bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PD03-01: Significant Reduction of Triple-Negative Breast Cancers in Diabetic Women on Metformin
Authors: Meiers PJ , Sharon E , DongYu W , Pooni A , McCready DR , Leong WL. 
Published: April 2011

Abstract
Background: Diabetes is an increasingly prevalent chronic disease. Many of these patients may develop breast cancer (BC). A meta-analysis by Larsson (2007)demonstrated that diabetic women have an increased risk (RR: 1.2) of BC particularly for estrogen receptor positive (ER+) subtypes (RR: 1.22). However, a recent study by Bodmer (2010) showed that women on long-term metformin have a reduced incidence of BC (OR 0.44, 95% CI 0.24-0.82). Metformin has antiproliferative effects on BC based on studies using proliferative marker Ki67. BC patients on metformin have better cancer-specific survival based on Landman (2010). We hypothesize that when compared to other diabetic medications; including exogenous insulin and other oral hypoglycemics; metformin specifically reduces the incidence of triple negative BCs (TNBC or ER-/PR-/Her2-). Methods: We conducted a retrospective chart review of an unselected cohort of patients who underwent surgical interventions for their primary BC to correlate the history of pre-existing diabetes and metformin use to the BC subtypes based on the immunohistochemistry of the surgical specimens. P-values were calculated using Chi-square and Fisher exact tests.
Results: There were 99 TNBC in the 1005 patients reviewed. Of the 90 diabetic patients, none of the 44 patients took metformin had TNBC, compared to 7 of the 46 diabetic patients not taking metformin had TNBC (0% vs. 15.2% p=0.007). Discussion: Studies that examined the incidence of BC in diabetics were not able to differentiate the effects of various diabetic treatments on the subtypes of BC. The reported increase in ER+ BC in diabetics is likely multifactorial but may be attributed to the proliferative effects of hyperinsulinemia. Interesting, of all the diabetic medications, Bodmer (2010) reported only metformin reduced the incidence of BC. In this study, we reported a statistical significant reduction in the incidence of TNBC. In fact, in our study population, there was no TNBC in patients who took metformin. Hirsch (2009) reported a selective inhibition of BC stem cells with metformin. Of interest, many studies have shown that BC stem cells were ER-/PR-/Her2-. This study supports the view that the phenotype of the BCs can be influenced by drug. At this point, we cannot differentiate if metformin can “protect” patients from developing TNBC, or “convert” TNBC to other subtypes of BC, further study is underway to address this question.
Figure available in online version.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD03-01.
Abstract PD03-07: Evaluation of the Anti-Diabetic Drug Metformin in the Methylnitrosourea (MNU)-Induced Model of ER+ Mammary Cancer and the MMTV-Neu/p53KO Model of ER-Mammary Cancer
Authors: Grubbs CJ , Bode AM , Steele VE , Lubet RA. 
Published: April 2011

Abstract
Metformin, an anti-diabetic drug, activates AMP-activated protein kinase (AMPK), and has generated a great deal of interest as a potential preventive agent for a variety of cancers, including breast. This interest is based both on epidemiologic studies showing that diabetics treated with metformin have a lower incidence of a variety of cancers, and on mechanistic considerations arguing that activation of AMPK is likely to be relevant to cancer treatment and prevention. We are examining the preventive efficacy of metformin in ER+ and ER-rodent mammary cancer models. Treatment of Sprague-Dawley female rats at 50 days of age with a single dose of MNU (75 mg/kg BW) resulted in the development of multiple ER+ mammary cancers beginning approximately 7 weeks after MNU treatment. This model has been highly responsive to a wide variety of agents that affect ER+ tumors in humans (SERMs, aromatase inhibitors, pregnancy, ovariectomy). Metformin was administered by gavage (7x/week) at either 150 or 50 mg/kg BW/day beginning 7 days after MNU dosing, and continuing for the duration of the study. Body weights were not altered by these dose levels and other signs of toxicity were not observed. Metformin failed to decrease mammary tumor incidence and, in fact, increased tumor multiplicity in this model by approximately 35%. In addition, we are evaluating the ability of metformin to inhibit mammary cancer in MMTV-Neu/p53KO mice (which spontaneously develop ER-cancers). In this study, metformin is being administered in the diet at a dose level of 1500 mg/kg diet. Initial supplementation of the diet with this agent began when the mice were 60 days of age, and will continue for 10 months. Preliminary results examined at 6 months into the study imply no efficacy of metformin in this model as well (average tumors/mouse: controls, 0.9; metformin, 1.6). Thus, these initial studies fail to observe any chemopreventive efficacy of metformin in two commonly employed models of ER+ or ER-mammary cancer in rodents. Supported by NCI contract number HHSN261200433001C.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD03-07.
Abstract PD04-03: Circulating Tumor Cells as Predictor of Metastatic Disease Spread in Patients with Breast Cancer
Authors: Giuliano M , Giordano A , Handy BC , Ueno NT , Alvarez RH , Hortobagyi GN , Reuben JM , Valero V , Cristofanilli M. 
Published: April 2011

Abstract
Background. The formation of distant metastases in each tissue is a tightly regulated biological event. The characteristic organ distribution of metastasis in the various cancers was first recognized in 1889 by Paget and gave rise to the “ seed and soil “ hypothesis. Several reports demonstrate that the presence of more than 5 circulating tumor cells (CTC) in peripheral blood is associated with short survival in patients (pts) with metastatic breast cancer (MBC). Interestingly, pts with bone metastasis had higher absolute number and percentage of ≥5 CTC (De Giorgi et al. 2010). Because of the correlation between CTC detection, metastatic site and prognosis, we hypothesized that the baseline detection of ≥5 CTC at the time of initial recurrence can predict the development of new metastatic sites, when progression of disease occurs.
Methods. We retrospectively evaluated a cohort of 516 MBC pts who had a CTC assessment before starting systemic treatment at the M.D. Anderson Cancer Center between September 2004 and November 2009. CTC were enumerated using the CellSearch™ technology. Among all pts, we selected 408 women with documented radiological progression of disease defined according to RECIST. Pts were divided in 2 categories: subjects who experienced progression of the pre-existing metastatic site(s) and those who developed new metastatic site(s). The rate of development of new metastatic sites was compared between groups according to baseline value of CTC (&lt;5 vs of ≥5), by Fisher Exact Test.
Results. At a median follow-up of 16 months (range, 1-58), 168 (41%) pts had died. The estimated overall survival was 28.6 months for pts with &lt;5 CTC and 19.1 months for those with ≥5 CTC (log-rank P=.001). The rates of development of new metastatic sites according to baseline value of CTC, and stratified by the original sites of disease are shown in table 1. Fifty-three (22%) pts with &lt;5 CTC and 52 (32%) with ≥5 CTC developed new metastatic sites when progression of disease was documented (P=.028). Pts presenting with baseline CTC ≥5, and bone metastases without visceral involvement had the highest rate of development of new metastatic sites.
Conclusions. Our analysis indicates that the presence of a high number of CTC before starting systemic treatment can predict for a higher probability to develop new metastatic sites on progression. This finding seems to be largely limited to pts with bone involvement at baseline. Our results may suggest the need to evaluate more effective bone-directed therapies for MBC pts with ≥5 CTC in order to prevent further progression of disease.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD04-03.
Abstract PD04-08: Circulating tumor cells (CTC) in peripheral blood of breast cancer patients two years after adjuvant chemotherapy depending on endocrine treatment — The German SUCCESS-Trial
Authors: Janni W , Zwingers T , Hepp P , Andergassen U , Schneeweiss A , Lichtenegger W , Beckmann MW , Sommer H , Pantel K , Salmen J , Jueckstock J , Rack BK. 
Published: April 2011

Abstract
Background: The prognostic significance of CTC in metastatic, as well as in primary breast cancer has been demonstrated (Rack et al., ASCO 2010). The optimal endocrine treatment strategy for postmenopausal patients (pts) with hormone sensitive breast cancer remains unclear.We analyzed the prevalence of CTC two years after primary diagnosis in patients with tamoxifen or anastrozole treatment.
Methods: As part of the translational research project of the German SUCCESS-trial, we analyzed 23ml of peripheral blood from 307 N+ and high risk N-postmenopausal pts with hormone sensitive breast cancer two years after adjuvant taxane based chemotherapy and with tamoxifen or anastrozole treatment. The presence of CTCs was assessed with the CellSearchSystem (Veridex, USA). After immunomagnetic enrichment with an anti-Epcam-antibody, cells were labelled with anti-cytokeratin (8,18,19) and anti-CD45 antibodies to distinguish between epithelial cells and leukocytes. Standard within the study was early switch treatment (tamoxifen for 2 years, followed by anastrozle), while pts with contraindications against tamoxifen were allowed to receive anastrozole up-front.
Results: In 10.1% of pts (n=31) &gt;1 CTC was detected after the completion of chemotherapy (range 2-33), while 7.8% (n=24) presented with &gt;1 CTC (range 2-99) two years after completion of chemotherapy. The median age in the tamoxifen group was 59.9 years and 59.8 in the anastrozole group. In the tamoxifen group, 33.0% of the pts had a pT1 tumor, 5.3% G1 grading and 21.6% of the pts were node negative. In the anastrozole group, 30.0% of the pts had a pT1 tumor, 7.5% G1 grading and 22.5% of the pts were node negative, respectively. None of these differences were statistically significant. After the completion of chemotherapy, 9.7% of the pts were CTC positive in the tamoxifen group (range number of cells: 2-33) and 11.3% in the anastrozole group (range of cells: 2-24), p=0.69. Two years after primary diagnosis, 7.9% of the pts were CTC positive in the tamoxifen group (range number of cells:2-99) and 7.5% in the anastrozole group (range cells: 2-5), p=0.90. Actuarial disease free and overall survival will be presented at the meeting.
Conclusions: The prognostic relevance of CTC in peripheral blood of early breast cancer patients both before and after chemotherapy has been demonstrated. The presented data will add information on the monitoring potential of CTC during adjuvant endocrine treatment.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD04-08.
Abstract PD04-09: Multiple Biomarker Expression in Circulating Tumor Cells from Metastatic Breast Cancer Patients
Authors: Bruce RH , Hsieh HB , Bennis R , Krivacic RT , Liu X , Frankel P , Lau S , Somlo G. 
Published: April 2011

Abstract
Background: Numeration of circulating tumor cells, CTCs, from metastatic breast cancer (MBC) patients (pts) is predictive of outcome. Biomarker characterization of CTCs may be a useful adjunctive guide for personalized targeted and systemic treatment (Rx) selection.
Method: A multimarker assay was used to simultaneously quantify expression of HER2, ER and ERCC1. A fast laser scanning instrument was used for sensitive location of CTCs on large glass substrates. CTCs are identified using automated digital microscopy by morphology, the presence of cytokeratin and a nucleus, and the absence of CD45. At the COHCC pts with newly diagnosed/progressing MBC were accrued. Blood samples (10 ml) were procured prior to initiating systemic Rx and at subsequent 3 month intervals and sent to PARC for analysis. Cell lines with expression of each marker were used for normalization of the cell intensities. Sample scores were derived from the percentage of CTCs expressing the marker and the average expression level.
Results: The multiple-marker assay was done on CTCs at repeat time points and results were compared to findings from the original primary BCs (P) and biopsied metastases (M) in 30 and 20 MBC pts respectively. While P and M tissue scores were concordant for HER2, the CTC score was discordant in 58% of the samples; HER2 expression changed during Rx in 19% of pts. While the status for ERCC1 was discordant between P and M tissue in 13% of the pts, CTCs scores were discordant with P and M tumors in 63% and 67% of the patients respectively, and CTC expression status changed during Rx in 15% and 7% of pts respectively. While the status for ER was discordant between P and M tissue in 15% of the pts, CTC scores were discordant from the P and M tumors in 42% and 71% of pts respectively, and CTC ER status changed in 7% and 17% respectively of pts during Rx.
Conclusions: Significant discordances in expression level of ER, HER2 andERCC 1 was observed between CTCs, and both primary and metastatic BC tissue. Changes in CTC expression patterns were also observed during the course of Rx for all three markers. Correlation of CTC biomarker expression patterns and changes with response to Rx therapy is ongoing to validate medical significance. Multimarker testing may ultimately lead to improvements in personalized Rx for pts with MBC.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD04-09.
Abstract PD05-06: Is ERα a Tamoxifen Predictive Factor in ERα Negative Breast Cancer in Premenopausal Women?
Authors: Källström A-C , Fernö M , Jönsson PE , Landberg G , Nordenskjöld B , Stål O. 
Published: April 2011

Abstract
Background: The majority of breast cancers are hormone receptor positive, defined as estrogen receptor (ERα) and/or progesterone receptor (PR) positive. Adjuvant tamoxifen decreases the risk of recurrence and improves survival in hormone positive breast cancer, irrespective of age. Still some do not respond to tamoxifen. The clinical significance of ERα is still unclear, even if studies indicate that ERα might be of importance. The aim of this study was to investigate the tumor expression of ERα in premenopausal women with breast cancer and the relationship to other clinical and pathological parameters and if there is any prognostic or predictive value. This is the first study of ERα based on a randomized study including only premenopausal women.
Material and Methods: Premenopausal women (n=564) with breast cancer, Stage II (UICC), were randomized to either two years of adjuvant tamoxifen (n=276) or no tamoxifen (n=288). The median follow-up was 13.9 years. The expression of ERα (n=303) and ERα (n=309) was analyzed by immunohistochemistry (IHC) using tissue microarrays (TMA). ERα was considered positive if more than 50% of the cells were stained (n=174). ERα was scored according to number of positive cells and the intensity of the staining. ERα negative (n=70) score 0, 1-49% (n=137) score 1, 50-100% (n=102) score 2 and the intensity negative (n=70) score 0, weak (n=119) score 1, strong (n=120) score 2. ERα summary score 4 was considered positive (n=118).
Results: ERα was correlated with lymph node status (p=0.024), ERα (p=0.00016), PR (p=0.0084), Ki67 (p=0.035), cyclin D1 (P&gt;0.00001) but showed a negative correlation to HER2 (p=0.042). Patients with ERα+/ERα- tumors showed significant benefit from 2 years of tamoxifen compared to those with ERα-/ERα — tumors (table1). In the control group ERα showed no prognostic value.
Recurrence free survival (RFS) at 10 years tamoxifen vs control
Discussion: ERα might be a tamoxifen predictive factor in ERα negative premenopausal breast cancer. If so, further studies are motivated to explore whether a subset of patients with triple negative breast cancer could benefit from endocrine therapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD05-06.
Abstract PD05-10: HOXB7 as a Key Regulator in the Development of Tamoxifen Resistance
Authors: Jin K , Bhujwalla ZM , Sukumar S 
Published: April 2011

Abstract
Multiple factors including long term treatment with tamoxifen are involved in the development of selective estrogen receptor modulator resistance of ERα positive breast cancer. It is well known in the endocrinology field that increased levels of ErbB/HER family members can also directly alter the cellular response to tamoxifen, but the mechanisms underlying increased expression of ErbB/HERs are not clear. In this report we show that HOXB7 is an ERα responsive gene and the downregulation of HOXB7 expression by estradiol is abrogated by tamoxifen in MCF7 cells. HOXB7 overexpression renders MCF-7 cells resistant to tamoxifen via cross-talk between receptor tyrosine kinases and ERα signaling. EGFR and HER2 expression is upregulated by overexpression of HOXB7, while knockdown of HOXB7 with siRNA in tamoxifen-resistant cell lines causes decrease of EGFR and HER2 expression and loss of tamoxifen resistance. In addition, our work demonstrates that to mediate upregulation of EGFR and HER2, HOXB7 binds to ER-alpha and promotes HER2 transcription activity through direct binding to the HER2 enhancer region by competing with other cofactors. Also, HOXB7 enhances EGFR transcription activity via binding to EGFR promoter region. However, depletion of HOXB7 affects the binding affinity of HOXB7 and the cofactors to the HER2 enhancer element. Higher expression levels of HOXB7 significantly correlated with poorer disease free survival in ERα positive breast cancer patients on adjuvant tamoxifen monotherapy. These findings implicate overexpression of HOXB7 as a key event in the initiation and maintenance of tamoxifen resistance. These studies suggest that HOXB7 acts as a key regulator orchestrating two major groups of target molecules in the oncogene heirarchy. Functional antagonism of HOXB7 could circumvent tamoxifen resistance.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD05-10.
Abstract PD06-02: Are Outcomes Really Similar after Lumpectomy and Mastectomy for Early Stage Invasive Breast Cancer? Evidence from Population-Based Data
Authors: Hwang ES , Gomez SL , Lichtensztajn D , Fowble B , Clarke CA. 
Published: April 2011

Abstract
Background: Randomized clinical trials have established equivalent survival for patients undergoing breast conserving therapy and radiation (BCT) compared to those undergoing mastectomy (M). However, these studies were conducted over two decades ago prior to the era of widespread systemic therapy and improved locoregional therapy and did not assess separately effects by age and tumor type types. We examined survival in a contemporary and representative series of women undergoing BCT or M without radiation for early stage (I-II) breast cancer to assess observationally whether survival varied by surgical treatment among age groups and tumor types.
Methods: We used the population-based California Cancer Registry supported by the NCI's Surveillance, Epidemiology and End Results (SEER) Program. We included women diagnosed with stage I and II breast cancer between 1990 and 2003, treated with either BCT or M, and followed for vital status for through the end of 2008. Overall survival (OS) and disease-specific survival (DSS) were compared between BCT and M groups using the Cox proportional hazards model, adjusting for tumor stage at diagnosis, tumor size, grade, number of positive nodes and race. Analysis was stratified by age group (&lt;50 years and ≥50 years) and tumor estrogen receptor (ER) status.
Results: 139,430 women fulfilling eligibility criteria and 15,917deaths were identified in the cohort between 1990 and 2003; overall 5-year survival was 93.7% (95% CI 93.6-93.9%). 26% of the total cohort were &lt;50 years of age at diagnosis; 62% were ER-positive. Stage at diagnosis, tumor size, grade, number of positive nodes and race differed significantly among the BCT and M groups. Adjusting for all of these factors, women undergoing BCT had a significantly lower hazard of mortality when compared to women who had M (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.79 - 0.89), with a more pronounced survival difference among women &gt;50 (HR 0.76, 95% CI 0.73 — 0.79). This effect did not differ by ER status among women aged &lt;50. However, among women aged ≥50, this effect was significantly stronger among ER(+) (HR 0.76, 95% CI 0.71-0.80) than ER(-) tumors (HR 0.81, 95% CI 0.75-0.89).
Conclusion: In a large, representative series of patients with early stage breast cancer, irrespective of age group or ER status, BCT was independently associated with a significant 19-32% improvement in OS. Although it is highly likely that at least some of this difference relates to unmeasured tumor characteristics or baseline health characteristics influencing treatment choice or overall survival, these findings are provocative and should be further explored in data resources with greater clinical detail.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD06-02.
Abstract PD06-07: Sentinel Node Biopsy Alone for Node Positive Breast Cancer, Report from the American College of Surgeon's National Cancer Database, 1998-2007
Authors: Yao K , Du H , Addie G , Winchester DJ , Barrera E , Jaskowiak N , Trocha S , Winchester DP. 
Published: April 2011

Abstract
Background: The decision to perform complete node dissection for a tumor positive sentinel node (SN) has become controversial especially in light of the results of a randomized trial of sentinel node biopsy alone for node positive disease. We report national trends in the United States of SN biopsy alone from 1998-2007 for node positive disease from the National Cancer Database (NCDB) of the American College of Surgeons. Patients and Methods: Utilizing the NCDB Participant User File we analyzed 994,883 patients diagnosed with invasive breast cancer from 1998 to 2007. Neoadjuvant cases and patients with clinically positive axillary nodes were excluded. All patients underwent breast surgery. After applying exclusion criteria, 104,548 SN tumor positive patients were identified. 15,643 (14.9%) patients underwent SN biopsy alone and 88,905 (85.1%) patients underwent SN biopsy followed by completion axillary node dissection. Cross tabulations with patient, tumor and hospital factors were performed.
Results: Over the 10 year period, there was a statistically significant increase in the number of patients undergoing SN biopsy alone, with 488 (9%) in 1998, and 1798 (17%) in 2007 (P&lt;0.001), and similar pattern was seen across age (all p&lt;.0001), income (all p&lt;.0001), census region (all p&lt;.001), tumor stage (all p&lt;.01), and facility type categories (all p&lt;.0001). Overall there was a significant increase in the number of patients undergoing sentinel node biopsy alone according to age, with 756 (10.2%) for patients ages 30 to 40 versus 1368 (24.2%) for patients ages 80 to 90 (P&lt;0.0001). 7,149 (15.3%) of patients in the highest income range had SN biopsy alone versus 1387 (13.8%) in the lowest income range (p=0.0002). There were significant differences according to the census region with the highest rate for SN alone in the Northeast region, 1263 (21%) and lowest in the Atlantic region, 2116 (12.8%) (26.5%) (P&lt;0.001). There were significant differences in SN biopsy alone according to tumor stage, with 14441 (16.8%) Stage II patients had SN alone versus 577 (3.5%) for those with Stage III tumors (P&lt;0.0001). There were minimal differences in the facility type, with 2090 (15%) patients treated at a community cancer program had SN alone versus 8646 (15%) at a comprehensive community cancer program versus 4907 (14%) at an academic/teaching program (p=0.501).
Conclusions: The utilization of SN biopsy alone for patients with node positive breast cancer has significantly increased from 1998 to 2007. Patient age, tumor size, and socioeconomic status, were significant predictive variables but facility type was not.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD06-07.