bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclin D1 expression in breast cancer patients and tamoxifen therapy
Authors: Filipits M. , Rudas M. , Lehnert M. , Kubista E. , Dietze O. , Greil R. , Lax S. , Samonigg H. , Jakesz R. , Gnant M. 
Published: March 2020

523 Background: Adjuvant tamoxifen therapy improves survival of hormone receptor-positive breast cancer patients, but there is a subset of patients who fails to respond or develops resistance to tamoxifen. Cyclin D1 plays a central role in cell cycle regulation, directly affects the estrogen receptor and may predict outcome of tamoxifen therapy. Methods: We determined expression of cyclin D1 in formalin-fixed, paraffin-embedded surgical breast cancer specimens by means of immunohistochemistry. The patients had been enrolled in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 5 (test set) or ABCSG Trial 6 (validation set). Comparison of cyclin D1 expression with clinical parameters and survival of the patients was performed with cyclin D1 as a continuous variable and as a dichotomized variable. The median value of the percentage of cyclin D1-positive tumor cells was a priori chosen as cut-off point to classify cyclin D1- positive and cyclin D1-negative tumors. The cutpoint was established in the test set and validated in the validation set. Overall survival and relapse-free survival were analyzed with Cox models adjusted for clinical and pathological factors. Results: Cyclin D1 was positive (>10% cyclin D1-positive tumor cells) in 140 of 253 (55%) tumors of the test set and in 569 of 948 (60%) tumors of the validation set. A benefit from adjuvant endocrine therapy was associated with absence of cyclin D1 in both cohorts. Overall survival was significantly shorter in patients with cyclin D1-positive tumors as compared to patients with cyclin D1-negative tumors (adjusted hazard ratio for death [test set], 2.47, 95% confidence interval [1.08–5.63] P=0.03; adjusted hazard ratio for death [validation set], 1.91, [1.45–2.51] P<0.001). Relapse-free survival was also shorter in patients with cyclin D1-positive tumors than in patients with cyclin D1-negative tumors (adjusted hazard ratio for recurrence or death [test set], 2.73, [1.50–4.96] P=0.001; adjusted hazard ratio for recurrence or death [validation set], 1.60, [1.19–2.16] P=0.002). Conclusions: Women with early-stage, hormone receptor-positive breast cancer and cyclin D1-negative tumors benefit more from adjuvant tamoxifen therapy than women with cyclin D1-positive tumors. No significant financial relationships to disclose.
BCIRG 001 molecular analysis: Identification of prognostic factors in patients (pts) receiving adjuvant therapy for node- positive (N+) breast cancer (BC)
Authors: Dumontet C. M. , Reed J. C. , Krajewska M. , Treilleux I. , Mackey J. R. , Martin M. , Vogel C. , Rupin M. , Brunel E. , Hugh J. 
Published: March 2020

525 Background: BCIRG 001 (1,491 pts) demonstrated significant superiority of docetaxel/doxorubicin/cyclophosphamide (TAC) over fluorouracil/doxorubicin/cyclophosphamide (FAC) given as adjuvant therapy for N+ operable BC in terms of disease-free survival (DFS) and overall survival (OS) (Martin et al, N Eng J Med, 2005). This ancillary study was aimed to identify tumor-associated factors related to DFS and OS. Methods: Formalin-fixed primary tumors from pts in BCIRG 001 were analysed by immunohistochemistry. Protocol- specified assessment of histological grade (GR), tumor size (TS), estrogen (ER) and progesterone receptors (PR), lymph node status (LN), HER2, MUC1, Mib, p53, Bcl-2, Bax, Bcl-X, Bag-1, tubulin β isotypes II, III and IV, tau protein and detyrosinated a tubulin was performed. Parameters were scored as the percentage of positive cells and analysed as lower or greater than median values. The samples were randomly split into training (2/3) and validation (1/3) sets. Associations between selected parameters and DFS or OS were tested through univariate analyses using the Kaplan Meier method (log-rank test) on the training set. A backward stepwise Cox regression analysis was performed to identify the final model of prognostic factors on the training set. Multivariate analyses were applied to the validation set. Results: 1,350 samples were split into a training (n=906) and a validation (n=444) set. In univariate GR, TS, LN, ER and PR, Mib, tau protein and HER2 were correlated with DFS in both sets. In multivariate ER, PR, TS, LN, Mib (all p<0.01) and tau (p=0.043) were significantly associated with DFS in the training set. In univariate GR, TS, LN, ER and PR, Mib, MUC1, Bcl-2, tubulin III and IV and tau were correlated with OS in both sets, with a trend for p53. In multivariate ER, TS, LN, Mib, p53 (all p<0.01) and PR (p=0.028) were independently correlated with OS in the training set. Conclusions: These data suggest that tau and p53 are independent markers of DFS and OS, respectively, while Mib is correlated with both DFS and OS in pts receiving these forms of adjuvant chemotherapy for N+ BC. Complementary analyses will be presented. No significant financial relationships to disclose.
Predictive gene expression patterns of response to adriamycin and cyclophosphamide (AC) in human breast cancers
Authors: Makris A. , Creighton C. , Osborne K. C. , Hilsenbeck S. , Harrison M. K. , Ostler P. J. , Spears C. , Brown P. , Elledge R. , Chang J. C. 
Published: March 2020

527 Background: Adriamycin and cyclophosphamide (AC) and docetaxel (D) are widely used in the treatment of breast cancer. We conducted a prospective, randomized, multicenter trial to discover predictive markers of AC and D and hypothesized that gene expression profiles can select appropriate patients who may respond to AC, and that these patterns are different from our published docetaxel (D) profiles Methods: One hundred and twenty patients were randomized to either 4 cycles of AC (60/600 mg/m2) or D (100mg/m2) prior to surgery. Core biopsies from 60 patients were obtained before treatment with neoadjuvant AC. Pathologic responses were assessed after AC. Gene expression patterns were determined using Affymetrix U133A GeneChips. Differential genes for AC response were then validated by QRT-PCR in an independent cohort of 33 patients treated with AC. Results: The median age was 48 yrs (range 30–72), clinical response rates were 57% (34/60), and pathological complete response (pCR) or near pCR (npCR) was observed in 22% (12/60) in AC arm. Differential expression between sensitive and resistant tumors with a low false discovery rate (FDR 5–10%) was obtained. Of these 82 differentially expressed genes, pathways up-regulated in sensitive tumors included TOP2A, metabolism (LYZ), survival (CFLAR, CASP3), cell cycle (MKI67), cytokines and other inflammatory genes. This molecular portrait for AC was not predictive of docetaxel response. By QRT-PCR of 4 genes (LYZ, CFLAR, MKI67 and TOP2A) in the independent tumor set, LYZ was predictive of AC pathologic complete response. Additional genes will be validated in the second cohort. Conclusions: The molecular profile for AC is different from the docetaxel expression profile. This potential predictive test may allow selection of the most appropriate chemotherapy schedule for women with breast cancer. No significant financial relationships to disclose.
The National Epirubicin Adjuvant Trial (NEAT) and Scottish Cancer Trials Breast Group (SCTBG) br9601 randomized phase III adjuvant early breast cancer trials: The updated definitive joint analysis
Authors: Earl H. , Hiller L. , Dunn J. A. , Bathers S. , Grieve R. J. , Spooner D. , Agrawal R. K. , Foster L. , Twelves C. , Poole C. J. 
Published: March 2020

534 Background: NEAT and the SCTBG BR9601 trial address the role of Epirubicin (E) as an adjunct to CMF in adjuvant chemotherapy for women with early breast cancer (EBC). Methods: NEAT compared E (100mg/m2 x4cycles) followed by classical (c)CMF (x4cycles) with cCMF (x6cycles); BR9601 compared E (100mg/m2 × 4cycles) followed by iv dose modified CMF q3w (750:50:600 ×4cycles) with iv CMF (x8cycles). Eligibility was completely excised EBC, requiring adjuvant chemotherapy, and start of treatment <10 wks from surgery. Primary outcome measures were relapse-free-survival (RFS) and overall survival (OS). A joint efficacy analysis of NEAT (n=2,021) and BR9601 (n=370) triggered by planned 5-year median follow-up (FU) and estimated 800 RFS events and 600 deaths has 85% power to detect 5% two-sided differences. Results: In 2,391 eligible patients, characteristics were balanced across treatments: 72% node +ve; 59% <50 years old; 47% pre-menopausal; 58% tumours grade 3; 55% >2cms; 32% ER-ve, 50% ER+ve (18% NA). At a median FU of 6.2 yrs, 710 relapses or deaths without relapse and 570 deaths are observed. Despite lower than anticipated event rates in the control arm, these updated results confirm a highly significant benefit in favour of ECMF for both RFS (HR 0.75 (95%CI 0.64–0.87) p=0.0002) and OS (HR 0.74 (0.62–0.87) p=0.0004), independent of trial and prognostic factors. In 1458 NEAT patients (in whom data are available), 68% were to receive tamoxifen; chemotherapy scheduling data is available for 843, of whom 46% were declared concurrent and 54% sequential. In a non-pre-planned retrospective analysis, sequential tamoxifen shows a trend for advantage on RFS (HR 0.78 (0.59–1.02) p=0.06). We have amenorrhoea data on 598 NEAT and BR9601 pre-menopausal women, of whom 72% became amenorrhoeic by the end of chemotherapy. In this instance, developing amenorrhoea showed no advantage for RFS (HR 0.90 (0.65–1.24) or OS (HR 0.99 (0.68–1.44)). Conclusions: This updated definitive analysis adds to the Overview in respect of an anthracycline advantage and confirms ECMF as an established and effective standard adjuvant therapy for EBC. [Table: see text]
Anthracycline-based sequential adjuvant chemotherapy in operable breast cancer: Five-year results of a randomized study by the Michelangelo Foundation
Authors: Moliterni A. , Mansutti M. , Aldrighetti D. , Merlini L. , Zuccarino L. , Bari M. , Farris A. , Mariani P. , Fava S. , Gianni L. 
Published: March 2020

535 Background: Anthracycline-based sequential chemotherapy significantly improves efficacy outcomes compared to CMF alone. Methods: 806 eligible patients with operable breast cancer were enrolled into a randomized study (ratio 1:1:1:1) of sequential chemotherapy. In a 2×2-type design patients were allocated to first receive 4 cycles of AT (doxorubicin, A 60 mg/m2 iv + paclitaxel, T 200 mg/m2 as 3 h inf q 3wks) or EV (epirubicin, E 75 mg/m2 iv + vinorelbine, V 25 mg/m2 iv D1,8 q3wks) followed either by 4 monthly cycles of iv CMF or 6 cycles of q3w T alone (100 mg/m2 as 1h inf D1,8). Tamoxifen was recommended for 5 yr after chemotherapy in patients with HR+ tumors. Patients with tumors > 2 cm in diameter were allowed to start primary chemotherapy with 4 cycles of either AT or EV followed by surgery and postoperative systemic treatment as detailed above. Aim of the study was to test the role of T vs V when combined with an anthracycline during the first 4 cycles of the regimen as well as the role of CMF vs T during the last 4 cycles. Results: At a median follow-up of approximately 48 months, the 5 year freedom from progression (FFP) and overall survival (OS) for the main endpoints were as in the Table : The four treatment sequences were fairly well tolerated, with only 1 treatment-related death after EV. Type and severity of hematological toxicities were similar in all treatment arms. The incidence of reversible G2–3 neurotoxicity was 21.9% after AT, 5.3% after EV and 29.1% after sequential T. Chemical phlebitis was more frequent after EV (6.5%) then after AT (0.3). Conclusions: The results indicate that vinorelbine-epirubicin and classical CMF when appropriately used in a sequential modality for high-risk breast cancer are as valid and less neurotoxic an option of adjuvant therapy than the more widely used taxane-containing adjuvant regimens. Supported in part by Bristol-Myers Squibb, Pierre Fabre and Pharmacia. [Table: see text] [Table: see text]
Disease-free survival (DFS) as surrogate end point for overall survival (OS) in adjuvant aromatase inhibitors (AIs) trials for breast cancer (BC): Meta-analysis of 10 randomized clinical trials (RCTs) exploring the magnitude of the benefit
Authors: Ciccarese M. , Bria E. , Cuppone F. , Nisticò C. , Carlini P. , Sperduti I. , Lorusso V. , Terzoli E. , Cognetti F. , Giannarelli D. 
Published: March 2020

539 Background. The issue regarding the eventual correlation of DFS with OS has not actually been explored in trials addressing the role of AIs. For this purpose, we meta-analyzed all RCTs in which patients were randomized to receive standard tamoxifen or AIs, whatever applied strategies. Methods. A literature-based meta-analysis was accomplished, and event-based relative risk ratios (RRs) with 95% confidence interval (CI) were derived. A fixed- (FEM) and a random-effect (REM) model and heterogeneity test were applied as well. Absolute benefits (AB) and the Number of patients Needed to Treat (NNT) were calculated. A linear regression model considering both each single outcome pair (5-years DFS and OS) has been adopted to explore for correlation, estimated according to Pearson, R2 (parametric) and Spearman (non-parametric) coefficients. Results. Ten RCTs were gathered (27,653 patients); two RCTs did not report the OS result, so they were not evaluable. DFS was significantly improved with AIs, with a AB of 2.3–3.5%, which translate into 29–43 NNT. OS was significantly improved in both overall and early switch strategy, with an AB of 0.8–1.61%, which translate into 120 and 62 NNT, respectively. A strong correlation was found between DFS and OS in the overall (r=0.78, R2=0.60, p=0.001; Rho=0.77, p=0.001) and in the early switch strategy (r=0.83, R2=0.68, p=0.003; Rho=0.84, p=0.002). Although a stronger correlation was found in the upfront strategy, the low number of RCTs did not allow to reaching statistical significance. Conclusions. The strong correlation between DFS and OS in AIs adjuvant endocrine treatment for early BC underlines the choice of DFS as a surrogate end-point for OS. The predictive value of earlier DFS (3-years) estimation for overall survival deserves a further analysis. [Table: see text] No significant financial relationships to disclose.
DUSP7 and DUSP8 promoter hypermethylations: Predictors of clinical outcomes in advanced epithelial ovarian carcinoma
Authors: Lim S. , Green J. A. , Wong H. , VanderBurg M. E. , Crook T. 
Published: March 2020

5501 Background: The Dual specificity phosphatases (DUSPs) are a subclass of the protein tyrosine phosphatase (PTP) gene family which appears to be selective for dephosphorylating the critical phosphothreonine and phosphotyrosine residues within the mitogen-activated protein kinases (MAPKs) leading to inactivation. MAPK activation is a downstream target of several oncogenes and may give rise to oncogenic transformation, and hence DUSPs are potential tumor suppressor genes. The aim of this study was to investigate if DUSPs are subject to methylation-dependent silencing in epithelial ovarian cancer. Methods: In this study, promoter methylation and gene expression of the DUSPs genes (DUSP1, DUSP2, DUSP3, DUSP4, DUSP5, DUSP6, DUSP7, DUSP8 and DUSP10) were investigated in 9 ovarian cancer cell lines and in 74 primary epithelial ovarian tumors (Stage III/IV), using methylation specific PCR (MSP) and Reverse- transcription PCR (RT-PCR). The 74 clinical samples were retrospectively retrieved from a large Phase III RCT (the EORTC 55931/NCIC OV10) with clinical follow-up in excess of 6.5 years. Results: Ovarian Cancer Cell lines: Aberrant CpG methylation detected in DUSP1, DUSP2, DUSP4, DUSP6, DUSP7 and DUSP8. DUSP7 promoter methylation was associated with downregulation of mRNA expression. Primary Ovarian Tumors: Methylation of DUSP1, DUSP2, DUSP7 and DUSP8 was observed in 15–38% of the primary tumors. DUSP7 methylation is a predictor of adverse PFS in both univariate (median PFS 10.6 m versus 13.3m, p=0.002) and multivariate (Cox Regression HR 2.76, p<0.001) analyses, and is associated with a trend for poorer OS (22.1 m versus 29.3 m, p=0.07). In contrast, DUSP8 methylation is an independent predictor of favorable PFS (median 23.7m versus 11.5m; Cox Regression HR 0.30, p=0.006) and OS (HR 0.31, p=0.013). 5-year OS for DUSP8 methylated patients was 58.3% compared with 16.1% for DUSP8 unmethylated (HR 0.277, p=0.005). Conclusion: This is the first report of DUSP methylation in epithelial ovarian cancer. The study suggests that methylation-dependent transcriptional silencing of DUSP7 in advanced epithelial ovarian cancer may represent an independent predictor of adverse PFS. DUSP8 methylation, on the other hand, is a favorable clinical outcome marker. No significant financial relationships to disclose.
Final results of After-6 protocol 1: A phase III trial of observation versus 6 courses of paclitaxel (Pac) in advanced ovarian cancer patients in complete response (CR) after platinum-paclitaxel chemotherapy (CT)
Authors: Conte P. F. , Favalli G. , Gadducci A. , Katsaros D. , Benedetti Panici P. L. , Carpi A. , Scambia G. , Ballardini M. , Nanni O. , Pecorelli S. 
Published: March 2020

5505 Background: The majority of advanced ovarian cancer patients (pts) in CR after debulking surgery and Platinum/Paclitaxel will eventually relapse. Role of maintenance CT is still questionable even if a SWOG/GOG trial has shown an improved progression free survival (PFS) with 12 vs 3 cycles of maintenance Pac. In March 1999, the After 6 Italian Cooperative Group initiated a phase III study to determine if maintenance Pac could prolong PFS in pts with a clinical (cCR) or pathological CR (pCR) after first line CT Methods: Pts with advanced ovarian cancer in cCR or pCR after 6 cycles of Platinum/Paclitaxel, were randomised to observation or 6 cycles of Pac 175 mg/sqm iv q 3 wks. Primary end point: PFS; secondary end points: overall survival (OS) and toxicities. Planned sample size: 250 pts to detect a 15% absolute increase in 2-yr PFS. Results: From 03/99 to 07/06, 200 pts were randomised. Due to the low accrual rate, an unplanned interim analysis of futility according to the Bayesian approach was performed. Main patient characteristics: median age 58 yrs, median PS 0 (neurotoxicity ≥ G 2 was an exclusion criteria), stage IIb/IIc 15%, stage III 79%, stage IV 6%; 105 pts (52.5%) were in pCR. 14% of pts randomised to observation received Pac; 22% of pts randomised to Pac stopped treatment after 2–5 cycles (progression or death: 3 pts; toxicity: 9 pts; refusal: 7 pts; others: 3 pts). A G ≥ 2 neurotoxicity was reported in 25% of pts treated with Pac; other toxicities were mild. After a median follow up of 44 months, 94 pts (47%) have relapsed and 42 pts (21%) died. Median PFS were 34 and 34.5 months in observation and Pac arm respectively; 3-yr OS was 88% in observation and 78% in Pac arm. Irrespectively of treatment arm, median PFS was 34.4 months for pts with pCR and 24.5 months for those with cCR; 3-yr survival rates were 87% and 79% respectively (p=0.04). Conclusions: Six courses of maintenance Pac do not prolong PFS or OS in pts in CR after first line platinum/paclitaxel. Irrespectively of assigned treatment, the outcome of these pts is more favourable than previously reported and significantly better in the pCRs. Maintenance CT remains an experimental treatment that should be tested in pts at high risk of relapse. [Table: see text]
Phase II trial of the novel epothilone ZK-EPO in patients with platinum resistant ovarian cancer
Authors: Rustin G. J. , Reed N. S. , Jayson G. , Ledermann J. A. , Adams M. , Stredder C. , Wagner A. , Giurescu M. ,   The ZK- EPO Study Group in Platinum-Resistant Ovarian Cancer
Published: March 2020

5527 Background: The rationally designed, fully synthetic epothilone ZK-EPO has demonstrated significant activity against ovarian cancer cell lines. The results of the first completed phase I study (one 30-min infusion q3w) indicated good tolerability, with peripheral neuropathy as the most common toxicity; signs of activity, including objective responses, were reported. A randomised phase II trial was performed to determine the efficacy, safety and tolerability of 2 infusion durations in patients with platinum-resistant ovarian cancer. Methods: Eligible patients were at first or second relapse, had a platinum-free interval of <6 months, and disease evaluable by RECIST or, if not measurable, by CA125 (GCIG criteria). Patients were randomised to receive 3-hour or 30-min infusions of 16 mg/m2 ZK- EPO administered 3-weekly. Simon’s two-step design was used; 13–34 patients were to be accrued per arm. An arm would be continued if at least 2/13 patients responded. The drug would be considered efficacious if ≥6/34 patients responded. Results: To date, 63 patients have entered the study (accrual completed November 2006). Data is currently available on the 30 patients in step 1. Four patients were excluded from efficacy analysis due to tumor histology (clear or mucinous), as per protocol. 24 patients were taxane pre-treated. 4/13 patients responded in the 3-hour arm so accrual continued; in the 30-min arm 1/13 responded. A total of 101 infusions were administered to patients in step 1. The most common drug-related toxicity >grade 1 in the 3-hour and 30-min arm was grade 2–3 peripheral sensory neuropathy (3-hour: 9/15 patients, 30 min: 5/15 patients). Two patients withdrew because of neuropathy, both in the 3-hour arm. Other drug-related toxicities >grade 1 occurring in >1 patient were fatigue (n=3), arthralgia (n=3), nausea (n=3) and lethargy (n=2). Conclusion: Preliminary results indicate that ZK-EPO, administered as a 3-hour infusion at a dose of 16 mg/m2, has promising activity against platinum-resistant ovarian cancer. Updated response data on all patients will be presented. Peripheral neuropathy currently appears to be the only noteworthy toxicity of ZK-EPO. [Table: see text]