tbuckley/cabot-search huggingface dataset:
The frequency of druggable targets in localized prostate cancer: Initial analysis from the Decipher GRID.
Authors: Nicholas Erho, Mohammed Alshalalfa, Penelope J. Wood, Mandeep Takhar, Hussam Al-Deen Ashab, Elai Davicioni
Journal: Journal of Clinical Oncology (2016)

98 Background: Prostate cancers patient management has been enhanced with commercially available genomic prognostic tests such as the Decipher prostate cancer classifier that are useful for making treatment decision-making. In addition to being the most validated predictor of metastasis in prostate cancer, Decipher is also a genome-wide assay that measures the expression of many druggable targets. Methods: Decipher GRID (Genomic Resource Information Database), was queried to assess the expression patterns of 14 genes from 5 biological pathways (Table) in 1,850 patients from previously published Decipher validation studies. The frequency of high (or low) expression of each gene was ascertained using a standard and more conservative thresholds based on the median absolute deviation (MAD) metric. For the standard threshold, genes whose high expression is of clinical relevance, patients with gene expression above the median + 1.48*MAD were annotated as high expression and for genes whose low expression is of clinical relevance, patients with gene expression below the median - 1.48*MAD were annotated as low expression. For the conservative threshold, median +/- 2*1.48*MAD was used. Results: See Table. Conclusions: Since every patient receiving the Decipher test also has a genome-wide expression profile, the Decipher GRID will allow researchers to evaluate on a systematic population-level the expression of genes that may be targeted with existing therapies. Such information may be useful for selection of optimal systemic therapy and inclusion into clinical trials of novel targeted agents. This rich genomic resource is being made available on a research use only basis to prostate cancer researchers and to clinicians seeking to uncover individualized genomic insights for patients to advance precision medicine. [Table: see text]
How to create a successful cancer self-management intervention: Development, evaluation, and lessons learned.
Authors: Jessica Goldberg, Jenna Hinchey, Shelli Feder, Dena Schulman-Green
Journal: Journal of Clinical Oncology (2014)

168 Background: Cancer self-management (SM) is individuals’ engagement in tasks related to the medical, physical, spiritual, and emotional management of cancer. Reports of SM interventions often focus on efficacy and do not detail processes of development and evaluation. We delineate our creation of a patient-oriented and informed cancer SM intervention, Managing Cancer Care: A Personal Guide (MCC), and share lessons learned to improve intervention efficacy and fidelity. Methods: We developed and evaluated MCC in 5 stages: needs assessment interviews (n=25); development of MCC; focus group (n=6); pilot testing with metastatic breast cancer patients (n=23); and population testing with non-metastatic breast cancer patients (n=110). We performed content analysis on qualitative data and used descriptive statistics to analyze module ratings and frequency of use in the pilot and population tests. Results: We identified cancer SM practices, preferences, facilitators, and barriers, and designed MCC based on interview data, related literature, and SM theory. The MCC prototypeconsisted of 7 magazine-style modules designed to be user-friendly, concise, and personalized. Although well-received, we made substantial changes based on focus group data, with additional revisions after the pilot test. Module ratings and frequency of use differed between pilot and population samples. Among metastatic patients, median ratings (1-10, low/high) for MCC as a whole on both content and format were 8 (range 2-10). The most popular module was Care Options, which tied with Managing Transitions as most frequently used. Among non-metastatic patients, median ratings were 8 (range 1-10) and 9 (range 2-10) on content and format, with the Managing Your Symptoms module being most popular and most frequently used. Conclusions: Data from our metastatic and non-metastatic samples suggest differing SM priorities. Lessons learned in creating patient-oriented cancer SM interventions include acknowledging that there are no “one size fits all” solutions, resisting assumptions about reception of potentially emotional content, maintaining flexibility, and negotiating the tension between research and real world settings.
Early targeted drug development: Pilot FDA review of PI3K inhibitor phase I studies using a knowledge management database.
Authors: G. M. Blumenthal, R. Charlab Orbach, I. Zineh, P. Cortazar, R. L. Justice, R. Pazdur
Journal: Journal of Clinical Oncology (2011)

3060 Background: Optimized phase 1 (ph1) clinical trials may increase the likelihood of successful oncology drug development. We developed a FDA knowledge management (KM) database that allows comprehensive assessment of ph1 trial features. Here we pilot whether the database can catalogue diversity in early phase studies of the PI3K inhibitor drug class. Methods: We evaluated the development programs of 6 PI3K inhibitors, including ph1 protocols, annual reports, and investigator brochures submitted to the FDA under the investigational new drug (IND). Key features of PI3K inhibitor ph1 trials were summarized in the KM database. Results: Of the 6 PI3K inhibitor ph1 trials surveyed, three agents (50%) targeted PI3K alone and 3 (50%) were dual PI3K and mTOR inhibitors. Four (66%) trials used a traditional 3+3 design, while two (33%) adopted a bayesian continual reassessment model. MTD was the primary endpoint of all trials. Three trials (50%) adopted an enrichment strategy for the expansion cohort, which varied from molecular enrichment (somatic alteration in PI3K, PTEN or EGFR) or clinical enrichment (Cowden syndrome). Pharmacodynamic (PD) assays included surrogate tissue (assessment of molecular changes in PBMCs, skin, and hair) and primary tissue (FDG-PET, flow cytometry of CLL, and tumor biopsy). Dose-limiting toxicities included hyperglycemia, anorexia, gastrointestinal, rash, mood alteration, uveitis, thrombocytopenia, elevated ALT, low phosphate, and ECG alteration. Two trials (33%) reported ≥ grade 3 hyperglycemia. Conclusions: FDA review of PI3K ph1 studies reveal a variety of designs, enrichment strategies based on molecular and clinical features, PD assays, tumor types, and toxicities. The KM database will assist in determining which features are important to successful development. Preliminary analysis of these trials (as well as prior experience with other targeted agents) indicate that early selection of an enriched population most likely to benefit, development of validated biomarker assays prior to pivotal trials, adoption of randomized ph2 designs, and exploration of combination strategies will accelerate the development programs and increase the likelihood of success.
Effect of the addition of platinum to gemcitabine on outcome in patients with advanced pancreatic cancer who progress on gemcitabine: A comprehensive analysis of published trials.
Authors: Osama E. Rahma, David J. Liewehr, Seth M. Steinberg, Austin G. Duffy, Tim F Greten
Journal: Journal of Clinical Oncology (2013)

275 Background: Pancreatic cancer is one of the deadliest cancers with an estimated 5 years survival rate of 5%. Until recently gemcitabine had been considered the first line treatment for locally advanced or metastatic disease. Although many chemotherapy regimens have been used there is no standard of care for second line therapy. The aim of this analysis was to identify superior regimen in the second line setting. Methods: We conducted a general search on PubMed for “second line therapy in advanced pancreatic cancer”. We limited our search to trials published in English from 2000 through 2012. Studies presented as abstracts in major meetings were also included. Trials that used targeted therapy other than erlotinib were excluded. We compared in an exploratory fashion the RR, PFS and OS of BSC and each of the following regimens to the rest of the treatments: 5FU+platinum, gemcitabine+platinum, taxol, erlotinib. In addition, we compared the combinations of platinum with either 5FU or gemcitabine. Finally, we explored the trend of these treatments outcomes over time. Results: Forty-four trialswere identified, of which 34 trials (T) met the inclusion criteria treating 1503 patients (N). There was a trend toward an improved overall survival with treatments (T: 33; N: 1269) compared to BSC (T: 2; N: 234) only (P= 0.013). The combination of gemcitabine and platinum (T: 5; N: 154) was the only regimen that showed a trend toward superior outcomes compared to the other regimens (T: 28; N: 1115) in terms of RR and PFS (P= 0.006 and 0.059, respectively). However, there was no difference in overall survival (P= 0.10). When compared to 5FU+platinum (T: 12; N: 450) the regimen of gemcitabine+platinum (T: 5; N: 154) showed only a trend toward significance in terms of improved RR (P= 0.030) with no difference in PFS or OS (P= 0.60 and 0.22, respectively). Overall, there was a trend toward a worse RR and PFS with no change in OS over the past 13 years. Conclusions: The combination of gemcitabine and platinum may provide a valid second line option in patients with locally advanced or metastatic pancreatic cancer who progress on gemcitabine.
<i>HLA-DRB1*07:01-DQA1*02:01</i> and <i>UGT1A1*28</i> allele carriage in hepatic serious adverse event cases identified during lapatinib clinical trials.
Authors: C. F. Spraggs, L. R. Budde, L. P. Briley, C. Cox, E. Rappold, G. Aktan, L. S. Williams, V. E. Mooser, L. R. Cardon
Journal: Journal of Clinical Oncology (2011)

547 Background: Previous pharmacogenetic experiments evaluating lapatinib associated liver safety signals identified and confirmed associations for HLA-DRB1*07:01 and DQA1*02:01with alanine-amino transferase (ALT) elevation during treatment and UGT1A1*28 with baseline and on-treatment total bilirubin (TBL) elevation, consistent with underlying Gilbert’s syndrome.The carriage of these alleles was investigated in 20 hepatic serious adverse events (SAE) identified during the conduct of lapatinib clinical trials in adjuvant (3 studies), metastatic breast cancer (3 studies) and head and neck cancer (one study). Methods: Twenty hepatic SAE cases that met criteria of concurrent ALT >3x, alkaline phosphatase (ALP) <2x (or missing) and TBL >2x ULN elevations, plus hepatic expert panel adjudication as “probable or possible drug induced liver injury” were selected. Five of these cases are currently treatment blinded due to participation in ongoing clinical trials. Germline DNA was extracted from peripheral blood and genotypes were determined by standard methods. Results: Of the 20 concurrent ALT/TBL elevation cases 14 (70%) were positive for both HLA-DRB1*07:01 and DQA1*02:01 allele carriage, six (30%) were negative for either. Population frequencies are reported between 15% to 25% across major ethnicities. Stratifying these subjects by HLA allele carriage suggested different phenotype characteristics, with a higher mean/median maximum ALT for the HLA-DRB1*07:01/DQA1*02:01 positive group (13.4x/8.0x ULN, n=14), than for the negative group (4.2x/4.2x ULN, n=6). Furthermore, the HLA allele positive group had carriage of the Gilbert’s syndrome UGT1A1*28 genotype (TA7/TA7) in 3/14 (21%) of cases, whilst TA7/TA7 carriage was higher in the HLA allele negative group (5/6, 83%). Conclusions: The previously confirmed lapatinib-associated hepatotoxicity markers HLA-DRB1*07:01/DQA1*02:01were carried by 70% of these hepatic SAE cases. For the six concurrent ALT/TBL cases that were HLA allelenegative, there appeared to be an excess carriage of the Gilbert’s syndrome UGT1A1*28 genotype TA7/TA7, which may contribute to their TBL elevation safety signal.
Coagulo-fibrinolytic activity as a predictor of efficacy in bevacizumab-combined chemotherapy in metastatic colorectal cancer patients.
Authors: M. Suenaga, S. Matsusaka, T. Watanabe, K. Takagi, Y. Kuboki, M. Ozaka, E. Shinozaki, K. Chin, N. Mizunuma, K. Hatake
Journal: Journal of Clinical Oncology (2011)

533 Background: The combination of bevacizumab (BV) and chemotherapy in the first-line and second-line treatment of metastatic colorectal cancer (mCRC) has been shown to improve survival. Bevacizumab is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor. However, the relationship between coagulo-fibrinolytic activity factors and treatment efficacy remains to be clarified. The aim of this study was to determine potential coagulo-fibrinolytic activity markers impacting survival. Methods: Among 119 consecutive patients included in the study, 85 received first-line FOLFOX4 plus BV 5 mg/kg and 34 received second-line FOLFIRI plus BV 5 mg/kg until progression of disease or unmanageable toxicity occurred. Coagulo-fibrinolytic activity factors, including D-dimer, thrombin antithrombin complex (TAT) and carbohydrate antigen 125 (CA125) encoded by the MUC16 mucin gene were evaluated as candidate predictors of outcome. Results: In first-line treatment, overall response, median progression-free survival (PFS) and two-year survival rate were 61.9%, 518 days and 67.3%, respectively. In second-line treatment, overall response, median PFS and median overall survival (OS) were 23.5%, 248 days and 651 days, respectively. The outcomes of the univariate analysis were as follows: normal D-dimer and CA125 levels at baseline were associated with better PFS and OS in first-line treatment; normal TAT and CA125 levels at baseline were associated with better PFS and OS in second-line treatment. According to the results of the multivariate analysis, normal D-dimer level was associated with longer PFS in first-line treatment, and only CA125 level at baseline was an independent predictor of both PFS and OS in second-line treatment. Conclusions: The results suggest that coagulo-fibrinolytic activity factors such as TAT, D-dimer or CA125 may be useful predictors of outcome in mCRC patients receiving BV in combination with chemotherapy. No significant financial relationships to disclose.
A phase II study of cisplatin, S-1 and concurrent thoracic radiotherapy for unresectable stage III non-small cell lung cancer
Authors: F. Ohyanagi, N. Yamamoto, A. Horiike, T. Horai, T. Kozuka, H. Murakami, T. Takahashi, Y. Nakamura, H. Harada, M. Nishio
Journal: Journal of Clinical Oncology (2008)

7556 Background: Concurrent chemoradiotherapy is the standard treatment for stage III non-small cell lung cancer (NSCLC). However, no optimal full-dose chemotherapy regimen has yet been established. S-1 (S), a fourth-generation oral fluoropyrimidine known as a radiosensitizer, is a new active agent for NSCLC. In addition, recent studies have shown that combining S and cisplatin (P) offers an active, well-tolerated regimen for metastatic NSCLC. The objective of this study was to assess the efficacy and safety of S plus P with concurrent thoracic radiation (TRT) for unresectable stage III NSCLC. Methods: Patients with histologically or cytologically confirmed NSCLC, 20–74 years old, performance status (PS) 0–1, with no prior chemotherapy were eligible for this study. Patients were treated with P (60 mg/m² on day 1) and S (orally at 40 mg/m²/dose b.i.d., on days 1–14) repeated every 4 weeks for 4 cycles and TRT (60 Gy/30 fr over 6 weeks starting on day 2). Primary endpoint was response rate (RR), and planned sample size was 50 patients. Results: Between August 2005 and April 2007, 50 patients were enrolled (43 men, 7 women; median age, 62.7 years; PS 0/1, 36/14; IIIA/IIIB, 23/27; ad/sq, 30/14). Partial response was observed in 42 of 48 evaluable patients (RR, 87.5%; 95% confidence interval, 78.1–96.9%). At a median follow-up of 21 months for surviving patients, progression-free survival was 13.4 months and overall survival had not reached median. Toxicities of this regimen were very mild and planned protocol treatments were completed in 44 of 50 patients (88%). Adverse events included G3/4 neutropenia (24%/0%), G3/4 leukopenia (24%/0%), G3/4 thrombocytopenia (2%/2%), G3 febrile neutropenia (6%), G3 esophagitis (12%) and G3 pneumonitis (4%). No toxic deaths have occurred. Conclusions: This chemoradiotherapy regimen provides a very active regimen that is well-tolerated in patients with stage III NSCLC. No significant financial relationships to disclose.
Serum C-reactive protein levels and colorectal cancer mortality.
Authors: Abhishek Goyal, Abby B. Siegel
Journal: Journal of Clinical Oncology (2013)

360 Background: Chronic inflammation has been causally linked to colorectal cancer (CRC), and use of NSAIDs has been associated with reduced risk. Prediagnostic C-reactive protien (CRP) levels, a highly sensitive marker of inflammation, have been weakly associated with increased CRC incidence. However, their relationship with CRC mortality has not been studied well. We hypothesized that elevated baseline CRP levels in general population will predict increased CRC mortality. Methods: This cohort study used CRP data from the Third National Health and Nutrition Examination survey, 1988-94 (NHANES III), with follow-up through 2006. Of the 15,832 eligible adults, NHANES III classified 65% as having CRP levels below detection (≤0.21mg/dL). Using this as the reference, we categorized the remaining participants in three approximately equal groups, and calculated hazard ratios for CRC, all-cancer mortality excluding CRC, and overall mortality due to non-cancer causes. Results: Median follow-up period was 14.2 years. In age adjusted (not shown) and multivariable adjusted models (Table), we observed strong, dose-response associations between CRP levels and CRC mortality. Associations between CRP levels and mortality due to other causes were much weaker. Conclusions: In this large, representative study of U.S. adults, we obtained significantly higher HRs for CRC mortality, as compared to mortality from other cancer and non-cancer causes, making these results unlikely to be explained by residual confounding or other biases. Further, since mortality is a function of both incidence and survival, it provides a more valid estimate of the prognostic value of CRP compared to incidence alone. Further evaluation of CRP may help stratify high risk groups for screening and prognosis, and potentially identify those who might benefit from anti-inflammatory therapy. [Table: see text]
Frequency, types of interventions and changes in symptoms after consultation with Rapid Access Supportive Care Clinic (RASCC).
Authors: Sriram Yennu, Sruthi Suravarapu, Janet L. Williams, Saneese Stephen, Zhanni Lu, Eduardo Bruera
Journal: Journal of Clinical Oncology (2015)

153 Background: ASCO recommends an integration of palliative care to oncology care so as to improve outcomes. Recognizing the importance our center created a pilot RASCC. The aim of the study was to determine the most frequent interventions by RASCC and symptom change at first follow-up visit. Methods: In this retrospective study all patients seen as a part of RASCC clinic (August 2012- June 2013) were reviewed. Pts with stage 4 NSCLC with oncologist estimated survival of ≤ 6 months were eligible. Delivery of standardized palliative care was ensured using Palliative Care Checklist and weekly meetings. Care followed a standardized management plan. Results: 156 patients were evaluable. The median age was 63, 56% were male, 74% were white. SDS scores improved at follow-up (Table 1). The most common interventions were counseling (including advance cancer planning), medication changes. At the initial consultation, all patients received counseling n = 176 (pts received counseling by more than one IDT member); among the medications, dose initiation and increase of analgesics/opioids n = 122, laxatives n = 123, antiemetics 66, appetite stimulants 18, corticosteroids 10, antidepressants 9, methylphenidate 8, gabapentin 8, neuroleptics 5, sedatives 0. Among analgesics, dose initiation/increased morphine, n = 53, hydrocodone 24, oxycodone 18, hydromorphone12, methadone and fentanyl 6, codeine 1, NSAIDS3. Conclusions: RASCC was associated significant improvement of symptoms and SDS scores at 1st follow-up and the most common interventions were counseling, medication changes related to pain. Further studies are needed. [Table: see text]
Endpoint comparison for osteoporosis assessment in cancer control studies (N02C1 and N03CC)
Authors: A. C. Dueck, P. J. Atherton, H. Liu, S. L. Hines, C. L. Loprinzi, E. A. Perez, A. D. Tan, K. Burger, X. Zhao, B. Diekmann, J. A. Sloan
Journal: Journal of Clinical Oncology (2008)

6627 Background: Methodological issues hamper efficacy assessment of agents to prevent osteoporosis in cancer survivors. The diagnosis of osteoporosis can vary depending upon which bone mineral density (BMD) site is used, which machine is used for the assessment, and which set of normative values are applied. This analysis compared different endpoints for the assessment of efficacy in 2 cancer control studies. Methods: Data from 2 NCCTG phase 3 cancer control studies were employed involving 216 (N02C1) and 558 (N03CC) patients each comparing 2 treatments for the prevention of osteoporosis. BMD data were collected from spine (primary endpoint), femoral neck, and total hip. Endpoints included raw BMD score (RawBMD); raw machine-based T-score (TRaw); sample-standardized T-score (TSamp); reference population standardized T-score (TRef); and Z-score percentile corresponding to TRef (TPerc). For each of the 5 endpoints, summary statistics were computed and the analytical comparison of treatment arms was carried out via Student's t-test, Wilcoxon rank-sum, and baseline BMD-adjusted ANCOVA using change from baseline (CB) and percentage change of baseline (%CB) at 1 year. Each study was analyzed separately. Results: Results differed by BMD site and whether CB or %CB was used (table below). Among the 5 endpoints, TRaw, TSamp, and TRef had 11, 8, and 7 statistically significant results out of 36 tests, respectively. TPerc and RawBMD produced the most statistically significant results, 13 and 14, respectively. Correlations among the 5 endpoints at baseline ranged from .79 to >.99. Conclusions: Treatment comparisons differed across BMD site and endpoint used. Transforming via sample statistics provided similar results to transforming via reference or machine norms. RawBMD and the new approach (TPerc) may be more sensitive to change with TPerc having the added benefit of being readily interpretable as a percentage. No. of significant tests (out of 15) N02C1 N03CC CB %CB CB %CB Spine 4 1 15 6 Femoral Neck 1 0 15 3 Total Hip 0 0 7 1 No significant financial relationships to disclose.
In Patients with Light-Chain (AL) Amyloidosis Myocardial Contraction Fraction (MCF) Is a Simple, but Powerful Prognostic Measure That Can be Calculated from a Standard Echocardiogram (ECHO)
Authors: Paolo Milani, Angela Dispenzieri, Morie A. Gertz, Martha Q. Lacy, Francis K. Baudi, Shaji K. Kumar, Mathew S. Maurer, Kyle Klarich, Suzanne R. Hayman, Nelson Leung, David Dingli, John A. Lust, Yi Lin, Prashant Kapoor, Ronald S. Go, Yi L. Hwa, Steven R. Zeldenrust, Robert A. Kyle, S. Vincent Rajkumar, Martha Grogan
Journal: Blood (2015)