tbuckley/cabot-search huggingface dataset:
Trends in androgen-deprivation therapy use among privately insured men with prostate cancer, 2001-2010.
Authors: Shellie D. Ellis, Stacie Dusetzina, Matthew Edward Nielsen, Nancy Lynn Keating
Journal: Journal of Clinical Oncology (2014)

e16021 Background: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists was widely used for primary treatment of localized prostate cancer in the 1990s and is now recognized to be costly and harmful in this context. The 2003 Medicare Modernization Act (MMA) cut fee-for-service reimbursement for GnRH agonists by 13% in 2004 and 43% in 2005. Although reimbursement changes in the Medicare program were associated with sharp declines in GnRH agonist use, concerns about drug safety were also emerging. No studies have described reimbursement and patterns of use among privately insured men. Methods: We studied men ages 18-64 with non-metastatic prostate cancer who were privately insured and included in MarketScan Commercial Claims for at least 24 months during 2002 through 2012 and received no prostatectomy or radiation during that time. We used propensity score methods to balance characteristics of men who did and did not receive GnRH agonists. We estimated changes in GnRH agonist use and reimbursement coincident with the two MMA payment changes and in the period following MMA using binomial regression models. Results: Among 41,362 men with prostate cancer, GnRH agonist use declined from a peak of 8.3% in 2003 to 3.4% in 2011, a 59% reduction in use (aRR: 0.41, 95% CI: 0.34-0.49). Median annual plan-level reimbursement for each GnRH agonist injection of leuprolide decreased from $2,482 in 2004 to $1662 in 2005 and $1,039 in 2006; reimbursement declined slightly again from 2007-2011 (Table). GnRH agonist use declined from 8.2% to 5.6% following the 2ndMMA cut and fell further to 3.4% by 2011. Conclusions: Declines in GnRH agonist use coincided with private payers’ reimbursement changes, but private payers’ reimbursement cuts lagged Medicare’s cuts by one year and continued in the post-MMA period. Further research is needed to understand the degree to which these declines reflected reimbursement changes or concerns about drug safety. MMA period Year Proportion of men receiving leuprolide Median reimbursement per administration Pre-MMA 2003 8.3% $2,458 First MMA cut 2004 8.2% $2,482 Second MMA cut 2005 5.6% $1,662 Post-MMA 2006 4.9% $1,039 2007 4.7% $999 2008 3.4% $853 2009 3.5% $824 2010 3.5% $862 2011 3.4% $853
Prospective evaluation of <i>BRCA</i> mutations in a large triple-negative breast cancer (TNBC) registry: Implications for germline testing.
Authors: Priyanka Sharma, Jennifer R. Klemp, Bruce F. Kimler, Anna Ludlow, Larry Geier, Manana Elia, Qamar J. Khan, Carol J. Fabian, Marilee McGinness, Carol Sue Connor, Joshua Mammen, Lori Ranallo, Catie Knight, Andrew K. Godwin
Journal: Journal of Clinical Oncology (2013)

1026 Background: Although current NCCN guidelines recommend genetic testing (GT) for all TNBC patients aged &lt;60 years (regardless of family history) however due to the lack of prospective information on prevalence of mutations in unselected TNBC patients, these guidelines have not been widely adopted by clinicians and insurance carriers (including Medicare). Data on BRCA mutations from unselected TNBC cohorts are lacking. Aims: In a large TNBC registry, to prospectively determine the 1) prevalence of germline BRCA mutations and 2) validity of current NCCN guidelines for GT. Methods: Patients with stage I-III TNBC presenting for treatment at an academic and surrounding community practices were approached for participation in a prospective registry. All patients underwent comprehensive BRACAnalysis (Myriad). Detailed FH was collected. Mutation prevalence in the entire cohort and in subgroups stratified by FH and age were calculated. A significant family history (SFH) was defined as 1st-/2nd-degree relatives with breast cancer aged &lt;50 years or ovarian cancer at any age. Results: 165 patients with stage I-III TNBC have been enrolled from 2011-2013. Median age 54 (range 24-84yrs), 58% postmenopausal, 29% LN +, 33%, 58% and 9% had stage I, II, III disease respectively. 82% Caucasian, 14% AA, 2% Hispanic, 0.6% Ashkenazi Jewish. Deleterious BRCA1/2 mutations were identified in 13.1% patients (20/152, 15 BRCA1, 5 BRCA2; results pending in 13). 27% of patients had a SFH and 64% had any FH. Mutation rates in patients with or without SFH was 32.5% and 6.1%, respectively. When examined by age at diagnosis, the mutation rates were: 16.6% (&lt;60yrs), 21.8% (&lt;50yrs), 10.6% (51-60yrs), and 0% (&gt;60 yrs). If SFH or age &lt;50, were the only criteria used 35% and 30% of mutations would have been missed. All mutations were identified using the NCCN guidelines. Conclusions: This is the first study to prospectively evaluate BRCA mutations in an unselected TNBC cohort. In this large academic and community registry with negligible Ashkenazi representation, the overall BRCA mutation rate was 13%; 16.6% in those &lt;60 years. These results validate GT based on current NCCN guidelines and support its use in routine clinical practice.
<i>CELF4</i> variant and Anthracycline-related Cardiomyopathy (anth-card) – A COG Study (ALTE03N1).
Authors: Xuexia Wang, Can-Lan Sun, Adolfo Quinones Lombrana, Purnima Singh, Wendy Landier, Lindsey Hageman, Molly Mather, Lu Chen, Saro Armenian, Naomi J. Winick, Jill P. Ginsberg, Joseph Philip Neglia, Kevin C. Oeffinger, Sharon M. Castellino, ZoAnn Eckert Dreyer, Melissa M. Hudson, Leslie L. Robison, Javier G. Blanco, Smita Bhatia
Journal: Journal of Clinical Oncology (2015)

10066 Background: Identification of genetic variants that modify anth-card risk can facilitate targeted interventions. Methods: Discovery: Case-control approach used to conduct GWAS in non-Hispanic white ( > 90% Europeans: Multidimensional Scale) childhood cancer survivors (CCS). Anth-card cases: n = 112; median ejection fraction (EF): 44%; age at ca dx: 7.5y; anth dose: 319 mg/m2. Ca controls: n = 219; EF: 65%; age ca dx: 7.9y; anth: 180mg/m2 matched on ca dx, age at ca dx, year ca dx, time from ca dx. 2-step method used to detect anth dose-SNP interaction (Genet Epidemiol, 2012; 36:183). Replication: Case-only design used in 54 CCS with anth-card (EF: 41%; all race/ethnicity; age at ca dx: 7.6y; anth: 300 mg/m2). Functional analysesconducted. Results: Discovery: No SNP was marginally associated with anth-card at GW level. 2-step GxE: Step 1: Top 1000 SNPs with modest main effect retained; 643 independent tests estimated after LD-based SNP pruning. Step 2: GxE interactions tested between SNPs retained in Step1 (P= 0.05/643independent tests= 7.77x10-5). SNP rs1786814 on CELF4 gene passed significance cut-off (P_ge= 1.14x10-5). (MAFcontrol: 0.249; minor allele: A). Multivariable analyses adjusted for anth dose, sex, chest RT: in CCS with AA genotype, anth-card was rare at all anth doses; in CCS with anth > 300mg/m2, GG genotype conferred 5.4-fold (95%CI, 1.8-16.2, P= 0.003) increased anth-card risk compared to AA/GA. Replication: GG genotype in anth > 300mg/m2: OR = 5.1, 95%CI 1.0-25.2, P = 0.046; ref: AA/GA. Functional analysis: CELF is implicated in alternative splicing of cardiac troponin T (cTnT) - a myocardial injury biomarker; > 1 cTnT variants results in temporally split myofilament response to Ca2+, and decreased contractility (seen in dilated cardiomyopathy) (Circ Res, 1995;76:681-6). DNA from 33 healthy non-anth-exposed hearts genotyped for rs1786814; RNA splice isoforms measured (RT-PCR), and verified (DNA sequencing). Coexistence of embryonic and adult cTnT (n = 23) more likely in GG hearts (GG: 78%; GA: 22%; AA: 0%, P= 0.016). Conclusions: We report a modifying effect of an intronic polymorphism of CELF4 (rs1786814) on dose-dependent anth-card risk, possibly through accumulation of > 1 form of cTnT protein.
Sexual functioning in long-term survivors of testicular cancer (TCSs)
Authors: A. A. Dahl, S. D. Fossa
Journal: Journal of Clinical Oncology (2004)

4526 Background: In TCSs conflicting results have been reported as to the association between treatment modalities and sexual function. We compared self-rated sexual function in Norwegian TCSs who during 1980 to 1994 received one of the following overall therapies: Surveillance (SURV); Retroperitoneal lymph node dissection only (RPLND); Radiation only (RAD) or Cisplatin-based chemotherapy with or without RPLND or RAD (CHEM). Methods: Sexual function was assessed in 1224 TCSs after a mean of 11 years follow-up (SURV: 112; RPLND only: 129; RAD: 543; CHEM: 458). Mean scores for sexual drive, erections, ejaculation, problem assessment, and overall satisfaction were assessed using The Brief Male Sexual Function Inventory. Patients who were very or mostly dissatisfied on overall satisfacation were defined as cases. Results: No significant differences were found between the treatment groups as to sexual drive, problem assessment, and overall satisfaction. SURV patients reported significantly better erectile function than RAD, but this effect disappeared when controlling for age. CHEM patients had significantly poorer ejaculatory function compared to SURV. No significant inter-group difference was obtained as to caseness. Conclusions: At long-term, sexual function and satisfaction in TCSs hardly differ between today's treatment modalities, and the risk of sexual dysfunction should not be decisive for the choice of treatment. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Norway
The development of complete personalized treatment plans for colon cancer patients utilizing three gene prediction models.
Authors: Jeng-Kai Jiang, Hung-Shin Lin, Jen-Kou Lin, Yu-Chung Wu, Teh-Ying Chou, Nien Wei
Journal: Journal of Clinical Oncology (2014)

e14553 Background: Combination chemotherapy using fluorouracil, leucovorin with or without oxaliplatin (5-FU and FOLFOX) are standard treatment for locally advanced colon cancer. However, about half of the patients developed recurrence. The objective of this study was to use gene profiling to predict treatment efficacy for colon cancer patients (stages 1-3). We developed three prediction models: the first determines the likelihood of recurrence after curative resection while the other two models determine the efficacy of 5-FU and FOLFOX. Methods: Formalin-fixed paraffin-embedded tissues from 513 patients treated during 2003 to 2011 at Taipei Veterans General Hospital (80% of them are treated between 2005 to 2009) were analyzed for gene expression using Nugen Ovation kits and Affymetirix’s ST arrays. The gene data was analyzed using supervised clustering K-nearest-neighbor method. The performance of the models was evaluated using a Hazard Ratio (HR) for disease-free survival. Results: In model one, for prediction of recurrence, the HR of non-recurrence vs. recurrence is 2.758 (P<0.0001). In model two, for determination of 5FU efficacy, the HR of responder vs. non-responder is 3.212 (P=0.0001). In model three, for determination of FOLFOX efficacy, the HR of responder vs. non-responder is 3.604 (P< 0.0001). Although these three models were developed separately, the cross predictions among models are consistent. For example: the non-responders predicted by the 5-FU or FOLFX models are also predicted to be recurrent patients by the recurrence prediction model. Patients predicted to be FOLFOX non-responders are also identified as 5-FU non-responders by the 5-FU treatment model. While most patients were predicted to respond similarly to 5-FU or FOLFOX treatment, our models were also able to identify a subset of patients that would fail 5-FU treatment but benefit from FOLFOX therapy. Conclusions: A consistent three-model-prediction has been developed that provides valuable indictors for colon cancer treatment.
Comparison of the effects of bevacizumab (BV) in combination with chemotherapy (CT) and CT alone on the incidence of brain metastases (BM) in non-small cell lung cancer (NSCLC): A retrospective clinical analysis.
Authors: Nan Du, Fang Li, Shunchang Jiao, Yan Fu, Xiaosong Li, Hui Zhao
Journal: Journal of Clinical Oncology (2013)

e19044 Background: The incidence of BM of advanced NSCLC is 20-40%, and there's a lack of effective treatment. This study aims to investigate the value of the angiogenesis marker VEGF in predicting the risk of BM in patients (pts) with NSCLC receiving CT+BV or CT alone and to explore the cumulative risk of BM of NSCLC with high VEGF expression that treated with BV. Methods: Pts with stage IIIB/IV NSCLC underwent CT and/or targeted therapy from 2008-1 to 2010-12 were included. Semi-quantitative detection of VEGF expression was carried out using conventional immunohistochemical staining of lung tissue specimens. Pts experienced BM prior to treatment were excluded. Pts underwent gemcitabine /carboplatin (GC) + BV treatment were included in observation group; pts underwent GC were included in control group. The cumulative risk of BM was calculated using death as a competing risk. Results: 177 pts were included (118 in BV+CT group; 59 in CT group). The median follow-up duration was 18.7 months. Up to 2012-12-31, BM occurred in 15 cases in BV+CT group and 17 in CT group (12.71% vs. 28.81%). 4 cases (33.89%) in BV+CT group survived, and 11 (18.64%) in CT group survived. In BV+CT group, the cumulative risks of BM at 6, 12, and 24 months were 0.86%, 7.52%, and 13.01%, respectively, and 6.74%, 18.88%, and 28.85% in CT group, respectively (P &lt; 0.001). HR of BM in BV+CT group was 0.048 (95% CI: 0.171-0.994) compared to CT group. In BV+CT group, the 6-, 12-, and 24-month cumulative risks of BM were 1.6%, 7.97%, and 12.63% in pts with VEGF(+) and 0, 7.24%, and 12.71% in pts with VEGF(-), respectively; in CT group, the 6-, 12-, and 24-month cumulative risks of BM were 9.35%, 27.04%, and 37.5% in pts with VEGF(+) and 3.52%, 10.71%, and 18.05% in pts with VEGF(-), respectively; there was no significant difference between them. Conclusions: BV+CT can effectively reduce the incidence of BM in pts with advanced NSCLC and improve their prognosis. This small data sample suggests that pts with VEGF(+) are more prone to BM than pts with VEGF(-). The incidence of BM in pts with VEGF(+) is reduced after BV treatment, though its specific mechanism still requires further study.
Vascular emboli as a prognostic factor in patients with stage III colorectal cancer undergoing radical surgery.
Authors: Haiping Pei, Qian Pei, Hong Zhu, Fengbo Tan
Journal: Journal of Clinical Oncology (2017)

570 Background: The significance of vascular emboli (VE) in stage III colorectal cancer (CRC), the mechanism of their formation and their therapy strategy remain obscure demanding enhanced research. Methods: Data from 323 consecutive patients (192 non-VE, 131 VE) receiving radical surgery and adjuvant chemotherapy in our institution between Jan. 2009 and Nov. 2014 were retrospectively collected. The follow-up deadline was Feb. 2016. Potential prognostic risk factors were tested using univariate and multivariate survival analyses. mRNAs differentially expressed between VE and non-VE stage III CRC were analyzed using Agilent Gene Expression oligo-microarrays (Version 6.5). Patient-derived xenograft (PDX) nude mouse models were constructed to evaluate the efficacy of adjuvant chemotherapy plus targeted drugs (cetuximab or bevacizumab) on VE and non-VE stage III CRC. Results: VE was significantly associated with gross tumor morphology (p = 0.001), histologic type (p &lt; 0.001), lymph node status (p &lt; 0.001), sub-class of stage III (p =0.001), and serum CA199 level (p = 0.022). VE and lymph node status were independent risk factors for overall survival (OS) (p &lt; 0.001, p = 0.008) and disease-free survival (DFS) (p &lt; 0.001, p = 0.007). The median OS and DFS in VE stage III CRC patients were 38 months and 24 months, respectively. Compared with pericarcinous tissue, 809 genes (396 up-, 413 down-regulated) were differently expressed in no-VE tissue, and 1513 genes (898 up-, 615 down-regulated) in VE tissue. The top ten up-regulated protein-coding genes in VE stage III CRC were ITGBL1 (p&lt;0.001), PROCR (p&lt;0.001), CENPW (p&lt;0.001), ZNF485 (p&lt;0.001), VEGFA (p&lt;0.001), DSG3 (p&lt;0.001), CYP24A1 (p=0.001), COL10A1 (p=0.001), HIST3H2A (p=0.001)and PSAT1 (p=0.002). Conclusions: VE appears to be an independent risk factor for the prognosis of stage III CRC patients treated with radical surgery and adjuvant chemotherapy. Differently regulated genes seem to be involved in the formation and progress of VE. The therapy scheme should be more individualized taking into account the VE status.
Abstract A29: Targeting adenylate kinase-4 modulation of HIF-1α: Stability identifies Withaferin-A suppresses lung cancer metastasis
Authors: Michael Hsiao
Journal: Cancer Research (2017)

Abstract Aberrant activation of hypoxia inducible factor (HIF-1α) often plays a crucial role in promoting metabolic reprogramming and metastatic dissemination. Here we report functional evidences of adenylate kinase 4 (AK4), one of the hypoxia-responsive genes, in enhancing HIF-1α; transcriptional activity to drive epithelial-to-mesenchymal transition (EMT). By analyzing lung adenocarcinoma microarray datasets, we identified AK4-associated metabolic gene signature and revealed HIF-1α; was transcriptionally activated and associated with poor prognosis. Immunohistochemistry analysis confirms the positive correlation between AK4 and HIF-1α; in non-small cell lung (NSCLC) cancer patients. Overexpression of AK4 induces metabolic shift towards aerobic glycolysis and increases intracellular reactive oxygen species (ROS), which exaggerates HIF-1a; protein expression under hypoxia and concurrently induces EMT in a HIF-1α-dependent manner. Furthermore, overexpression of AK4 reduces hypoxic necrosis in tumors and promotes liver metastasis in vivo. Connectivity map analysis of AK4 gene signature identifies Withaferin-A as a potential inhibitor to inverse AK4 signature and proven to be a potent anti-metastatic agent in orthotopic xenograft model of lung cancer. Our findings offer an alternative strategy to treat metastatic lung cancer via targeting AK4-HIF-1α axis.α Citation Format: Michael Hsiao. Targeting adenylate kinase-4 modulation of HIF-1α: Stability identifies Withaferin-A suppresses lung cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A29.
The risk factors for vomiting and nausea in patients with oxaliplatin-based chemotherapy: Subgroup analysis of SENRI trial.
Authors: Junichi Nishimura, Toshihiro Kudo, Hiroyoshi Takemoto, Takamichi Komori, Ho Min Kim, Hirofumi Ota, Rei Suzuki, Masakazu Ikenaga, Masataka Ikeda, Hirofumi Yamamoto, Taroh Satoh, Taishi Hata, Ichiro Takemasa, Tsunekazu Mizushima, Yuichiro Doki, Masaki Mori
Journal: Journal of Clinical Oncology (2017)

779 Background: We previously reported, in the SENRI trial, usefulness of aprepitant for prevention of chemotherapy-induced nausea and vomiting (CINV) in colorectal cancer patients receiving an oxaliplatin-based regimen which is classified as moderately emetogenic cancer chemotherapy. In this study, we assessed the risk factors for CINV in colorectal cancer patients who received Oxaliplatin-based chemotherapy. Methods: A total of 370 patients was analyzed as for the rate of vomiting, and significant nausea in overall phase. We also assessed the proportion of CINV in patients divided by gender. Results: First, we analyzed the risk factors for vomiting and nausea. Female gender and aprepitant use were associated with the incidence of vomiting and significant nausea. Significantly more women suffered from vomiting than men (84.5 % vs. 92.9 % in women and men, respectively; P= 0.0001). The rate of no nausea, complete response, complete protection, and total control was also lower in women. The rate of use of rescue therapy was significantly higher in women. We compared the rate of CINV between aprepitant and control groups and found that, in women, the rate of no nausea, no vomiting, and total control was higher in the aprepitant group than in the control group. Conclusions: Gender and no aprepitant use were risk factors of CINV in colorectal patients who received oxaliplatin-based chemotherapy.Aprepitant therapy was more effective for women than for men in the prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen. Clinical trial information: NCT01344304.
Seizure rates in enzalutamide (ENZ)-treated men with metastatic castration-resistant prostate cancer (mCRPC) at increased risk of seizure: UPWARD study.
Authors: Susan F. Slovin, William Clark, Joan Carles, Andrew Krivoshik, Jung Wook Park, Fong Wang, Daniel George
Journal: Journal of Clinical Oncology (2017)

147 Background: ENZ is an androgen receptor inhibitor that improved survival in studies of men with mCRPC. Seizure is a risk of ENZ treatment, and patients (pts) with seizure risk factors were excluded in prior studies. In the TRUVEN report (data on file), pts with mCRPC and potential seizure risk factors, but no ENZ exposure, had a seizure rate of 2.8/100 pt-years. The UPWARD study assessed the seizure risk in ENZ-treated pts with mCRPC who had potential seizure risk factors. Methods: This was a global, multicenter, single-arm, open-label safety study. Enrolled pts had ≥ 1 baseline potential seizure risk factor, including medications lowering seizure threshold, stroke, or prior seizure history. Evaluable pts had ≥ 3 months (ms) of treatment with ENZ or ≥ 1 confirmed seizure in a 4-m treatment period. Exclusion criteria included seizure within the past 12 ms and receipt of anti-epileptic medication. Pts received ENZ (160 mg/day). The primary end point was the proportion of evaluable pts with ≥ 1 confirmed seizure during the 4-m treatment period. Results: A total of423 pts received ENZ; 366 were evaluable. Baseline seizure risk factors were medications lowering seizure threshold (n = 242), brain injury (n = 112), and cerebrovascular accident/transient ischemic attack history (n = 94). Four (1.1%) evaluable pts had ≥ 1 confirmed seizure within 4 ms of ENZ initiation. Four (1.1%) pts had a first seizure after 4 ms. The rate of confirmed seizure was 2.6/100 pt-years. 357 pts (84.4%) experienced ≥ 1 treatment-emergent adverse event (TEAE); 141 (33.3%) had ≥ 1 serious TEAE and 29 (6.9%) had ≥ 1 drug-related serious AE. 38 (9.0%) deaths were reported during treatment/within 30 days of discontinuation; four deaths were considered possibly drug related (cerebral hemorrhage, mCRPC progression, sudden cardiac death, and general deterioration). Conclusions: The incidence of confirmed seizures in the UPWARD study is similar to pts with mCRPC and similar risk factors but no ENZ exposure in the TRUVEN report. ENZ was generally well tolerated, and TEAE data are consistent with its known safety profile. These results suggest that ENZ did not increase the risk of seizures in the UPWARD study. Clinical trial information: NCT01977651.