bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-20-03: A phase 2, double-blind, randomized, placebo-controlled, dose-finding study of sotatercept for the treatment of patients with chemotherapy-induced anemia and metastatic breast cancer.
Authors: Auerbach M , Osborne CRC , Klesczewski K , Laadem A , Sherman ML , Bianca R
Published: August 2014

Background: Sotatercept is a recombinant activin receptor IIA (ActRIIA) ligand trap and is comprised of the extracellular domain of ActRIIA linked to the Fc domain of human IgG1 (ActRIIA-IgG1). Results of preclinical and early clinical studies provide evidence that sotatercept increases the concentration of hemoglobin (Hb) in blood and may constitute a novel treatment for chemotherapy-induced anemia (CIA), a condition that results in significant morbidity.

Methods: This study evaluated the safety of, and hematopoietic response to, sotatercept in patients with CIA and metastatic breast cancer (MBC). Response was defined as increase in Hb ≥1 g/dL for ≥28 consecutive days during treatment or ≤2 months following the last dose, in the absence of red blood cell (RBC) transfusion or treatment with an erythropoiesis stimulating agent (ESA). If RBC transfusion or treatment with an ESA was required, no Hb measurements within 28 days of the RBC transfusion or administration of ESA were used to determine the Hb response. Subjects were randomized to subcutaneous injection of sotatercept (0.1, 0.3, or 0.5 mg/kg) or placebo and were treated on day 1 of each of four 28-day cycles.

Results: Thirty (30) subjects were enrolled and treated (5 placebo, 25 sotatercept). Increases in mean Hb in the 0.3 and 0.5 mg/kg groups were greater than in 0.1 mg/kg and placebo groups. Increases peaked approximately 15 days following treatment and declined over the remaining interval between treatments. Among 23 subjects with confirmed CIA and administered ≥1 dose and followed for ≥57 days (per-protocol analysis), 5/18 (28%) administered sotatercept responded (0/5 [0%] at 0.1 mg/kg; 3/9 [33%] at 0.3 mg/kg; 2/4 [50%] at 0.5 mg/kg) vs 1/5 [20%] administered placebo. Among 13 nonresponders administered sotatercept, 5 (39%) experienced ≥1 dose interruption/reduction, as per protocol, due to elevated Hb. The incidence of adverse events (AEs) was consistent with that reported in patients with MBC. No dose-limiting or dose-related toxicity was observed.

Conclusions: Sotatercept demonstrated dose-dependent hematopoietic activity in subjects with CIA and MBC. The safety findings were generally consistent with the known safety profile of sotatercept. These data suggest that a greater dose of sotatercept or a dose interval <28 days might result in a more sustained, and greater rate of, hematopoietic response.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-03.
Abstract P5-20-08: Phase II trial of ixabepilone (Ixa) and dasatinib (D) for treatment of metastatic breast cancer (MBC)
Authors: Schwartzberg LS , Tauer KW , Schnell FM , Hermann R , Rubin P , Christianson D , Weinstein P , Epperson A , Walker M
Published: August 2014

Background: Ixa is a novel semi-synthetic epothilone microtubule blocking agent with activity in taxane and anthracycline-resistant MBC. D is a potent small molecule tyrosine kinase inhibitor with substantial activity against SRC family non-receptor kinases, known to play multiple roles in promoting tumor growth and metastases. D inhibits cellular SRC autophosphorylation in cell lines that highly express SRC and inhibits in vivo activation in a broad array of tumors in nude mice. Ixa and D have synergistic effects in preclinical models suggesting this strategy would be of clinical benefit as combination therapy. A phase I trial of the combination determined the maximally tolerated doses of ixabepilone at 20 mg/m2 weekly and dasatinib 100 mg po daily with objective responses seen. Neutropenia was the dose limiting toxicity.

Methods: Multicenter single arm phase II trial. Eligibility: Measurable or evaluable disease by RECIST 1.0, ECOG PS 0–2, HER2− or HER2 refractory, no CYP 3A4 inducers or inhibitors, no H2 blockers or PPIs, no pleural/pericardial effusion, exposure to 1 or 2 prior lines of chemotherapy in the metastatic setting, peripheral neuropathy ≤ grade 1. The primary endpoint was progression-free survival (PFS). Assessment for response was performed every 8 weeks. The treatment schedule was D at 100 mg po daily starting day 1, and Ixa 20 mg/m2 Day 1, 8, 15 every 28 days (1 cycle).

Results: The study met its accrual goal with 50 patients (pts) enrolled on the phase II dosing, including six from the phase I portion. As of May 21, 2012, 47 pts are evaluable. The median age was 55 (range, 34–70), 19 African-American, 46 ECOG PS 0–1, median number of metastatic sites, three. Forty pts had prior taxanes, 24 prior anthracyclines. Median PFS was 6.0 months (95% CI, 2.9–8.0), achieving pre-specified value of interest for further study of the combination. The overall unconfirmed response rate was 14.9% with a clinical benefit rate (CR+PR + stable at 24 weeks) of 25.5%. Six pts continued D monotherapy after eight cycles of Ixa + D. All-grade adverse events (AEs) occurring in >15% of pts included anemia (45%), neutropenia (32%), nausea (51%), vomiting (32%) diarrhea (51%), fatigue (53%), anorexia (25%) dysgeusia (32%), headache (28%), peripheral neuropathy (34%) cough (28%) alopecia (21%) and hypokalemia (19%). Grade 3/4 adverse events occurred in 30 patients, with only four experiencing grade 4 AEs, three neutropenia and one chest pain. No grade 3/4 febrile neutropenia occurred. Grade 3 AEs of interest included two pts with peripheral neuropathy and 1 with pleural effusion.

Conclusions: The combination of Ixabepilone weekly + Dasatinib orally daily is an active and well tolerated regimen in pretreated MBC with manageable toxicity. Updated results will be reported.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-08.
Abstract P5-20-13: Preliminary report of a phase I/II study of entinostat (IND#NSC 706995, /M275) and lapatinib (IND#NSC 727989) in patients with HER2-positive metastatic breast cancer in whom trastuzumab has failed
Authors: Ueno NT , Jackson SA , Alvarez RH , Willey JS , Hortobagyi GN , Angulo-Gonzalez AM , Giordano SH , Booser DJ , Valero V
Published: August 2014

Background: Entinostat is a novel, potent, orally bioavailable, class I selective histone deacetylase inhibitor. Pre-clinical data has shown that Entinostat can enhance the activity of Lapatinib in HER2+ metastatic inflammatory and non-inflammatory breast cancer. The primary objective of the phase I portion of this study is to determine the recommended phase II dose for Entinostat in combination with Lapatinib in patients who have received Trastuzumab for HER2+ metastatic breast cancer.

Methods: This is a single center, open-label study to evaluate the safety and tolerability of every other week entinostat in combination with a 28-day cycle of Lapatinib. Patients with metastatic breast cancer in whom trastuzumab has failed were included. The phase I portion of the study is a conventional 3+3 dose-escalation design. Dose levels include 0 (starting dose) Entinostat 10 mg orally every other week, I Entinostat 12 mg, and II Entinostat 15 mg. Lapatinib 1,250 mg orally is given every day without dose escalation. Toxicities are evaluated at the end of each cycle.

Results: Here we report the phase I portion of the study. To date, 9 patients were enrolled, 3 were in level 0, and 6 were in level I. In Level 0, 2 patients were taken off study due to disease progression (PD) at the end of cycle one and 1 patient was taken off study due to PD at the end of cycle two. In Level I, 1 patient was taken off study due to PD at the end of cycle one and 2 patients were taken off study due to PD at the end of cycle 2. 1 patient had stable disease. The median age is 41 (range, 26–69). Seven of the nine patients are evaluable for toxicity. Most common toxicities reported by the patients are nausea grade 3 (1), fatigue grade 3 (1), muscle aches/pain grade 2 (3), skin rash grade 3 (1), paresthesias grade 2 (2), heartburn grade 1 (4), and diarrhea Grade 2 (1). Lapatinib dose was reduced in 2 patients. The most common hematological toxicities were neutropenia grade 1 (3), anemia grade 2 (1), and thrombocytopenia grade 4 (1).

Conclusions: Overall, patients have tolerated the combination regimen relatively well. We have not reached the maximum tolerated dose, so patient enrollment will continue until the phase I portion of the study is complete, most likely in July 2012. We plan to proceed with phase II portion in two parallel cohorts (HER2+ inflammatory and non-inflammatory metastatic breast cancer).

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-13.
Abstract P6-04-10: Comprehensive gene and protein assessment of the role of Her2 in the response to neoadjuvant Letrozole suggests patients without amplification may also benefit from anti-Her2 treatment
Authors: Webber V , Turnbull AK , Larionov AA , Sims AH , Harrison D , Renshaw L , Dixon JM
Published: August 2014

Background: Older postmenopausal patients with large operable or locally advanced oestrogen receptor positive, invasive breast cancers are candidates for treatment with neoadjuvant letrozole. HER2 positivity is a potential marker for early endocrine therapy resistance. In this study we have evaluated the effects of HER2 amplification, gene and protein expression at diagnosis and following 14 and 90 days of treatment with neoadjuvant Letrozole.

Methods: 70 postmenopausal women with large operable and locally advanced oestrogen receptor (ER) positive invasive breast cancers were treated with neoadjuvant letrozole. Response was assessed by 3D ultrasound. Sequential core biopsies were taken at 0, 14 days and 3 months of treatment. 12 patients were HER2 positive (either 3+ or 2+ FISH positive), 20 were HER2 2+ FISH negative and 38 were HER2 negative (0 or +).

Results: 43 patients were responders to letrozole and 17 were non-responders. 7 of the 17 non-responders were HER2 positive. Analysing response in two groups (HER2 2+ and 3+ together versus 0 or +) there was a greater difference in response rate between these two groups than when splitting into conventional HER2 positive and negative groups (P < 0.0001). In non-responding patients HER2 gene expression levels from the microarrays taken at baseline were significantly higher than the HER2 expression in responding patients (p = 0.01). There was also an increase in HER2 gene expression seen during the first 14 days of treatment in non-responding but not responding patients (p = 0.08). Rank product analysis of gene expression identified 34 down-regulated genes and 7 up-regulated genes which were shared between the HER2 2+ FISH negative samples and samples which were HER2 3+ or HER2 2+ FISH positive.

Conclusion: This large cohort of patients treated with neoadjuvant letrozole shows that:

HER2 expression correlates with response to letrozole.

A better cut off for prediction of response to letrozole is the split between 0 and + versus 2+ and 3+ rather than the traditional 3+.

Patients with increased MRNA expression at diagnosis for HER2 have a significantly lower response rate to neoadjuvant letrozole.

Endocrine therapy together with anti-HER2 therapies should be considered for patients having neoadjuvant endocrine therapy for cancers which over express HER2.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-10.
Abstract P6-04-25: Genomic Deregulation and Therapeutic Role of Nemo-like Kinase in Luminal B Breast Cancer
Authors: Cao X , Qin L , Kim J-A , Tan Y , Wang X , Schiff R
Published: August 2014

Luminal B breast tumors are notoriously known as high grade breast cancer prone to Tamoxifen resistance and early recurrence. Chromosomal abnormalities are a crucial class of drug targets in cancer which can be classified into numerical and structural rearrangements. Gene amplification is the result of numerical rearrangement that generates multiple copies of an otherwise normal human gene, such as Her2 amplification observed in breast cancer. Gene fusion is the result of structural rearrangement that fuses together pieces of two different genes, such as BCR-ABL gene fusion identified in leukemia.

Due to their critical role in causing human cancers and their presence exclusively in the tumor tissues, gene amplifications and fusions provide highly specific drug targets with only minimal side effects. In order to identify these chromosome aberrations that can serve as new therapeutic targets in breast cancer, we developed a novel bioinformatics analysis called “copy number signature analysis”. This is based on the observation that driving gene fusions and their original (wild-type) genes are often amplified in fusion-positive tumors, or tumors without the fusions respectively. This suggests that gene fusions and amplifications may synergize to activate important oncogenes; if directly druggable, these aberrations will provide substantial opportunities for new therapies.

Applying this analysis to the newly emerged genomic data from the Cancer Genome Atlas (TCGA) project nominated Nemo-like kinase (NLK) as a lead therapeutic target for invasive breast cancer. NLK encodes a serine-threonine mitogen activated protein kinase that plays a pivotal role in transforming growth factor beta pathway and embryo development. Genomic amplifications and rearrangements at NLK locus happen in 7%–9% of breast tumors, which may lead to deregulated serine-threonine kinase activity. Of note, these aberrations preferentially present in luminal B or Her2 positive breast tumors, suggesting their association with these high grade tumors. Most interestingly, transient inhibition of NLK through small RNA interference in multiple breast cancer cell lines harboring NLK deregulations, we observed potent inhibition of cell growth and capability of forming tumor-like colonies, as well as increased sensitivity to Tamoxifen treatment.

These data suggest that NLK might be deregulated by genetic events which may promote growth-factor signaling and Tamoxifen resistant phenotype. Molecular assays detecting NLK chromosomal aberrations may serve as a predictive biomarker for endocrine resistance in breast cancer as well as selection of patients for appropriate treatment.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-25.
Abstract P6-04-28: Changes in BAG-1 expression level affect the Tamoxifen-induced apoptosis and Gegitinb-induced apoptosis in breast cancer cells
Authors: Lu S , Zhuang X , Liu H
Published: August 2014

BAG-1 (bcl-2-associated athanogene-1) is a multifunctional protein which can interact with a number of molecules to regulate diverse biological processes including apoptosis, proliferation, signal transduction and transcription. BAG-1 protects cells from a wide range of apoptotic stimuli including radiation, hypoxia and chemotherapeutic agents and growth factor withdrawal. Therefore, BAG-1 may contribute to reduced cell death in cancer development, as well as to resistance to important therapeutic agents. Our study showed that the TAM sensitive cell line MCF-7 expressed lower levels of BAG-1 than the TAM resistant cell line MCF-7/TAMR, which was induced from MCF-7 cell line by culturing in medium containing 4-OH TAM (1×10-7M) for 6 months. Our study also found that down-regulation of BAG-1 significantly enhanced the sensitivity of the TAMR/MCF-7 cells to TAM treatment. Additionally, we used vectors carrying the individual BAG-1 isoforms to transfect the MCF-7 cells, and found that BAG-1 p50 was the only isoform that inhibited the TAM-induced apoptosis in the MCF-7 cells, while the other isoforms had little effect. Besides, we detected strong expression of BAG-1 in several breast cancer cell lines including T47D, MCF-7, MDA-MB231 and SK-BR-3. We even observed a 1.56 fold increase of EGFR in T47D cells transfected with BAG-1 siRNA when compared with the negative control. To further explore the association between BAG-1 expression and Gefitinb response in breast cancer cell lines, we used Gefitinb of different concentrations to treat cells for 24 hours, 48 hours and 72 hours respectively. The results of cell viability assay indicated that the down-regulation of BAG-1 in breast cancer cell line T47D significantly enhanced the T47D cells' sensitivity to Gefitinb-induced apoptosis.

In summary, our results indicated that BAG-1 may have influence in the development of TAM resistance and Gefitinb resistance in breast cancer. However, our study was conducted in breast cancer cells in vitro; further studies on the relationship between BAG-1 expression and response to TAM and Gefitinb in a large cohort of breast cancer patients may be needed to confirm our findings.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-28.
Abstract P6-05-01: Evaluation of the prognostic significance of androgen receptor (AR) expression in relation to ER expression in breast cancer (BC)
Authors: Gucalp A , Datko FM , Patil S , Hedvat CV , Kalinsky K , Hudis CA , Traina TA , Moynahan ME
Published: August 2014

Background: AR is expressed in 60–80% of invasive BC. Emerging data suggest that AR expression may have a prognostic role in BC irrespective of ER and that the androgen-signaling pathway may be involved in BC pathogenesis. We previously identified an AR-dependent subset of ER/PR(−) BC and reported clinical benefit from AR-inhibition (Gucalp, ASCO 2012). We now describe the prevalence, clinicopathologic characteristics, and survival outcomes of AR(+) BC in relation to expression of ER in a single-institution retrospective cohort.

Methods: We identified 590 patients (pts) with resectable BC (tumor >1cm) who had surgery at MSKCC from 1992–1996. IRB approval was obtained. Tissue microarray (TMA) construction/scoring has been described (Kalinsky CCR 2009). TMAs were stained, scanned and digitally scored (Aperio ScanScope XT) for nuclear steroid receptors (ER, AR), HER2, p53, and MIB1 (Ki67). Using digital quantification of tumor cell nuclear staining, pts were categorized into the following 7 groups: ER dominant (ERD, both ER and AR >10% with ER>AR by >5%), ER only (ER>10%, AR <10%), ER=AR (both >10%, <5% difference), AR dominant (ARD, both >10%, AR>ER by >5%), AR only (AR>10%, ER<10%), hormone receptor negative (HRN, both <10%) and unknown. Due to small pt numbers, ER=AR and ARD data were combined as were AR only and HRN. Associations between IHC expression and clinicopathologic features were assessed using the Chi-square/t-test. The Kaplan-Meier method, Cox proportional hazards models, and log-rank test were used to evaluate the association of IHC expression category on disease-free survival (DFS), distant (d)-DFS, and overall survival (OS).

Results: 528 pts had adequate tumor cores for image analysis/quantification of AR; 302 (57%) tested AR(+). Median followup 12.8 years (yr). A significant difference in DFS (P = .0145), d-DFS (P = .006) and OS (P = .0485) was observed among the following groups: ERD, ER only, ER=AR/ARD and HRN/AR only, with a more favorable outcome associated with ERD (Table 1).

In ER+ BC, ER=AR and ARD are associated with a high frequency of tumor MIB1, p53 and HER2 over-expression (Table 2).

Conclusions: The degree of AR expression relative to ER may be prognostic as survival appears attenuated when AR is the more highly expressed steroid transcription factor. Other poor prognostic factors, including p53, HER2 and higher proliferation indices associate with this finding. The biology associated with AR dominance in ER+ BC needs further study. The inferior clinical outcome of the ER only category is in agreement with recent reports. Further analysis of PIK3CA mutational status and PI3K signaling pathway activation in relation to AR is ongoing. Supported in part by Geoffrey Beene Cancer Research Center at MSKCC.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-01.
Abstract P6-05-05: Triple receptor comparison between primary breast cancer and metachronous or synchronous liver metastasis
Authors: Tuyls S , Brouckaert O , Vanderstichele A , Vanderhaegen J , Amant F , Leunen K , Smeets A , Berteloot P , Van Limbergen E , Weltens C , Peeters S , Vanbeckevoort D , Floris G , Moerman P , Paridaens R , Wildiers H , Vergote I , Christiaens M-R , Neven P
Published: August 2014

Background: Decisions about systemic treatment in women with metastatic breast cancer are currently based on the presence of estrogen receptors (ER), progesterone receptors (PR) or Human Epidermal growth factor Receptor 2 (HER2 receptors) in the primary tumor. Recently, several studies have reported significant discordances in ER, PR and HER2 status between the primary tumor and metastatic lesions and this may vary by metastatic site. Prognostic implications remain unclear although alterations in ER, PR and/or HER2 can influence metastatic management. This study represents one of the largest studies evaluating how frequent receptor discordances occur in liver metastasis, whether this alters therapeutic options and impacts prognosis.

Patients and methods: 246 breast cancer patients with histological confirmed liver metastasis were analyzed in this retrospective study. Immunohistochemistry (IHC) and/or FISH were used to determine ER, PR and HER2 receptor status. We excluded patients when comparison between receptors of primary tumor and metastasis was impossible due to missing data (n = 85), when liver metastasis did not originate from breast cancer (n = 36) and when pathology was obtained from autopsy specimens (n = 38).

Results: 87 patients had matched tissue samples of primary tumor and liver metastasis with possible comparison of at least one of the receptors. Table 1 summarizes changes in ER, PR, HER2 between primary and metastatic lesion. Discordance in receptor status was associated with shorter time to death (63.3 months) compared to the concordant group (75.5 months).

Conclusions: A significant proportion of ER and PR show discordance between primary tumor and liver metastasis. However we could not establish the same level of discordance for the HER2 receptors as in other studies. In general, only about 1 in 5 patients gained new (endocrine or targeted) therapeutic options. Tissue confirmation remains important to evaluate whether metastatic disease has become endocrine insensitive (in approximately 1 in 5 patients), avoiding unnecessary delay in chemotherapy. Discordance in receptors may be associated with inferior prognosis.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-05.
Abstract P6-05-11: Leptin and Leptin receptor expression in human breast cancer
Authors: Wazir U , Al Sarakbi W , Jiang WG , Mokbel K
Published: August 2014

INTRODUCTION: Leptin is a protein that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones and has been suggested to act as a growth factor in neoplasms. Obesity has been linked to increased risk of breast cancer in postmenopausal women. Increased peripheral production of oestrogen has been regarded as the main cause for this association, but other factors affecting fat metabolism may be implicated. There is recent evidence that Leptin stimulates cancer cell proliferation in MCF-7 cancer cells. Both Cox2 and hTERT have been proposed as mediators of Leptin's carcinogenic role.

Our objective was to determine, using quantitative PCR, whether the mRNA expression levels of Leptin and Leptin receptor were consistent with a tumour proliferative function and whether levels from these genes were positively correlated with clinical outcome in breast cancer.

METHODS: A total of 153 samples were analysed. The levels of transcription of Leptin and its receptor were determined using quantitative PCR and normalised against (CK19). Transcript levels within breast cancer specimens were compared to normal background tissues and analysed against conventional pathological parameters and clinical outcome over a 10 year follow-up period.

RESULTS: The levels of Leptin and Leptin receptor mRNA were significantly higher in malignant samples (p = 0.0011 and 0.0014 respectively). This difference remained statistically significant when comparing levels between normal samples and all malignant subgroups according to their NPI, grade, stage, local recurrence, and distant metastasis in both ER receptor positive and negative samples. It was also present across all histological types for both Leptin and its receptor.

There was no significant change in mRNA transcription levels correlating with tumour grade, stage, disease free survival, or development of loco regional recurrence.

There was also no statistically significant difference in levels of expression of both Leptin and its receptor when comparing ER positive to negative patients (p = 0.74 and 0.27 respectively).

Leptin levels showed a significantly positive correlation with Leptin receptors (r = 0.504, 0.0000000222). We have observed no significant correlations between Leptin and hTERT or Cox2.

CONCLUSION: This study demonstrates compelling evidence that both Leptin and Leptin receptor mRNA transcription levels are more readily expressed in cancerous tissues providing further evidence that it plays a significant role in the process of breast carcinogenesis. However, Leptin levels did nor correlate with tumor's stage, clinical outcome, hTERT or Cox-2 levels.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-11.
Abstract P6-07-25: Annexin expression and survival outcomes in women with breast cancer
Authors: Dawood S , Gonzalez-Angulo AM , Liu S , Chen H , Li Y , Albarracin CT
Published: August 2014

Background: The annexin superfamily of proteins has been implicated in several cellular processes. In particular, annexin A1 is known to have anti-inflammatory, anti-proliferative and pro-apoptotic functions. The expression and precise role of annexin A1 in breast cancer have been conflicting. The goal of this retrospective study was to explore the association of annexin A1 expression and survival outcome among women with breast cancer.

Methods: 426 women with breast cancer whose tumor samples and associated data was available were identified. Annexin A1 expression was measured using RPPA and was considered as a categorical and continuous variable. Range of annexin A1 levels for the cohort was −1.90 to 2.36. Patients were divided into four groups according to the annexin A1 level: a) negative (annexin A1 <-0.84), b) low (annexin A1 > = −0.84 and <0.23), c) medium (annexin A1 >=0.23 and < 1.29) and d) high (annexin A1 >=1.29). Recurrence free survival (RFS) was estimated using the Kaplan-Meier product limit methods and compared across groups using log rank statistic. Cox proportional hazards models were used to determine the association of survival outcomes and annexin expression (continuous variable) adjusted by patient and tumor characteristics.

Results: Median age at diagnosis was 62 years. 41 (9.6%), 245 (57.5%), 25 (5.9) and 115 (27.0%) patients had Her2 positive, hormone receptor (HR) positive, metaplastic and triple negative (TNBC) disease respectively. For the whole cohort 44 (10%), 235 (55.2%), 119 (27.9%), 28 (6.6%) breast tumors were classified as having negative, low, medium and high annexin expression respectively. High annexin A1 levels were associated with hormone receptor positive disease, increased age, post-menopausal status, low grade and lower disease stage. Median annexin A1 level was −0.19, 0.0, −0.34, −0.2 among tumors that were HER2 positive, HR positive, metaplastic and TNBC disease respectively. 5-yearRFS was 65.8% and 84.9% respectively among women with negative/low and medium/high annexin A1 levels respectively (p < 0.0001). Among women with Her2 positive, HR positive, metaplastic or TNBC disease 5-year RFS was significantly higher among tumors with medium/high annexin A1 levels. In the multivariable model an increase in annexin was associated with a 13% reduction in the risk of recurrence (HR = 0.87, 95% CI 0.60–1.26, p = 0.46).

Conclusion: In this large dataset with long follow up our results indicate that high annexin A1 expression among women with breast cancer was associated with favorable patient and tumor characteristics and an improved RFS. Annexin A1 should be explored further as a potential prognostic biomarker.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-25.
Abstract P6-07-26: Prognostic significance of the maximal value of the baseline standardized uptake value on fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography for predicting pathologic malignancy of operable breast cancer with neoadjuvant chemotherapy
Authors: Kadoya T , Akimoto E , Emi A , Shigematsu H , Masumoto N , Okada M
Published: August 2014

PURPOSE: [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is potentially useful in predicting pathological complete response (pCR), disease free survival (DFS) and overall survival (OS) of breast cancer patients with neoadjuvant chemotherapy.

MATERIALS AND METHODS: 77 breast cancer patients (mean age ± SD: 52.6 ± 11.2 years) with clinical Stage I∼III between January 2006 and December 2011, were prospectively evaluated (median follow up period:26.5 months). Neoadjuvant chemotherapy of an anthracycline-based regimen and taxane was performed, and patients underwent a whole-body FDG PET/CT before and after chemotherapy. The maximal value of the baseline standardized uptake values (SUVmax) were assessed for predicting pCR, DFS and OS. For the evaluation of relationship between SUVmax values and prognosticators such as hormone receptors, human epidermal growth factor receptor 2 (HER2), nuclear grade, lymph node metastasis and tumor size, statistical analyses were performed using Student t test and log-rank test, and p values of less than 0.05 were considered to indicate statistically significant differences.

RESULTS: Clinical Stage included were I (n = 2, 2.6%), II (n = 62, 80.5%) and III (n = 12, 15.6%). Tumors with estrogen receptor positive were 52 (67.5%) and negative were 24 (31.2%). Therapeutic response by neoadjuvant chemotherapy was obtained in 15 patients (19.5%) with pCR and 60 (77.9%) without pCR. Patients were divided into two groups according to cut-off SUVmax established on the basis of receiver operating characteristic (ROC) analysis (<6.0 vs. ≥6.0, AUC=0.721). When related to the biologic parameters, estrogen receptor (OR:3.75, 95%Cl:1.36–10.35, p = 0.02), but not progesterone receptor (OR:2.31, 95%Cl:0.89–6.00, p = 0.08) nor HER2 status (OR:1.51, 95%Cl:0.47–4.85, p = 0.70) were found strong relation to SUVmax values.

There was a significant difference in OS between two groups (p = 0.05), but, pCR (OR:1.07, 95%Cl:0.34–3.40, p = 0.86) and DFS (p = 0.07) did not show strong relationship with SUVmax values.

CONCLUSION: SUVmax on FDG PET/CT before neoadjuvant chemotherapy have a predictive value for high-grade malignancy and prognosis in clinical Stage I∼III breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-26.
Abstract P6-07-27: Body mass index and survival after breast cancer diagnosis in Japanese women
Authors: Kawai M , Minami Y , Nishino Y , Ohuchi N , Kakugawa Y
Published: August 2014

Background: Body mass index (BMI) may be an important factor affecting breast cancer outcome. Studies conducted mainly in Western countries have reported a relationship between higher BMI and a higher risk of all-cause death or breast cancer-specific death among women with breast cancer, but only a few studies have been reported in Japan so far. In the present prospective study, we investigated the associations between BMI and the risk of all-cause and breast cancer-specific death among breast cancer patients overall and by menopausal status and hormone receptor status.

Methods: The study included 653 breast cancer patients admitted to a single hospital in Japan, between 1997 and 2005. BMI was assessed using a self-administered questionnaire. The patients were completely followed up until December, 2008. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated according to quartile points of BMI categories, respectively: <21.2, ≥21.2 to <23.3 (reference), ≥23.3 to <25.8 and ≥25.8 kg/m2.

Results: During the follow-up period, 136 all-cause and 108 breast cancer-specific deaths were observed. After adjustment for clinical and confounding factors, higher BMI was associated with an increased risk of all-cause death (HR = 2.61; 95% CI: 1.01–6.78 for BMI ≥25.8 vs. ≥21.2 to <23.3 kg/m2) among premenopausal patients. According to hormonal receptor status, BMI ≥25.8 kg/m2 was associated with breast cancer-specific death (HR = 4.95; 95% CI: 1.05–23.35) and BMI <21.2 kg/m2 was associated with all-cause (HR = 2.91; 95% CI: 1.09–7.77) and breast cancer-specific death (HR = 7.23; 95% CI: 1.57–33.34) among patients with ER+ or PgR+ tumors. Analysis by hormonal receptor status also showed a positive association between BMI and mortality risk among patients with ER+ or PgR+ tumors and with BMI ≥21.2 kg/m2 (p for trend: 0.02 and 0.031 for all-cause and breast cancer-specific death, respectively).

Conclusions: Our results suggest that both higher BMI and lower BMI are associated with an increased risk of mortality, especially among premenopausal patients or among patients with hormonal receptor positive tumors. Breast cancer patients should be informed of the potential importance of maintaining an appropriate body weight after they have been diagnosed.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-27.
Abstract P6-08-01: Perceptions of breast cancer risk, psychological adjustment and behaviors in adolescent girls at high-risk and population-risk for breast cancer
Authors: Bradbury AR , Patrick-Miller L , Egleston B , Schwartz L , Tuchman L , Moore C , Rauch P , Sands C , Shorter R , Rowan B , Malhotra S , van Decker S , Schmidheiser H , Sicilia P , Bealin L , Daly M
Published: August 2014

BACKGROUND: Preliminary evidence suggests that many girls from breast cancer (BC) families are aware of their increased risk for BC. How this awareness impacts their psychosocial adjustment and health behaviors remains unknown.

METHODS: 11–19 YO girls at high-risk (HR) or population-risk (PR) for BC completed self-administered quantitative surveys informed by the Self-Regulation Theory of Health Behavior. Girls with a first or second-degree relative with BC were classified as HR. For hypothesis testing, we used simple linear and logistic regressions. To account for correlation of responses within families, we used robust (cluster-corrected) standard errors or Generalized Estimating Equations.

RESULTS: 47 PR and 89 HR girls have completed surveys. Age did not differ between groups (Mage = 15.6; SD=2.4). 30% of HR girls have a mother with BC. 67% of HR girls vs. 30% of PR girls reported self-perceived risk for adult BC to be “higher than other girls my age,” (p = <0.01, Table 1).

Perceived risk was associated with an increasing number of first and second-degree relatives with BC (p = 0.002) and older age (p = 0.01). There was no evidence that the relationship between perceived risk and age was moderated by risk status (p = 0.740 for interaction terms). The majority of both HR and PR girls reported that there are things women and girls their age can do to prevent BC. (table 1) Perceived controllability of BC did not differ significantly by age or risk status. HR girls reported higher general anxiety (p = 0.07), but not depression than PR girls. HR girls more frequently reported tobacco use than PR girls (p = 0.05). HR girls also reported greater alcohol use, more frequent performance of self-breast exams and less frequent physical activity than PR girls, although these differences were not significant.

CONCLUSION: Girls from BC families are more likely to perceive themselves to be at increased risk for BC, to experience more general anxiety, and to have engaged more frequently in risk behaviors, particularly tobacco use. The majority of girls perceive BC to be preventable both for women in general and for themselves, suggesting a potential “teachable moment” among adolescents that might be sustainable across the lifespan. Further research evaluating knowledge and perceptions of breast cancer risk throughout adolescent development and differences among subgroups could inform strategies to optimize adolescent psychosocial responses to hereditary cancer risk and promote preventive health behaviors among both HR and PR girls.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-08-01.
Abstract P6-09-04: The Association of Low Level Arm Volume Increases with Lymphedema Symptoms Following Treatment for Breast Cancer
Authors: Skolny MN , Miller CL , Shenouda M , Jammallo LS , O'Toole J , Niemierko A , Taghian AG
Published: August 2014

Purpose/Objective: The symptoms associated with breast cancer-related lymphedema are well-documented, and include sensations of heaviness, swelling, and tightness in the upper extremity and trunk. However, the clinical significance of low-level arm volume changes frequently experienced by breast cancer patients is not well understood. We sought to determine the association of low level arm volume changes with patient-reported lymphedema symptoms in women treated for breast cancer.

Methods: 267 patients who underwent surgical treatment for breast cancer from 2010–2012 were identified from a cohort of patients prospectively screened for lymphedema at our institution. Patients were assessed with perometer arm volume measurements and a survey of lymphedema symptoms pre and post operatively, and at 3–7 month intervals thereafter. Inclusion in this analysis was limited to unilaterally affected women with ≥ 3 assessments and ≥ 6 months of post-surgical follow-up. Arm volume changes were quantified as Relative Volume Change (RVC): RVC = (A2*U1)/(U2*A1) − 1, where A1 is pre-operative arm volume and A2 is post-operative arm volume on the affected side, and U1 and U2 are arm volumes on the unaffected side at these time points. Low level arm volume change was defined as a measurement with RVC ≥ 5% <10% at an assessment ≥ 3 months post-operatively. Actuarial univariate and multivariate regression analysis was performed to determine the association of low level arm volume change with patient-reported lymphedema symptoms and clinicopathological characteristics.

Results: Low level arm volume changes occurred in 21.7% (58/267) of patients during the follow-up period at a median of 10.4 months post-operatively. Median post-operative follow-up was 12.4 months and 5 assessments per patient. By actuarial univariate analysis, symptoms of larger arm, shoulder, or neck (p < 0.001), tighter sleeve, sleeve cuff, or ring (p < 0.001), and having undergone axillary lymph node dissection (p = 0.02) or regional lymph node radiation (p = 0.01) were significantly associated with low-level arm volume change. By actuarial multivariate analysis, only symptoms of larger arm, shoulder, or neck (p < 0.0001) were associated with low level arm volume change.

Conclusions: This data suggests that patients may be symptomatic for lymphedema even when experiencing low level arm volume changes. These patients should be followed closely for progression of measured arm volume or heightened lymphedema symptoms suggesting progression of the condition.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-09-04.
Abstract P6-10-05: SU2C Phase 1b Trial of Dual PI3K/ mTOR Inhibitor BEZ235 with Letrozole in ER+/HER2− Metastatic Breast Cancer (MBC)
Authors: Mayer IA , Abramson VG , Balko JM , Isakoff SJ , Forero A , Kuba MG , Sanders ME , Li Y , Winer E , Arteaga CL
Published: August 2014

Background: Mutations in PIK3CA, the gene encoding the p110alpha subunit of PI3K, have been associated with antiestrogen resistance in ER+ BC. In general, antiestrogen-resistant cancers retain ER and responsiveness to estradiol, suggesting that treatment of ER+/PI3K mutant BC should include PI3K inhibitors plus endocrine therapy.

Methods: We are conducting a phase Ib open-label trial of letrozole (2.5 mg/d) with the dual PI3K/ mTOR inhibitor BEZ235 (400 mg BID, sachet formulation) in post-menopausal patients with ER+/HER2 negative MBC. Upon toxicity, BEZ235 was reduced to 400 mg in AM/ 200 mg in PM (dose level 1), and 200 mg BID (dose level 2), in a standard 3+3 de-escalation design. Treatment continues until unacceptable toxicity or disease progression. Tumor assessments are performed every 2 months. All tumor biopsies are being analyzed for PI3K pathway alterations.

Results: To date, 9 patients have been accrued; 6 on dose level 1 (400 mg BID) and 3 on dose level 1 (400 mg in AM/ 200 mg in PM). Of note, the latter 3 patients have been on treatment for less than 2 weeks at the time of abstract submission. Median age was 55 years (range 40–65); all patients had disease progression on previous endocrine therapy, and 100% had bone metastases and 30% had visceral metastases. Preliminary toxicities for dose level 1 cohort (400 mg BID) are summarized in the table below. The DLT was grade 3 mucositis, which happened less than 3 weeks of study initiation, in a total of 3 out of 6 patients. All grade 3 mucositis cases improved after BEZ235 interruption for 7 days and subsequent dose reduction. These 3 events triggered activation of the dose level 1 cohort (400 mg AM/ 200 mg PM). The first 3 patients on dose level 1 cohort (2 of which have PIK3CA mutated tumors) had their tumor assessment scans at 8 weeks post treatment initiation; all patients were found to have stable disease.

Discussion: The combination of letrozole/BEZ235 is still being evaluated in patients with ER+/HER2MBC. Safety, tolerability and preliminary antitumor activity data will be updated at the meeting.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-10-05.
Abstract P6-11-05: Novel sorafenib-derivatives induce apoptosis in breast cancer cells through STAT3 inhibition
Authors: Liu C-Y , Tseng L-M , Chang K-C , Chu P-Y , Su J-C , Shiau C-W , Chen K-F
Published: August 2014

Background: STAT3 has emerged as a novel potential anti-cancer target and its signaling is constitutively activated in various cancers including breast cancer. Our previous study has shown that STAT3 is a major kinase-independent target of sorafenib in HCC. (J Hepatol. 2011). Moreover, recent evidence has shown that p-STAT3 can be down-regulated by phosphatases, such as SHP-1 tyrosine phosphatase. We have designed and synthesized a series of sorafenib analogues devoid of sorafenib's kinase inhibition activity, some of which showed stronger p-STAT3 inhibition and apoptosis-inducing effects than sorafenib in HCC cells (Eur J Med Chem. 2011). Here, we tested the efficacy of novel sorafenib derivatives, SC-1 and SC-43, in breast cancer cells and examined the drug mechanism.

Methods: Six Breast cancer cell lines were used for in vitro studies. Cell viability was examined by MTT-assay. Apoptosis was examined by both flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western Blot. SHP-1 activity was measured by a phosphatase activity assay kit. In vivo efficacy of Sorafenib, and sorafenib derivatives were tested in xenografted nude mice.

Results: Sorafenib, SC-1 and SC-43 induced apoptosis in association with down-regulation of P-STAT3 and its downstream proteins Cyclin D1 and survivin in a dose-dependent manner in breast cancer cell lines (HCC-1937, MDA MB-468, MDA MB-231, MDA MB-453, SKBR-3, MCF-7) and the apoptotic effects induced by SC-1 and SC-43 were more potent than Sorafenib. Over-expression of STAT3 in MDA MB-468 cells protected cells from apoptosis induced by sorafenib, SC-1 and SC-43. Moreover, SC-1 and SC-43 up-regulated higher SHP-1 activity than sorafenib by in vitro phosphatase assays. Knockdown of SHP-1 by siRNA reduced apoptosis induced by SC-1 and SC-43. Importantly, SC-1 and SC-43 showed in vivo efficacy in MDA-468 xenografted tumor.

Conclusions: Our data indicated that inhibiton of p-STAT3 by up-regulating SHP-1 activity mediated apoptotic effects of sorafenib, SC-1 and SC-43 in breast cancer cells.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-05.
Abstract P6-14-02: Disease recurrence in the breast after treatment for occult primary breast cancer: a prospective, population-based study
Authors: de Maat Michiel FG , Steevens Jessie , Hulsewe Karel W
Published: August 2014

Withdrawn by Author

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-14-02.
Abstract PD01-08: Differences in estrogen receptor signaling in non-malignant primary ER-positive breast epithelial cells and breast cancer.
Authors: Lim E , He HH , Chi D , Yeung TY , Schnitt S , Liu SX , Garber J , Richardson A , Brown M
Published: August 2014

Background: The estrogen receptor (ER) is expressed in ∼70% of sporadic breast cancer and activates genes driving cell proliferation and tumorigenesis. We have previously performed genome-wide analysis of ER binding sites in MCF-7 breast cancer cells, and identified distinct mechanisms of ER signaling. We have also previously used EpCAM and CD49f as markers to enrich for viable ER-positive (ER+) cells obtained from non malignant breast tissue. Here, we seek to elucidate differences in ER signaling between non-malignant and ER+ breast cancer cells.

Methods: Primary breast epithelial cells were obtained from patients undergoing reduction mammoplasties and surgical excision of ER+ breast cancer. After dissociation of breast reductions into a single-cell suspension, ER+ mature luminal (ML; EpCAM+CD49f−) and luminal progenitor (LP; EpCAM+CD49f+) subpopulations were obtained by flow cytometry. Following estrogen stimulation, RNA was extracted for gene microarray analysis. ER chromatin immunoprecipitation and DNA sequencing (ChIP-seq) was performed. These results were compared to MCF-7 breast cancer cells.

Results: Reduction mammoplasty and ER+ breast cancer tissues were analyzed, and compared to MCF-7 cells. Gene expression profiles were different between non-malignant tissue and ER+ breast cancer cells following estrogen stimulation, with a 2–3 fold higher number of ER regulated genes in ER+ breast cancer compared to ER+ non malignant cells, and few overlapping estrogen regulated genes. Genes that promotes cell cycling and cell proliferation were downregulated in non-malignant tissue, but were upregulated in breast cancer cells (P < 10–5). CYP1A1, a major estradiol metabolizing enzyme, was upregulated in normal cells but downregulated in ER+ breast cancer cells. Motif analysis of ER ChIP-seq data in normal and ER+ breast cancer tissues demonstrated an enrichment of ER motifs in the overlapping sites and an enrichment of FOXA1 motifs in ER+ breast cancer cells and TCF12 motifs in non-malignant ER+ epithelial cells.

Conclusions: There are contrasting differences in ER signaling between normal mammary and breast cancer cells, with estrogen having anti-proliferative effects in normal luminal cells compared to pro-proliferative effects in breast cancer. ER ChIP-Seq has identified TCF12 as a major co-factor in non-malignant breast tissue whilst FOXA1 is a major co-factor in ER+ breast cancer. Our data provides evidence for key alterations in ER-signaling during tumorigenesis, and identifies potential mechanisms to target cancer specific ER signaling.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD01-08.