bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of germ-line genetic variation with failure of androgen ablation (AA) in hormone-sensitive advanced prostate cancer.
Authors: Kohli Manish , McDonnell Shannon , Bevan Graham H. , Riska Shaun M. , Costello Brian Addis , Longenbach Sherri , Dronca Roxana Stefania , Moynihan Timothy Jerome , Pitot Henry Clement , Quevedo Fernando , Tan Winston , Cerhan James Robert 
Published: March 2020

5082 Background: We evaluated the association of germ-line variation in 10 candidate genes important in prostate cancer biology (NKX3-1, JAK2, SLCO2B1, STAT3, CYP19A1, HSD17B4, TRMT11, PRMT3, HSD17B12, NCOA4) with failure of AA in advanced prostate cancer patients. Methods: Patients (N=619) were enrolled for genotyping at the time of AA failure. Candidate genes were selected from the literature and previous pilot studies in smaller cohorts which had identified variation in TRMT11 and HSD17B12 to be associated with AA failure. Genes were tagged using single nucleotide polymorphisms (SNPs) from HapMap with minor allele frequency of >5% and r2≥0.8. DNA was extracted from peripheral blood and genotyped using Illumina Veracode platform. The primary endpoint was time to failure on AA, defined as time from initiating continuous AA to two serial PSA increases over the nadir or clinical or imaging based progression, whichever came first. Principal component analysis was used for gene-levels tests. Association with the primary endpoint was assessed using proportional hazards regression models at the gene-level and at the SNP level. For SNP level results we estimated per allele (ordinal model) hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression, adjusted for Gleason score (GS). Results: We successfully genotyped 60 SNPs (from 10 genes) in 519 subjects. The median age of the cohort was 71 years (range 43, 92). The GS distribution was 51% subjects with GS≥8; 33% with GS=7 and 17% with GS<7. Median time to AA failure for the cohort was 2.3 years (IQ range: 1.0-4.5). In gene level analyses adjusting for GS, TRMT11 (p=0.004), HSD17B12 (p=0.016), and JAK2 (p=0.044) genes were associated with time to AA failure. Four of the 18 genotyped SNPs in JAK2 were associated with AA failure after adjustment for GS (Table). Conclusions: Variation in the JAK2 gene is significantly associated with time to AA failure. Validation is needed to develop these as predictive biomarkers for AA in advanced prostate cancer. [Table: see text]
The role of advanced genetic testing in the management of prostate cancer post radical prostatectomy.
Authors: Schaeffer Edward M. , Vergara Ismael A. , Crisan Anamaria , Erho Nicholas , Ghadessi Mercedeh , Feng Felix Yi-Chung , Davicioni Elai , Ross Ashley E. 
Published: March 2020

5089 Background: The genomic classifier (Decipher, GC) is a prospectively validated assay that predicts clinical metastasis post radical prostatectomy (RP) more accurately than standard clinicopathologic factors. While over 70% of high risk patients tested in a previous validation had low GC scores and good prognosis, patients with high GC scores had a cumulative incidence of metastasis over 25% over the study duration. Among men diagnosed with localized prostate cancer, these most at risk patients may derive the greatest benefit from novel therapies. We thus examined differential expression (DE) of druggable genes that may be targeted in this group. Methods: High-density microarray expression profiles of primary FFPE tumor specimens from 764 men treated with RP at the Mayo Clinic (1987-2006) were evaluated. A subset of 323 patients was flagged as high risk of clinical metastasis (mets) by virtue of having GC score ≥ 0.4. Enrichment and identification of DE genes as druggable targets were pursued using DAVID and DrugBank. Results: Median follow-up of patients was 15.1 years. Among the 323 patients with high GC scores, 62% had mets during follow-up.We identified 2,262 genes DE between mets and non-mets, 230 of which are associated with 331 approved pharmaceuticals and 547 experimental agents. These agents included multiple established anti-neoplastic therapies not currently used to treat prostate cancer such as bortezomib, capecitabine, dasatinib, etoposide, gemcitabine, imatinib, irinotecan, pemetrexed and vinblastine. The two most enriched pathways, spliceosome and ubiquitin-mediated proteolysis, have been proposed previously as therapeutic targets in cancer. Conclusions: Advanced genomic testing that includes validated molecular risk scores as well as transcriptome profiling from a single assay may better enable application of directed, multimodal therapy for individual patients with high risk prostate cancer.
Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients (pts) with breast cancer brain metastases (BCBM).
Authors: Lin Nancy U. , Gelman Rebecca Sue , Younger W. Jerry , Sohl Jessica , Freedman Rachel A. , Sorensen A. Gregory , Bullitt Elizabeth , Harris Gordon J , Morganstern Daniel , Schneider Bryan P. , Krop Ian E. , Winer Eric P. 
Published: March 2020

513 Background: The anti-tumor and anti-edema effects of BEV provide a rationale for testing in BCBM. Carboplatin (C) is associated with CNS responses across multiple tumor types. We evaluated BEV + C in pts with BCBM. Methods: Pts with progressive, measurable BCBM (>/= 1 cm in longest dimension) were eligible. Cycle 1: BEV 15 mg/kg on Day 1, followed on Day 8 by carboplatin AUC=5 (plus trastuzumab if HER2+). In subsequent cycles, pts received BEV + C on Day 1 (plus trastuzumab if HER2+) of a 3 week (wk) cycle. Standard brain MRI was obtained at baseline (BL) and every 2 cycles. Non-CNS scans (CT or MRI) were performed after 2 cycles, 4 cycles, then every 4 cycles. Correlative brain imaging was obtained at BL, 12-96 hours after the first dose of BEV, and after 2 cycles. Circulating tumor cells and blood for VEGF polymorphisms were also collected. The primary endpoint was composite CNS objective response rate (CNS ORR). CNS partial response required all of the following: >/= 50% reduction in volumetric sum of target CNS lesions compared to BL, no progression of non-target lesions, no new lesions, stable/decreasing steroid dose, no progressive neurologic signs or symptoms, and no progression of non-CNS disease by RECIST 1.0. The study used a 2-stage design to distinguish between ORR 5% vs 20% (responses in >/= 1/12 pts to enter 2ndstage; responses in >/= 4/37 pts needed to be promising). Results: 38 pts were enrolled between 11/3/09-8/24/12 (30 HER2+; 8 HER2-negative). Most (76%) pts had received >/=2 lines of metastatic chemotherapy. 97% of pts with HER2+ disease received prior trastuzumab; 73% had prior lapatinib. All but 5 pts progressed after WBRT and/or SRS. As of 1/15/13, 3 pts remain on protocol therapy; 22 patients have died. The composite CNS ORR was 63% (95% CI 46%-78%). CNS ORR by RECIST was 45%. CNS responses were observed in both HER2+ and HER2-negative pts. Of 34 pts with >/= 24 wks potential follow-up time, median number of cycles was 8 (range 1-19). One grade 2 CNS hemorrhage event was reported; there were no cases of grade 3/4 CNS hemorrhage. Conclusions: BEV + carboplatin is associated with a high rate of durable CNS response in pts with BCBM. Updated results, including progression-free and overall survival will be presented. Clinical trial information: NCT01004172.
TBCRC 018: Phase II study of iniparib plus chemotherapy to treat triple-negative breast cancer (TNBC) central nervous system (CNS) metastases (mets).
Authors: Anders Carey K. , Deal Allison Mary , Abramson Vandana Gupta , Liu Minetta C. , Storniolo Anna Maria , Carpenter John T. , Puhalla Shannon , Nanda Rita , Melhem-Bertrandt Amal , Lin Nancy U. , Marcom Paul K. , Van Poznak Catherine H. , Stearns Vered , Melisko Michelle E. , Smith J. Keith , Karginova Olga , Winer Eric P. , Perou Charles M. , Wolff Antonio C. , Carey Lisa A. ,   Translational Breast Cancer Research Consortium
Published: March 2020

515 Background: Nearly half of women with advanced TNBC develop CNS mets. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that penetrates the blood brain barrier (BBB), and the topoisomerase I inhibitor, irinotecan, in patients (pts) with TNBC CNS mets. Methods: Eligible pts had TNBC with new or progressive CNS mets with at least 1 measurable (> 5mm) lesion. Pts received irinotecan 125mg/m2 IV days (d) 1, 8 and iniparib (initial dose 5.6mg/kg, later changed to 8mg/kg) IV d 1, 4, 8, 11 every 21d. Tumor response rate (RR) was assessed by brain MRI and body CT every 9 weeks. The Kaplan Meier method estimated the primary endpoint of time to progression (TTP, intracranial [modified RECIST] or extracranial [RECIST 1.1]). Secondary endpoints were RR, PFS, OS, quality of life (QOL) and correlative endpoints. Results: Of 37 pts who began treatment, 34 were evaluable for efficacy. Mean age was 48 yrs (34 – 80 yrs). BRCA status was known for 16 patients of whom 5 had a mutation (4 BRCA1, 1 BRCA2). 88% received prior (neo)adjuvant and 68% prior metastatic chemotherapy (median 2 [1–14] lines). While 15% were CNS radiation (RT) naïve, 32% had received whole brain RT, 21% stereotactic RT, and 32% both. The most common grade (gr) 3/4 adverse events were neutropenia (14%), fatigue (5%), leukopenia (5%), hypokalemia (5%). Diarrhea was common (54%), but gr 3/4 was rare (3%). Median TTP (CNS and non-CNS) was 2.1 months (mos) (95% CI 1.7–4.3) and OS was 7.6 mos (95% CI 5.1-10.2). First progression site was CNS in 39%, non-CNS in 29% or both in 32%. CNS best RR was (12%; 0 CRs, 4 PRs); CNS clinical benefit rate (CBR, CR + PR + SD ≥ 6 mos) was 30%. Non-CNS RR was 5% (0 CRs, 1 PR) and CBR was 11%. Conclusions: Iniparib and irinotecan was well-tolerated among pts with TNBC CNS mets. While TTP was shorter than expected and contribution of iniparib to irinotecan remains uncertain, 30% of pts demonstrated CNS clinical benefit raising the question of whether predictive biomarkers could be identified. QOL, volumetric analysis of CNS lesions and translational studies evaluating molecular subtype, germline BRCA1/2, and DNA repair gene expression/methylation are ongoing. Clinical trial information: NCT01173497.
Is the proportion of patients with synchronous stage IV breast cancer surviving > 2 years increasing over time?
Authors: Dawood Shaheenah S. , Haaland Benjamin , Albarracin Constance T. , Gonzalez-Angulo Ana M. , Gupta Sudeep , Cortes Javier , Yap Yoon Sim , Dent Rebecca 
Published: March 2020

524 Background: Studies have shown a moderate increase in survival over time among pts with stageIV breast cancer. Median survival is approximately 2 yrs. The aim of this study was to evaluate trends over time of pts with synchronous stage IV disease who survive >2 yrs. Methods: Using the SEER registry we identified female pts with synchronous stage IV breast cancer diagnosed between 1990-2007. Pts were divided into 3 groups according to year of diagnosis(1990-1995, 1996-2000, 2001-2007). Probability of surviving more than >2 yrs was computed within each group. A multivariable logistic regression model was then fitted to determine the association between year of diagnosis and the probability of surviving >2 yrs after adjusting for other prognostic factors. Results: 22,492 pts were identified of whom 9,388 (41.7%) had a survival of >2 yrs. The probability of surviving >2 yrs was 36.2%, 40.1%, and 44.2% among pts diagnosed in periods 1990-1995, 1996-2000, and 2001-2007 respectively (p-value < 0.0001). The probability of surviving >2 yrs was 55.3% and 29.3% among pts with ER+ and ER- disease respectively (p-value <0.0001) and was 32.9% and 43.5% among pts of black and white race respectively (p-value <0.0001). In the multivariable model the probability of surviving >2 yrs increased with increasing year of diagnosis (OR 1.04, 95% CI 1.03-1.05, p <0.0001). Other factors significantly associated with an increased probability of surviving >2 yrs included radiation therapy, lower grade, younger age, hormone receptor (HR) positive disease and non-inflammatory disease. Interaction term between race and year of diagnosis was marginally significant, such that black pts had a more slowly increasing probability of surviving >2 yrs compared to whites (OR 0.97, 95% CI 0.96-1.00, p = 0.037). Interaction term between HR status and year of diagnosis was not significant. Conclusions: Our results indicate that among pts with synchronous stage IV breast cancer the probability of surviving >2 yrs has increased over time reflecting the introduction and FDA approval of multiple efficacious chemotherapeutic and endocrine therapeutic options. Of concern, the probability of surviving >2 yrs has increased more slowly among pts of black race.
Preoperative letrozole plus lapatinib/placebo for HR+/HER2 negative operable breast cancer: Biomarker analyses of the randomized phase II LET-LOB study.
Authors: Guarneri Valentina , Frassoldati Antonio , Generali Daniele Giulio , Bottini Alberto , Cagossi Katia , Bisagni Giancarlo , Boni Corrado , Cavanna Luigi , Piacentini Federico , Bettelli Stefania Raffaella , Ficarra Guido , Maiorana Antonino , Marini Luca , Conte Pier Franco 
Published: March 2020

530 Background: This is a randomized, double-blind, placebo controlled study aimed to evaluate the clinical and biological effects of letrozole + lapatinib or placebo as neoadjuvant therapy in previously untreated hormone receptor positive/HER2 negative operable breast cancer. Methods: 92 postmenopausal patients with stage II-IIIA breast cancer were randomly assigned to 6 months letrozole-lapatinib (Arm A, n=43) or letrozole-placebo (Arm B, n= 49). Clinical response was evaluated according to RECIST. The following biomarkers were centrally evaluated by IHC on diagnostic core biopsy and on surgical specimens: HER2, Ki-67, EGFR, pAKT, PTEN. PIK3CA mutations were evaluated by pyrosequencing. Results: 81 patients were evaluable by USG, 8 were assessed with mammography and/or palpation. Three patients who discontinued therapy and withdrew consent were counted as non-responders according to the ITT analysis. No differences in terms of objective response rate (partial+complete response) were observed between the two arms (70% vs 63%). The percentage of patients achieving disease progression, disease stabilization, partial response and complete response were 2%, 23%, 58%, 12% respectively in the letrozole-lapatinib arm, and 6%, 29%, 61%, 2% respectively in the letrozole-placebo arm. No patients achieved pCR. All the patients were centrally confirmed as having HER2 negative disease. A significant decrease in Ki67 and pAKT expression from baseline to surgery was observed in both arms. A trend for a greater Ki67 suppression was observed in responding patients (mean Ki67 suppression -8.8 in responders vs -3.6 in non responders, p= 0.06). A mutation in PIK3CA exon 9 or 20 was observed in 37% of the patients. Overall, no differences in response were observed according to PIK3CA mutations, however, in the letrozole-lapatinib arm, the probability of achieving a clinical response was significantly higher in the PIK3CA mutation subgroup (ORR 93% vs 63% in PIK3CA WT, Pearson’s chi2 p=0.040). Conclusions: This is the first trial showing a significant correlation between PIK3CA mutation and response to letrozole-lapatinib in Hormone Receptor +/HER2- disease. Clinical trial information: NCT00422903.
Impact of routine tumor genotyping on enrollment in targeted therapy trials for metastatic breast cancer (MBC): 4-year review.
Authors: Bardia Aditya , Isakoff Steven J. , Juric Dejan , Borger Darrell R. , Dias-Santagata Dora , Iafrate Anthony John , Flaherty Keith , Moy Beverly , Ellisen Leif William 
Published: March 2020

533 Background: Major barriers to enrollment in therapeutic clinical trials (<5% in United States) include low response rate in phase 1/2 trials and low enthusiasm among oncologists. Stratified clinical trial enrollment based on molecular profiling of tumors represents a potential paradigm shift in drug development. Here we assess the clinical utility of tumor genotyping for identification of oncogenic driver mutations and enrollment in therapeutic clinical trials for patients with MBC. Methods: A robust, high-throughput tumor genotyping assay (Snapshot), was developed at our institution to assess for presence of potentially actionable oncogenic driver mutations (15 genes, 130 mutations) using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. The tumor genotyping assay was ordered by oncologists in clinic for patients with MBC. Relevant clinical information was gathered from chart reviews. Descriptive statistics were used for analysis. Results: From 2009-2012, 347 breast tumors were prospectively genotyped in the study population (median age = 50, range 27-90). PIK3CA mutation (23.3%) was the most common mutation detected overall, albeit at varying frequency in tumor subtypes: HR+ (29.1%, N= 210), HER-2+ (21.5%, N = 65), TN (8.3%, N = 72). Unanticipated mutations in KRAS, BRAF, IDH, and HER-2 were also discovered. Clinical genotyping helped identify breast origin for carcinomas of unknown primary and revealed changes in mutation profile in metastatic tumors from primary tumors. Enrollment in clinical trials for MBC almost quadrupled from 2005-2008 to 2009-2012, with 35.5% of patients undergoing tumor genotype testing enrolling in trials, particularly phase-1 genotype-directed targeted therapy, such as PI3K inhibitors, Akt inhibitors, and combined PI3K/MEK inhibitors. Conclusions: Routine tumor genotyping can be successfully incorporated into clinical practice to significantly enhance therapeutic clinical trial enrollment and potentially accelerate development of genotype-directed targeted therapies for MBC.
Frequent LOH of CYP2D6 in ER+ breast cancer determined by next-generation sequencing (NGS).
Authors: Ratain Mark J. , Sun James , Nakamura Yusuke , Cox Nancy J , Sahmoud Tarek , Stephens Phil , Chen David , Miller Vincent A. , Ross Jeffrey S. , Yelensky Roman 
Published: March 2020

534 Background: The role of CYP2D6 genetic variation in predicting response to tamoxifen in ER+ breast cancer is a subject of ongoing debate. There has been great variability in approaches to both genotyping and phenotyping, and in particular many investigators have extracted DNA from breast cancer samples rather than peripheral blood. We hypothesized that CYP2D6 gene copy number alterations are common in ER+ breast cancer, affecting genotype results, and used NGS to characterize CYP2D6 in patients with ER+ disease. Methods: CYP2D6 sequencing was performed as part of a comprehensive NGS profile of cancer-related genes for 261 predominantly relapsed and metastatic ER+ breast cancer FFPE specimens. Sequence data were resolved into genotypes according to the * allele nomenclature. Tumor LOH was determined at CYP2D6, and its error impact on genotyping methods was estimated. To assess biological significance, the prevalence of CYP2D6 alleles and LOH in ER+ disease was compared against a control set of 99 ER- tumors. Results: CYP2D6 allele frequencies in our full cohort (ER+, 261; ER-, 99) were consistent with prior studies; 64.4%, 16.8%, 9.0% vs. 63.1%, 17.2%, 7.0% for *1/*2, *4, and *41 respectively, and 1%-2% for the rarer alleles *9, *10, and *5. The rate of CYP2D6 LOH was higher in ER+ disease (41% vs. 26%, p<0.01), with all excess arising from copy-loss (as opposed to copy-neutral) changes (22% vs. 7%, p<0.002). The estimated impact of LOH on germline genotype assessment from tumor was considerable; an assay sensitive at >20% minor allele frequency (e.g., Sanger sequencing) can misclassify >10% of heterozygotes, leading to significant Hardy-Weinberg disequilibrium (e.g., p=8.3x10-8 for *4). Interestingly, an enrichment of reduced or non-functional CYP2D6 alleles in ER+ samples was observed (61% vs. 47%, p<0.03). Conclusions: Our results demonstrate the distorting effect of extensive LOH on genotype assessment of CYP2D6 in breast cancer. Therefore, tumor DNA should not be routinely used for determination of germline 2D6 genotype, although it appears possible to use NGS. The apparent association between reduced function CYP2D6 alleles and ER+ breast cancer in our dataset requires further investigation.
Final results of a phase II trial of trabectedin (T) in patients with hormone receptor-positive, HER2-negative advanced breast cancer, according to xeroderma pigmentosum gene (XPG) expression.
Authors: Awada Ahmad , Cortes Javier , Martin Miguel , Aftimos Philippe , Oliveira Mafalda , Espie Marc , Lardelli Pilar , Extremera Sonia , Kahatt Carmen Maria , Delaloge Suzette ,   PharmaMar
Published: March 2020

547 Background: Hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (BC) is currently associated with 3-4 years survival and, after ≥2 relapses, therapeutic approaches are reduced. XPG expression is frequently modified in BC. T forms cytotoxic complexes with XPG inducing apoptosis, thus, the inhibitory effects of T may depend on XPG presence. In fact, a better response to T in BC pts with XPG RNA overexpression has been observed. Methods: Pts withHR positive, HER2 negative advanced BC, pretreated with anthracyclines and/or taxanes, who had progressed after 2-5 chemotherapy lines, were stratified according to their XPG expression from paraffin embedded tumor samples, to stratum A (XPG high [>3]) or to stratum B (XPG low [≤3]) (threshold was selected from median XPG expression values observed in a previous trial) and treated with T (1.3 mg/m2 in 3-hour iv infusion every 3 weeks). Primary endpoint: to evaluate the efficacy of T as progression free survival rate at 4 months (PFS4) according to XPG expression. Secondary endpoints: Comparison of PFS, overall response rate, duration of response, overall survival and safety in XPG high and XPG low pts. Statistical methods: A 2-stage design was chosen: at a 1st stage, 20 pts were enrolled in each stratum. A futility analysis (O’Brien Fleming boundary) based on the primary endpoint was done once 40 evaluable pts were recruited. If ≥ 7 out of 20 pts achieved PFS4, recruitment would continue to a maximum of 50 pts per stratum. Results: 44 pts (21 XPG high and 23 XPG low) were enrolled from three countries and five centers. Efficacy is shown in the Table. Most frequent AEs were nausea (54%) and fatigue (70%). ALT increase G4 occurred in 7% of pts and neutropenia G4 in 28%. Conclusions: Trabectedin showed modest activity in advanced HR-positive, HER2-negative BC previously treated with anthracyclines and taxanes, with an acceptable safety profile. XPG does not seem to be a predictor of outcome to T treatment in this patient population. Clinical trial information: 2010-022968-13. [Table: see text]