bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract OT2-6-15: Efficacy and safety of vintafolide alone and vintafolide plus paclitaxel vs paclitaxel alone in advanced triple negative breast cancer subjects using etarfolatide subject selection
Authors: Schmidt EV , Leighton-Swayze AM , Hanson ME , Brown H , Gause CK , El Galta R , Denker AE , Yao S-L 
Published: August 2014

Abstract
Background: Vintafolide (V) is a folic acid-vinca alkaloid small molecule drug conjugate that targets tumors that over-express the folate receptor (FR). 99mTc-etarfolatide (EC20) is a folate-targeted molecular imaging agent being developed to identify FR-positive tumors. Data suggest that triple negative breast cancers (TNBCs) expressing high levels of FR are likely to benefit from treatment with vintafolide.
Trial design/Patient eligibility: This is a multicenter, randomized, open-label, Phase IIa trial in subjects with advanced TNBC. Patients will be evaluated for tumor specific expression of the FR using a EC20 SPECT/CT scan and classified as FR(100%) if 100% of RECIST 1.1 target lesions are FR-positive. Only FR(100%) patients are eligible for treatment and will be randomized in a 1:1:1 ratio to V alone, V + paclitaxel (P) or P alone. V will be administered at 2.5 mg IV 3x/week for 2 weeks on Days 1, 3, 5, 15, 17 and 19 of a 28-day cycle. P will be administered at 80 mg/m2 IV on Days 1, 8, 15, and 22.
Specific aims: The primary endpoint for the trial is centrally assessed progression free survival (PFS). Secondary objectives include: assess the frequency of target tumors expressing FR(100%) vs FR(20-80%) vs FR(0%) in subjects with TNBC using EC20 SPECT scans; compare the clinical activity in subjects with advanced TNBC of V alone vs P and V + P vs P alone as measured by objective response rate (ORR), (complete response [CR] + partial response [PR]), clinical benefit rate (CBR; CR + PR + stable disease for ≥6 months), and overall survival; and assess the safety and tolerability of V alone vs P alone and V + P vs P alone in subjects with advanced TNBC.
Statistical methods and target accrual: PFS and overall survival will be assessed in the intention to treat population using a stratified Cox model with Efron's tie handling method, and Kaplan-Meier method for PFS and OS curve estimation, respectively, in each treatment group.
Inferential comparisons between the arms will be tested using the stratified log-rank test at one sided alpha level of 5%. This study will randomize 34 subjects into each treatment group with total study duration of ∼16-17 months. The study has 80% power to demonstrate that either patients treated with V or patients treated with V + P combination have a higher median time to an event of PFS than subjects treated with P at an unadjusted one-sided, 5% alpha-level, if the underlying constant hazard ratio between treatment groups is 0.5 and median survival time of 2.6 months. First patient enrollment is targeted for October.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-15.
Abstract P1-08-15: Prognostic value of five different histologic scoring systems for tumor regression after neoadjuvant chemotherapy of breast cancer in luminal type breast cancer
Authors: Sinn P , Elsawaf Z , Kaip G , Heil J , Aulmann S , Marmé F , Schneeweiss A 
Published: August 2014

Abstract
Background: Complete pathologic tumor regression (pCR) and molecular tumor characteristics are the major determinants for the outcome of patients undergoing neoadjuvant chemotherapy. Recently, we have raised the question, if complete pathologic tumor regression (pCR) is a reliable endpoint in cohorts with an abundance of luminal subtypes (Marmé et al., Int J Cancer 2013). Therefore, we have compared the prognostic value of different histologic scoring systems for the evaluation of partial tumor regression in luminal type breast cancer in this study.
Methods: We retrospectivly reviewed tumor resection specimens of the GEDOC/GEsDOC (Schneeweiss et al., Eur J Cancer 2004) and H3E-MC-S080 (Schneeweiss et al., Ann Oncol 2010) clinical trials. Histologic tumor regression was scored according to five different regression scoring systems (Sataloff, Miller-Payne, RCB score, Sinn, and NSABP). Molecular subtypes were classified according to established immunohistologic definitions of intrinsic subtypes.
Results: A total of 152 luminal type breast cancers were available for histologic evaluation (139 with HER2 negative and 13 with HER2 positive phenotype). Median follow-up was 63 months (9-105). pCR was observed in 10 patients according to the NSABP criteria. Overall survival was significantly better for patients with complete or near complete response (RCB class 0, 1) compared to moderate or extensive residual disease (RCB class 2, 3) with 5-y OAS of 97.6%+/- 1.6% vs. 81.7%+/-6.7% (p&lt;0.001). Tumor response in lymph nodes (Sataloff lymph node score) was of similar prognostic value with 5-y OAS of 96.6%+/-2.3% (NA and NB responses) vs. 84.1%+/-5.6% (NC and ND responses, p&lt;0.005). However, scores based on tumor cellularity (Miller-Payne or Sataloff tumor score) could not reliably identify prognostic subgroups. The Sataloff ND category of patients with viable lymph node metastasis and no therapeutic effect identified the worst outcome group (5-y OAS 69.2%+/-20.7%). In multivariate analyses only the RCB score and the HER2 status remained predictive parameters for survival (both p&lt;0.05).
Conclusions: In luminal type breast cancers, the use of regression scoring systems that include the lymph node status (RCB score and Sataloff LN score) was superior to scoring systems which are based solely on tumor cellularity such as the Miller-Payne system. The HER2 status was of independent significance.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-15.
Abstract P1-08-32: Endothelin-1 genetic polymorphism as predictive marker for bevacizumab in metastatic breast cancer
Authors: Gampenrieder SP , Hufnagl C , Brechelmacher S , Huemer F , Hackl H , Rinnerthaler G , Romeder F , Muß C , Pircher M , Ressler S , Kronberger C , Mlineritsch B , Greil R 
Published: August 2014

Abstract
Background: Biomarkers predicting response or toxicity of bevacizumab containing therapy in breast cancer are of urgent need. The genetic variability of VEGF, its receptor or other genes involved in angiogenesis could explain the inter-patient variability of drug effects and treatment resistance.
Patients and methods: DNA was extracted from 180 paraffin-embedded tumor tissue blocks of patients with locally advanced or metastatic breast cancer treated with bevacizumab in combination with chemotherapy at our institution. We assessed the correlation of 11 SNPs in VEGF-A, VEGFR-1, STK39, endothelin-1 and uromodulin with outcome and toxicity.
Results: Only one SNP in endothelin-1 (rs5370 TT) was significantly associated with worse median progression-free survival (HR 2.13, 95% CI 1.04 to 4.35, P = .038) and median overall survival (HR 2.88, 95% CI 1.40 to 5.93, P = .0042) compared with the alternate genotypes combined. One VEGF genotype (VEGF-634 GG) was associated with a significantly higher rate of treatment-induced hypertension when compared with the alternate genotypes combined (P = .048).
Conclusion: Although these data need to be confirmed in larger trials, germline polymorphisms could help identifying patients who do not gain any benefit from anti-VEGF agents or who are at high risk of toxicity.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-32.
Abstract P1-13-11: Supervising circulating tumor cells during and beyond maintenance therapy with SERM or aromatase inhibitors. A way to better support our patients to make decisions in long-term survivorship
Authors: Pachmann K , Rabenstein C , Camara O , Ingo RB , Ulrich P 
Published: August 2014

Abstract
Background: Although current guidelines still support 5 years of hormone blocking therapy after primary breast cancer due to earlier results showing no benefit of longer treatment, recent data have shown that longer treatment with tamoxifen can better reduce recurrence and death. However, side effects with this therapy can be considerable and compliance declines with time. We, here, report data on monitoring circulating epithelial tumor cells (CETC) beyond maintenance therapy showing that even if maintenance therapy with SERM or aromatase inhibitors had been effective in reducing tumor cells in blood, there can be a reincrease after the end of maintenance therapy and that this is highly correlated with relapse.
Materials and methods: 7.5ml of anti-coagulated blood was drawn before the start of chemotherapy, after each cycle and after the end of chemotherapy. Using a nondissipative approach with only red blood cell lysis the white blood cells including the tumor cells were stained with a fluorescent labelled anti-epithelial antibody, positive events counted using an automated image analysis microscope and calculated per volume blood.
Results: 96 patients with nonmetastatic breat cancer were observed beyond maintenance treatment with hormone blocking therapy. Results on CETC were evaluable from 35 patients even after completion of therapy. Increasing cell numbers after the end of therapy were able to predict relapsing from long term relapse free survivors (p = 0.0001).
Conclusion: In breast cancer, a debate has been reiinitated with respect to the length of maintenane treatment. Even if hormone blocking maintenance treament is capable of reducing or even eliminating tumor cells circulating in peripheral blood and this is related to improved relapse free survival there may remain tumor cells in the body capable of regrowing and leading to late relapse. Monitoring of CETC in peripheral blood even after completion of maintenace therapy can early predict imminent relapse and help to decide whether to reinitiate hormone blocking therapy.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-11.
Abstract P1-13-12: Intermittent letrozole as adjuvant treatment in postmenopausal hormone-receptor positive early breast cancer patients
Authors: Balduzzi A , Bagnardi V , Volpe S , Cancello G , Iorfida M , Dellapasqua S , Sandri M , Goldhirsch A , Colleoni M 
Published: August 2014

Abstract
Background: Low-dose estrogen might induce apoptosis in breast cancer cells that develop resistance to antihormonal therapy. Letrozole withdrawal for 3-month might permit estrogenic stimulation in residual resistant disease susceptible to letrozole reintroduction. We investigated the impact of a 3-month letrozole free interval on serum Estradiol levels in patients with early stage breast cancer.
Patients and methods: Postmenopausal women with ER and/or PgR ≥ 10% of the cells, node-negative early breast cancer were eligible. Patients (pts) received letrozole (2.5 mg daily) for five years with a 3-month treatment free interval after the 1st year of therapy. The primary endpoint was to evaluate the increase in serum estradiol absolute levels after 3-month treatment free interval. The secondary endpoints were the evaluation of others biological markers (e.g. FSH, LH, Cholesterol, HDL, triglycerides, osteocalcin). Estradiol levels were quantified by ECLIA assay that measured estradiol concentrations with a 5 pg/ml lower detection limit. FSH and LH levels (mU/ml) were measured by ECLIA assay, Osteocalcin (ng/ml) by RIA assay, Cholesterol, HDL, and Triglycerides (mg/ml) by colorimetric assay.
Results: From November 2007 to February 2012, 130 evaluable pts were enrolled. The median age was 61 years. One-hundred ten pts (85%) had pT1 tumor, 88 pts (68%) presented grade 2 and 83 pts (64%) showed a Ki-67 LI &lt;20%. Mean values of estradiol levels at time of discontinuation were 5.6 pg/ml (standard deviation: 1.7). Estradiol levels increased after a 3-month free interval by a mean of 3.3 pg/ml (66%; P &lt;0.0001). FSH and LH levels decreased from baseline by a mean of 7.5 mU/ml (P&lt;0.0001), and 1.4 mU/ml (P = 0.0062) respectively. Triglycerides decreased from baseline by a mean of 8.6 mg/dl (P = 0.036), and osteocalcin increased by a mean of 2.8 ng/ml (P = 0.013).
Conclusions: Intermittent Letrozole significantly impact on estradiol levels. This study provides further evidence supporting the role of intermittent letrozole in the adjuvant treatment of postmenopausal patients with endocrine responsive breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-12.
Abstract P2-01-04: High-density lipoprotein cholesterol is associated with mammographic density in premenopausal women
Authors: Flote VG , Frydenberg H , Ursin G , Wilsgaard T , Iversen A , Ellison PT , Wist EA , Egeland T , Thune I , Furberg A-S 
Published: August 2014

Abstract
Background: High-Density Lipoprotein Cholesterol (HDL-C), and ovarian steroid hormones and mammographic density have independently been associated with breast cancer development. However, little is known regarding the association between HDL-C, ovarian hormones and mammographic density in premenopausal women. Material and Methods: We assessed fasting HDL-C among 202 healthy women, aged 25-35 years, participating in the Energy Balance and Breast cancer Aspects (EBBA) study-I. Progesterone and estrogen were assessed both in serum (three times) and daily saliva across an entire menstrual cycle. Computer-assisted mammographic density (Madena) was obtained from digitized mammograms taken at days 7-12 of the menstrual cycle during a narrow time frame, thereby avoiding potential bias due to variations in mammographic density during the menstrual cycle. The association between HDL-C, in combination with progesterone or estrogen and absolute mammographic density were studied in multivariable linear and logistic regression models, and potential confounding factors and effect modifiers were tested. Results: The participating women had a mean age of 30.7, mean HDL-C of 1.54 mmol/l, and absolute breast density of 34.7 cm2 (median 32.4 cm2). Among women in the lowest tertile of HDL-C (≤1.38mmol/l), we observed a positive association between midmenstrual salivary 17β-estradiol and absolute breast density (p = 0.014), and between luteal salivary progesterone and absolute breast density (p = 0.029). Among these women in the lowest tertile of HDL-C, we also observed that high 17β-estradiol throughout the menstrual cycle was associated with higher absolute mammographic density (above median absolute density, &gt;32.4 cm2). Odds Ratio (OR) per standard deviation (SD) increase in salivary midmenstrual 17β-estradiol was 2.49 (95% confidence interval [CI] 1.12-5.53) for having a higher absolute mammographic density (&gt;32.4 cm2). These associations between HDL-C, ovarian steroids and absolute mammographic density were not observed in the middle or highest tertiles of HDL-C. Conclusion: Our findings suggest that low HDL-C, a marker of dyslipidemia, in combination with high levels of either progesterone or estradiol may be associated with higher absolute mammographic density in premenopausal women.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-01-04.
Abstract P2-09-19: Zerumbone suppresses IL-1b-induced cell migration and invasion through inhibition of IL-8 expression and MMP3 expression in human triple negative breast cancer cells
Authors: Bae SY , Han JH , Kim S , Lee SK , Lee JH , Lee HC , Kim M , Kim J , Kil WH , Kim SW , Lee JE , Nam SJ 
Published: August 2014

Abstract
Background: Inflammation is a key regulatory process in breast cancer progression and severity. Several studies have demonstrated that prolonged exposure of breast tumor cells to inflammatory cytokines leads to epithelial-mesenchymal transitions (EMT), which is the principle mechanism involved in metastasis and tumor invasion. Disruption of the signaling pathways involved in EMT may therefore provide an effective treatment strategy for currently difficult to treat or untreatable cancers such as TNBC. The interleukin (IL)-1 plays a pivotal role on breast cancer proliferation, invasion and/or inflammation. Here, we investigated the correlation of MMP-3 and IL-8 on IL-1b-induced cell migration and invasion as well as the inhibitory effect of zerumbone on IL-1β-induced MMP-3 and IL-8.
Methods: Triple negative breast cancer cells (Hs578T and MDA-MB231) were cultured DMEM with 10% FBS and 1% antibiotics. The levels of IL-8 and MMP-3 mRNA were analyzed by real-time PCR. The levels of secreted IL-8 and MMP-3 protein expression were analyzed by ELISA and western blot analysis, respectively. Cell viabilities by drug were analyzed by MTT assay. Cell invasion and migration was detected by Boyden chamber assay.
Results: The level of IL-8 and MMP-3 mRNA and protein expression significantly increased by IL-1β treatment in both Hs578T cells and MDA-MB231 cells. In addition, IL-1β-induced cell migration and invasion also increased in Hs578T and MDA-MB231 cells. On the other hand, the levels of basal and IL-1β-induced IL-8 and MMP-3 expression were decreased by zerumbone.
Conclusion: IL-1β induces the migration and invasion of breast cancer cells through IL-8 and MMP-3 expression. These effects are significantly suppressed by zerumbone. Therefore, we suggest that zerumbone may act as a useful therapeutic agent for treatment of triple negative breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-19.
Abstract P2-12-07: The correlation between Myriad Genetic Laboratories, Inc. mutation prevalence table and clinicopathological characteristics of breast cancer patients in Okinawa
Authors: Arakaki M , Kamada Y , Uehara K , Tamaki K , Tamaki N 
Published: August 2014

Abstract
Introduction
The two major susceptibility genes for breast cancer and ovarian cancer, BRCA1 andBRCA2 were discovered in 1994 and 1995, respectively. Various risk prediction algorithms and models have been developed to identify putative BRCA1/2 mutation carriers. Myriad Genetic Laboratories, Inc. released Mutation Prevalence Tables (http://www.myriad.com/lib/brac/brca-prevalence-tables.pdf#search = ‘Myriad+Genetic+Laboratories%2C+Inc.+Mutation+Prevalence+Table’) through its clinical testingservice. To the best of our knowledge, this is the first study to examine the correlation between this risk prediction model and clinicopathological characteristics of breast cancer patients.
Methods
The cases were 148 female breast cancer patients without any previous breast cancer history who initially visited Nahanishi Clinic Okinawa in Okinawa, Japan, between May 2012 and March 2013. The median ages were 55 years old (26-84). We examined the correlation between Myriad Genetic Laboratories, Inc. released Mutation Prevalence Tables and clinicopathological characteristics including age, ER, PgR, HER2, triple negative status, histological grade and Ki67. The presence of ER and PgR was determined by nuclear staining with positive cases defined as more than 1% staining according to ASCO CAP. With regard to HER2 evaluation, membranous staining was graded as 0-1+, 2+, and 3+. Samples scored as 2+ were subjected to FISH. Positivity was defined as a HER2:CEP17 signal ratio&gt;2.2. Ki-67 labeling index was obtained by selecting the hot spots after evaluation at low power magnification and counting 1000 tumor cells in the hotspots.
Results
There was statistically negative correlation between the risk prediction rates and age (r = -0.480, r2 = 0.230, p&lt;0.001). The risk prediction rates of ER negative and positive were 2.93±4.12% and 4.06±9.53% with statistically significant differences (p = 0.049).On the other hand, tendency was detected in PgR status (p = 0.058), and the risk prediction rates were 3.21±1.92% of PgR negative and 4.24±3.34% of PgR positive, respectively. The risk prediction rates of triple negative cases and non triple negative cased were 2.58±0.94% and 4.06±3.11% with statistically significant differences (p&lt;0.001). There were not statistically significant differences in HER2 status, histological grade and Ki67, respectively.
Conclusion
Previous studies demonstrated that BRCA1/2 mutation was associated with triple negative and high grade malignant breast cancer. However, the results of this study suggested that Myriad Genetic Laboratories, Inc. released Mutation Prevalence Tables was not associated with triple negative and/or high risk breast cancer patients in Okinawa.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-12-07.
Abstract P2-14-08: Plasma pro-enkephalin and pro-neurotensin for the risk prediction of incident breast cancer in healthy women
Authors: Melander O , Orho-Melander M , Almgren P , Manjer J , Hedblad B , Engström G , Struck J , Nilsson P , Bergmann A , Belting M 
Published: August 2014

Abstract
Experimental settings have indicated that Neurotensin regulates both satiety and breast cancer growth. Proneurotensin 1-117 (pro-NT), which stems from the same precursor as Neurotensin, has been developed as a reliable plasma surrogate biomarker for the unstable Neurotensin and has been shown to be associated with the development of incident breast cancer.
Enkephalins and related opioid peptides may negatively regulate carcinogenesis and the growth of breast tumors through stimulation of the immune tumor defense system as well as direct inhibitory effects on breast cancer cells. However, little is known about their role in the development of breast cancer in humans. Enkephalin can be assessed in plasma by measuring a stable surrogate marker, Pro-Enkephalin A 119-159 (pro-ENK).
OBJECTIVE:
To test if plasma pro-ENK in healthy women is associated with the development of incident breast cancer and if it adds information to pro-NT for the risk prediction.
DESIGN, SETTING, AND PARTICIPANTS:
We measured pro-ENK and pro-NT in fasting plasma from 1929 women (mean age 58 +/- 5.9 years) of the population based Malmo Diet and Cancer Study (MDCS), who were free from breast cancer prior to the baseline exam. We used Cox proportional hazards models to relate pro-ENK and pro-NT to first breast cancer events (n = 123) within 15 years of follow-up.
RESULTS:
Decreasing concentrations of pro-ENK were significantly associated with the risk of women to develop breast cancer: Women belonging to quartiles 3, 2 and 1 of pro-ENK compared to those of quartile 4 had Hazard ratios (HR) for breast cancer of 1.41 (0.74-2.69), 2.3 (1.27-4.14) and 3.19 (1.82-5.62).
Pro-NT: As compared to women belonging to the 1st quartile of pro-NT, women belonging to quartiles 2, 3 and 4 of pro-NT had HRs for the devlopment of breast cancer of 1.24 (0.69-2.24), 1.61 (0.92-2.82) and 2.37 (1.4-4.01).
Pro-ENK significantly added prognostic value to pro-NT (p = 0.00006) and vice versa (p = 0.00002). The HR for women with pro-ENK in the 1st quartile and pro-NT in the 4th quartile (high risk group) was 4.17 (2.48-7.03) as compared to women with pro-ENK in quartiles 2-4 and pro-NT in quartiles 1-3 (low risk group). Women with one of the biomarkers in high risk still had a slightly increased risk (HR 1.71 (1.16-2.52)) as compared to the low risk group.
CONCLUSION:
Biomarker based risk prediction for the development of breast cancer is significantly improved, when plasma pro-ENK is added to pro-NT.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-14-08.