bluuebunny/crossref_metadata_2025_split huggingface dataset:
P2-12-31: Moderate Immunohistochemical Expression of HER2 (2+) without HER2 Gene-Amplification Is a Negative Prognostic Factor in Early Breast Cancer.
Authors: Rossi V , Sarotto I , Maggiorotto F , Tomasi Cont N , Redana S , Aglietta M , Ponzone R , Montemurro F 
Published: June 2012

Abstract
Purpose: We sought to evaluate whether moderate HER2 immunohistochemical (IHC) expression (2+ and no HER2/amplification) identifies early breast cancer (EBC) with a distinct prognostic profile.
Methods: A total of 1295 women (median age 58, range 22–94) undergoing surgery for EBC from Jan 1995 to Sept 2009 were retrospectively reviewed. All patients had undergone HER2 testing by the HercepTest and, when needed, by fluorescence in-situ hybridization (FISH). All tests were carried on at our Institutional Surgical Pathology laboratory. The impact of HER2 status on disease-free survival (DFS) was corrected for other clinical and pathological potential covariates by Cox Proportional Regression Analysis.
Results: A total of 494 (38%), 486 (38%), 119 (9%) and 196 (15%) of the patients had HER2 0+, 1+ 2+ and positive (3+ or FISH+) tumors, respectively. Sixty-one of 196 patients with HER2−positive EBC received adjuvant trastuzumab. A total of 298 DFS events occurred at median follow-up of 59 months (4-137 months). By using HER2 0+ status as reference, multivariate analysis revealed that HER2 2+ expression was associated with a significant increase in the risk of a DFS event (HR 2.303, 95% C.I. 1.501−3.533, p&lt;0.001), whereas HER2 1+ was not (HR 0.976, 95% C.I. 0.698−1.365, p=0.889). We performed exploratory two-group comparisons by further classifying tumors according to hormone-receptor status (cutoff for ER and PgR positivity ≥10% of stained cells). Results are summarized in the table. HER2 2+ expression was associated with worse prognosis in both ER and/or PgR positive and ER/PgR negative tumors. In the latter group, HER2 2+ expression was associated with a particularly high rate of DFS events, with a 60-month projected DFS of 20%. Furthermore, while DFS curves plateaued at 60 months for HER2−positive tumors (with and without adjuvant trastuzumab) and for ER/PgR negative tumors with HER2 0/1+ expression, hormone receptor positive/HER2 2+ tumors displayed a particularly high rate of late relapses (beyond 60 months). Results did not change using a 1% cutoff to define ER and PgR positivity.
Conclusion: Moderate HER2 positivity (IHC 2+/FISH negative) identifies EBC patients at increased risk of a DFS event, regardless of hormone receptor status. Due to suggestions from large randomized trials that the benefits of trastuzumab may not be limited to HER2−positive tumors, patients with HER2 2+ EBC are ideal candidates for studies testing this hypothesis.
Multivariate Hazard Ratios, corrected by age, lymph-node status, tumor diameter, tumor grade, proliferation (Ki 67 index) and receipt of adjuvant chemotherapy

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-31.
P2-18-05: Cardiotoxicity Risks of Adjuvant Trastuzumab in Asian Breast Cancer Patients.
Authors: Shih V , Chan A , Sim MH , Teo C , Chen W , Wong ZW 
Published: June 2012

Abstract
Background: Adjuvant trastuzumab (T)-based chemotherapy reduces relapse and improves overall survival in early breast cancer. However, T-associated cardiotoxicity potentially limits its use. Our study aims to report the incidence, severity and reversibility of cardiotoxicity amongst Asian breast cancer patients.
Methods: This is a retrospective review of patients who have received adjuvant T from June 2005 to March 2011 at our centre. CT was defined as a drop in left ventricular ejection fraction (LVEF) to less than 50% and / or reduction of ≥ 10% of baseline. Cardiovascular (CVS) risk factors were defined as having at least one of the following factors: family or previous history of CAD, hypertension, diabetes mellitus, hyperlipidemia and smoking. One-way repeated measures ANOVA was used to evaluate the mean LVEF change and Chi-square test to evaluate the association of demographics and CT.
Results: A total of 314 female patients were reviewed. CT was reported in 124 (39.5%), of whom 96 had asymptomatic decline in LVEF and 28 were symptomatic. T was withheld (n=53) due to asymptomatic decline in LVEF (n=40), symptomatic heart failure (n=3) and both (n=10). Forty-three patients with resolution of CHF (n=11) or LVEF recovery (n=32) were rechallenged. Cardiotoxicity recurred in 14 - asymptomatic decline in LVEF (n=10), recurrent CHF (n=1) and both (n=3). Overall, there were no cardiac-related deaths. Factors that predicted for CT included low normal pre-trastuzumab LVEF (&lt;60%) (p=0.01), prior anthracyclines (p=0.011), decline in LVEF pre-anthracycline and before T (p=0.022) and BMI ≥ 23kg/m2 (p=0.018). Three-monthly LVEF showed statistically significant decline against baseline over the time points (p=0.005). As expected, the decline in LVEF demonstrated significant interaction with CT groups and non CT group (p&lt;0.001).

Conclusions: A higher incidence of CT (39.5%) was observed among Asian breast cancer patients compared to previously reported in Caucasians (24%). Although 77.4% of patients presented with asymptomatic decline in LVEF, approximately one-third of patients experienced recurrent CT upon rechallenge.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-18-05.
P3-05-10: Standardized Quantitative Methods for Investigating the Intratumor Heterogeneity of HER2 in FFPE Breast Cancer Specimens Utilizing the Vectra System, inForm and AQUA Technology.
Authors: Hoyt CC , Gustavson MD , Davis WL , Lane KA , Scott CG , Graves, Jr LL 
Published: June 2012

Abstract
Background: While intratumoral heterogeneity of HER2 gene expression is well documented, the HER2 intratumor protein expression heterogeneity and its clinical relevance is largely unknown but generally believed to be worth of investigation to ascertain its impact on HER2 targeted treatment outcome. Methods for investigating intratumor protein expression heterogeneity must preserve tissue architecture yet provide quantitative protein measurement. Immunohistochemistry (IHC) generally lacks standardization and quantitative capabilities and furthermore, current scoring methods do not account for, or report, heterogeneity. Robust and automated methods for characterizing and quantfication of heterogeneity are needed.
Material and Methods: Whole tissue samples stained for HER2 expression by fluorescent quantitative IHC methods were analyzed by digital imaging microscopy (Vectra system with inForm software, Caliper, Hopkinton MA) providing automated pattern-recognition-based selection of area of interest and field of view sampling strategies. Quantitative image analysis (AQUA technology, HistoRx, Branford, CT) for quantitative measurement of HER2 protein expression as well as objective, quantitative determination of heterogeneity were performed. Requirements for percent tumor sampling at high-power to capture heterogeneity were assessed, to support optimization of slide scanning.
Results: Heatmap representation of HER2 expression levels, and a statistical heterogeneity score developed based on the Simpson's biodiversity index (Simpson 1949) demonstrate visually as well as quantitatively HER2 heterogeneity in breast cancer tissues. Heterogeneity as a function of % area needed for accurate determination of whole section score along with confidence intervals as a function of percentage tumor analyzed inform appropriate sampling strategies. Conclusion: This study demonstrates the suitability of standardized quantitative methods for measuring heterogeneity and the feasibility of its use in investigations exploring the clinical relevance of HER2 intratumor heterogeneity with respect to both measurement strategies as well as treatment outcome. Through characterization of heterogeneous HER2 expression in tumors and optimized measurement strategies, it should be possible to design optimized treatment strategy aimed at treating the whole tumor as a function of objective quantitative assessment of HER2 expression.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-05-10.
P3-09-03: Long-Chain Polyunsaturated Fatty Acid Intake and Its Relationship to Long-Chain Polyunsaturated Fatty Acids in Serum, Red Blood Cells and Breast Tissue.
Authors: Harvey KE , Li S , Carlson SE , Sullivan DK , Klemp JR , Kimler BF , Fabian CJ 
Published: June 2012

Abstract
Background
Long chain omega-3 (n-3) poly unsaturated fatty acids (LCPUFA) have anti-inflammatory effects and are able to counteract the effects of the pro-inflammatory omega-6 (n-6) fatty acids such as arachidonic acid (AA) by substituting for the n-6 fatty acids in triglycerides (TG) and phospholipids (PL). Several pre-clinical, observational, and case control studies suggest that intake or tissue content of n-3 LCPUFA such as eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), relative to intake or tissue content of long chain n-6 fatty acids such as AA may be associated with reduced risk of breast cancer. The goal of this study was to determine the relationships between dietary intake of fatty acids, tissue levels of fatty acids, and breast tissue biomarkers for risk of breast cancer.
Methods: Women (n=74) were recruited from a clinic in which women at increased risk for breast cancer had breast tissue acquired by random periareolar fine needle aspiration (RPFNA). Breast epithelial cells were assessed for cytomorphology and proliferation (Ki-67 immunochemistry). Fatty acid dietary intake was assessed with the National Cancer Institute Diet History Questionnaire. Plasma, erythrocyte, and breast specimens were processed for membrane PL and TG and analyzed for individual fatty acids by gas liquid chromatography.
Results: Total intake of n-3 PUFA was 1.1 ± 0.5 g/d, and the ratio of EPA+DHA:AA was 0.1:1.0 (n=66). Dietary n-3 LCPUFA correlated with n-3 LCPUFA in both plasma and erthyrocyte PL (n=62). Breast epithelial cell number, Masood cytomorphology score, and percent Ki-67 positive cells were higher in RPFNA specimens which exhibited cytologic atypia compared to those which did not (n=74; p&lt;0.001, Mann-Whitney Test). Subjects with atypia consumed less dietary n-3 PUFA (n=66, p=0.020), had lower plasma and erythrocyte PL and plasma TG EPA, DHA, total n-3, and EPA+DHA:AA (n=70; p&lt;0.05). In breast tissue TG, the ratio of n-3:n-6 was also lower in subjects with atypia (n=40; p=0.025).
Conclusions: Overall, women in this high risk cohort consumed very low amounts of n-3 LCPUFAs. Dietary intake of n-3 LCPUFA was related to levels of n-3 LCPUFA in erythrocyte and plasma PL. Given the association of low levels of n-3 fatty acids with cytologic atypia (a known risk factor for breast cancer development), an intervention to increase n-3 fatty acids and n-3:n-6 ratios has merit and clinical trials in high risk women have been initiated.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-09-03.
P3-10-02: Gene Expression Changes in Methylnitrosourea (MNU)-Induced ER+ Mammary Cancers Following Short-Term Treatment of Rats with the Aromatase Inhibitor Vorozole.
Authors: Lubet RA , Grubbs CJ , Bode A , You M , Lu Y 
Published: June 2012

Abstract
Aromatase inhibitors have proven to be highly effective in both therapy and prevention of ER+ breast cancer. Vorozole (R83842), a high affinity competitive inhibitor of aromatase (similar to letrozole and anastrozole) showed strong activity in early clinical trials against ER+ breast cancer. Furthermore, vorozole was highly effective in the prevention and therapy of ER+ cancers in the MNU-mammary cancer model (Lubet, et al., Carcinogenesis 19, 1345, 1998). In the present study, rats bearing mammary cancers induced by MNU were exposed to vorozole (1.25 mg/kg BW/day) for 5 days. Global gene expression analysis showed that 162 genes were down-regulated and 180 genes up-regulated in cancers treated with vorozole (p &lt; 0.05 and fold change &gt; 1.5). The genes modulated by vorozole were compared with two additional sets of data. First, thirty-two genes and a number of pathways exhibited significantly concordant changes with aromatase inhibitors both in the animal model and in at least three of four published human data sets. In particular, differentially expressed genes enriched in the cell cycle pathway that were related to chromosome condensation in prometaphase [including Aurora-A, Aurora-B, Bub1B, non-SMC condensin I complex, subunit H (BRRN1), Condensin, CAP-G, CAP-G/G2, CAP-H/H2, CAP-D2/D3, CAP-E, TOP2, Cyclin A, Cyclin B, CDK1, Histone H1 and inner centromere protein (INCENP)] were downregulated after treatment with the aromatase inhibitor. These results appear to be in agreement with the strong anti-proliferative effects of aromatase inhibitors in both animal and clinical studies. A second comparison was with an in vitro study in which estrogen was removed from MCF-7 cells in culture. Decreases in genes related to the E2F1 transcription factor were observed. In our study, 13 modulated genes exhibited E2F-1 binding sites in their promoter regions, and 7 genes contained both ER binding and E2F binding sites. We were able to confirm modulation of the cell cycle related and E2F-related genes in a large independent set of human samples treated with anastrozole. The results on RNA changes for Bub 1B, Cyclin A and CDK-1 were verified by employing IHC analysis. In summary, gene changes observed in the rat closely paralleled gene changes associated with aromatase treatment and estrogen withdrawal in humans.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-10-02.
P3-11-02: Changing Paradigms for Breast Cancer Chemoprevention?
Authors: Chlebowski RT 
Published: June 2012

Abstract
The SERMs tamoxifen and raloxifene are approved for breast cancer risk reduction but their acceptance in clinical practice has been poor largely related to rare but potentially life threatening side effects which requires identification of populations at higher breast cancer risk and careful risk benefit discussion (Visvanathan 2009). Recent findings from randomized placebo-controlled clinical trials suggest potential alternative approaches. In the MAP.3 placebo-controlled trial including 4,650 postmenopausal women, exemestane decreased breast cancer incidence by 65% (P=0.002) (Goss 2011) with no significant difference between groups for fractures, CVD events, other cancers or treatment-related deaths. While the median Gail 5-yr risk score of participants was 2.3, eligibility factors included age alone (≥ 60 years) regardless of calculated breast cancer risk and accounted for 49% of entries. With extended follow-up from the Women's Health Initiative (WHI) randomized, placebo-controlled trial evaluating estrogen alone in 10,739 postmenopausal women with prior hysterectomy, a statistically significant decrease in breast cancer incidence of 23% was seen with estrogen use (P=0.02) (LaCroix 2011). Younger postmenopausal women (age 50–59 years at entry) randomized to estrogen alone had lower risk of myocardial infarction (HR 0.54, 95% CI 0.34−0.86) and death (HR 0.73, 95% CI 0.53−1.00). These findings contrast to those in the WHI trial evaluating combined estrogen plus progestin in 16,608 postmenopausal women with an intact uterus where breast cancers were increased 25% (P=0.004) as was breast cancer mortality (increased by 96%, P=0.049) (Chlebowski 2010). The apparently paradoxical findings that in postmenopausal women estrogen addition, as conjugated equine estrogen, lowers breast cancer incidence and estrogen reduction, by aromatase inhibitor use, also lowers breast cancer incidence are consistent with preclinical studies indicating condition dependent change in estrogen influence on mammary cancers (Jordan 2011). Major eligibility for the WHI trials included anticipated 3-yr survival regardless of breast cancer or CVD risk. The findings from the MAP.3 and WHI trials highlight the complex relationships between estrogen and breast cancer and suggest potential strategies for chronic disease risk reduction in select populations of postmenopausal women which may not require formal breast cancer risk assessment.
Visvanathan K, Chlebowski RT, et al. J Clin Oncol 2009;27:3235–3258.
Goss PE, Ingle JN, Ales-Martinez J, Cheung A, Chlebowski RT, et al. The NCIC CTG MAP.3 Trial. N Engl J Med 10.1056/NEJMos 1103507.
Chlebowski RT, Anderson GL, et al. JAMA 2010;304(15):1684–1692.
LaCroix AZ, Chlebowski, RT, et al. JAMA 2011;305(13):1305–14. Jordan VC, Ford LG. Cancer Prev Res. 4:633–7 (2011).
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-11-02.
P3-14-08: A Phase II Study of Gemcitabine and Carboplatin (GC) Plus Iniparib (BSI-201) as Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation-Associated Breast Cancer.
Authors: Telli ML , Kurian AW , Jensen KC , Vinayak S , Flaherty P , Lipson JA , Wapnir I , Daniel B , Carlson RW , Mills MA , Chang P-J , Schackmann E , Rocha C , Sherman B , Blackwood-Chirchir A , Bradley C , Ford JM 
Published: June 2012

Abstract
Background
The combination of gemcitabine, platinum and inhibition of DNA repair results in synergistic chemosensitivity in triple-negative and BRCA1-deficient breast cancer cell lines. This study was designed to assess efficacy, safety and predictors of response to iniparib, a small molecule whose mechanism of action is under investigation, in combination with GC in early-stage triple-negative and BRCA1/2 mutation-associated BC.
Methods: This single-arm, phase II study (NCT00813956) enrolled patients with clinical stage I-IIIA (T ≥1cm by MRI) estrogen receptor-negative (≤ 5%), progesterone receptor-negative (≤ 5%), and HER2−negative or BRCA1/2 mutation-associated BC. Neoadjuvant gemcitabine (1000 mg/m2; IV; D1, 8), carboplatin (AUC 2; IV; D1, 8), and iniparib (5.6 mg/kg; IV; D1, 4, 8, 11) were given every 21 days for 4 cycles, until the protocol was amended to increase the treatment duration to 6 cycles with enrollment of 36 patients. The protocol was further amended to increase the patient number with expansion to additional centers. Prior to expansion, reporting of interim safety and efficacy results was specified. The primary endpoint is pathologic complete response (pCR), defined as the absence of invasive carcinoma in the breast and axilla. Pathologic response was assessed using the residual cancer burden (RCB) index. Secondary endpoints included safety, radiographic response by MRI, breast conservation eligibility and correlation of baseline gene expression with response.
Results: The pre-expansion cohort consisted of 13 patients assigned to 4 cycles of treatment and 36 patients assigned to 6 cycles of treatment. Among these 49 patients (50 tumors), median tumor size is 35 mm, and median age is 48 years. The overall pCR rate is 34% (95% CI = 22–48); the pCR rate at 6 cycles is 41% (95% CI = 26–57). RCB 0/I was observed in 5/13 pts (38%; 95% CI = 18–64) treated with 4 cycles; 21/37 (57%; 95% CI = 41–71) treated with 6 cycles; and 9/9 pts (100%) with known BRCA1/2 mutations. Two pts experienced disease progression, two locoregional relapse, and three distant relapse. Among 45 tumors with Affymetrix-based RNA microarray gene expression data, 39/45 (87%) are classified as basal-like, 3/45 (7%) luminal B, and 3/45 (7%) normal breast-like. Most common G3/4 adverse events include neutropenia (31%), anemia (10%), and elevated ALT/AST (10%). Alopecia and chemotherapy-induced amenorrhea were uncommon. Analyses of secondary endpoints are ongoing and will be presented.
Conclusions: Preoperative GC plus iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-08.
P3-16-10: The Efficacy of Zoledronic Acid in Breast Cancer Adjuvant Therapy: A Meta-Analysis of Randomized Controlled Trials.
Authors: Lu J , Yan T , Yin W , Zhou Q , Zhou L , Jiang Y , Du Y , Shao Z 
Published: June 2012

Abstract
Background: The effect of zoledronic acid in breast cancer adjuvant therapy concerning improvement of patient survival has yet to be confirmed. We performed a meta-analysis of published and unpublished randomized controlled trials with the aim of accurate evaluation between clinical outcome and the association of the addition of zoledronic acid to adjuvant therapy.
Methods: We searched Pubmed (from 1966 to present) and online abstracts from the proceeding Annual Meetings of the American Society of Clinical Oncology (ASCO) (years 1992–2010) and online abstracts from San Antonio Breast Cancer Symposium (years 2004–2010). A total of five eligible studies including 3676 subjects and 3678 controls met our search criteria and were evaluated. Random and fixed-effects meta-analytical models were used where indicated, and between-study heterogeneity was assessed. The primary study endpoints were the DFS. Secondary endpoints were OS, distant or loco-regional recurrence free survival and bone metastasis free survival.
Results: Compared with the control arm, adjuvant breast cancer treatment with zoledronic acid did not significantly improve overall survival (OS), disease free survival (DFS), bone metastasis free survival, distant and locoregional recurrence free survival. However, in the postmenopausal subgroup, the addition of zoledronic acid to standard therapy could significantly improve DFS (RR=0.763, 95%CI 0.658−0.884, p&lt;0.001) and reduce the risk of distant (RR=0.744, 95% CI 0.611−0.906, p=0.003) and locoregional recurrence (RR=0.508, 95% CI 0.340−0.760, p=0.001).
Discussion: Adjuvant zoledronic acid may potentially improve the prognosis of postmenopausal patients. Additional studies are needed to evaluate the value of adjuvant treatment of zoledronic acid in premenopausal couterparts, differing disease stages, and various pathological types of breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-10.