bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of loss of tumor suppressor ZFP36 with lethal prostate cancer.
Authors: Sweeney Christopher , Gerke Travis , Beltran Himisha , Sboner Andrea , Karnes R. Jeffrey , Klein Eric A. , Davicioni Elai , Yousefi Kasra , Ross Ashley , Mucci Lorelei , Trock Bruce J. 
Published: September 2018

5062 Background: Inflammation has been linked to prostate cancer (PCa) progression which may be mediated by the transcription factor nuclear factor kappa B (NFκB). Using a bioinformatic screen focused on NFκB pathway activation in lethal PCa, we identified the tumor suppressor ZFP36 as a key node of the NFκB network. We also showed in vitro that ZFP36 expression was inversely associated with both NFκB-controlled gene levels and proliferation and sensitivity to enzalutamide. We examined the role of ZFP36 and PCa progression in patient cohorts. Methods: The association between low mRNA expression of ZFP36 (levels in the lower quartile) and lethal PCa (defined as metastatic disease or death) was assessed with logistic regression among men with localized PCa in two independent cohorts treated with radical prostatectomy (RP). The discovery cohort was RP samples from Health Professional Follow-up Study and Physicians Health Study and the validation cohort was RP samples from Cleveland Clinic, Mayo Clinic, Johns Hopkins and MSKCC. In a third cohort from Cornell University, ZFP36 expression levels were assessed in RP samples from patients with localized PCa and biopsies of metastatic castration resistant prostate cancer (mCRPC). Results: Table 1 shows men with localized PCa and lower quartile of tumor ZFP36 expression had a nearly 2-fold higher risk of lethal PCa after adjusting for known clinical and histological prognostic features (age, RP Gleason score, T-stage); an association confirmed in the validation cohort. ZFP36 gene expression was also significantly lower in mCRPC (n=53) compared with a localized RP cohort (n=68) (p-value <0.0001). Conclusions: In humans lower ZFP36 in RP specimens is associated with clinically significant risk of lethal PCa after treatment with curative intent and lower ZFP36levels are found in metastatic tissue. [Table: see text]
Serum androgens and survival in metastatic castration resistant prostate cancer (mCRPC) patients treated with docetaxel and prednisone: Results from CALGB 90401 (Alliance).
Authors: Ryan Charles J. , Dutta Sandipan , Kelly William Kevin , Middleberg Rob , Russell Carly , Small Eric Jay , Morris Michael J. , Taplin Mary-Ellen , Halabi Susan 
Published: September 2018

5067 Background: Higher baseline androgens have been previously shown to be associated with an improved overall survival (OS) in mCRPC patients treated with the androgen synthesis inhibitors, ketoconazole or abiraterone. The purpose of this analysis was to determine whether baseline serum androgen levels (Testosterone (T), Androstenedione (A) and DHEA (D) are associated with OS in mCRPC patients treated with docetaxel-based chemotherapy. Methods: Data from 1,050 men treated on CALGB 90401 with docetaxel, prednisone and either bevacizumab or placebo were used. Eligibility required progressive mCRPC and no prior chemotherapy. Pre-treatment serum assays for T, A and D were performed via tandem Liquid Chromatography-Mass Spectrometry (LC-MS/MS) at NMS labs. The proportional hazards model was used to assess the prognostic significance of T, A, and D in predicting OS adjusting for known prognostic factors. Results: Median values for T, A, and, D were 1.00, 13.00 and 8.12, ng/dL respectively.Values above the median were defined as low, above as high. Median OS for low vs high levels was 22.7 and 23.1 month for T, 22.4 and 21.7 month for A and 21.8 and 24.0 month for D, respectively, all NS. In multivariable analysis adjusting for 10 known prognostic values and prior keto use in mCRPC (Halabi JCO 2014), A (p-value = 0.013) levels were associated with OS. The HR for A was = 0.99 (95% CI = 0.98-0.99). Conclusions: In multivariate analysis, baseline androstenedione levels are prognostic factors for OS in mCRPC patients receiving chemotherapy. Low or undetectable levels of other androgens are associated with shorter OS, consistent with prior results in androgen synthesis inhibitor treated pts in both the chemotherapy naive and post chemotherapy settings. This relationship may reflect more aggressive tumor biology that evolves in an extreme androgen deprived milieu. Clinical trial information: NCT00110214.
Translating prostate cancer working group (PCWG) criteria into a quantitative progression biomarker in metastatic castration resistant prostate cancer (mCRPC).
Authors: Anand Aseem , Heller Glenn , Scher Howard I. , Morris Michael J. 
Published: September 2018

5068 Background: mCRPC is a bone dominant lethal disease. A validated endpoint in mCRPC trials is bone scan progression, which is semi-quantitative and rely on the appearance of new lesions as proposed by the PCWG. The validated automated bone scan index (BSI) quantifies the bone tumor burden as the fraction of total skeletal weight. To build on the current definition of disease progression, we sought to compare the association of time to progression with overall survival (OS) using PCWG criteria and BSI increase. Methods: mCRPC patients (pts) enrolled on trials of agents targeting androgen-receptor (AR) were assessed. Pts were required to have a raw bone scan image for BSI analysis concurrent with disease assessments. The EXINI automated computing platform generated the BSI values. Thresholds for the absolute and relative increase in BSI from 1st follow-up (≤12 weeks) were explored for the time to BSI progression. The association with survival time was computed for each threshold defined time to BSI progression. Kendall’s Tau, derived from the Clayton copula, was used to associate time to BSI progression with survival time, where both endpoints may be censored. Results: A total of 257 pts were assessed, of whom 169 had raw bone scans images needed for the BSI analysis. 90 pts (53%) met progression by PCWG criteria, the association between the time to PCWG progression and OS was 0.52. The association between time to BSI progression and OS was comparable to the PCWG progression when the absolute increase in BSI was 0.6 or more (table below). Conclusions: Progression in bone can be expressed as a single quantitative metric that describes the increase in total disease burden while retaining the same association that PCWG has with OS. These data represent the first steps to a quantitative expression of bone disease progression as a clinical trials endpoint. [Table: see text]
A phase III trial of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2+ breast cancer: The TRAIN-2 study (BOOG 2012-03).
Authors: Van Ramshorst Mette S. , van Werkhoven Erik , Mandjes Ingrid A. , Kemper Inge , Dezentjé Vincent O. , Oving Irma M. , Honkoop Aafke H. , Tick Lidwine W , Van de Wouw Agnes W , Mandigers Caroline M , Wesseling Jelle , Vrancken Peeters Marie-Jeanne , Linn Sabine C. , Sonke Gabe S. ,   Dutch Breast Cancer Research Group (BOOG)
Published: September 2018

507 Background: Neoadjuvant chemotherapy with dual HER2 blockade boosts pathologic complete response (pCR) rates in HER2+ breast cancer. The optimal chemotherapy backbone in this setting is unknown. We conducted a multicenter phase III trial to study whether anthracyclines would improve outcome compared to a carboplatin-taxane regimen (NCT01996267). Methods: We randomly assigned (1:1) patients with stage II-III HER2+ breast cancer to receive 9 cycles paclitaxel (80mg/m2 day 1 and 8) and carboplatin (AUC = 6mg/ml·min) (arm A) or 3 cycles 5-fluoruoracil (500mg/m2), epirubicin (90mg/m2), and cyclophosphamide (500mg/m2) followed by 6 cycles paclitaxel and carboplatin (arm B). Both arms received trastuzumab (6mg/kg, loading dose 8mg/kg) and pertuzumab (420mg, loading dose 840mg) concurrent with all chemotherapy cycles, and cycles were repeated every 3 weeks. The primary endpoint was pCR in breast and axilla (ypT0/is,ypN0). Results: 438 patients were included and 418 (arm A 206 vs arm B 212) were evaluable for the primary endpoint. The pCR rate did not differ between arms (arm A 68% [95% CI 61-74] vs arm B 67% [95% CI 60-73], p = 0.75). Hormone receptor (HR) negative tumors had significantly higher pCR rates (87% vs 54%, p < 0.0001), but we found no evidence for treatment-by-HR interaction (p = 0.23). Common adverse events grade ≥3 were neutropenia (arm A 53% vs arm B 57%, p = 0.34), febrile neutropenia (arm A 2% vs arm B 11%, p = 0.0001), and diarrhea (arm A 17% vs arm B 12%, p = 0.14). Neuropathy grade ≥2 was common in both arms (arm A 31% vs arm B 29%, p = 0.83), while left ventricular ejection fraction (LVEF) decline grade ≥2 (defined as ≥10% decline from baseline or LVEF < 50%) was more common in arm B (arm A 18% vs arm B 29%, p = 0.007). Symptomatic left ventricular systolic dysfunction was rare ( < 1%) in both arms. Conclusions: Anthracyclines increase the incidence of febrile neutropenia and grade ≥2 LVEF decline, but do not improve pCR rate in the contemporary neoadjuvant treatment of HER2+ breast cancer with dual HER2 blockade. Therefore, we currently favor a carboplatin-taxane based regimen. Follow-up is required to confirm these results with regard to long-term outcome. Clinical trial information: NCT01996267.
Identification of low prostate-specific antigen, high Gleason prostate cancer as a unique hormone-resistant entity with poor survival: A contemporary analysis of 640,000 patients.
Authors: Yang David Dewei , Mahal Brandon Arvin Virgil , Sweeney Christopher , Trinh Quoc-Dien , Feng Felix Yi-Chung , Nguyen Paul L. 
Published: September 2018

5080 Background: The clinical implications of a low prostate-specific antigen (PSA) in high-grade prostate cancer are unclear. We examined the prognostic and predictive value of a low PSA in high-grade prostate cancer. Methods: We identified 642,975 patients in the National Cancer Database (n = 491,505) and Surveillance, Epidemiology, and End Results program (n = 151,470) with localized or locally advanced prostate cancer from 2004-2013. Patients were stratified by Gleason score (8-10 vs. ≤7) and PSA (≤2.5, 2.6-4.0, 4.1-10.0, 10.1-20.0, and > 20.0 ng/mL) for analyses. Multivariable Fine-Gray competing risks and Cox regressions were used to analyze prostate-cancer specific mortality (PCSM) and all-cause mortality (ACM), respectively. Results: 5.6% of Gleason 8-10 tumors were diagnosed with PSA ≤2.5 ng/mL. Among Gleason 8-10 disease using PSA 4.1-10.0 ng/mL as referent, PCSM was U-shaped with respect to PSA, with adjusted hazard ratio (AHR) of 1.75 (95% CI 1.05-2.92, P = 0.032) for PSA ≤2.5 ng/mL vs. 1.31, 0.88, and 1.60 for PSA 2.6-4.0, 10.1-20.0, and > 20.0 ng/mL. In contrast, PCSM was linear for Gleason ≤7 disease with AHR of 0.32 (95% CI 0.10-1.00, P = 0.050) for PSA ≤2.5 ng/mL vs. 1.13, 1.69, and 3.22 for PSA 2.6-4.0, 10.1-20.0, and > 20.0 ng/mL (PGleason*PSA interaction< 0.001). Gleason 8-10 disease with PSA ≤2.5 ng/mL had a much higher risk of PCSM than standard NCCN high-risk disease (AHR 1.92, 95% CI 1.18-3.14, P = 0.009; 47-month PCSM 14.0% vs. 10.5%). For Gleason 8-10 tumors treated with definitive radiotherapy, androgen deprivation therapy (ADT) was associated with decreased ACM for PSA > 2.5 ng/mL (AHR 0.87, 95% CI 0.81-0.94, P < 0.001) but trended toward increased ACM for PSA ≤2.5ng/mL (AHR 1.27, 95% CI 0.89-1.81, P = 0.194; PADT*PSA interaction= 0.026). Conclusions: Low PSA, high-grade prostate cancer appears to be a unique hormone-resistant entity with a high risk of PCSM that responds poorly to standard treatment. Further molecular classification and trials are urgently needed to develop biological insight into this entity and establish new treatment paradigms, potentially including chemotherapy or novel systemic agents.
Phase 3 randomized study of adjuvant anastrozole (A), exemestane (E), or letrozole (L) with or without tamoxifen (T) in postmenopausal women with hormone-responsive (HR) breast cancer: The FATA-GIM3 trial.
Authors: Perrone Francesco , Gallo Ciro , De Laurentiis Michele , Bisagni Giancarlo , Arpino Grazia , Sarobba Maria Giuseppa , Riccardi Ferdinando , Russo Antonio , Del Mastro Lucia , Cogoni Alessio Aligi , Cognetti Francesco , Gori Stefania , Frassoldati Antonio , Amoroso Domenico , Laudadio Lucio , Moscetti Luca , Montemurro Filippo , Nuzzo Francesco , Carlini Paolo , De Placido Sabino ,   On Behalf of GIM Investigators
Published: September 2018

515 Background: Uncertainty still exists regarding the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors (AI) and no trial has ever compared all the three AI. Methods: FATA-GIM3 is a multicenter, open label, 2x3 factorial phase 3 randomized study of adjuvant A, E and L upfront (UP - for 5 years) or sequentially (SEQ - for 3 years after 2 years of T) in postmenopausal HR breast cancer pts. Two comparisons were planned: UP vs SEQ and A vs E vs L. DFS (including local or distant relapse, second breast or non-breast cancer, DCIS and death, whichever came first) was the primary end-point; 2% at 5 yrs (corresponding to a HR of 0.79) was defined as the minimum difference required to declare superiority of UP vs SEQ. With two-tailed alfa 0.05, power 80%, 669 events and the enrolment of 3600 patients were planned. Following Data Monitoring Committee advice, final analysis was performed after 5yrs median follow-up. For each comparison a Cox regression model was applied adjusted by stratification factors and stratified by the other treatment factor. Analyses were based on intention-to-treat. Results: from 3/2007 to 7/2012, 3697 patients were enrolled at 76 centres. Median age 64, pT1 69.7% , pN0 64.3%, ER and PgR positive 88.9%, HER2 positive 8.9%, previous chemotherapy 38.3%. At 60 months median follow-up, 401 events were reported. 5yrs DFS was 89.8 with UP and 88.5 with SEQ (delta 1.32%, 95% CI -0.90-3.54; HR 0.89, 95% CI 0.73-1.08; P=0.23). 5yrs DFS was 90.0 with A, 88.0 with E and 89.4 with L (P=0.19). Conclusions: in the FATA-GIM3 trial there is a small non statistically significant DFS advantage for UP vs SEQ. No significant difference is evident among the three AI. Supported by the FARM5K3MEE AIFA grant from the Italian Drug Agency. Clinical trial information: NCT00541086.
Standard anthracycline-based vs. docetaxel-capecitabine in early breast cancer: Results from the chemotherapy randomization (R-C) of EORTC 10041/ BIG 3-04 MINDACT phase III trial.
Authors: Cardoso Fatima , Piccart-Gebhart Martine J. , Rutgers Emiel J. , Litière Saskia , Van't Veer Laura , Viale Giuseppe , Pierga Jean-Yves , van den Berkmortel Franchette W.P.J. , Brain Etienne , Gomez Patricia , Goulioti Theodora , Knox Susan , Luporsi Elisabeth , Nitz Ulrike , Rubio Isabel T , Stork Lisette , Vuylsteke Peter , TRYFONIDIS KONSTANTINOS , Bogaerts Jan , Delaloge Suzette 
Published: September 2018

516 Background: The MINDACT trial demonstrated that 46% of breast cancer patients (pts) at high clinical (C) but low genomic (G) risk based on MammaPrint (70-gene signature), might safely forego adjuvant CT (Cardoso NEJM 2016). A second 1:1 randomization (R-C) was optional in all pts for whom CT was decided, between standard anthracycline-based regimens (AT) and experimental docetaxel 75 mg/m² IV + oral capecitabine 825 mg/m² bid x 14 days (DC), q3wks for 6 cycles after surgery. Methods: MINDACT included 6693 pts, of whom 2895 received CT. C-low/G-low pts were allocated to no CT, C-high/G-high to CT and those with discordant G/C results were randomized to use either G or C risk to decide use of CT. Primary endpoint for R-C was disease-free survival (DFS). Secondary endpoints included OS and safety. Statistical hypothesis: HR-0.76 in favour of DC. Results: A total of 1301 pts (45%), of whom 787 (61%) were C-high/G-high, 351 (27%) C-high/G-low, 137 (11%) C-low/G-high, and 26 (2%) C-low/G-low, were randomized to AT or DC. Main reason for not inclusion in R-C was CT given outside the trial. Compliance rates for R-C were 97% overall. At 5-years median follow-up, DFS was not significantly different between AT (649 pts) and DC (652 pts) [HR = 0.83 (0.60- 1.15, p = 0.263], and OS was similar in both arms (HR 0.91, 95% CI, 0.54- 1.53). For the relevant C-high/G-high group, DFS was also not different (5-years DFS 86.1 vs 88.1%; HR 0.83, 95% CI, 0.58-1.21). Of note, number of events is still small (AT: 30; DC: 27). Commonest adverse events in DC were grade 2 hand/foot syndrome (28.5% vs 3.3%), grade 2 diarrhea (13.7% vs 5.8%) and grade 1 peripheral neuropathy (27.1% vs 11.2%). Grade 2 anemia (14.2% vs 5.1%) and grade 4 neutropenia (24.6% vs 20.5%) were higher in AT. Cardiac events occurred in 9 pts overall, including 1 cardiac failure (AT), while 53 pts developed secondary cancers (AT: 32; DC: 21; leukemia: 2 in AT vs. 1 in DC). Four deaths occurred (AT:1 and DC:3) while on therapy. Conclusions: Docetaxel-capecitabine did not improve DFS or OS, compared with standard anthracycline-based CT, including for the C-high/G-high group. Safety profile of both regimens was as expected. Clinical trial information: NCT00433589.
Effects of neoadjuvant chemotherapy (NAC) on tumor infiltrating lymphocytes (TIL) and PD-L1 expression in the SWOG S0800 clinical trial.
Authors: Pelekanou Vasiliki , Barlow William E. , von Wahlde Marie-Kristin , Wasserman Brad , Lo Ying-Chun , Hayes Daniel F. , Hortobagyi Gabriel N. , Gralow Julie , Tripathy Debu , Livingston Robert B. , Porter Peggy , Nahleh Zeina A. , Rimm David L. , Pusztai Lajos 
Published: September 2018

519 Background: Higher baseline TILs and PD-L1 expression are associated with greater pathologic complete response (pCR) rates, but how chemotherapy affects these immune parameters is unknown. The goal of this study was to examine TIL and PD-L1 expression in pre- and post-NAC tumor specimens from the S0800 clinical trial that compared weekly nab-paclitaxel/bevacizumab + dose-dense doxorubicin and cyclophosphamide (AC) with nab-paclitaxel + AC as NAC for HER2-negative cases. Association between immune parameters, pCR and NAC-induced changes were tested using ER and NAC-arm adjusted logistic regression. Methods: TILs were assessed on H&E stained full sections of 120 pre- and 62 post-NAC tissues (tumor bed of pCR) including 59 matched samples. PD-L1 immunohistochemistry was performed using the FDA cleared 22C3 assay and results were available for 121 baseline and 43 matched post-NAC samples. Results: At baseline, the mean TIL count was 18%; 16% had no TILs and 9% had > 50% TILs. Higher baseline TILs were associated with higher pCR rate (p = 0.043, trend test p = 0.014) but there was no interaction with NAC arm. Post-NAC, the mean TIL counts was 11%; 5% had no TILs and 1.6% had > 50% TILs. In the matching post-NAC samples, the mean change was 15% decrease in TILs, but in 32% of cases TILs increased. Cases with residual disease (n=44) had lesser average decrease (p=0.029) than cases with pCR (n=15). The post-NAC decrease in TILs was also observed after excluding cases with pCR. At baseline, PD-L1 expression either in the stroma or on epithelial cells or in both was detected in 52 (43%) of 121 cases (5 tumor only, 29 stroma only, 18 tumor + stroma). Those with baseline PD-L1 expression had higher pCR (63% vs. 37%; p=0.008). Post-NAC, PD-L1 expression was seen in 14 of 43 (33%) cases (7 stroma only, 7 tumor + stroma). In the 39 matching pre- and post-NAC samples, PD-L1 expression was negative in both in 20, positive in both in 10 cases and 6 patients had PD-L1 expression at baseline but not in the post-NAC sample. Conclusions: TIL counts and PD-L1 expression generallydecreased, but in a minority of cases increased after NAC. The decrease in TIL was significantly greater in cases achieving pCR. Clinical trial information: NCT00856492.
Anastrozole after tamoxifen in early breast cancer patients with chemotherapy-induced ovarian function failure.
Authors: Tjan-Heijnen Vivianne C. , Van Hellemond Irene , Vriens Ingeborg , Peer Petronella , Swinkels Astrid , Smorenburg Carolien H. , Van Der Sangen Maurice , Kroep Judith R. , de Graaf Hiltje , Honkoop Aafke H. , Erdkamp Frans , van den Berkmortel Franchette , De Boer Maaike , de Roos Wilfred , Linn Sabine C. , Imholz Alexander , Seynaeve Caroline ,   Dutch Breast Cancer Research Group (BOOG)
Published: September 2018

523 Background: The DATA study compared 6 and 3 years of anastrozole therapy in postmenopausal women with hormone-receptor positive early breast cancer previously treated with 2-3 years tamoxifen (oral presentation SABCS 2016 #S01-03). The study included postmenopausal women, allowing those with chemotherapy-induced ovarian function failure (CIOFF). However, these may be at risk of ovarian function recovery (OFR). The current analysis compared the survival of women with CIOFF with definite postmenopausal women and examined the influence of OFR on survival. Methods: We selected patients from the DATA study aged 45-57 years at randomization who had received (neo-)adjuvant chemotherapy. They were classified by menopausal status at randomization (definite postmenopausal before chemotherapy or by ovariectomy, versus CIOFF). The latter were monitored by estradiol measurements for OFR during anastrozole. Endpoints: Disease-free Survival (DFS), Distant Recurrence-free Survival (DRFS), and Overall Survival (OS), corrected for tumor size, nodal status, grade, and hormone-receptor status. We used the landmark method to calculate residual 5-year survival rates. Results: In total, 261 patients were definite postmenopausal and 395 had CIOFF, of whom 39 experienced OFR while 290 did not (66 were excluded from the landmark analysis because follow-up estradiol levels were lacking). When comparing the CIOFF with the definite postmenopausal women, the 5-year survival rates were not significantly different. Within the group with CIOFF, experiencing OFR was associated with a trend for worse outcome (DFS-event HR 1.33 (95% CI 0.61-2.90), P=0.48; DRFS-event HR 2.11 (95% CI 0.89-5.02), P=0.09; and OS-event HR 2.24 (95% CI 0.92-5.45), P=0.07). Patients who experienced OFR in the first year had a residual 5-year rate for DFS of 73.1% compared with 87.4% in those who did not. For DRFS these rates were 76.9% vs. 92.1%, and for OS 80.8% vs. 94.4% respectively. Conclusions: These results suggest that women with CIOFF undergoing anastrozole treatment may be at increased risk of disease recurrence if experiencing OFR despite close monitoring of estradiol levels and adjusting endocrine treatment. Clinical trial information: NCT00301457.