bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract S1-10: Association between the 21-gene recurrence score (RS) and benefit from adjuvant paclitaxel (Pac) in node-positive (N+), ER-positive breast cancer patients (pts): Results from NSABP B-28
Authors: Mamounas EP , Tang G , Paik S , Baehner FL , Liu Q , Jeong J-H , Kim S-R , Butler SM , Jamshidian F , Cherbavaz DB , Sing AP , Shak S , Julian TB , Lembersky BC , Wickerham DL , Costantino JP , Wolmark N 
Published: August 2014

Abstract
Background: The RS result predicts outcome in N- and N+, ER+ pts treated with adjuvant endocrine therapy. RS also predicts benefit from adjuvant chemotherapy (CT) and pts with a high RS result receive most of the benefit. We evaluated the association between RS and paclitaxel (Pac) benefit in N+, ER+ pts from NSABP B-28.
Methods: B-28 compared 4 cycles of doxorubicin/cyclophosphamide (AC) vs. AC followed by Pac × 4 (AC→Pac). Pts ≥50 yrs and those&lt;50 yrs with ER+ and/or PR+ tumors also received 5 yrs of tamoxifen starting with CT. From 8/95 to 5/98 3060 pts were accrued. The present study includes 1065 pts, ER+ by central tissue microarray IHC assay, tamoxifen-treated, and with a RS result from the Oncotype DX 21-gene assay by standard processes. Sub-distribution analyses were used for loco-regional recurrence (LRR) to account for competing risks, including distant recurrence (DR), second primary cancers, and death. Kaplan-Meier estimates and Cox models were used for other clinical outcomes.
Results: Median follow-up time was 11.2 yrs. Of the 1065 pts, 386 (36%) had low RS (&lt;18); 364 (34%) intermediate RS (18–30); and 315 (30%) high RS (≥31). RS was a significant predictor of LRR, DFS event, DR, and death in univariate analyses both in pts treated with AC and in those treated with AC→Pac (Table). Pts with low RS had similar outcomes at 10 yrs when treated with AC→Pac vs. AC (Table). The majority of Pac benefit was observed in pts with intermediate/high RS (Table). Interaction tests between RS and Pac benefit were not statistically significant (LRR: p = 0.75, DFS: p = 0.65, DR: p = 0.93, death: p = 0.30).

Conclusions: RS significantly predicts risk for LRR, DR, DFS event, and death in N+, ER+ pts treated with AC or AC→Pac adjuvant CT. Pts with a low RS value have similar outcomes whether treated with AC or with AC→Pac and most of Pac benefit is evident in pts with intermediate/high RS. Although there was no significant interaction between RS and Pac benefit, these results support previous findings of lack of CT benefit in pts with a low RS result.
Supported by: NCI grants U10-CA-12027, -69651, -37377, -69974, U24-CA-114732, and CA-75362; Susan G. Komen for the Cure® grants; and Bristol-Myers Squibb Pharmaceutical Research Institute
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-10.
Abstract S1-8: Prolactin-humanized mice: an improved animal recipient for therapy response-testing of patient-derived breast cancer xenotransplants
Authors: Rui H , Utama FE , Yanac AF , Xia G , Peck AR , Liu C , Rosenberg AL , Wagner K-U , Yang N 
Published: August 2014

Abstract
Eighty percent of newly diagnosed breast cancer represents estrogen receptor(ER)-positive luminal subtypes. Many patients with luminal breast cancer develop antiestrogen resistant disease. It has historically been particularly difficult to establish ER-positive breast cancer lines from primary breast cancer in the laboratory or in mice. Murine and bovine prolactins, the major lactogens in current laboratory experimental in vivo and in vitro conditions, fail to activate human prolactin receptors because of species incompatibility. In fact, murine prolactin is a potent antagonist for human prolactin receptors. Because ER-positive, luminal breast cancers also express prolactin receptors, we hypothesized that lack of human lactogenic activity under experimental conditions selected against establishment of ER-positive breast cancer in the laboratory. We therefore genetically engineered mice to express physiological levels of human prolactin in place of mouse prolactin and backcrossed the mice for ten generations into the immunodeficient NSG strain. The resulting hPRL.NSG mice have a greatly improved take rate for ER positive, luminal type of breast cancer, suggesting key tumor-promoting roles for prolactin in luminal breast cancer. A panel of novel transplantable human breast cancer lines has been established in hPrl.NSG mice, the majority of which are ER-positive. The transplantable lines maintain key histopathological characteristics and expression of major marker proteins of the primary patient tumors. Intriguingly, initial tumor establishment and growth rates of breast cancer xenografts were consistently greater in the hPrl.NSG mice than in wildtype NSG mice. Furthermore, tumors grown in hPrl.NSG were more responsive to tamoxifen than size-matched tumors grown in wildtype NSG mice. At least two new tumor lines examined so far develop spontaneous distant metastases in hPrl.NSG mice, with evidence of prolactin-dependent progression of ER-positive disease. Collectively, these observations validate the hPrl.NSG mice as an improved recipient for preclinical modeling of human breast cancer in vivo, both for therapeutic targeting of prolactin-pathways and other growth and survival pathways, as well as overcoming anti-estrogen resistance.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-8.
Abstract S4-4: Independent validation of Genomic Grade in the BIG 1-98 study
Authors: Sotiriou C , Ignatiadis M , Desmedt C , Azim Jr HA , Veys I , Larsimont D , Lyng M , Viale G , Leyland-Jones B , Ditzel H , Giobbie-Hurder A , Regan M , Piccart M , Michiels S 
Published: August 2014

Abstract
Background: We have reported that a 97-gene signature, the Genomic Grade Index (GGI) can separate histological grade (HG) 2 breast tumors into low vs high GGI tumors with different outcomes. We have also developed a quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) tool including 6 reporter and 3 control genes that can reliably evaluate Genomic Grade (GG) in paraffin embedded tumors.
Methods: We evaluated the qRT-PCR GG in women treated with either tamoxifen or letrozole monotherapy in the Breast International Group (BIG) 1–98 study with 8.1 year median follow-up. The association between continuous GG and distant recurrence-free interval (DRFI) was evaluated in Cox regression models stratified for the 2 vs 4 arm randomization option, chemotherapy and hormonotherapy use, with and without adjustment for clinicopathological characteristics. Estrogen, progesterone receptor (ER, PR), Ki67 and HG were centrally reviewed. The clinicopathological model included age and log2 tumor size, ER and PR as continuous variables, nodal status (N0 vs 1–3 vs &gt;3), HG (1 vs 2 vs 3) and HER2 (negative vs positive). Similar analyses were performed for log2 Ki67 as continuous variable. Added prognostic value was assessed using the likelihood ratio statistic.
Results: We obtained GG in 883 (62%) of 1428 samples. Non evaluable results were due to pre-analytical issues or technical failure. Among the 883 patients, 521 (59%) had N0 disease, 435 (49%) were treated with tamoxifen and 84 (10%) had distant recurrences. The GG classified 502 patients with HG2 tumors as either GG1 (N = 202, 40%), equivocal (N = 220, 44%) or GG3 (N = 80, 16%). In univariate analysis, increasing GG and Ki67 were significantly associated with lower DRFI (Table). When the 773 N0/1-3 patients were analyzed based on HG, the Kaplan-Meier estimate for 10-year DRFI was 98% (95% confidence intervals 96–100%) for the 123 HG1, 92% (88–95%) for the 456 HG2 and 84% (78–90%) for the 194 HG3 patients. In the N0/1-3 population, 10 year DRFI based on GG was 95% (96–100%) for the 290 GG1, 92% (89–95%) for the 309 GG equivocal and 84% (77–90%) for the 178 GG3 patients. Interestingly, when the 456 HG2 and N0/1-3 patients were analyzed based on GG, the 10-year DRFI was 95% (92–100%) for the 185 HG2/GG1 patients, 92% (88–96%) for the 202 HG2/GG equivocal patients, 86% (76–96%) for the 69 HG2/GG3 patients. In all patients either GG or Ki67 as continuous variable significantly improved the clinicopathological model in predicting distant recurrence (Table).
Conclusion: Either Genomic Grade or centrally reviewed Ki67 provides independent prognostic information for risk of distant recurrence beyond clinicopathological characteristics in patients treated with endocrine therapy.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S4-4.
Abstract S5-2: HERA TRIAL: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow up
Authors: Goldhirsch A , Piccart-Gebhart MJ , Procter M , de Azambuja E , Weber HA , Untch M , Smith I , Gianni L , Jackisch C , Cameron D , Bell R , Dowsett M , Gelber RD , Leyland-Jones B , Baselga J ,   the HERA Study Team
Published: August 2014

Abstract
Background: One year (yr) of trastuzumab (T) significantly improves disease-free (DFS) and overall survival (OS) in patients with HER2-positive early breast cancer (EBC) and is considered the standard of care. HERA is the only randomized trial investigating whether longer duration of T can further improve efficacy outcome.
Materials and Methods: HERA (BIG 01–01) is an international, multicenter, phase III randomized trial involving 5102 women with HER2-positive EBC. Pts were randomized, after completion of primary therapy [surgery, chemotherapy and radiotherapy as indicated], to T every 3 weeks for 1 yr, 2 years (yrs), or observation. This landmark efficacy analysis compares the outcome of pts randomized to either 2 yrs or 1 yr of T who were disease-free at 1 yr after randomization (N = 1553 for 2 yrs, and N=1552 for 1 yr). The primary endpoint is DFS and secondary endpoints are OS and time to distant recurrence (TTDR). Updated efficacy analyses of the T arms vs. observation at 8-yrs of median follow-up (FU) are also presented.
Results: On 12 April 2012 HERA reached the target number of 725 DFS events needed for 80% power to detect a true hazard ratio (HR) of 0.80 for the comparison of 2 yrs vs. 1 yr of T. The unadjusted HR for an event in the 2-yr vs. 1-yr T arms was 0.99 (95% CI 0.85–1.14; p = 0.86). OS in the two arms was comparable [HR=1.05 (95% CI 0.86–1.28; p = 0.63)]. TTDR results were similar. The primary cardiac endpoint* was comparable (1.0% vs. 0.8% for 2-yr and 1-yr arms, respectively), but the secondary cardiac endpoint** was higher in the 2-yr arm (7.2% vs. 4.1%). Importantly, the durable benefit in DFS and OS for both 1 yr and 2 yrs of T compared with observation remains stable at 8 yrs of median FU. Subgroup analyses including by hormone receptor status will be available for the meeting.
Conclusions: These results confirm that 1 yr of adjuvant T remains the standard of care for HER2-positive EBC pts. It is also reassuring that the significant improvement in DFS and OS persists over time and that the incidence of cardiac endpoints remains low at a median FU of 8 yrs.
* NYHA class III or IV, confirmed by a cardiologist, and LVEF &lt; 50% and ≥ 10% below baseline, OR cardiac death.
** LVEF &lt; 50% and ≥ 10% below baseline confirmed by repeat assessment, excluding patients with a primary cardiac endpoint.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S5-2.
Abstract S5-5: Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: Final planned joint analysis of overall survival (OS) from NSABP B-31 and NCCTG N9831
Authors: Romond E , Suman VJ , Jeong J-H , Sledge GW , Geyer CE , Martino S , Rastogi P , Gralow J , Swain SM , Winer E , Colon-Otero G , Hudis C , Paik S , Davidson N , Mamounas EP , Zujewski JA , Wolmark N , Perez EA ,   National Surgical Adjuvant Breast and Bowel Project (NSABP) Operations and Biostatistical Centers
Published: August 2014

Abstract
Background: Preplanned combined analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial and North Central Cancer Treatment Group (NCCTG) (Alliance) N9831 Trial compared adjuvant chemotherapy with or without trastuzumab in women with HER2-positive breast cancer. The initial results were reported in 2005 and updated in early 2011
Methods: 4045 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The definitive analysis for OS will occur when 710 events have been reported.
Results: Median time on study is 8 years. The required number of events have occurred for the definitive analysis for OS to be conducted by the end of September 2012. Updated analyses of disease free survival and related subgroups will also be presented.
Supported by NCI grants U10-CA-12027, -69651, -37377, -69974, -44066, U24-CA-114732, CA25224; Breast Cancer Research Foundation; Genentech 35–03
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S5-5.
Abstract BS01-1: Genetic and non-genetic mechanisms contribute to longterm clonal growth dynamics and therapy resistance
Authors: Dick JE 
Published: August 2014

Abstract
The cellular and molecular basis for intra-tumoral heterogeneity is poorly understood. Tumor cells can be genetically diverse due to mutations and clonal evolution resulting in intra-tumoral functional heterogeneity. Often proposed as mutually exclusive, cancer stem cell (CSC) models postulate that tumors are cellular hierarchies sustained by CSC heterogeneity due to epigenetic differences (i.e. long term tumor propagation only derives from CSC). Two lines of evidence support the CSC model in leukemia. We have recently developed gene signatures specific to either AML LSC or normal HSC and found they share a set of genes that define a common stemness program. Only these stem cell related gene signatures were significant independent predictors of patient survival in large clinical databases. Thus, determinants of stemness influence clinical outcome of AML across a spectrum of mutations indicating that many genetic abnormalities coalesce around stem cell properties. Second, we have carried out a series of combined genetic and functional studies of the LSC from either B-ALL or AML that point to commonalities between clonal evolution and CSC models of cancer. LSC from diagnostic patient samples were genetically diverse and reconstruction of their genetic ancestry showed that multiple LSC subclones were related through a complex branching evolutionary process. The discovery that specific genetic events influence L-IC frequency and that genetically distinct L-IC evolve through a complex evolutionary process indicates that genetic and functional heterogeneity are highly inter-related. Finally, we have also begun to study paired diagnostic (Dx) and relapse (Rx) samples and found that rare Dx subclones are chemotherapy resistant and become enriched at Rx. Collectively, our study points to the need to develop therapies that effective target all genetic subclones present in a tumor and also ensure that cells possessing stemness properties are eliminated to prevent further evolution and recurrence.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr BS01-1.
Abstract OT2-6-02: Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer at high risk of disease recurrence (D-CARE): A global, placebo-controlled, randomized, double-blind, phase 3 clinical trial
Authors: Goss PE , Barrios CH , Chan A , Finkelstein DM , Iwata H , Martin M , Braun A , Zhou Y , Maniar T , Coleman RE 
Published: August 2014

Abstract
Background: In women with early-stage breast cancer, the skeleton represents one of the most common sites for metastases and represents approximately 40% of all first recurrences. Preclinical studies demonstrated that inhibition of RANKL significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab, a human IgG2 monoclonal antibody, binds RANKL with high specificity and affinity thus inhibiting RANKL activity. Denosumab has been approved for the prevention of skeletal-related events (SREs) in patients with established bone metastases from solid tumors.
Purpose: The D-CARE trial is designed to assess if denosumab treatment prolongs bone metastasis-free survival (BMFS; primary endpoint) in the adjuvant breast cancer setting. Secondary endpoints include disease-free survival (DFS) and overall survival. Additional endpoints include safety, patient reported outcomes (pain, health utilities), as well as exploratory including breast density, time to first on-study SRE following the development of bone metastasis and biomarkers.
Methods: In this global, randomized, double-blind, and placebo-controlled phase 3 trial, approximately 4500 women with stage II or III breast cancer at high risk for recurrence were randomized. High risk is defined as biopsy evidence of breast cancer in regional lymph nodes, tumor size &gt; 5 cm (T3), or locally advanced disease (T4). Patients must be receiving or planned to receive standard-of-care adjuvant/neoadjuvant therapy (chemo-, endocrine, or HER-2 targeted), alone or in combination. Patients with a prior history of breast cancer (except DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization, or any intravenous BP use, were not eligible. Patients were randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. Supplemental vitamin D (≥ 400 IU) and calcium (≥ 500 mg) are required. The primary efficacy and two interim efficacy analyses are planned and will be event-driven. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154, began enrolling patients in June 2010 and completed enrollment in late 2012.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-02.
Abstract P1-01-14: Extracorporeal shock wave therapy for lymphedema after axillary lymphadenectomy
Authors: Imboden S , Herzig D , Rabaglio M , Hohermuth R , Mueller MD , Günthert AR , Eser P , Schmid J-P 
Published: August 2014

Abstract
Introduction: Lymphedema is a frequent complication of local treatment for breast cancer. Substantial differences in the incidence of lymphedema have been reported depending on the extent of surgery, presence of lymph node metastasis and postoperative radiotherapy. The classical treatment of lymphedema includes manual lymph drainage and compressive bandages. No pharmacological treatment has been shown to be effective. In animal experiments extracorporeal shock wave therapy (ESWT) has been shown to stimulate angiogenesis and lymphatic vessel regeneration. However, whether ESWT reduces lymphedema after axillary lymphadenectomy is unknown.
Patients and Method: We randomized patients with lymphedema after axillary lymphadenectomy (2004 to 2011) into a treatment and a placebo group. Informed consent was obtained from all patients. All but one patient had at least one positive lymph node. A mean of 21.9 (5-43) lymph nodes were removed. 8/10 had an adjuvant radiotherapy of the axilla. ESWT of the whole edematous limb was performed once a week for 10 weeks (2000 shots, energy density 0,25-0,69 mJ/mm2). The placebo group underwent similar treatment, but the shock waves were absorbed in the probe. At baseline and at the end of treatment a clinical and oncological control was performed, including tolerability of the therapy (pain, local skin changes or infections) and oncological safety (recurrence rate). The response to ESWT was measured by volumetry (water displacement of the whole arm) and peripheral quantitative computed tomography (pQCT, change in total cross sectional area of the most swollen part of the arm). Also questionnaires on subjective body feeling, activity score and body image were applied.
Results: We report the preliminary results of the first 10 patients (placebo n = 5, verum n = 5) after 10 weeks. The median change water displacement volume in the verum group corresponded to -192.5 ml (25% percentile: -366.3 ml, 75% percentile -148.8 ml) vs. -12.5 ml (25% percentile: -192.8 ml, 75% percentile: 147.5 ml) in the placebo group (p-value for Mann-Whitney U test: 0.093). Cross sectional area decreased by -3.05% (25% percentile: -8.73%, 75% percentile: 1.49%) in the verum group vs. -1.36% (25% percentile -3.47%, 75% percentile 4.20%) in the placebo group (p-value: 0.394). No treatment had to be interrupted due to local complications. Conclusion: ESWT is well tolerated in patients treated for lymphedema after axillary lymphadenectomy. Our preliminary results show a promising trend towards both objective and subjective improvement of the lymphedema. The statistical significance of these improvements has to be confirmed after inclusion of all patients (N = 30).
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-01-14.
Abstract P2-09-02: BMN 673 is a PARP inhibitor in clinical development for the treatment of breast cancer patients with deleterious germline BRCA 1 and 2 mutations
Authors: Mina LA , Ramanathan RK , Wainberg ZA , Byers LA , Chugh R , Sachdev JC , Matei D , Zhang C , Henshaw JW , Dorr A , Kaye SB , de Bono JS 
Published: August 2014

Abstract
Background: BMN 673 is the most potent and specific inhibitor of poly-ADP ribose polymerase (PARP) 1 and 2 in clinical development (IC50&lt;1nM). In BRCA-related tumors, which are genetically dependent on PARP-mediated DNA repair by base excision repair, PARP inhibition induces synthetic lethality. Initial phase 1 results have been presented (de Bono et al JCO 31:5s, 2013 suppl; abstr 2580), showing good tolerability and anti-tumor activity with an MTD on a daily, oral dosing schedule of 1000 μ/day.
Methods: In this 2-stage study, patients with solid tumors including BRCA-related cancers, were enrolled during dose-escalation followed by an expansion phase at the MTD in breast, ovarian, and pancreatic cancer patients with deleterious germline BRCA mutations and in small cell lung cancer and Ewing sarcoma patients to further characterize safety and efficacy. This abstract summarizes demographics and safety for all patients and efficacy for patients with BRCA-related cancers.
Results: As of 17May2013, a total of 1 pancreatic, 18 breast (17F/1M), and 28 ovarian cancer pts with germline BRCA mutations were enrolled at doses from 100-1100 μg/day. All breast cancer patients were treated from 900-1100 μg/day. The median (range) age for all 70 patients is 51.5 (18-81), PS 0 (0-1) and # of prior therapies 4 (1-13), with 47 patients having deleterious BRCA mutations. An MTD of 1000 μg/day was established with thrombocytopenia being dose-limiting. Related adverse events occurring in &gt; 10% of all 70 patients included fatigue, nausea, alopecia, anemia, thrombocytopenia and neutropenia. One patient has had related grade 4 thrombocytopenia. Grade 3 related AE's included fatigue in 1 patient (1%), anemia and thrombocytopenia in 9 each (13%) and neutropenia in 4 (6%). Dose reductions occurred in 11 pts due to myelosuppression. No patients discontinued for adverse events.
Response in Germline BRCA PatientsBRCA Tumor TypeNDose Range (μ/day)ResponseBreast18900-11001CR/6PR/5SD≥12 weeksOvarian28100-11001CR/10PR/19GCIG/4SD≥24 weeksPancreas110001 SD ≥ 12weeksTwo of 2 BRCA breast responders had responded to prior platinum while 0 of 4 non-responders to prior platinum responded to BMN 673. Five of 12 breast cancer pts with no prior platinum have responded.
Conclusions: BMN 673 is well tolerated with impressive anti-tumor activity in pts with deleterious germ line BRCA mutations. Myelosuppression and fatigue are the primary side effects associated with need for dose reduction. A phase 3 trial in metastatic breast cancer patients with deleterious germ line BRCA mutations is planned with single-agent, once-daily oral dosing of 1000 μg (1 mg) per day.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-02.