tbuckley/cabot-search huggingface dataset:
Genomics of Acute Myeloid Leukemia Diagnosis and Pathways
Authors: Lars Bullinger, Konstanze Döhner, Hartmut Döhner
Journal: Journal of Clinical Oncology (2017)

In recent years, our understanding of the molecular pathogenesis of myeloid neoplasms, including acute myeloid leukemia (AML), has been greatly advanced by genomics discovery studies that use novel high-throughput sequencing techniques. AML, similar to most other cancers, is characterized by multiple somatically acquired mutations that affect genes of different functional categories, a complex clonal architecture, and disease evolution over time. Patterns of mutations seem to follow specific and temporally ordered trajectories. Mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1, and IDH2, are commonly acquired early and are present in the founding clone. The same genes are frequently found to be mutated in elderly individuals along with clonal expansion of hematopoiesis that confers an increased risk for the development of hematologic cancers. Furthermore, such mutations may persist after therapy, lead to clonal expansion during hematologic remission, and eventually lead to relapsed disease. In contrast, mutations involving NPM1 or signaling molecules (eg, FLT3, RAS) typically are secondary events that occur later during leukemogenesis. Genetic data are now being used to inform disease classification, risk stratification, and clinical care of patients. Two new provisional entities, AML with mutated RUNX1 and AML with BCR- ABL1, have been included in the current update of the WHO classification of myeloid neoplasms and AML, and mutations in three genes— RUNX1, ASXL1, and TP53—have been added in the risk stratification of the 2017 European LeukemiaNet recommendations for AML. Integrated evaluation of baseline genetics and assessment of minimal residual disease are expected to further improve risk stratification and selection of postremission therapy. Finally, the identification of disease alleles will guide the development and use of novel molecularly targeted therapies.
Parental preparedness for late effects in survivors of childhood cancer.
Authors: Katie Greenzang, Angel Cronin, Jennifer W. Mack
Journal: Journal of Clinical Oncology (2016)

85 Background: Parents of children with cancer desire information on late effects of treatment. In a prior study conducted at diagnosis, we found that parents felt they received better quality information about treatment than about late effects. Methods: We conducted a cross-sectional survey of parents of children with cancer at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center at least 5 years after diagnosis; all parents had previously participated in a study about communication at diagnosis. In this follow-up study, 65% of parents of children who were still living, and whom we were able to contact, participated (n = 90). 77% of respondents (n = 69) were parents of disease-free survivors; 23% (n = 21) were parents of children with relapsed disease. We assessed parental preparedness for cancer care and late effects of treatment. Results: Most parents reported feeling extremely or very well prepared for their child’s pediatric oncology treatment (86%), daily care needs during treatment (85%), and for the chance of their child being cured (87%). Compared with preparation for treatment, fewer parents felt extremely or very well prepared for future limitations experienced by their children (63/88 = 72%, McNemar’s Test p = 0.003) or for life after cancer (42/66 = 64%, p &lt; 0.001). In bivariable analysis among parents of disease-free survivors, parents were more likely to feel prepared for future limitations when they believed their child had no limitations in quality of life (OR 4.00, 95% CI 1.32, 12.1; p = 0.01), and when they felt that communication with their child’s oncologist had helped them deal with worries about the future (OR 4.38, 95% CI 1.31, 14.7; p = 0.02). Conclusions: Parents feel prepared to manage their child’s cancer treatment, but they feel less prepared for survivorship. High quality communication with providers may help parents feel more prepared for life after cancer therapy.
Comprehensive next-generation sequencing for clinically actionable mutations from formalin-fixed cancer tissues.
Authors: J. S. Ross, D. Lipson, R. Yelensky, M. Jarosz, A. Parker, C. E. Sheehan, F. Juhn, Z. Zwirko, K. Brennan, T. Bloom, S. Downing, J. Curran, M. T. Cronin
Journal: Journal of Clinical Oncology (2011)

10564 Background: With the increasing availability of genomically targeted therapies, the comprehensive description of patient tumor genomes can be an effective diagnostic approach that informs optimal therapy selection. Whereas individual gene sequencing (e.g., EGFR) is widely used in cancer diagnosis, the feasibility of genome-scale testing in routinely collected formalin-fixed paraffin-embedded (FFPE) cancer specimens has not previously been demonstrated. Methods: Sequences of 176 oncogenes, tumor suppressor genes and drug-metabolizing enzyme genes were analyzed from FFPE cancer biopsies. Two 20 micron sections were obtained from 101 specimens of colorectal cancer, non-small cell lung cancer or melanoma. Extracted DNA was subjected to hybrid capture and paired-end sequencing of 2574 exons encompassing the 176 genes. Results: We report sequence analysis of 176 genes in the first 33 cancer specimens that were previously subjected to conventional diagnostic sequencing or genotyping of EGFR, KRAS and/or BRAF. Our 176-plex assay at an average median coverage of 301 (range 24 to 461) automatically recovered 9 of 10 previously reported mutations, with the 10th observable following manual review. This result indicates that standard-of-care single-gene sequencing results are recapitulated by our multiplexed next generation sequencing assay. Overall, at least one previously described somatic mutation documented in the COSMIC database was observed in 30/33 cancer specimens (91%). In addition to mutations in well-known cancer genes such as TP53, STK11, APC, MLH1, BRCA2, and SMAD4 we detected many mutations that are plausibly clinically actionable beyond well-known expected mutations in EGFR, KRAS and BRAF. These included activating mutations in the PI3 kinase subunit gene PIK3CA along with mutations in MET, KIT, ERBB2 and CDKN2A. Conclusions: Our results indicate that comprehensive, high quality sequencing of hundreds of genes is feasible from routinely collected FFPE tissues, and that plausibly actionable mutations will be discovered by this approach. We suggest that clinical-grade sequencing should become a routine part of all clinical trials, and increasingly, of clinical care.
Relationship between methylation status of PTEN and point mutation of the EGFR L2 domain and efficacy of cetuximab in metastatic colorectal cancer.
Authors: Y. Ito, Y. Yamada, K. Asada, T. Ushijima, S. Iwasa, K. Kato, T. Hamaguchi, Y. Shimada
Journal: Journal of Clinical Oncology (2011)

458 Background: The KRAS mutation has been associated with resistance to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in metastatic colorectal cancer (mCRC). However, the predictive biomarkers of cetuximab resistance in KRAS wild-type mCRC remain unknown. We explored the possible roles of PTEN methylation and mutation of the EGFR L2 domain, which is the site of binding to cetuximab, in cetuximab resistance in KRAS wild-type mCRC. Methods: The subjects were 247 mCRC patients screened for KRAS status at the National Cancer Center Hospital between September 2008 and April 2010. Genomic DNA was extracted from formalin- fixed paraffin-embedded colorectal cancer tissue samples. Mutation analysis of KRAS and the EGFR L2 domain was performed by direct sequencing. Methylation analysis of PTEN was performed by quantitative real-time methylation-specific PCR with a set of primers specific to the methylated and unmethylated sequences, using sodium bisulfate-modified DNA. Results: Of the 247 mCRC patients, 136 patients had wild-type KRAS (55%). In 9 of these patients, the quality of the DNA was sufficient for analysis of PTEN methylation levels. Eight of the 9 patients received a cetuximab-based regimen (with irinotecan: 4, monotherapy: 4). The best response was PR in 4 patients (25%), SD in 2 (12.5%), and PD in 2 (12.5%). The best response of the one patient with methylated PTEN treated with cetuximab and irinotecan was SD. Mutation analysis of the EGFR L2 domain was performed in 65 of the 136 patients with wild-type KRAS. All of them received a cetuximab-based regimen (with irinotecan: 50, monotherapy: 15). The best response was PR in 13 patients (20%), SD in 26 (40%), PD in 20 (31%). The one patient who had a mutation at exon 9 showed a partial response to cetuximab and irinotecan. Conclusions: Methylation of PTEN and mutation of the EGFR L2 domain were analyzed in Japanese mCRC patients. Our findings do not provide sufficient evidence that EGFR L2 domain mutation and methylation of PTEN are correlated with resistance to cetuximab. No significant financial relationships to disclose.
Induction of NK Cell Reactivity Against Myeloid Leukemia By a Novel Fc-Optimized CD133 Antibody
Authors: Kathrin Rothfelder, Samuel Koerner, Maya Andre, Julia Leibold, Philaretos Kousis, Hans-Jörg Bühring, Sebastian P. Haen, Ayline Kuebler, Lothar Kanz, Ludger Grosse-Hovest, Gundram Jung, Helmut R Salih
Journal: Blood (2015)
Development and validation of biomarker assays to assess pharmacodynamic modulation of MET.
Authors: A. K. Srivastava, M. G. Hollingshead, J. Weiner, S. Khin, S. Borgel, P. Risbood, T. D. Pfister, S. M. Lawrence, R. J. Kinders, D. P. Bottaro, J. E. Tomaszewski, R. E. Parchment, J. H. Doroshow
Journal: Journal of Clinical Oncology (2011)

3042 Background: Deregulation of c-MET (MET), a receptor tyrosine kinase (RTK), signaling has been implicated in the initiation, progression, and metastasis of human cancers, and therefore represents an attractive target for anticancer therapy. Monitoring the phosphorylation status of relevant tyrosine residues provides an important method of assessing MET modulation. To support the clinical development of Met inhibitors, we describe development of pharmacodynamic assays to assess in vivo MET kinase inhibition, which will be suitable for use in evaluating biopsy specimens in the clinical trial setting. Methods: Two novel rabbit monoclonal antibodies specific to phosphorylated Y1235 and Y1356 MET were combined with an N-terminal MET specific capture antibody to develop sandwich immunoassays for intact MET. Wild type recombinant intact MET (P08581) was used to create a calibrator. To demonstrate a fit-for-purpose response, we investigated the growth suppression effect of two potent MET inhibitors in human gastric tumor xenografts, and analyzed the degree of inhibition of pY1235 and pY1356 in the excised tumor biopsies. Drugs were given daily for 10 days and biopsies were collected 4 hours after each dose on days 1, 3, 6, 8 and 10. Results: We developed and validated chemiluminescence immunoassays that provided a robust measurement of MET and pMET with a total analytical error (CV) <20% in tumor biopsy extracts. A single IP dose of PHA665752, 25 mg/kg and 50 mg/kg, reduced intra-tumor pY1235 levels within 4-hours by approximately 60% (p<0.05) and 80% (p<0.001), respectively. A single oral dose of PF02341066 (25 mg/kg) decreased pY1235 MET levels by approximately 70% (p<0.01) within 4 hours. At the highest dose, mean intra-tumor pMET levels of pY1235 and pY1356 were consistently lower (50-80%) in treated mice on days 3, 6, 8, and 10, as compared to pMET levels in vehicle treated group. Conclusions: Currently, several small molecule inhibitors and therapeutic antibodies are in clinical trials to treat cancer driven by the MET pathway. Our new pharmacodynamic assays provide a means to confirm and quantify the intended mechanism of action of MET inhibitors during early phase clinical trials. Funded by NCI Con#HHSN261200800001E.
A 21-year analysis of lymph node trends in colon cancer: Do quality measures really matter?
Authors: Danielle M. Hari, Alexander Stojadinovic, Connie G. Chiu, Anna M. Leung, Myung-Shin Sim, Anton J. Bilchik
Journal: Journal of Clinical Oncology (2012)

539 Background: Lymph node (LN) number has been endorsed as a quality measure (QM) in colon cancer (CC) because of the impact on survival. However, the current mandate requiring &gt; 12 LNs has been questioned. We evaluated whether compliance of this QM has improved and whether this has impacted overall survival (OS). Methods: The Surveillance, Epidemiology, and End Results (SEER) Database was queried to identify patients (pts) with pathologically confirmed, localized and regional CC (Stage I-III) diagnosed between 1988 and 2008. Interval trends in lymph node (LN) harvest and OS were evaluated over time (Year Strata (YS): 1988-1993, 1994-1998, 1999-2003 and 2004-2008). Results: For pts with local and regional CC, 181,035 had confirmed LN examinations. For Stages I-III, there has been a dramatic improvement in compliance for pts with &gt; 12 LNs harvested over the recent two 5-yr periods (19, 21, 18% respectively, p&lt;0.0001) whereas previously only a 5-7% increase occurred over time (see Table ). This rise in compliance had the greatest effect on the increased survival trend for stage II CC with minimal change for those with Stage I and Stage III CC. Irrespective of LN examined there has been a significant increase in OS for all stages over time (p&lt;.0001). Conclusions: In the largest time-dependent assessment of lymph node examination in colon cancer, significant improvements in surgical quality measures have occurred over the past decade for Stage I, II and III. These measures have translated into improvements in overall survival particularly for Stage II disease. Lymph node yield alone is not an adequate quality measure for patients with stage I and III colon cancer. [Table: see text]
Pathologic upgrading on confirmatory biopsy in a racially diverse group of men on active surveillance for prostate cancer.
Authors: Allison H. Feibus, Nora M. Haney, John Boxberger, Justin Levy, Robert Scott Libby, Jordan J. Kramer, Elisa M. Ledet, Krishnarao Moparty, Raju Thomas, Brian E. Lewis, Jonathan L. Silberstein, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2016)

142 Background: To evaluate the clinical variables associated with upgrading at confirmatory biopsy among a racially-diverse group of men with prostate cancer (PCa) who elect Active Surveillance (AS). Methods: Following IRB approval, of the more than 260 men from our multi-institutional prospective AS database we identified 140 that had undergone at least 1 confirmatory biopsy since their initial diagnosis. Patients whose diagnosis was made on TURP, had any Gleason 4 on their initial biopsy or whose initial and confirmatory biopsy were more than 2 years apart were excluded. The analysis cohort included 121 men who had Gleason Score ≤ 6, clinical stage ≤ T2a and PSA ≤ 20 ng/mL. Disease upgrading on confirmatory biopsy was Gleason score ≥ 7. Multiple variables were examined as univariate and MV predictors of upgrading. Results: We identified 121 men who fit inclusion criteria, 55 (45%) African Americans (AA) and 66 non-AA (55%) with a median follow-up of 22 months. The median age was 66, median number of biopsy cores taken at diagnostic biopsy was 12 and median time interval between diagnostic and confirmatory biopsy was 12 months. On confirmatory biopsy, no evidence of disease was noted for 51 (42%) men (26 AA, 25 non-AA), 48 (40%) men (18, AA, 30 non-AA) had findings consistent with their initial biopsy and 22 men (11 AA, 11 non-AA) experienced upgrading at repeat biopsy. Of the 22 (18%) men who were upgraded, 18 (8 AA, 10 non-AA) upgraded to a Gleason score of 7, 3 (2 AA, 1 non-AA) were upgraded to a Gleason score of 8 and 1 (AA) had a Gleason score of 9. In univariate analysis AA race was associated with a greater number of positive cores (p = 0.04) and greater total prostate volume (p = 0.03) at confirmatory biopsy. Multivariate analysis was performed and none of the clinical variables examined (race, age, BMI, PSA, volume, PSAD, number of positive cores, total number of cores, percentage of positive cores, time between biopsies) were associated with upgrading on repeat biopsy. Conclusions: Our findings suggest that race is not associated with an increased risk of upgrading at confirmatory biopsy. AA with low-risk PCa are reasonable candidates for inclusion in most AS protocols and should not be excluded based on race alone.
Genomically adjusted radiation dose to predict for survival with adjuvant radiation in resectable pancreatic cancer.
Authors: Tobin Joel Crill Strom, Sarah E. Hoffe, Jessica M. Frakes, William J. Fulp, Domenico Coppola, Gregory M. Springett, Mokenge Peter Malafa, Cynthia L. Harris, Steven A. Eschrich, Ravi Shridhar, Javier Torres-Roca
Journal: Journal of Clinical Oncology (2016)

240 Background: The median survival of patients with resectable pancreatic cancer remains low at approximately 2 years. A major limitation of treating patients with postoperative radiation therapy (RT) is the close proximity of the small bowel, which confines the RT dose. We hypothesized that a subset of patients might exist who would benefit from an escalated RT dose based on their underlying tumor radiosensitivity. Methods: Genomically-profiled patients with pancreatic cancer were identified from an IRB-approved prospective observational protocol. Patients treated with upfront surgery and postoperative RT were included. Briefly, the radiosensitivity index (RSI) is derived from the expression of 10 specific genes and a linear regression algorithm modeled on SF2 of 48 cancer cells. The RSI was combined with the delivered RT dose to derive a genomically adjusted RT dose (GAD). The GAD patient subsets were split at the middle GAD value and rounded up to the nearest integer (27). Our primary endpoint was to assess whether the GAD would predict for survival. Results: Forty patients underwent surgery and postoperative RT with GAD and clinical outcome data available. The median RT dose was 50.4 Gy (range 45-54) and the median follow-up among surviving patients was 68 months (range 42-141). Eighteen patients with a GAD &gt; 27 had a median survival of 32.1 months, while 22 patients with a GAD &lt; 27 had a median survival of 17.9 months (p = 0.48). On Cox multivariate analysis, both high-risk pancreatic cancer patients (positive margins, positive lymph nodes or a postoperative CA 19-9 &gt; 90) and patients with a GAD &lt; 27 had significantly decreased survival (Hazard ratio [HR] 5.0 [95%CI 1.8,13.6], p = 0.002 and HR 2.6 [1.1-6.0], p = 0.03, respectively). Among patients with a GAD &lt; 27, 3 of 22 (14%) would have exceeded a GAD of 27 with an escalated RT dose of 54 Gy, and 8 of 22 (36%) patients would have exceeded a GAD of 27 with an escalated dose of 56 Gy to the pancreatic bed. Conclusions: GAD is predictive of survival among patients with resectable pancreatic cancer when combined with known prognostic factors. The GAD provides a tool to determine who might benefit from dose-escalated RT based on the underlying tumor radiosensitivity.
Cancer care decision support for WBC growth-factors (GF): Geographic differences in utilization and provider malleability.
Authors: Charles L. Bennett, Kenneth Sherman Wurtz, Anna DiMarco, Lourdes Feliciano, Dinah Faith Q. Huff, Kevin B. Knopf, William J. Hrushesky, Michael Baum
Journal: Journal of Clinical Oncology (2016)

128 Background: Growth factor use is the largest single category of drug expenditure for US cancer patients. Oncology Analytics is a decision support company that assists physicians in determining the appropriate use of GF based on the NCCN, ASCO, and ASH guidelines and the level one data that underlies these guidelines. We hypothesized that there would be geographic variation among GF preference and in the malleability of those practice patterns after OA entered a market. We determined the proportion of initial pegfilgrastim requests for preauthorization over other types of GF as well as the review outcomes and final drug of choice after OA intervention of inappropriate GF requests across three specific jurisdictions: Florida, Puerto Rico, Georgia and Texas. Methods: We analyzed data from drug preauthorization requests for febrile neutropenia prophylaxis submitted by providers in these four states from 10/01/2013 through 09/30/2015. We tested geographic differences in the preference for pegfilgrastim over other GFs; and in review outcomes and final GF of choice after OA intervention for inappropriate pegfilgrastim requests. Chi-square test and linear regression was employed at 95% CL. Results: Oncologists in PR are among the most evidence-based of all GF users, preferring to order the more cost-effective filgrastim. Our research indicates that, on average, 2-3 doses of filgrastim are given at a total cost of $600 to $900 per cycle, compared to pegfilgrastim at $3,800 per cycle. GA and TX oncologists, on the other hand, chose pegfilgrastim over other GFs more than their colleagues (70% GA vs. 72% TX vs 60% FL vs 33% PR) but reduced their pegfilgrastim preference substantially in the last two years by 11% and 36% respectively (linear trend, p &lt; 0.05). Filgrastim was the most common replacement of pegfilgrastim across all states. Conclusions: There are significant geographic variations in the management of febrile neutropenia. These variations contribute to differences in financial toxicity without clinical benefit. Optimizing growth factor utilization management needs to be focused upon certain locales to be most effective. The impact of GF biosimilars has not yet been evaluated.
RX-5902: A phosphorylated p68 targeting agent to treat subjects with advanced solid tumors.
Authors: Martin Gutierrez, S. Gail Eckhardt, W Larry Gluck, Ely Benaim
Journal: Journal of Clinical Oncology (2016)

TPS778 Background: Phosphorylated p68 may play a vital role in cell proliferation and tumor/cancer progression. RX-5902 is a novel compound that targets phosphorylated p68 RNA helicase (also known as DDX5), a member of the DEAD box family of RNA helicases. As a single agent, RX-5902 inhibits tumor growth and enhances survival in a variety of xenograft tumor models (e.g., pancreatic, renal, ovarian, melanoma). Methods: This Phase 1, open-label, multicenter study evaluates the efficacy and safety of RX-5902 in subjects with solid tumors. RX-5902 is administered orally 1, 3 or 5 times per week for 3 weeks with 1 week of rest in each 4 week cycle. Dose escalation starts with an accelerated design treating 1 subject per dose followed by a standard 3 + 3 design using a modified Fibonacci sequence after the occurrence of a single Grade 2 or greater adverse event that is considered at related to RX-5902. The primary endpoint is the overall safety profile characterized by the type, frequency, severity, timing of onset, duration and relationship to study therapy of any adverse events, or abnormalities of laboratory tests or electrocardiograms as well as the description of any dose limiting toxicities that occur during Cycle 1, serious adverse events, or adverse events leading to discontinuation of study treatment. Secondary endpoints include pharmacokinetic parameters (e.g., time to maximum observed concentration [T max ], maximum observed plasma concentration [C max ], trough concentration [C trough ], area under the concentration-time curve [AUC]) and Indices of anti-tumor activity (e.g., overall response rate, time to response, duration of response, and progression-free survival during treatment. Exploratory endpoints are biochemical levels of drug targets in blood and tumor samples. Eligible subjects must have confirmed histologic or cytologic evidence of metastatic or locally advanced solid neoplasm that has failed to respond to standard therapy, progressed despite standard therapy or for which standard therapy does not exist. There is no limit on the number of prior treatment regimens. Clinical trial information: NCT02003092.