tbuckley/cabot-search huggingface dataset:
Copy number changes in triple-negative breast cancer: New molecular targets.
Authors: Vladimira Koudelakova, Lenka Radova, Marek Svoboda, Wenbin Wei, Gvantsa Kharaishvili, Jan Bouchal, Radek Trojanec, Marian Hajduch, Zdenek Kolar, Katerina Bouchalova
Journal: Journal of Clinical Oncology (2013)

1063 Background: Triple negative breast cancer (TNBC) is associated with tumor aggressiveness and high recurrence rate. Treatment options are limited due to lack of molecular-genetic markers and targeted therapy. The aim of our research is assessment of copy number changes in TNBC patients and identification of potential markers for personalized therapy. Methods: Fresh-frozen tumor tissues were collected from 148 patients with TNBC stage I-III. Genomes of these samples were profiled by Affymetrix SNP6.0 arrays. Arrays were normalized using R/Bioconductor and GISTIC 2.0 was used to identify copy number changes. Results: TNBC showed a high level of chromosomal instability and heterogeneity. More than 200 significantly altered chromosomal regions (q value &lt; 0.25) were identified with frequency from 7.4 to 48% cases. Amplification of cell proliferation regulators (MYC, FGFR2, cyclins E1 and E2, PIK3CA, NFIB), regulators of vascularization (VEGFA) and epithelial–mesenchymal transition (CAV1 and CAV2) were found with high significance (q value &lt; 0.1). Deletions of CDK regulators CDKN2B and CDKN2A, and tumor suppressors PTEN, RB1, APC and POT1 were also detected with highly significant q value &lt; 0.1. Importantly, novel copy number changes of genes influencing inflammation, expression regulation and chromatin modification, localized on 1q, 7p, 8q, 9p, 17q and 19p, were found in more than 15% of samples. Conclusions: Despite the fact that TNBC is a heterogeneous group, several common copy number changes were identified. Our analysis confirmed copy number changes of important known genes as well as identified novel markers involved mainly in inflammatory and regulatory processes which could be targets of future therapies. Grant: Biomedreg CZ.1.05/2.1.00/01.0030.
The Mayo Clinic experience with the use of kinase inhibitors (KIs), ipilimumab, and bevacizumab in the treatment of metastatic ocular melanoma.
Authors: Justin Moser, Jose Pulido, Roxana Stefania Dronca, Svetomir Markovic, Aaron Scott Mansfield
Journal: Journal of Clinical Oncology (2014)

e20011 Background: We sought to evaluate our experience treating metastatic ocular melanoma (metOM), for which no standard treatment exists. Methods: We retrospectively reviewed all cases of metOM seen at our institution, including those in clinical trials, originally diagnosed between 1/1/2000 and 8/1/2013 with survival and treatment data. Survival from diagnosis for patients who received local therapies (LT) [surgical resection, radiation, radio frequency ablation, embolization (Emb), chemoEmb, immunoEmb, radioEmb, and intra-arterial therapy], ipilumumab, bevacizumab, or KIs (vemurafenib, temsirolimus, everolimus, selumetinib, vatalanib, sorfaranib, or sirolimus) was compared, using log-ranks analysis, to those who did not receive the specified treatment and analyzed in univariate and multivariate models. Results: 102 patients were evaluable of which 60% were male, the mean age was 62 years [interquartile range (IQR) 54-71] and 92% had an ECOG performance status of 0-1. Treatment with LT, KIs, and ipilimumab were all associated with increased overall survival: 31 m (n= 46; IQR 20-44) vs. 12 m (n=56; 4.3-20), p=<0.0001; 31m (n=22; 13-59) vs. 17 m (n=80; 5.3-26), p=0.04; and 30 m (n=24; 20-40) vs. 19 m (n=78; 5.3-26), p=0.04; respectively. No significant benefit in survival was with the use bevacizumab (26 m vs. 20 m; p=0.16). Multivariate analysis of treatment categories and prognostic markers showed LT as the only therapy to have a significant risk ratio (0.37, p=0.005). Patients amenable to LT were more likely to have an ECOG performance status of 0, only one site of metastasis, and a normal LDH compared to patients who received systemic therapies. Longer survival was seen in patients who received multiple categories of therapy: 32 m (IQR 28-40) for patients who received four categories (n=4); 41 m (27-59) for three categories (n=10); 21 m (12-26) for two categories (n=18), and 20 m (6.8-28) for one category of therapy, (n=40). Conclusions: There is no standard therapy for patients with metOM. These data suggest that survival was improved in patients who were amenable to LT; however, patients treated with LT had more favorable prognostic factors at presentation.
Predictors of receipt of immunotherapy for stage II and III melanoma in United States clinical practice.
Authors: Sheenu Chandwani, Kendall Lee Stevinson, Janice M. Mehnert
Journal: Journal of Clinical Oncology (2014)

e20003 Background: Recent National Comprehensive Cancer Network guidelines for management of early stage resected melanoma highlight the significance of tumor pathology and involved lymph nodes in treatment decision making. The current clinical use of adjuvant immunotherapy in United States (US) is not well understood. We identified patient, facility, and tumor characteristics associated with use of adjuvant immunotherapy among patients with high-risk resected melanoma in the National Cancer Database (NCDB), an oncology outcomes database for accredited cancer programs in the US and Puerto Rico. Methods: Retrospective analysis of the NCDB was conducted for stage II and III melanoma patients who were diagnosed and underwent surgical resection from 1998-2011. Multivariate binomial regression model was used to examine the association of each predictor with receipt of immunotherapy. Results: A total of 13,291/107,134 resected stage II-III patients (12%) received adjuvant immunotherapy. By stage, 7% of IIB, 9% of IIC, 29% of IIIA, and 26% each of IIIB/C patients were treated; and the use was similar in presence of micrometastasis or ulceration for stage IIIA-C. Treatment with adjuvant immunotherapy was independently associated with age< 70 years, private health insurance, higher education, Charlson/Deyo comorbidity score≤ 1, facilities located in the Northeast, Midwest and West vs. South, superficial spreading (Risk Ratio [RR]=1.40), acral lentiginous (RR= 1.51) and nodular (RR= 1.54) histology vs. lentigo maligna, regional lymph node examination and status (RR= 2.49 and 1.13 for positive and negative nodes respectively vs. no nodal examination), and stage≥ IIB (RR= 3.76 for IIB vs. IIA and RRs ranged from 4.89-5.49 for IIC-IIIC vs. IIA). Conclusions: Adjuvant immunotherapy use was associated with younger age, higher socioeconomic status, lower comorbidity, facility location, histology, positive nodes, and stage≥ IIB. Less than one third of stage III resected melanoma patients were treated and use was comparable across stage IIIA-C as well as by micrometastasis or ulceration status. Further study to gain insight into which factors physicians consider to influence their prescribing patterns is warranted.
Clinical applications of extended ctDNA RAS mutation determination in metastatic colorectal cancer.
Authors: Joana Vidal Barrull, Laura Muinelo, Alba Dalmases, Alicia Abalo, Maria Carmen Vela, EM Brozos, Maria Merce Muset, Juan Ruiz BaÃ±obre, Mar Iglesias, Cristina Blanco, Eva Lopez, Carmela Rodriguez Lopez, Frederick S. Jones, Dan Edelstein, Antje Lukas, Joan Albanell, Beatriz Bellosillo, Sonia Candamio, Clara Montagut, Rafael Lopez
Journal: Journal of Clinical Oncology (2017)

607 Background: Tumor tissue is currently used for RAS testing in metastatic colorectal cancer (mCRC) patients, but detection of circulating tumor (ct) DNA in plasma is being actively investigated as an alternative for detection and monitoring RAS mutations during therapy. Methods: Concordance of RAS testing in plasma using the OncoBEAM RAS CRC test and RAS testing in tissue using standard-of-care RAS detection techniques was evaluated in 114 mCRC antiEGFR-naïve patients. In discordant cases, tissue samples were re-examined by BEAMing. OncoBEAM RAS CRC assay was also used to monitor RAS mutation status in serial plasma samples from 34 patients treated with anti-VEGF +/- chemotherapy or anti-EGFR based therapy. Results: The overall agreement of the two methods was 93% (106/114 patients), with positive agreement of 96.2% (51/53) and negative agreement of 90.2% (55/61). Longitudinal monitoring of plasma samples from 13 patients with RAS mutated tumors treated with chemotherapy +/- anti-VEGF, showed a significant decrease (or disappearance) of RAS mutant allele fraction (MAF) in all cases at the time of CT-scan (8-12 weeks after onset of treatment). In 3 patients, plasma was also analyzed at week 4 showing the same dramatic decrease in MAF. RAS decline mirrored clinical and radiological response to treatment. Interestingly, RAS decline was also observed in patients with stable disease in CT-scan by RECIST1.1. In 7 of 9 patients that subsequently progressed, RAS ctDNA fraction increased accordingly. On the other hand, among 22 patients RAS wt treated with cetuximab, 6 showed emergence of RAS mutations at progression. In two cases, multiple RAS mutations were concomitantly present. Conclusions: The high overall agreement between basal plasma and tissue RAS mutation status indicates that blood-based testing with OncoBEAM RAS CRC is a viable alternative to tissue RAS testing in mCRC patients. Moreover, this study highlights the utility of OncoBEAM RAS CRC to monitor treatment of mCRC patients in two setting: (a) evaluation of response to anti-VEGF +/- chemotherapy in RAS mutant patients, as a complement to RECIST radiological criteria and (b) to monitor emergence of resistant clones during anti-EGFR treatment in RAS wt patients.
Correlation of blood eosinophil level with the clinical benefit of sorafenib in metastatic renal cell carcinoma.
Authors: Hailiang Zhang, Yao Zhu, Xiaojian Qin, Chunguang Ma, Hongkai Wang, Bo Dai, Guohai Shi, Dingwei Ye
Journal: Journal of Clinical Oncology (2014)

e15545 Background: There is an urgent need for biomarker-driven treatment selection in renal cell carcinoma (mRCC) that could provide rational guidance for optimal treatment selection. The objective of our study is to determine whether blood eosinophil level could have predictive value for the patients treated by sorafenib. Methods: Sorafenib was administered to 146 clear cell mRCC patients as second line treatment after cytokine therapy according to an institutional treatment protocol from Jun 2006 to Dec 2011. Before treatment and every 4 weeks after first administration of sorafenib, routine hematology tests including eosinophil counts were performed. Response to therapy was assessed every 8 weeks using RECIST v1.0. Correlation coefficient between peripheral eosinophil percentage and the change in tumor size was investigated. Kaplan-Meier and Cox regression analyses on overall survival (OS) were applied. Results: Baseline eosinophil percentage in patients ranged from 0.5% to 4.3%, and 48 (32.9%) patients had an elevated eosinophil percentage (>5.0%) after 4weeks sorafenib treatment. Best response to sorafenib in the 146 patients was CR, PR, SD, PD in 3(2.1%), 36(24.6%), 96(65.8%), 11(7.5%), resulting in an objective response (OR) rate of 27%. The median progression free survival (mPFS) was 12.3 months, and the median overall survival time (mOS) was 31.6 months. The eosinophil percentage after 4 weeks sorafenib administration were positively correlated to the change in tumor size (Pearson's correlation coefficient=-0.402, p<0.001). Furthermore, patients with elevated eosinophil percentage (≥5.0%) after 4 weeks sorafenib treatment have a higher median overall survival than patients with low eosinophil percentage (<5.0%), 52.7 months vs. 22.4 months(p<0.001). Multivariate Cox Regression Model analysis revealed that ECOG performance status, Fuhrman nuclear grade, and elevated eosinophil level were independent prognostic factors for overall survival. Conclusions: Elevated blood eosinophil percentage may correlate with the tumor response of second-line sorafenib treatment, and is also an independent prognostic factor for overall survival in clear cell mRCC patients.
Examining progression-free survival in first- and second-line treatment for BRAF-mutant metastatic colorectal cancer (CRC).
Authors: Belinda Lee, Angelyn Anton, Margaret Lee, Rachel Wong, Phillip Parente, Jeremy David Shapiro, Desmond Yip, Simone Anne Steel, Louise M. Nott, Greg Stefanou, Mahesh Y. Iddawela, Peter Gibbs, Ben Tran
Journal: Journal of Clinical Oncology (2017)

728 Background: BRAF mutated (BRAFm) CRC represents ~10% of all CRC and is associated with significantly poorer prognosis. However, responses to chemotherapy do still occur. Some data suggest that the poor prognosis associated with BRAFm CRC is dominated by substantially poorer second line PFS (PFS2), whereas first line PFS (PFS1) was similar for both BRAFm and BRAF wildtype (BRAFwt) CRC. Using a large multicenter dataset, our study aimed to examine PFS1 and PFS2 in BRAFm versus BRAFwt CRC. Methods: Prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) database was interrogated. PFS was calculated and compared in patients with BRAFm versus BRAFwt CRC. Median survival was determined by the Kaplan-Meier method and compared using the log rank test. Results: TRACC identified 523 CRC patients with known BRAF mutation status, who received first-line chemotherapy: 53 (10%) were BRAFm, while 470 (90%) were BRAFwt. At the time of data analysis, only 231 (44%) CRC patients had received second-line chemotherapy, of which 21 (9%) were BRAFm and 210 (91%) were BRAFwt. PFS1 analyses demonstrated significantly poorer survival in the BRAFm population (Median 7.8mo versus 11.5mo, HR 1.72, p = 0.0026). PFS2 analyses revealed similar findings for the BRAFm population, albeit non-significant due to smaller numbers (Median 5.5mo versus 7.7mo, HR1.26, p = 0.44). Conclusions: Our study demonstrated that BRAFm CRC was associated with poorer PFS in both first- and second-line settings. Additional analyses will be performed to examine the impact of different treatment strategies and other clinicopathological features.
Inpatient Palliative Care After Hematopoietic Stem Cell Transplantation—Reply
Authors: Areej El-Jawahri, Jennifer S. Temel
Journal: JAMA (2017)

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A combination of both testosterone and white blood count as predictive factors of overall survival in localized prostate cancer.
Authors: Daniel Taussky, Denis Soulieres, Laurent Azoulay, Hui Yin, Houda Bahig, Jean-Paul Bahary, Guila Delouya
Journal: Journal of Clinical Oncology (2017)

129 Background: Low testosterone is generally associated with a higher overall mortality rate. We previously published that an increase in neutrophils is associated with lower overall survival in a large population of patients with localized prostate cancer. In this study, we tested a combination of both testosterone and neutrophils to predict for overall survival in a prospective cohort of patients treated with radiotherapy for localized prostate cancer. Methods: 414 patients from our institutional database were enrolled prospectively in phase 2 or 3 studies. To be included in this present analysis, patients had to have a baseline testosterone and complete blood count before enrollment in their respective study. Thirty-three patients were excluded for missing data for a total of 381 (92%) patients were included for analysis. Multivariate cox proportional hazards models were used to analyze the influence of white blood count (WBC = neutrophils + lymphocytes) and testosterone level on biochemical recurrence (Phoenix definition) and overall survival (OS). A cutoff level for testosterone of 10.4 nmol/l ( = 300ng/dL) was used as an indicator of hypogonadism and a WBC cutoff of 6.2 (10 9 /L) representing the median value of this study population. Results were adjusted for cancer characteristics, comorbidities and androgen deprivation therapy. Results: Median age (range) was 71 (52-82) years. The median follow-up for biochemical recurrence and OS analysis were 72 and 78 months, respectively. WBC and testosterone were not predictive of biochemical recurrence, but CAPRA score 6-10 vs. ≤ 2 was (HR 5.39, 95% CI 1.19-24.45). WBC ≥ 6.2 alone was not associated with OS (HR 0.66, 95% CI 0.30-1.46), but when combined with a testosterone &gt; 10.3 nmol/l, it was associated with a HR of 2.96 (95%CI 1.45-6.06) when compared to a WBC &lt; 6.2, P-interaction = 0.01. Conclusions: A combination of high WBC and normal testosterone levels seem to be associated with increased mortality in patients with localized prostate cancer. Validation in larger samples is needed and could help to identify patients with increased risk of mortality within the first 6-7 years post treatment.
Biomarker profiling of bladder cancer patients undergoing radical cystectomy: Relevance of thrombotic and inflammatory processes.
Authors: Melanie Clark, Marcus Lee Quek, Daniel Kahn, Debra Hoppensteadt, Josephine Cunanan, Jawed Fareed
Journal: Journal of Clinical Oncology (2012)

e15008 Background: Postsurgical thrombosis represents a serious comorbidity in bladder cancer. Inflammation and hemostatic activation mediators contribute to thrombotic pathogenesis. Our study profiles biomarkers antiphospholipid antibody, IgG subtype (APA), procoagulant microparticles (MP) and antiglycosaminoglycan antibody (AGA). Protein and peptide biomarkers were profiled using SELDI-TOF mass spectrometry. Methods: This study was done retrospectively using an IRB approved protocol with 134 baseline serum samples collected from patients undergoing radical cystectomy. The samples were banked at -70C and thawed prior to analysis. The APA were measured with an ELISA for IgG specific antibodies (American diagnostica, Stanford CT). The MP were measured using an anexin capture chromogenic substrate to quantify functional procoagulant activities (Hyphen Biomedical, Paris France). The AGA were measured with a commercially available method with a polysulfonate polymer capture probe for the antibodies (GTI Madison, WI). The proteomic profile was analyzed on a GoldChip in the range of 5-150 kDa. Results: Although a wide scatter in values was noted in the test samples, they exhibited a higher prevalence of elevated biomarkers compared to normal. The average MP value was 3.1 5.8 (range 0.1-34.6nM) with 26 of 134 samples above normal. The average APA value was 6.7 11 (range 4-65nM) with 32 above normal. The average AGA value was 0.22 0.09 (range .01-.8OD) with 10 above normal. The SELDI analysis showed unique biomarkers in the area of 11-12kDa, 15.1-15.4kDa, and 15.8-16.2kDa. Conclusions: The biomarker upregulation suggests that bladder cancer patients have subclinical activation of thrombotic and inflammatory processes. The MP may be generated in cellular damage whereas the APA and AGA suggest vascular endothelial damage and activation. The unique proteomic biomarkers in these patients suggest endogenous protease activation. A clinical correlation in the subset with higher markers may provide insight into the biomarker role in prognosis, risk stratification and treatment of bladder cancer.
Targeted agents (TA) for advanced solid tumors (AST): What is the likelihood of being helped or harmed (LHH)? Assessing the clinical impact of therapies with FDA/EMEA approval.
Authors: Emilio Bria, Sara Pilotto, Maria Bonomi, Michele Milella, Francesco Massari, Antonio Tito Fojo, Isabella Sperduti, Diana Giannarelli, Giampaolo Tortora
Journal: Journal of Clinical Oncology (2013)

e17555 Background: Health care agencies adopt systems to inform patients and health care providers about relative risks and benefits using Evidence Based Medicine (EBM) measures, such as the number of patients needed to be treated/harmed (NNT/NNH), and LHH. This analysis was undertaken to provide an overview of the LHH provided by TA for AST. Methods: Randomized clinical trials (RCTs) supporting FDA/EMEA approval for TA (tyrosine kinase inhibitors, TKI, and monoclonal antibodies, MoAb) were evaluated provided efficacy (PFS, OS), and safety (grade 3-4 specific toxicities) data were available. NNT/NNH were calculated from absolute differences determined for PFS/OS rates (reported/extracted from Kaplan-Meier (K-M) curves and for the worst drug-specific toxicities. LHH was calculated for PFS or OS. A sensitivity analysis according to the randomized comparison (placebo controlled [P] or accepted standard [STD] vs add-on) was performed. Results: Thirty-five separate approvals were identified (23/12 for PFS/OS advantage, respectively). Results are shown in the Table. Hypertension and rash were most frequent drug specific toxicities. LHH &gt;1 may be interpreted as "number of times drug is more likely to provide a benefit than to harm." Conclusions: Despite limitations (estimation from K-M curves and differences in drug toxicities) the data demonstrate the greatest benefit as measured by LHH was achieved with TKI against P or STD with PFS as the endpoint. Marginal benefits were achieved in the majority of OS analyses, and with add-on design. The latter may reflect difficulty of the OS endpoint, marginal benefits of the TA added (bevacizumab and cetuximab) or may indicate TAs combine only poorly with conventional regimens. These data should be complemented with a cost-analysis and put in the context of the general health care system. [Table: see text]