bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-07-03: The impact of Carcinoma in situ of the breast and family history on risk of subsequent breast cancer events and mortality - a population based study from Sweden
Authors: Sackey H , Hui M , Czene K , Edgren G , Frisell J , Hartman M
Published: August 2014

Purpose: To evaluate the long-term risk of subsequent breast cancer and mortality among women diagnosed with carcinoma in situ of the breast.

Patients and Methods: Using the population-based Swedish Multi-Generation and Cancer Registers we selected 8,111 women diagnosed with in situ breast cancer between 1980 and 2004. We estimated the relative risks of subsequent ipsi- and contralateral invasive breast cancer or a contalateral in situ expressed as standardized incidence ratios (SIRs), in relation to age, year, time since diagnosis and family history (1st degree relative) for breast cancer. The relative risk of death was expressed as standardized mortality ratio, (SMR).

Results: Of 8,111 women identified with first in situ, 859 had a family history for breast cancer. The overall risk of a subsequent invasive breast cancer is over four fold and the risk for contralateral in situ breasts cancer was almost seven fold, compared with the risk in healthy women.

Women with a family history had almost a 50% increased risk for a contralateral invasive breast cancer, IRR 1.49 (95% CI 1.06–2.09) compared to women without, but had no increased risk for a contralateral in situ cancer or ipsilateral invasive breast cancer.

The risk for subsequent breast cancer decreased over time after diagnosis, but still 15 years after first in situ diagnosis the risk was over three times higher compared to the general population. Women below 40 years at diagnosis had the highest risk for a subsequent breast event, SIR 8.54 (95% CI 6.07–11.67).

The overall mortality for women with no second invasive event was the same as for women in the general population, SIR 1.01 (95% CI 0.95–1.08). Women below 50 years at first in situ diagnosis, with a second invasive cancer, had a higher mortality compare to women above 50 years, SIR 8.3 (95% CI 5.38–11.54) and SIR 1.70 (95% CI 1.39–2.06) respectively.

Conclusion: The risk for a subsequent invasive breast cancer, as well as mortality was substantially higher in younger women, which should be taken into account when planning their treatment and follow-up. Family history did not increase the risk for a subsequent ipsilateral invasive cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-07-03.
Abstract P4-01-07: The Relationship of Breast Density in Mammography and Magnetic Resonance (MR) Imaging in a High Risk Population
Authors: Chun J , Refinetti AP , Schnabel F , Leite AP , Price A , Billig J , Schwartz S , Moy L
Published: August 2014

Background: Mammographic breast density (BD) is associated with a 4 to 6-fold increased risk for developing breast cancer. Increased breast density on mammography is also known to decrease the diagnostic sensitivity of the exam, which is of great concern to women at increased risk for breast cancer. There is well-established medical literature describing the benefit of MRI in screening high risk women. A previous study has shown that background parenchymal enhancement (BPE) as measured on MRI can be correlated with breast cancer risk. The purpose of this study was to evaluate the relationship between BD, BPE, and FGT (assessment of the amount of fibroglandular tissue with contiguous MR images through both breasts) in pre and post-menopausal women who are at high risk for developing breast cancer.

Methods: The High Risk Breast Cancer Consortium (HRBCC) database at NYU Langone Medical Center was queried for our study population. A total of 56 women had both screening mammograms and MRIs completed at our center. Variables of interest included BD, BPE, FGT, BMI, Gail scores, and menopausal status. BD was defined by ACR classifications 1–4. FGT was assessed on a similar scale 1–4. BPE was categorized as minimal, mild, moderate, or marked. BMI (kg/m2) was grouped into 4 categories: underweight (≤18), normal (19–24), overweight (25–29), and obese (≥30). Statistical analyses were performed using Spearman Correlation Coefficients.

Results: The median age in our cohort was 48 years (range 24–70 years). The majority of women were Caucasian (74%) with a median 5-year Gail score of 3.35. There was no correlation between BD and BPE (r = 0.08) and BPE and FGT (r = 0.18). However, there was a moderate positive correlation between BD and FGT (r = 0.65). When we stratified by menopausal status, the correlation for BD and FGT was stronger for post-menopausal women (r = 0.73) versus premenopausal women (r = 0.57). When we stratified by BMI, we found a stronger positive association for BD and FGT among women who were overweight and obese (r = 0.62).

Conclusions: In our study cohort of patients at high risk for developing breast cancer, BD and BPE were not correlated, even after adjusting for menopausal status. This implies that BD and BPE may represent different characteristics of breast tissue and may have different implications. We found a strong correlation between BD and FGT. This association was strongest in women who were overweight and obese. FGT is a more objective and quantitative measurement of breast density and may be more useful in quantitative breast cancer risk assessment. Further studies are necessary to determine if BPE and FGT are independent risk factors for breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-01-07.
Abstract P4-01-12: Compliance with Recommended Follow-Up after MRI-guided Core Needle Biopsy of Suspicious Breast Lesions: A Retrospective Study
Authors: Thompson MO , Lipson JA , Daniel BL , Harrigal CL , Mullarkey PJ , Ikeda DM
Published: August 2014

Purpose: The purpose of this study was to assess patient compliance with recommended follow-up after MRI-guided core needle biopsy and investigate the reasons why patients did not comply with their recommended MRI imaging follow-up.

Materials and Methods: A HIPAA compliant retrospective review was performed of 576 MRI-guided core needle biopsies between 2007–2010 with IRB approval and waiver of informed consent. Of 576 biopsies, 73.3% (422/576) were compliant and 26.7% (154/576) were noncompliant with follow-up recommendations and composed this study. Imaging and surgical planning was determined by comparing imaging findings, clinical findings, and biopsy histology.

Results: Out of 135 lesions in patients noncompliant with follow-up imaging, 50.4% (68/135) were referred for biopsy by non-affiliated physicians, 41.5% (56/135) received a screening MRI, and 40.3% (56/135) were a focus or foci. Referring physicians provided information regarding the follow-up status of 88/154 (57%) lesions in noncompliant patients, of which 44/88 (50%) were followed by mammogram instead of MRI. Among compliant patients, 7/178 (3.9%) lesions seen on follow-up MRI were found to be high risk or malignant.

Conclusion: Compliance with follow-up MRI recommendation after core needle biopsy is low. Three characteristics were found to be associated with noncompliance with follow-up imaging: referral from non-affiliated physician, screening MRI, and a focus lesion. Moreover, patients who do not comply with recommended MRI follow-up are more likely to have follow-up mammography. Follow-up imaging among compliant patients found high-risk lesions and malignancy. Facilities performing MRI-guided core biopsies should therefore be aware of a high risk of noncompliance with follow-up.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-01-12.
Abstract P4-02-06: Molecular imaging with trastuzumab and pertuzumab of HER2-positive breast cancer in mice: a step towards personalized medicine
Authors: Collin B , Oudot A , Vrigneaud J-M , Moreau M , Raguin O , Duchamp O , Tizon X , Denat F , Varoqueaux N , Brunotte F , Fumoleau P
Published: August 2014

Introduction: The accurate and reliable assessment of HER2 status is an essential step in the diagnostic workup and selection of targeted treatment strategy in breast cancer patients. However, current ex vivo methods do not evaluate HER2 status possible discordance between primary tumor and distant metastases, nor immediate response to therapeutic intervention. Non-invasive imaging of HER2 expression could be a relevant alternative with additional benefits such as a better selection of patients for HER2-targeted therapies and the possible optimization of treatment strategies. Recent clinical trials suggest a better efficacy of trastuzumab/pertuzumab doublet but a lower activity of pertuzumab monotherapy over trastuzumab alone.

Aim: The aim of our study was therefore to evaluate preclinically the use of radiolabeled DOTAGA (2, 2′, 2″-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) conjugated trastuzumab and pertuzumab for SPECT/CT (Single Photon Emission Computed Tomography/Computed Tomography) HER2 imaging purposes.

Methods: Trastuzumab and pertuzumab were conjugated to a new bifunctional chelating agent: DOTAGA anhydride (DOTA analog) and subsequently radiolabeled with the gamma-emitter Indium 111. The functionality of [111In]-DOTAGA-antibodies analogs was evaluated by in vitro saturation assays using HER2-overexpressing human breast cancer cell line (HCC1954). In vivo biodistribution was studied by SPECT/CT imaging at 24h, 48h and 72h after intravenous injection of [111In]-DOTAGA-antibodies in subcutaneous BT474 tumor-bearing rodents.

Results: [111In]-DOTAGA-trastuzumab and [111In]-DOTAGA-pertuzumab showed respectively 2.6 and 2.7 DOTAGA/antibody. Both [111In]-DOTAGA-trastuzumab and [111In]-DOTAGA-pertuzumab achieved a radiochemical purity > 95%. Biological activity of [111In]-DOTAGA-trastuzumab and [111In]-DOTAGA-pertuzumab was maintained: the affinity determined on HER2 expressing HCC1954 cell lines, was 5.5 and 5.6 nM. SPECT/CT imaging experiments in tumor-bearing rodents and gamma-counting of organs both showed that at 72h post-injection, more than 60 % of the activity was localized in the tumor (66.9±0.9 %ID/g for [111In]-DOTAGA-trastuzumab and 63.8±6.3 %ID/g for [111In]-DOTAGA-pertuzumab) and that an excess of non-radiolabeled corresponding antibody significantly shifted down tumor-targeting (to 17.6±2.4 %ID/g for [111In]-DOTAGA-trastuzumab and 8.7±0.8 %ID/g for [111In]-DOTAGA-pertuzumab.

Conclusions: Our results demonstrate a similar HER2 binding of trastuzumab and pertuzumab. Both radiolabeled [111In]-DOTAGA-trastuzumab and [111In]-DOTAGA-pertuzumab should be considered and might be promising tools for molecular imaging diagnosis of HER2 overexpression in breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-02-06.
Abstract P4-03-01: Distance of breast cancer from the skin influence axillary nodal metastasis
Authors: Kim EJ , Chae BJ , Song BJ , Kwak HY , Chang EY , Kim SH , Jung SS
Published: August 2014

Background: In breast cancer, axillary lymph node status is one of the most important prognostic variables and a crucial component to the staging system. Moreover, cancers underlying skin are willing to access to the lymphatics and cause lymphatic dissemination. Therefore, there seems an association between proximity of breast cancer to the skin and the incidence of axillary node positivity or local recurrence.

The aim of this study was to determine whether distance of breast cancers from the skin affects the the clinical and pathologic features including the likelihood of axillary nodal metastases, ipsilateral breast cancer recurrence, and recurrence free survival.

Methods: Between January 2003 and December 2009, data were collected prospectively regarding 1005 consecutive breast cancer patients who underwent surgical treatment. The exclusion criteria were non-invasive carcinoma (e.g. Ductal Carcinoma In Situ), prior breast surgery, previous radiotherapy or neo-adjuvant chemotherapy and previous endocrine therapy. The distance of the tumor from the skin surface was measured from the skin to the most anterior hypoechoic leading edge of the lesion.

Results: A total of 891 patients were included in the statistical analysis, 603(68%) had no axillary nodal metastasis, 288(32%) had axillary nodal metastasis. Distance of breast cancer from the skin less than 3mm induced more axillary nodal metastasis (P = 0.039). However, there was no statistical significant correlation between distance of breast cancer from the skin less than 3mm and ipsilateral breast tumor recurrence (P = 0.788) or recurrence-free survival (P = 0.353).

Conclusion: Breast cancers located closer to the skin have a higher incidence of axillary nodal metastasis. When evaluating a breast cancer patient and considering the risk of nodal metastasis the distance of the tumor from the skin should be considered.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-03-01.
Abstract P4-06-19: Astemizole and calcitriol: A novel targeted therapeutic strategy for breast cancer
Authors: García J , García R , Villanueva O , Santos N , Barrera D , Avila E , Ordaz D , Halhali A , Camacho J , Larrea F , Díaz L
Published: August 2014

Calcitriol antiproliferative effects include inhibition of the oncogenic ether-à-go-go-1 potassium channel (Eag1), which expression and activity are necessary for cell cycle progression and tumorigenesis. Astemizole, a new promising antineoplastic drug, targets Eag1 by blocking ion currents. In vitro, we showed that astemizole synergized calcitriol antiproliferative effects by downregulating CYP24A1, the enzyme that degrades calcitriol, and upregulating the vitamin D receptor (VDR), which mediates calcitriol actions. In this study we investigated the antineoplastic effect of astemizole and calcitriol in a murine model xenografted with T-47D and invasive ductal carcinoma-derived breast cancer cells (IDC). Tumor-bearing nude mice were treated with oral astemizole (50 mg/kg/day) and/or i.p. calcitriol (30 μg/kg/twice a week) during 3 weeks. Astemizole and calcitriol significantly inhibited, while the coadministration of both drugs further reduced, tumor growth compared to untreated controls. These results were supported by immunohistochemistry studies of Ki-67, a proliferation marker, which revealed less staining in tumors from mice with the co-treatment compared to controls and calcitriol or astemizole alone. In a similar manner as reported in vitro, we observed that the concomitant administration of astemizole and calcitriol upregulated VDR tumor expression (P < 0.05).

Conclusion: Coadministration of calcitriol and astemizole increased the antineoplastic effects of both drugs. Our results indicate that astemizole may improve calcitriol bioactivity by upregulating tumoral VDR. In addition, the findings in this study suggest that VDR-negative tumors could be sensitized to calcitriol antineoplastic effects by concomitant administration with astemizole, which would also allow for less calcitriol dosing without sacrificing overall therapeutic efficacy. Herein we suggest a novel combined adjuvant therapy for the management of breast cancer tumors. These results provide scientific bases for further studies designed to test both compounds simultaneously in patients bearing solid or metastatic tumors.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-06-19.
Abstract P4-07-04: Methioninase cell-cycle synchronization potentiates chemotherapy for breast cancer
Authors: Yano S , Li S , Han Q , Tan Y , Fujiwara T , Hoffman RM
Published: August 2014

Deprivation of methionine selectively arrests cancer cells during late S-phase (Proc. Natl. Acad. Sci. USA 77, 7306–7310, 1980; Biochim. Biophys. Acta, Reviews on Cancer 738, 49–87, 1984), where they are highly sensitive to chemotherapy drugs which damage DNA (J. Natl. Cancer Inst. 76, 629–639, 1986). Cancer cells, transformed to express different color fluorescent reporters during specific phases of the cell cycle (Cell 132, 487–498, 2008), were used to monitor the onset of the S/G2-phase block due to methionine deprivation effected by recombinant methioninase (rMETase). The S/G2-phase blocked cancer cells fluoresced yellow or green in contrast to cancer cells in G1 which fluoresced red. Cancer cells, including MCF-7 breast cancer, synchronously blocked in S/G2-phase by rMETase, were identified by their yellow-green fluorescence and allowed to accumulate to the maximum extent. At the point of maximum yellow/green cells in the culture, the cells were administered chemotherapy drugs which interact with DNA or block DNA synthesis such as doxorubicin. We termed this procedure color-coded chemotherapy (CCC). CCC was highly effective against the cancer cells (90% cell kill). In contrast, treatment of cancer cells with drugs only, and without rMETase-effected S/G2-phase synchrony, led to the majority of the cancer cell population being blocked in G1 phase (red fluorescent) where they were resistant to the drugs (40% cell kill). CCC, which identifies, by fluorescent color, when cancer cells are blocked in S/G2-phase by a unique cell-cycle-blocking agent, rMETase, demonstrates the potential of cell-synchronization-based chemotherapy for breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-07-04.
Abstract P4-08-10: Systematic expression analysis of the genes related to drug-resistance in isogenic docetaxel- and adriamycin-resistance breast cancer cell lines.
Authors: Tang J , Li W , Zhong S , Xu J , Zhao J
Published: August 2014

Background: Docetaxel (Doc) and Adriamycin (Adr) are two of the most effective chemotherapeutic agents in the treatment of breast cancer. However, their efficacy is often limited by the emergence of multidrug resistance (MDR). The purpose of this study was to investigate MDR mechanisms through analyzing systematically the expression changes of genes related to MDR in the induction process of isogenic drug resistant MCF-7 cell lines.

Material and Methods: Isogenic resistant sublines selected at 100 and 200nM docetaxel (MCF-7/100nM Doc and MCF-7/200nM Doc) or at 500 and 1500 nM adriamycin (MCF-7/500nM Adr and MCF-7/1500nM) were developed from human breast cancer parental cell line MCF-7/S, by exposing MCF-7/S to gradually increasing concentrations of docetaxel or adriamycin in vitro. Flow cytometry, MTT cytotoxicity assay and cell growth curves were preformed to demonstrate the MDR characteristics developed in sublines. Some key genes on the pathways related to drug resistance (including drug-transporters: MDR1, MRP1 and BCRP; drug metabolizing-enzymes: CYP3A4 and GST pi; target gene: Topo IIα and β-tubulin III; apoptosis genes: Bcl-2 and Bax) were analyzed at RNA and protein expression levels by real time RT-qPCR and western blot, respectively.

Results: MCF-7/100nM Doc and MCF-7/200nM Doc was 22- and 37-fold resistant to docetaxel, and 18- and 32-fold to adriamycin, respectively. MCF-7/500nM Adr and MCF-7/1500nM Adr was 61- and 274-fold resistant to adriamycin, and 3- and 12-fold to docetaxel, respectively. Meantime, they also showed cross-resistance to the other anticancer drugs in different degree. Compared to sensitive MCF-7/S, RT-qPCR and Western blot results revealed that the expression of MDR1, MRP1, BCRP, Bcl-2 were elevated in both MCF-7/Doc and MCF-7/Adr, and Topo IIα, Bax were down-regulated in both the sublines, while CYP3A4 and β-tubulin III were increased only in MCF-7/Doc and GST pi was increased only in MCF-7/Adr. Furthermore, these changes above were dose-dependent, i.e. acquirement of MDR is dependent on docetaxel or adriamycin concentrations in breast carcer model resistant MCF-7 cells.

Conclusions: The established MCF-7/Doc or MCF-7/Adr has the typical MDR characteristics, which can be used as the models for resistance mechanism study. The acquired process of MCF-7/S resistance to docetaxel or adriamycin is gradual, and is also complicated with the various pathways involved in. There are some common mechanisms as well as drug-special mechanisms between MCF-7/Doc and MCF-7/Adr.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-08-10.
Abstract P4-09-08: HOXB9, a gene promoting tumor angiogenesis and proliferation, is significantly associated with poor clincal outcomes in ER-positive breast cancer patients
Authors: Seki H , Hayashida T , Jinno H , Takahashi M , Suzuki K , Kaneda M , Hara H , Osaku M , Asanuma F , Yamada Y , Mukai M , Kitagawa Y
Published: August 2014

Background: Studies have suggested that HOXB9 expression in breast cancer cells promotes cellular invasiveness, metastatic ability, and tumor neovascularization in the surrounding tissue in in vitro and in vivo assays. These findings imply that HOXB9 overexpression may alter tumor-specific cell fates and the tumor stromal microenvironment, contributing to breast cancer progression (Hayashida et al., PNAS 2010). We previously reported that clinical outcomes were significantly decreased in HOXB9-positive patients (Seki et al., Ann Surg Oncol. 2012). In this study, it was demonstrated that HER2 type and basal-like breast cancers were more associated with HOXB9 positivity than the luminal type. Therefore, it is required to identify more detail clinicopathological features most likely to be associated with HOXB9 overexpression. We investigated the correlation between HOXB9 overexpression and clinicopathological variables, and clinical outcomes in estrogen receptor (ER)-positive breast cancer patients.

Patients and methods: A consecutive series of 118 ER-positive breast cancer patients who underwent surgical treatment were examined. HOXB9 expression was analyzed immunohistochemically using the anti-human HOXB9 polyclonal antibody. Immunostaining of Ki-67 and CD31 were also performed to evaluate tumor proliferation and angiogenesis.

Results: The median age was 59 years and median observation period was 62 months. Of 118 tumor specimens immunostained for HOXB9, 49 specimens (41.5%) were positive staining. Univariate logistic regression revealed high nuclear grade (p < 0.001), lymph node metastasis (p = 0.019), the number of micro vessel density (p < 0.001) and the Ki-67 ratio (p = 0.019) as significant variables associated with HOXB9 positive. The disease-free survival (DFS) was significantly decreased in HOXB9-positive patients (HR = 4.262, 95% CI = 1.531 — 11.869, p = 0.006) A Multivariate analysis indicated that HOXB9 expression was the only independent prognostic factor for DFS (HR = 3.380 95% CI=1.160 — 9.849, p = 0.026).

Conclusions: Our results suggest that HOXB9 expression promoting the cellular proliferation and the angiogenesis in tumor microenvironment is a significant prognostic factor for clinical outcomes in ER-positive breast cancer patients. Further study might help to determine the application of anti-angiogenic therapy for metastatic ER-positive breast cancer patients.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-09-08.
Abstract P4-12-05: Enrichment of aldosterone synthase (CYP11B2) gene C-allele carriers in women at high risk in the OncoVue® polyfactorial risk model
Authors: Jupe ER , Pugh TW , Knowlton NS , DeFreese DC
Published: August 2014

Background: Models for accurately assessing breast cancer risk are utilized for guiding clinical decisions regarding early detection and prevention. We developed a polyfactorial risk model (PFRM; OncoVue) from analysis of a large case-control database including both functional gene polymorphism and clinical factor data. A multivariate logistic regression based statistical protocol was used to derive a single risk model consisting of 22 single nucleotide polymorphisms (SNPs) in 19 genes and 5 traditional risk factors. Several studies have shown that the PFRM is significantly improved in individualized risk estimation compared to the Breast Cancer Risk Assessment Tool (BCRAT) or Gail model. Here we have examined the genotype frequencies of women placed in the highest decile of risk by the PFRM compared to both the overall control population and to women in the control population placed at the lowest decile of risk.

Materials and Methods: Analyses were performed on 1671 breast cancer cases and 3351 controls that enrolled in a case-control study conducted in six regions of the United States. DNAs were genotyped for the 22 genetic polymorphisms and combined with clinical risk factor information to calculate PFRM risk estimates for the individual participants. The PFRM lifetime scores were used to stratify the upper and lower deciles of risk. The genotype frequencies for these stratified risk groups were determined and compared to the overall control population and to each other (upper vs. lower decile). Odds Ratios (OR) were determined for the CYP11B2 genotypes because they exhibited the largest differences in frequency among the groups.

Results: For CYP11B2 comparison of the genotype frequencies in the highest decile risk group to the overall genotype frequencies of controls identified significant enrichment of the C-allele carriers in the highest risk group. The OR for C-allele carriers (C/C+C/T) compared to the most common T/T genotype was 3.0 (1.9, 4.8; 95% C.I.) with a p-value <0.0001. Similarly for the upper decile risk group compared to the lower decile risk group the association of C-allele carriers was even stronger with OR = 11.0 (6.6,18.4; p <0.0001). In the upper decile of risk 86% of the individuals were C-allele carriers compared to only 38% in the lower decile of risk.

Conclusions: Our previous studies have shown an age dependent association of the CYP11B2 C/C and C/T genotypes with breast cancer risk. The enrichment of these genotypes in women in the upper decile risk group as determined by the PFRM further reinforces the role of this genotype in influencing breast cancer risk and suggests that intervention in the aldosterone synthase pathway be explored as a method of breast cancer prevention.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-12-05.
Abstract P4-13-01: Racial Disparities in the Incidence of Dose-limiting Chemotherapy Induced Peripheral Neuropathy
Authors: Speck RM , Sammel MD , Farrar JT , Hennessy S , Mao JJ , Stineman MG , DeMichele A
Published: August 2014

Objective: To determine the incidence of and risk factors for dose-limiting chemotherapy induced peripheral neuropathy (CIPN) in non-metastatic breast cancer.

Methods: This retrospective cohort study included 488 women with an adjuvant or neoadjuvant treatment plan with docetaxel or paclitaxel from June 1, 2009 to December 31, 2011. Exclusion criteria were: metastatic disease, previous neurotoxic chemotherapy, pre-existing neuropathy, pregnant or within 3 months post-partum, and prosthetic limb. The primary outcome was dose-limiting CIPN, defined as a treatment modification event (dose delay, dose reduction, or treatment discontinuation) attributed to CIPN. The primary risk factor of interest was obesity (BMI≥30). Covariates included race, age, menopausal status, diabetes, and other comorbidities, node status, tumor size, regimen, and oncologist. With 80% power and 0.05 type I error rate, the study could detect a risk ratio of 1.8 in the obese versus non-obese.

Results: Fifty (10.2%) women had a treatment modification event attributed to CIPN (TM-CIPN). TM-CIPN incidence differed significantly by agent (docetaxel = 2.4% (N = 5/209), paclitaxel=16.1% (N = 45/279); p < 0.001). In analyses restricted to patients treated with paclitaxel with complete covariate data (N = 273), the odds of TM-CIPN did not differ by obesity, OR = 1.17 (95% CI 0.59–2.35). After adjusting for black race, menopausal status, disease severity, and type II diabetes the TM-CIPN and obesity association was attenuated. The attenuation occurred after adjustment for black race, which was a confounder of the obesity and TM-CIPN relationship, and associated with obesity (OR = 3.78, p = <0.001). Post-menopausal status, disease severity, and type II diabetes were associated with obesity, but were not confounders. Compared to whites, and after controlling for disease severity, menopausal status, and oncologist, blacks and other non-whites had significantly increased odds of CIPN-TM (OR = 2.5, p < 0.02; OR = 4.8, p < 0.01; respectively). Tests of homogeneity indicated the race and TM-CIPN association was not modified by oncologist or disease severity.

Conclusion: Obese and non-obese women have a comparable likelihood of having their treatment modified due to CIPN. Women of racial minorities had over 2-to 4-fold increased odds of TM-CIPN compared to white women. Investigations addressing the mechanistic explanations for this association are warranted.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-13-01.
Abstract P4-13-06: Association of Age, Obesity and Incident Breast Cancer Phenotypes
Authors: Scheri R , Power S , Marks J , Seewaldt V , Marcom K , Hwang S
Published: August 2014

Background: Obesity has been shown to be associated with increased risk of breast cancer in postmenopausal women. However, it is unclear whether this risk is isolated to a specific phenotype. We hypothesized that the increased levels of insulin, IGF-1 and estrogens associated with obesity preferentially drive an increased proportion of the luminal A phenotype of breast cancer.

Methods: Between 2008 and 2011, 1001 women were diagnosed with invasive breast cancer at Duke University Medical Center and had weight and height recorded at the time of diagnosis. Tumor phenotypes were based on hormone receptor (HR: ER− and/or PR-positive) and Her2 testing with subtypes defined as follows: Luminal A: HR(+), Her2(−); Luminal B: HR(+), Her2(−); Her2: HR(−), Her2(+); triple negative: HR(−), Her2(−).

Results: Median age of the cohort was 55.7 years; median BMI was 27.7. As expected, increasing BMI was associated with older age, with BMI almost evenly distributed between three groups: ≤ 25, 25–30, and >30. In the overall group, proportion of luminal B, Her2, and triple negative subtypes did not differ by BMI; however the proportion of patients with luminal A cancer increased from 65% for the lowest BMI group to 70% for the highest BMI group. Analysis stratified by age ≤ 40, 40 to 59, and ≥60 years showed a lower proportion of the triple-negative (19% vs. 6% vs. 4%, p < 0.001) and higher proportion of the luminal A (11% vs. 23% vs. 32%; p < 0.001) phenotype with older age group. This finding was limited to women with higher BMI only.

Conclusions: Although there were no trends observed between BMI and incident phenotype in the overall cohort, age stratified analysis revealed striking correlations. High BMI was associated with triple negative phenotype in the youngest age group and luminal A phenotype in older age groups. These results suggest that obesity likely exerts different effects on tumor progression based on patient age and/or menopausal status.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-13-06.
Abstract P5-01-16: Value of ultrasonography appearance of breast mass in prediction of histologic type
Authors: Xu Z , Sun L , Yang H , Song Y , Sun G
Published: August 2014

Objective to determine the relationship of sonographic features to the histological typing and grading of breast mass.

Methods: 292 breast masses were prospectively evaluated with ultrasonography. Sonographic features included irregular shape, microlobulation, spiculated margin, halo, posterior attenuation, microcalcification, ductal distortion. Lesion morphology was analyzed and correlated with histopathologic results, which included tumor typing and grading. Then we make a retrospective analysis and evaluation of patients scanned completely by qualitative and semi-quantitative methods. All patients have signed the informed consent form before the test, together with the recognition of the Ethics Committee.

Resuls: Among these masses, there are breast cancer accounted for 45.89% (134/292), A rounded or lobular mass was strongly associated with ductal carcinoma in situ(DCIS), poorly differential invasive ductal carcinoma(IDC), or some of the specific invasive cancer. Mastitis accounted for 8.22% (24/292), fibroadenoma accounted for 43.84% (128/292), and phyllodes tumor accounted for 2.05% (6/292). In 134 breast cancer cases, 92.70% (127/134)have obviously sonographic features with justled growth was found around the turmor with lamellar necrosis in different extents and lympholeukocytic infiltration, microlobulation, speculated margin, halo, posterior attenuation, microcalcification, ductal distortion, with justled growth was found around the turmor, neoplastic cell array showed as massive nest, patchy and satin ribbon structure, and the membrane of tumor cells was unsharpness with less cytoplasma, round or oval nucleus, great heteromorphism, higher karyoplasmic ratio and common nuclear mitotic figures. Other 7 cases with fibrous tissue hyperplasia under microscope show a regular shape. In fibroadenoma, phyllodes tumor and mastitis team, they shows unobviously sonographic features and the cell morphology contrast with breast cancer are quite different.

Conclusions:Ultrasonography appearance of breast masses is related to pathologic characteristics and can be a predictor of histopathologic pattern preoperatively.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-01-16.
Abstract P5-03-10: HIF-1alpha knockout radiosensitizes select Inflammatory Breast Cancer cells through reduction of stem-like cancer cells
Authors: Xu W , Debeb BG , Smith DL , Li JL , Ueno NT , Alvarez de Lacerda LC , Larson RA , Schwba LP , Seagroves TN , Woodward WA
Published: August 2014

Independent of the tumor stroma, HIF-1α regulates tumor cell metabolism, cell proliferation and DNA repair pathways, which may produce conflicting responses to radiation, promoting either radioresistance or radiosensitization. Recently, HIF-1α was shown to increase tumor initiating cells (TICs) activity in normoxic tumor cells derived from the MMTV-PyMT trasngenic mouse model of luminal-like breast cancer. While TICs have been reported to be relatively radio-resistant, the role of HIF-1α in mediating the radation response in breast cancer TICs remains unknown. Herein, we examined radiosenstitivity of TICs derived from either PyMT HIF-1α knock out (KO) tumor cells or human breast cancer cell lines transduced with a HIF-1α dominant negative (DN) construct. Consistent prior results that loss of HIF-1 activity reduces TIC frequency, down-regulation of HIF-1 activity through the HIF DN construct reduced mammosphere formation in SUM-159, SUM-149 and MCF-7 cells (by 5.0-, 2.0-, and 2.0-fold respectively). Moreover, β-catenin expression was down-regulated in SUM-149 and SUM-159 cells transfected with the HIF-1α DN construct. Moreover, SUM-149 cells expressing the HIF-1α DN construct exhibited delayed tumor growth in vivo (p = 0.05). Standard clonogenic assays demonstrated that PyMT HIF-1α KO cells and SUM-149 cells expressing the HIF-1α DN construct were more sensitive to radiation therapy (SF6 of PyMT, HIF-1α:Control, 0.016:0.087), but that the PyMT KO and SUM-149 mammospheres that persisted after radiation were completely radioresistant (SF6 of PyMT, HIF-1 α: Control, 0.48:0.44). In contrast, MCF-7 cells were not radiosensitized in either standard or mammosphere assays. Interestingly, in HIF-1α DN MCF-7 cells, molecular features of IBC were observed, such as the increased expression of E-Cadherin and loss of Wisp3. But, Notch1 protein expression was unchanged between HIF-1α DN MCF7 or SUM149 cells. Moreover, concurrent radiation in the presence of a gamma secretase inhibitor or with a p53-MDM2 inhibitor nutlin failed to radiosensitize HIF KO mammosphere clonogens. We conclude that downregulation of HIF-1 activity selectively radiosensitizes IBC clonogenic cells but fails to radiosensitize the residual mammospheres. These data suggest that the known HIF-1α mediated mechanisms that favor radiosensitivity, such as the promotion of glycolysis and proliferation under stress, may predominate in mammospheres, which ultimately leads to radioresistance in residual mammospheres after HIF inhibition.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-10.
Abstract P5-03-11: Possible role for cancer stem cells: results from a pilot neoadjuvant trial of HER-2 positive breast cancer patients treated with a combination of (Nab)-paclitaxel and lapatinib.
Authors: Siziopikou KP , Gradishar WJ , Kaklamani VG
Published: August 2014

Background: Lapatinib, a dual kinase inhibitor against both epidermal growth factor (EGFR) and human epidermal factor 2 (HER-2) and nanoparticle albumin bound (nab) paclitaxel was recently used by our group in a pilot study of early stage HER-2 positive breast cancer. We reported that the combination was well tolerated and showed good efficiency in this patient group. Cancer stem cells were recently identified in solid tumors including breast carcinomas. These tumor initiating stem cells are reported to be increased in HER-2 positive breast cancers. Lapatininb is postulated to reduce the percentage of breast cancer stem cells following HER-2 inhibition. This study aimed to investigate such an effect in this patient population of early stage HER-2 positive breast cancer cases uniquely treated by a combination of nab-paclitaxel and lapatininb.

Design: 30 patients with stage I-III HER-2 positive breast cancer were treated in a neoadjuvant setting with lapatinib 1,000mg/day and nab-paclitaxel 260 mg/m2 every 2 weeks for 4 cycles. The expression of the stem cell markers aldehyde dehydroganase (ALDH1) (BD), CD24 and CD44 (both Santa Cruz Biotechnology) was assessed immunohistochemically in breast cancer specimens prior to treatment and at the time of definitive surgery. Staining was considered negative if < or = 1%, and positive if >1%.

Results: Of the 30 patients, 28 underwent surgery and were evaluated for pathologic response. Complete pathologic response (pCR) was observed in 5/28 (17.9%) of the patients. Of the 17 patients for whom pre-treatment material was available 13 (76.5%) were positive for ALDH1 expression and 4 (23.5%) were negative. Of the 22 patients with material available for testing at the time of surgery, 5 showed pCR, 3 were negative and 14 (63.6%) were positive for ALDH-A1 expression. The CD44+/CD24- phenotype was variable and showed no difference between groups.

Conclusions: 1. Combination of lapatinib and nab-paclitaxel resulted in a complete pathologic response in almost 1/5 of the HER-2 positive early stage breast cancer patients. 2. Overall, there is a reduction in the number cancer stem cells following neoadjuvant treatment with lapatinib and nab-paclitaxel. Our results support the hypothesis that lapatinib may have an effect in manipulating the numbers of cancer stem cells in patients with HER-2 positive breast cancer. Additional studies are currently under way to further characterize these findings.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-11.
Abstract P5-05-06: Spatio-temporal computational modeling of the p53-Mdm2 pathway
Authors: Sturrock M , Thompson AM , Chaplain MAJ
Published: August 2014

Background: The p53 transcription factor is a well-established regulator of the cell cycle and key to preventing cancer. In response to a variety of cellular stresses (e.g., DNA damage or oncogene activation) p53 is activated and translocates to the nucleus where it activates transcription of target genes which can induce cell cycle arrest, senescence or apoptosis. One of the target genes for p53 is the gene for Mdm2, a negative regulator of p53 function in cells. Mdm2 represses p53 function through two main mechanisms: by promoting p53 ubiquitination and proteasomal degradation and, through direct inhibition of p53 transcriptional activity. Experimental data have revealed that in response to gamma irradiation, p53 and Mdm2 concentrations exhibit spatial and temporal oscillatory dynamics in individual MCF7 breast cancer cells. The precise function of these oscillations is still under investigation.

Method: Using in vitro laboratory data, we have developed a computational model to study the spatio-temporal evolution of the p53-Mdm2 pathway. The model comprises a system of coupled nonlinear partial differential equations, including transport terms and reaction kinetics. The transport is assumed to include both random (diffusion) and active mechanisms with proteins convected in the cytoplasm toward the nucleus, modeling transport along microtubules. Internal structures such as ribosomes and the nuclear membrane are also explicitly modeled.

Results: Using computational simulations we have found ranges of values for the model parameters such that sustained oscillatory dynamics occur, consistent with available experimental measurements. To bridge the gap between in vitro and in silico experiments realistic cell geometries using imported images of cells have informed our computational domain. The effects of microtubule-disrupting drugs, proteasome inhibitor drugs, and mutations in the DNA binding site of p53, have been modeled yielding data in agreement with published experimental laboratory studies.

Conclusions: This mathematical computational model enables us to compare the effects of clinically relevant therapeutic approaches at the single cell level. In particular, the precise temporal and spatial distributions of p53 can be determined and the cellular consequences modeled.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-05-06.
Abstract P5-07-03: Gallotannins and Gallic acid From Mango Fruit (Mangifera Indica L) Suppress Breast Cancer Tumor Growth by Targeting Phosphatidylinositol3-kinase (PI3K)-Akt-NF-kB Pathway and Associated microRNAs
Authors: Banerjee N , Kim H , Krenek K , Talcott S , Talcott SM
Published: August 2014

The cytotoxic and anti-inflammatory properties of polyphenolics have been demonstrated in numerous types of cancer and the objective of this research was to understand the post-transcriptional targets involved in anti-inflammatory and pro-apoptotic pathways in the breast cancer cell line BT474, treated with a polyphenolic extract (2.5–40µg/ml) rich in gallotannins and gallic acid from mango fruit in vitro and in athymic nude mice bearing BT474 cells as xenografts.

Results show that cell proliferation as well as tumor size and weight in vivo was decreased by polyphenolics 60% and 70% in vitro and vivo, respectively. NF-kB protein and mRNA expression as well as activation were decreased in a dose-dependent manner (0.6 fold).

The extract also inhibited PI3K-dependent phosphorylation of AKT and expression and this was accompanied by down-regulation of miRNA 126 of BT474 (2.25 fold) and in vivo. NFκB-dependent genes involved in apoptosis-inhibition, metastasis and angiogenesis, such as survivin, VCAM-1, and VEGF were also decreased, in vitro and in vivo.

A microRNA-array was also used to investigate whether microRNAs with target regions within affected genes were affected by the polyphenolic extract and results show that in addition to miR-126, miR-let-7a and miR-let-7b among others were significantly increased by the extract.

In summary the anti-carcinogenic and anti-inflammatory activity of mango polyphenolics in breast cancer cells were at least in part due to targeting miR-126 -Phosphatidylinositol 3-kinase (PI3K)-Akt-NF-kB which plays an important role in the proliferative/ inflammatory phenotype exhibited in this breast cancer cell line.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-07-03.
Abstract P5-10-07: Luminal A breast cancer: identification of novel circulating miRNA biomarkers
Authors: McDermott AM , Miller N , Ball G , Sweeney KJ , Kerin MJ
Published: August 2014

Introduction: Breast cancer is a prevalent disease in need of a reliable circulating biomarker with a role in combination with mammography to facilitate early diagnosis. Mi(cro)RNAs are a group of small molecules with ideal biomarker characteristics. The knowledge that miRNAs are aberrantly expressed in cancer, and can be detected in the circulation supports their potential role in minimally invasive cancer diagnostics. Intrinsic breast cancer subtypes provide well characterized phenotypes to study the biomarker potential of miRNAs. The aim of this study was to identify systemic miRNAs differentially expressed in Luminal A (ER+PR+HER2/neu−) breast cancer, and to study their utility as oncologic biomarkers in the clinical setting.

Material and Method: Whole blood samples were collected prospectively from women diagnosed with Luminal A breast cancer (n = 57) and healthy controls (n = 57). Luminal A phenotype was confirmed by immunohistochemistry and fluorescence in situ hybridization (FISH). RNA was extracted, reverse transcribed and a Taqman Low-Density Array (TLDA, microarray) conducted on a test cohort (10 Luminal A; 10 Control). Differentially expressed miRNAs were identified using Artificial Neural Networks (ANN). Expression of specific miRNAs were validated using RQ-PCR on an independent whole blood cohort (n = 47 Luminal A; n=47 Control) and tissue (n = 30). Results were analyzed using Q-Base and Minitab V16.0.

Results: The microarray performed on the test cohort identified 77 differentially expressed miRNAs. Artificial Neural Networking highlighted seven miRNAs for further analysis (Table 1).

RQ-PCR quantification of expression of these seven candidate miRNAs in the validation group confirmed the biomarker potential of two miRNAs. MiR-181a and miR-652 were significantly under-expressed in the cancer group compared to the control group (p = 0.005 and p = 0.001 respectively). Circulating miR-181a expression correlated with invasive tumour size (r = −0.592, p = 0.008). Furthermore, a combination of these two miRNAs provided a sensitivity and specificity for detection of Luminal A breast cancer of 70% and 65%, respectively (Area Under the Curve, AUC=0.77). MiR-181a and miR-652 were also under-expressed in Luminal A tumor tissue compared to Tumor Associated Normal (TAN, p = 0.019 and p = 0.001, respectively).

Conclusion: This study provides insight into the underlying molecular portrait of the Luminal A subtype by identifying 77 miRNAs with altered systemic expression levels. Two novel miRNA oncologic biomarkers are identified, which are altered in both the tumor and circulation. These miRNAs may have a role in combination with mammography to facilitate accurate subtype-specific breast tumor detection.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-10-07.