bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P1-13-03: ER, PR, HER2, and Ki67 index and responsiveness to adjuvant tamoxifen in postmenopausal high-risk breast cancer patients enrolled in the DBCG 77C trial
Authors: Knoop AS , Lænkholm A-V , Jensen M-B , Nielsen KV , Andersen J , Nielsen D , Ejlertsen B 
Published: August 2014

Abstract
PURPOSE: The DBCG 77C trial compared one year of tamoxifen in postmenopausal, steroid-receptor unknown, high-risk breast cancer patients to no adjuvant systemic therapy. After a potential follow-up of 30 years we report overall efficacy for the study and results according to subtypes subsequently assessed by immunohistochemistry and FISH.
METHODS: Between 1977 and 1982, 1716 postmenopausal patients with tumors larger than 5 cm or positive axillary nodes were randomly assigned to no systemic therapy or tamoxifen 30 mg daily for one year. The main study is reported as an ITT analysis with the predefined DFS and BCM as endpoint. For multivariate analysis the Cox proportional hazards regression model was applied to assess the adjusted hazard ratio of treatment regimen, and to explore interactions. Formalin-fixed, paraffin-embedded primary breast tumor tissue blocks were available from 1548 (90%) of the 1716 participants enrolled and 1428 were assessable for ER, PR, HER2 and Ki67. The hormone receptor positive (ER and/or PR) cancers were defined as luminal A if Ki67 low and HER2-negative; as luminal B if Ki67 high or HER2-positive; and otherwise as HER2 positive or triple negative.
RESULTS: In the intent-to-treat (ITT) population one year of tamoxifen improved the disease-free-survival (DFS) (Hazard ratio (HR) = 0.87; 95% CI 0.77-0.98), the recurrence-free-survival (RFS) (HR = 0.79; 0.69-0.90) and reduced the breast-cancer-specific-mortality (BCM) (HR = 0.83; 0.73-0.93). Recurrence-free survivals were improved significantly by tamoxifen in luminal A (HR = 0.66; 0.53-0.84) and luminal B/HER2- (HR = 0.54; 0.39-0.74) but not in the other subsets, and with similar results for BCM with 30 years follow-up.
CONCLUSION: One year of treatment with tamoxifen significantly improves RFS and BCM in postmenopausal patients with ER positive breast cancers. The benefit from tamoxifen was not significantly different in luminal A and B subtypes.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-03.
Abstract P1-14-04: Subsequent endocrine therapy after becoming to resistance of ‘estrogen therapy’ is beneficial as a salvage treatment for the late stage metastatic breast cancer
Authors: Iwase H , Yamamoto Y , Yamamoto-Ibusuki M , Murakami K-I , Inao T , Okumura Y , Omoto Y 
Published: August 2014

Abstract
BACKGROUND: Aromatase inhibitor (AI) is a most commonly used as the endocrine therapy in postmenopausal hormone-dependent breast cancer. Paradoxically, estrogen additive therapy, high-dose estrogen using ethinylestradiol, can be useful after long-term estrogen deprivation therapies with AI. Furthermore, there is a possibility of the beneficial effect of AI or fulvestrant as a subsequent endocrine therapy after EE2 failure.
METHODS: Ethinylestradiol (EE2; 3mg/day, TID) therapy was performed in 22 patients with metastatic breast cancer (median; 62 years-old, the mean observation time: 13.6 months.), who were heavily treated by sequential endocrine therapies (3rd or more line) including cytotoxic chemotherapies. We examined the efficacy of a subsequent endocrine therapy using aromatase inhibitor or fulvestrant after becoming resistance to the EE2 therapy in the patients who got the disease control by the prior EE2 therapy. The primary endpoint was clinical benefit rate (CBR) and the secondary endpoint was time to treatment failure (TTF). (Registration number; UMIN 000002831, additional analysis)
RESULTS: Median of TTF of EE2 treatment was 46 weeks (23-62+, 2 cases were ongoing). The response rate was 41% (9/22), the clinical benefit rate was 50% (11/22). The stable disease (&lt; 6 months) was 18% (4/22) and another 3 cases were judged as progressive disease. Four cases withdrew due to nausea, fatigue and muscle-skeletal pain. In 13 cases progressed after disease control (SD or more) of EE2, a subsequent endocrine therapy, fulvestrant for 6 cases and AI for 7 cases, was performed. Fulvestrant group showed 50% (3 in 6) of CBR and 15 weeks (5-55+) of TTF, and AI-treated group showed 43% (3 in 7) of CBR and 19 weeks (5-33+) of TTF. Two in three cases, who became resistance to anti-estrogen treatment, got long SD by further EE2 re-therapy.
DISCUSSION: EE2 therapy could be beneficial for heavily treated metastatic breast cancer. Some cases showed clinical benefits of a subsequent therapy by AI or fulvestrant after becoming to EE2 failure. Taken together, sequential use of estrogen and anti-estrogen therapy (vice versa) could be one of the options as a salvage endocrine therapy for the end stage breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-14-04.
Abstract P2-06-06: ALU and LINE-1 hypomethylation is associated with HER2+/ER- subtype of breast cancer
Authors: Jung HY , Park SY , Jung N , Cho N-Y , Kang GH 
Published: August 2014

Abstract
The changes in DNA methylation status in cancer cells are characterized by hypermethylation of promoter CpG islands and diffuse hypomethylation of non-coding genomic regions. ALU and long interspersed nucleotide element-1 (LINE-1) are non-coding genomic repetitive sequences and methylation of these elements can be used as a surrogate marker for genomewide methylation status. This study was designed to evaluate the changes of ALU and LINE-1 hypomethylation during breast cancer progression from normal to pre-invasive lesions and invasive breast cancer (IBC), and their relations with characteristics of IBC. We analyzed the methylation status of ALU and LINE-1 in 145 cases of breast samples including normal breast tissue (n = 30), atypical ductal hyperplasia/ flat epithelial atypia (ADH/FEA, n = 30), ductal carcinoma in situ (DCIS, n = 35) and IBC (n = 50), and another set of 129 cases of IBC by pyrosequencing. LINE-1 methylation was significantly decreased from normal to ADH/FEA, while ADH/FEA, DCIS and IBC were not different each other. There was no difference in ALU methylation levels during progression of breast cancer. In IBC, ALU hypomethylation was correlated with negative estrogen receptor (ER) status (p = 0.007) and LINE-1 hypomethylation was associated with negative ER status (p&lt;0.001), positive HER2 status (p = 0.005) and p53 overexpression (p = 0.024). ALU-1 and LINE-1 methylation status was significantly different between breast cancer subtype and the HER2+/ER- subtype had significantly lower methylation levels and frequencies than the other subtypes. Our findings suggest that LINE-1 hypomethylation is an early event during breast cancer progression and prominent hypomethylation of ALU and LINE-1 in HER2+/ER- subtype may be related to chromosomal instability of this specific subtype.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-06-06.
Abstract P2-09-05: The potent anti-androgen enzalutamide demonstrates broad anti-tumour activity across all androgen receptor-positive triple-negative breast cancer subtypes
Authors: Denne L , Shia A , Komulainen E , Haley V , Lenihan C , Cavicchioli F , O'Leary K , Schmid P 
Published: August 2014

Abstract
Background: Up to 30% of triple-negative breast cancers (TNBC) show expression of the androgen receptor (AR) and may therefore be candidates for AR-targeted therapy. Molecular profiling of TNBC has identified the luminal AR (LAR) subset, which shares many aspects of ER-positive luminal cancers but is resistant to ER-targeted therapy. LAR cancers highly express the AR, are heavily enriched in hormone-regulated pathways and demonstrate tumour growth in response to androgen stimulation that can be inhibited by the mixed AR agonist/antagonist bicalutamide. The objective of this study was to investigate the role of AR signalling in TNBC in more detail and to evaluate the potential of the second generation anti-androgen Enzalutamide in this setting relative to bicalutamide.
Methods: A panel of 13 TNBC breast cancer cell lines was selected, representing different molecular subtypes of TNBC (including 4 LAR cell lines). Baseline AR expression was determined using qPCR (Taqman) and Western-Blot (Antibody, Santa Cruz Biotechnology). The effects of enzalutamide and bicalumatide on cell proliferation and survival were determined using MTT assays with and without DHT stimulation. Comprehensive molecular profiling (including Illumina Human HT-12 v4 whole genome mRNA and Illumina Human 450K methylation microarrays) was applied before and after enzalutamide treatment to define the molecular signature associated with sensitivity to enzalutamide therapy. All statistical calculations and IC50 doses were calculated using Prism v6.0 (GraphPad).
Results: A wide range of AR expression was confirmed across the cell line panel defining 3 groups with complete lack of AR expression, low/moderate AR expressions levels, or very high expression in the LAR subtype (with up to 100-fold greater AR expression compared to other TNBC subtypes). Enzalutamide demonstrated broad anti-tumour activity across all AR+ TNBC subtypes (but not in AR-negative subtypes), with IC50 values being similar in LAR and non-LAR cell lines. Treatment with enzalutamide resulted in more effective growth inhibition and a broader range of activity compared to bicalutamide. Data on molecular profiles of enzalutamide sensitivity will be presented at the meeting.
Conclusion: AR inhibition is a promising therapeutic strategy for both LAR and non-LAR AR-expressing TNBC. The potent anti-androgen enzalutamide shows broad activity across all AR+ TNBC subtypes and warrants further clinical evaluation. A phase 2 study of enzalutamide in AR+ TNBC has been initiated.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-05.
Abstract P2-11-11: Clinical utility of a radiosensitivity molecular signature: Identification of breast cancer patients that benefit from RT boost dose
Authors: Torres-Roca JF , Servant N , Bollet MA , Eschrich SA 
Published: August 2014

Abstract
Objective: In previous studies we developed a radiosensitivity molecular signature (RSI) that has been independently validated in multiple disease sites (n = 652) including breast cancer 1-3. Here, we test whether RSI can be utilized to identify sub-populations in breast cancer that benefit from RT dose intensification (boost).
Methods: RSI was tested in two published breast cancer datasets (n = 342) 4. Patients were selected if they had experienced a local recurrence within the first 10 years after primary treatment or were free of local recurrence for a minimum of 10 years after treatment. Primary treatment was initial breast-conserving surgery plus whole breast RT with/without a boost (no boost, n = 94, low boost &lt; = 66 Gy, n = 148, high boost &gt;66 Gy, n = 100). Patients were treated between January 1984 and November 2002. RSI was generated as previously described 1-3. Time to local recurrence was used as the endpoint for the study.
Results: Increased RT dose (&gt;66 Gy vs. &lt; = 66 Gy) resulted in a slight decrease in local recurrence risk that did not reach statistical significance (p = 0.11). As hypothesized, RSI-high patients (more radioresistant) were sensitive to increased RT dose (high RT-boost) which resulted in a decrease in local recurrence (HR = 0.3418, CI 0.1195-0.9777, p = 0.036). In contrast, RSI-low and intermediate patients had similar local recurrence risk independent of RT dose (RSI-low HR = 0.7687, CI 0.3404-1.736, p = 0.53, RSI-intermediate, HR = 0.9115, CI 0.5125-1.621, p = 0.75). Importantly, there were no statistical differences in the distribution of known prognostic variables between RSI-determined sub-populations (RSI-low, intermediate, high) including age, T-stage, margin status, nodal status, adjuvant chemotherapy, hormonal therapy, grade and molecular subtype.
Conclusions: RSI identifies a sub-population of breast cancer patients that benefit from increased RT-dose. RSI may be utilized to support RT-based decisions (high boost vs. low boost vs. no boost) in breast cancer.
1. Eschrich S, Fulp WJ, Pawitan Y, et al: Validation of a Radiosensitivity Molecular Signature in Breast Cancer. Clin Cancer Res, 2012
2. Eschrich S, Zhang H, Zhao H, et al: Systems biology modeling of the radiation sensitivity network: a biomarker discovery platform. Int J Radiat Oncol Biol Phys 75:497-505, 2009
3. Eschrich SA, Pramana J, Zhang H, et al: A gene expression model of intrinsic tumor radiosensitivity: prediction of response and prognosis after chemoradiation. Int J Radiat Oncol Biol Phys 75:489-96, 2009
4. Servant N, Bollet MA, Halfwerk H, et al: Search for a gene expression signature of breast cancer local recurrence in young women. Clin Cancer Res 18:1704-15, 2012.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-11.
Abstract P2-11-14: Does the Nottingham prognostic index further refine survival within the breast cancer subtypes?
Authors: Caggiano V , Parise C 
Published: August 2014

Abstract
Background
The Nottingham Prognostic Index (NPI), based on tumor size, lymph node status, and histologic grade, is a well established method of predicting survival of operable breast cancer. Breast cancer survival of the luminal, triple negative, and HER2 overexpressing subtypes has been previously described. The purpose of this study is to determine if the NPI can further refine survival of these subtypes within the AJCC stages of breast cancer.
Method
We identified 118,923 cases of stages 1-3 first primary female invasive breast cancer from the California Cancer Registry diagnosed between January 1, 2000 and December 31, 2010 with known ER/PR/HER2 status. The subtypes were classified as Luminal A (ER and/or PR-positive, HER2-negative), Luminal B (ER and/or PR-positive, HER2-positive), triple negative (ER-/PR-/HER2-), or HER2-overexpressing (ER-/PR-/HER2+). The NPI was computed and cases were stratified as having good (NPI &lt;3.4), moderate (3.4-5.4) or poor (&gt;5.4) prognosis. Kaplan Meier survival analysis (95% CIs) was used to compare survival among the NPI categories within each subtype and stage.
Results
The table shows that in stage 1, there was a statistically significant difference in survival between the good versus the moderate and poor NPI categories for luminal A, luminal B, and the triple negative subtypes. For the HER2-overexpressing subtype, the only difference was between the good and poor NPI category. For stage 2, the only difference in survival was for Luminal A where both the moderate (94.6%; 93.4%, 95.8%) and poor (84.3%; 83.6%, 85.0%) NPI categories had worse survival than the good category (99.9%; 97.1%, 100.0%). For stage 3, there were no differences among the NPI categories for any of the subtypes.
Eight year survival of stage 1 breast cancer subtypes within the NPI categories 8-Year Survival95% LCL*95% UCL*Luminal A Good95.695.196.2Moderate94.493.994.9Poor90.389.191.5Luminal B Good95.894.097.5Moderate94.393.195.5Poor88.686.291.0Triple Negative Good93.690.197.0Moderate88.186.090.1Poor86.084.287.8HER2-overexpressing Good92.387.697.1Moderate89.786.992.4Poor86.483.389.5*CL = Confidence Limit
For stage 2, the only difference in survival was for Luminal A where both the moderate (94.6%; 93.4%, 95.8%) and poor (84.3%; 83.6%,85.0%) NPI categories had worse survival than the good category (99.9%; 97.1%, 100.0%). For stage 3, there were no differences among the NPI categories for any of the subtypes.
Conclusion
The NPI is a valuable addition to AJCC stage 1 for all breast cancer subtypes. The NPI and AJCC staging systems both incorporate lymph node status and tumor size. However, histologic grade, found only in the NPI, may improve the accuracy of survival, especially in stage 1.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-14.
Abstract P2-14-03: Development and evaluation of a prediction model based on routine clinicopathological variables for predicting underestimated invasive breast cancer in women with ductal carcinoma in situ at stereotactic large core needle biopsy
Authors: Diepstraten SCE , van de Ven SMWY , Pijnappel RM , Peeters PHM , van den Bosch MAAJ , Verkooijen HM , Elias SG 
Published: August 2014

Abstract
Purpose: To develop a multivariable model for prediction of underestimated invasiveness in women with ductal carcinoma in situ (DCIS) at stereotactic large core needle biopsy (LCNB), that can be used to select patients for sentinel node biopsy (SNB) at primary surgery.
Methods: From the literature, we selected potential preoperative predictors of underestimated invasive breast cancer. Data of patients with nonpalpable breast lesions who were diagnosed with DCIS at stereotactic LCNB, drawn from the COBRA (Core Biopsy after RAdiological localization) and COBRA2000 studies, were used to fit the multivariable model and assess its overall performance, discrimination, and calibration.
Results: 348 women with LCNB-proven DCIS were available for analysis. In 100 (28.7%) patients invasive carcinoma was found at subsequent surgery. Nine predictors were included in the model. In the multivariable analysis, the predictors with the strongest association were lesion size (OR 1.12 per cm, 95% CI 0.98-1.28), the number of cores retrieved at biopsy (OR per core 0.87, 95% CI 0.75-1.01), presence of lobular cancerization (OR 5.29, 95% CI 1.25-26.77), and microinvasion (OR 3.75, 95% CI 1.42-9.87). The overall performance of the multivariable model was poor with an explained variation of 9% (Nagelkerke's R2), mediocre discrimination with area under the receiver operating characteristic curve of 0.66 (95% confidence interval 0.58-0.73), and fairly good calibration.
Conclusion: The evaluation of our multivariable prediction model in a large, clinically representative study population, proves that routine clinical and pathological variables are not suitable to select patients with LCNB-proven DCIS for SNB during primary surgery.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-14-03.
Abstract P2-16-06: Influence of trastuzumab pre-exposure in non metastatic disease to first line metastatic treatment efficacy including trastuzumab: The University Cancer Center - University Pierre & Marie Curie (IUC-UPMC) experience
Authors: Gligorov J , Vignot S , Richard S , Lotz J-P , Khayat D , Spano J-P 
Published: August 2014

Abstract
Background: Trastuzumab (TZB), is approved in France in adjuvant setting since 2005 for patients with HER2-positive breast cancer. The effectiveness of this treatment is well established, but little is known about the impact of pre-exposure to this drug in non metastatic disease and its effectiveness during its reintroduction in the metastatic disease.
Methods: We extracted from the database of two Medical Oncology Departments from University Cancer Institute - University Pierre & Marie Curie (IUC-UPMC), clinical parameters of patients treated in first-line HER2 positive metastatic breast cancer with treatments including TZB as the only antiHER2 treatment, between 2005 and 2011. We analyzed the impact of this treatment in patients who received adjuvant TZB and also in patients who did not.
Results. During this period, 456 patients were treated with TZB for a non metastatic HER2 positive disease, and 103 patients for a metastatic HER2 positive disease. Among the 456 patients treated in the (neo)adjuvant setting, the relapse rate was 3% (n = 16). The remaining 87 patients treated with first-line metastatic TZB were not previously treated with TZB in the adjuvant setting (n = 68) or had HER2 positive metastatic disease at time of initial diagnosis (n = 19). For patients previously exposed to TZB (n = 16), response rate (RR) of first-line treatment including TZB was 57% (95% CI: 35-81%) and time to failure treatment (TTF) was 243 days (95% CI: 114 to 330 days). For patients who have not been previously exposed to TZB (n = 87), the RR of first-line treatment including TZB was 61% (95% CI: 49-74%) and TTF was 267 days (95% CI: 182-343 days).
Conclusions: Despite the lack of direct comparison, it does not appear that treatment including TZB in non metastatic disease, will influence the efficacy of first-line treatment of metastatic featuring TZB reexposure.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-06.
Abstract P2-16-08: LORHA: Efficacy and safety of 1st-line trastuzumab based treatment, administered for at least 3 years, in patients with HER2-positive metastatic or locally advanced breast cancer - Final results
Authors: Ferrero J-M , Levy C , Spano J-P , Beuzeboc P , Coeffic D , Arnould L , Lortholary A , André F , Mayer F 
Published: August 2014

Abstract
Background: A subset of patients with HER2-positive metastatic (mBC) or locally advanced breast cancer (aBC) respond to 1st line trastuzumab-based regimen and have no disease progression for several years. These long-term responders were evaluated in daily practice in the LORHA study. Patients and disease characteristics were presented earlier (ESMO 2012).
Material and Methods: Lorha is an ambispective, multicenter, non-interventional study conducted in 57 centers in France. Eligible patients were women aged more than 18 years with HER2-positive mBC or aBC treated with 1st line trastuzumab and progression-free for at least 3 years after starting trastuzumab. The primary objective was to describe clinical and tumor characteristics. Secondary objectives included Progression Free Survival (PFS), Overall Survival (OS), treatment administration and safety. Patients were followed-up for 12 months.
Final results are presented here.
Results: Overall 160 patients were enrolled; 128 were eligible for efficacy analysis and 154 for safety analysis. Median age was 61 years [34-95]. Tumor characteristics were: invasive ductal carcinoma for 112 patients (88%), positive hormonal receptors in 72 patients (58%). At initial diagnosis, 91 patients (71%) had stage I - II tumors and 37 patients (29%) had de novo mBC or aBC. The main metastatic localizations were bone, liver, lymph nodes and lung in 54 (43%), 44 (35%), 25 (20%) and 24 (19%) patients, respectively. Median 1st line trastuzumab treatment duration was 4.5 years [0.8 - 12.1]. Trastuzumab 1st line was associated with a taxane-based chemotherapy in 104/128 patients (81%). Median PFS was 6.4 years [5.7; - Not reached] and median overall survival was not reached. At 1-year follow-up, 23 deaths (15% of patients) were reported, mainly due to disease progression (21 patients - 91%). No toxic death related to trastuzumab was observed. Grade 3-4 adverse events reported prospectively occurred in 14 patients (10%) and included two patients (1.2%) with grade 3-4 cardiac events related to trastuzumab (congestive cardiac failure and left ventricular dysfunction), both events resolved, one with sequelae.
Conclusions: Final results of the LORHA study show that long responding patients receiving first-line trastuzumab-based treatment for aBC or mBC in daily practice, can reach a median PFS of more than 6 years, combined with an acceptable safety profile. Median overall survival is still not reached.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-08.