tests were at a two sided significance level of 0.05. Results: Of 495 pts with a RS value, 482 had a BMI within 6 months of diagnosis. Median BMI was 27.7 kg/m2 (range 17-63). BMI for pts presenting with stage 2 disease is significantly higher (30±6.9) than those with stage 1 (29±7.8), p=0.04 (Wilcoxon rank sum test). No association was found between BMI level and stage, grade or RS. See Table. Mean RS was 18.8 vs 18.2 (BMI &lt;30 vs ≥30), p=0.79 (Wilcoxon rank sum test). Conclusions: This is the largest study of the association between BMI and the RS. Obesity (BMI≥30) has been associated with increased recurrence and death from BC. However, we found no association between BMI and RS. This suggests that poorer outcomes among obese ER+ breast cancer patients may not be due to intrinsic tumor biology (as reflected in the RS), but to other non-tumor factors, whether higher circulating estrogen levels, reduced efficacy of aromatase inhibitors, other comorbidities, difficulty with chemotherapy or other unidentified factors. Further study is warranted. [Table: see text]
Neoadjuvant chemotherapy in operable breast cancer with docetaxel, doxorubicin, and cyclophosphamide (TAC) or TAC followed by vinorelbine and capecitabine (NX): Final results and analysis of markers predicting response to treatment
Authors: J. Huober, G. von Minckwitz, C. Denkert, A. Kleine-Tebbe, E. Weiss, D. Zahm, G. Köhler, K. Mehta, S. Loib
Journal: Journal of Clinical Oncology (2009)

524 Background: The aim of this analysis was to determine the pathological complete remission rate (pCR) for the entire Gepartrio study population and to identify markers predicting response to NACT. Methods: The design of the Gepartrio study was described elsewhere (von Minckwitz et al.). Age at diagnosis, tumor size, lymph node status, estrogen (ER), progesterone (PgR), HER-2 status, histological type, and grade were assessed in uni- and multivariate analysis. Clinical response after 2 cycles TAC and pCR at surgery were used as efficacy endpoints. Results: 2072 pts were randomized depending on response after 2 cycles TAC. 1122 pts (54.2%) had a clinical response after 2 cycles and 385 (18.6 %) pCR. The highest pCR rate (60%) was observed in pts with triple neg tumors and &lt; 40 years. In the HR pos/HER-2 pos pts the pCR rates were 17.6% vs. 9% for HR pos/HER-2 neg pts (p&lt;0.001). In the HR neg subset absence of HER-2 overexpression (“triple neg tumors”) resulted in significantly improved pCR rates compared to the HR neg HER-2 pos subset (40.7% versus 31.6%, p=0.041). In univariate analysis predictors for both an early response and a pCR at surgery were age &lt; 40 years, non T4 tumor, grade 3, neg hormone receptors (HR) and a triple neg status. Non lobular histology was only predictive for a pCR in univariate analysis. In multivariate analysis independent factors for early response were non T4 tu, tumors ≥ 40 mm, poor grading and neg HRs. Independent predictors for a pCR remained age &lt; 40 years, poor grading, a non lobular subtype and triple neg tumors. Conclusions: The pCR rate for the whole study population of the Gepartrio trial was comparable to other neoadjuvant regimens. Markers identified as independent predictors may help in decision making for pts being considered for neoadjuvant chemotherapy. [Table: see text]
Effect of perioperative transfusion on recurrence and survival after resection of distal cholangiocarcinoma: A 10-institution study from the U.S. Extrahepatic Biliary Malignancy Consortium.
Authors: Alexandra G Lopez-Aguiar, Cecilia Ethun, Timothy M. Pawlik, George A. Poultsides, Thuy Tran, Kamran Idrees, Chelsea A Isom, Ryan C Fields, Bradley Krasnick, Sharon M. Weber, Ahmed Salem, Robert C. G. Martin, Charles Raben Scoggins, Perry Shen, Harveshp Mogal, Carl Richard Schmidt, Eliza W Beal, Ioannis Hatzaras, Rivfka Shenoy, Shishir Kumar Maithel
Journal: Journal of Clinical Oncology (2017)

236 Background: Perioperative allogeneic blood transfusion is associated with poor oncologic outcomes in several malignancies. Its effect on recurrence and survival in distal cholangiocarcinoma (DCC) is unknown. Methods: All patients with DCC who underwent curative-intent pancreaticoduodenectomy at 10 institutions from 2000-2015 were included. 30-day mortalities were excluded. Primary outcomes were recurrence-free (RFS) and overall survival (OS). Results: Of 314 pts with DCC, 206 (66%) underwent curative-intent pancreaticoduodenectomy. Median age was 67yrs, and 53 pts (28%) received perioperative blood transfusions, with a median of 2 units.There were no differences in baseline demographics or operative data between transfusion and no-transfusion groups.Compared to no-transfusion, patients who received a transfusion were more likely to have (+)margins (28vs14%; p &lt; 0.03) and major complications (46vs16%; p &lt; 0.001). Receipt of neoadjuvant or adjuvant therapy was similar between groups. Transfusion was associated with lower median RFS (19vs32mos; p = 0.006) and OS (15vs29mos; p = 0.003), which persisted on multivariable (MV) analysis for both RFS (HR 1.8; 95%CI 1.1-3.1; p = 0.03)and OS (HR 1.9; 95%CI 1.1-3.2; p = 0.03), after controlling for portal vein resection, EBL, margin status, grade, LVI, LN status, and major complications. Similarly, transfusion of ≥ 2 pRBC units was associated with lower RFS (17vs32mos; p &lt; 0.001) and OS (14vs29mos; p &lt; 0.001), which again persisted on MV analysis for both RFS (HR 2.6; 95%CI 1.4-4.6; p = 0.002) and OS (HR 3.9; 95%CI 2.1-7.5; p &lt; 0.001). The RFS and OS of patients transfused 1 unit was similar to those not transfused. Conclusions: Perioperative blood transfusion is associated with decreased RFS and OS after resection for distal cholangiocarcinoma, after accounting for known adverse pathologic factors. Volume of transfusion seems to exert an independent effect, as 1 unit is not associated with the same adverse effects as ≥ 2units. This supports the judicious use of perioperative transfusion; protocols should be developed and followed.
Multiplex genomic profiling of non-small cell lung cancer patients enrolled in the LETS phase III trial of first-line S-1/carboplatin versus paclitaxel/carboplatin (WJOG6611LTR).
Authors: Hiroshige Yoshioka, Isamu Okamoto, Kazuko Sakai, Satoshi Morita, Hiroyasu Kaneda, Koji Takeda, Tomonori Hirashima, Yoshihito Kogure, Tatsuo Kimura, Toshiaki Takahashi, Shinji Atagi, Takashi Seto, Toshiyuki Sawa, Masashi Yamamoto, Miyako Satouchi, Motoyasu Okuno, Seisuke Nagase, Kazuhiko Nakagawa, Yoichi Nakanishi, Kazuto Nishio
Journal: Journal of Clinical Oncology (2014)

8095 Background: High-throughput genotyping tests to evaluate large numbers of genetic abnormalities in non–small cell lung cancer (NSCLC) are needed. Methods: Archival formalin-fixed, paraffin-embedded (FFPE) tumor specimens were collected from patients with advanced NSCLC enrolled in the LETS phase III trial. With the use of the multiplex platform of Sequenom’s MassARRAY assays, we performed high-throughput genotyping for 214 somatic hotspot mutations in 26 genes (LungCarta Panel) and 20 major variants of ALK, RET, and ROS1 fusion genes (LungFusion Panel). We also evaluated MET amplification by fluorescence in situ hybridization. Results: The numbers of evaluable patients were 275 for somatic gene mutations, 240 for fusion genes, and 229 for MET amplification. A somatic mutation in at least one gene was identified in 105 (48%) of the 217 patients with nonsquamous cell carcinoma (non-SCC) and in 26 (45%) of the 58 patients with SCC. Overall, we identified EGFR mutations in 46 patients (17%), TP53 mutations in 30 (11%), STK11 mutations in 27 (9.8%), MET mutations in 21 (7.6%), KRAS mutations in 17 (6.2%), PIK3CA mutations in 6 (2.2%), and BRAF and NRAS mutations in 3 each (1.1%). Median overall survival of EGFR mutation–positive patients was significantly longer than that of those without EGFR mutations (23.7 vs. 12.6 months, P = 0.004). Conversely, patients with KRAS mutations had a significantly shorter survival time than did those with wild-type KRAS (9.9 vs. 15.3 months, P = 0.04). ALK fusions were detected in six cases (2.5%), ROS1 fusions in five (2.1%), and RET fusions in one (0.4%), with these three types of rearrangement being mutually exclusive. Median overall survival was 19.5 versus 13.8 months for fusion gene–positive and –negative patients, respectively (P = 0.89). De novo MET amplification was identified in 9 patients (3.9%). Conclusions: This first multiplex genotyping of NSCLC accompanying a phase III study demonstrates that MassARRAY-based testing performs well with nucleic acid derived from FFPE tissue obtained from patients with advanced NSCLC.