bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-09-01: Odds of the triple negative subtype and survival of stages 1–3 breast cancer: Variation by race/ethnicity
Authors: Parise C , Caggiano V
Published: August 2014

Background: Triple negative (TN) breast cancer is known to be more common in black and Hispanic women and associated with poor survival. This study assesses the differences in the odds and survival of the TN versus the ER+/PR+/HER2− (the most common subtype) by race/ethnicity separately for AJCC stages 1, 2, and 3.

Methods: Using the California Cancer Registry for years 2000–2010, we examined 91,393 cases of stages 1–3 TN and ER+/PR+/HER2− first primary female invasive breast cancer. Race/ethnicity was defined as white, black, Hispanic, and Asian/Pacific Islander (API). Logistic regression was used to assess the association of race with odds of the TN subtype. Kaplan-Meier was used to compute 6-year survival. Cox proportional hazards was used to assess the risk of mortality of the TN subtype by race adjusting for age, grade, year of diagnosis, and socioeconomic status. All analyses were run separately for stages 1, 2, and 3.

Results: The table shows the distribution of the TN and ER+/PR+/HER2-subtypes by stage and race/ethnicity.

Blacks had increased odds of the TN compared with whites for stages 1 (OR = 2.24; 95%CI=1.96–2.56); 2 (OR = 2.01; 95%CI=1.81–2.25) and 3 (OR = 2.00; 95%CI=1.66–2.40).

Hispanics had increased odds for the TN in stages 1 (OR = 1.23; 95%CI=1.11–1.35) and 2(OR = 1.20; 95%CI=1.11–1.31). APIs had decreased odds of the TN in stages 2 (OR = 0.85; 95%CI=0.77–0.93) and 3 (OR = 0.77; 95%CI=0.64–0.92).

KM survival showed that APIs had the best 72 month survival for the TN in stages 1 (86%), 2 (78%), and 3(59%).

Hazard ratios (HRs) indicated that all races with TN had the same risk of mortality in stage 1. Only in stage 2 did blacks have an increased risk of mortality (HR = 1.17; 95%CI=1.02–1.36) while APIs had a decreased risk (HR = 0.78; 95%CI=0.65–0.94). In stage 3, Hispanics (HR = 0.85; 95%CI=0.72–0.99) and APIs (HR = 0.70; 95%CI=0.55–0.89) had decreased risk of mortality compared with whites.

Conclusions: Race/ethnicity is an important factor for survival of the TN subtype: 1. Although blacks and Hispanics are more likely to have the TN subtype, blacks have an increased risk of mortality compared with whites only in stage 2.2. For stage 1, all races have the same risk of mortality.3. Hispanics have decreased risk of mortality in stage 3.4. APIs have decreased risk of mortality in both stages 2 and 3.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-09-01.
Abstract P3-09-02: The HER2 –positive subtypes by stage and race/ethnicity
Authors: Caggiano V , Parise C
Published: August 2014

HER2-positivity is often associated with poor survival. The purpose of this study is to determine if there are differences in mortality among the HER-positive subtypes when stratified by stage and race/ethnicity.

Methods: Using the California Cancer Registry for years 2000–2010, we examined 99,897 cases of stages 1–3 ER+/PR+/HER2− and all HER2-positive first primary female invasive breast cancers. Race/ethnicity was defined as white, black, Hispanic, and Asian/Pacific Islander (API). Kaplan-Meier (KM) and the Log-Rank test were used to compute 6-year survival. Cox proportional hazards was used to assess the risk of mortality of each of the HER2-positive subtypes when compared with the ER+/PR+/HER2− subtype (the most common subtype). All analyses were adjusted for age, grade, year of diagnosis (<2007, 2007+), and socioeconomic status and run separately by race for stages 1, 2, and 3.

Results: For all stages combined, of the subtypes comprising the luminal B-HER2 positive category, the ER+/PR+/HER2+ had the best survival (85%), only 2% less than the ER+/PR+/HER2−.

When compared with the ER+/PR+/HER2− subtype, no difference in KM survival was noted for stage 1 luminal B (ER+/PR+/HER2+;ER+/PR−/HER2+; ER−/PR+/HER2+). Both had 90% 72-month survival. The ER−/PR−/HER2+ had 88% survival (p < 0.02).

For stage 2, luminal B had 83% survival and ER−/PR−/HER2+ had 76% survival. Both were significantly different (p < 0.001) from the ER+/PR+/HER2− subtype (86%).

The luminal B had 68% survival and the ER−/PR−/HER2+ had 55% survival for stage 3. Both were statistically significantly worse (p <.006) than the ER+/PR+/HER2− (72%).

Adjusted mortality for the ER+/PR+/HER2+ was only increased for blacks in stage 1 (HR = 1.59; 95%CI=1.09–2.33). Mortality for the ER−/PR−/HER2+ was increased for whites in all stages; for blacks in stages 1 (HR = 1.82; 95%CI=1.11–3.00) and 3 (HR = 1.90; 95%CI=1.36–2.66); for Hispanics in stages 2 (HR = 1.58; 95%CI=1.28–1.95) and 3 (HR = 2.19; 95%CI=1.73–2.78); and APIs only in stage 2 (HR = 1.70; 95%CI=1.31–2.19)

Year of diagnosis made no difference in risk of mortality in stage 1 for any race. For stage 2, blacks had slightly reduced mortality if diagnosed in 2007 or later, and for stage 3, all races except blacks had reduced risk of mortality when diagnosed in 2007 or later.

Conclusions:  1. There is variation in survival among the luminal B-HER2 positive subtypes.2. The driving force behind the increased mortality of the HER2 positive subtype is the ER−/PR−/HER2+ subtype, the molecularly defined HER2 overexpressing subtype.3. Year of diagnosis does not influence survival in stage 1 for any race.4. There are differences in mortality among the HER2 positive subtypes when stratifying by stage and race and adjusting for age, grade, year of diagnosis, and SES.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-09-02.
Abstract P3-09-04: The associations between body mass index and breast cancer intrinsic subtypes in Japanese women
Authors: Kimura K , Tanaka S , Iwamoto M , Uchiyama K
Published: August 2014

Purpose: The purpose of this study was to examine the associations between body mass index (BMI) and breast cancer intrinsic subtypes in Japanese women. A more complete understanding of the subtypes of breast cancer may help elucidate mechanisms affecting etiology and mortality associated with each subtype.

Methods: Tumor data on 531 invasive breast cancer cases subtyped by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (Her2) status were obtained (luminal A, luminal B, TN, and Her2-type). Demographics (age at diagnosis, menopausal status, and BMI) were collected from medical records. Case-only odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusting for age at diagnosis.

Results: In all cases, the patients were Japanese. Of the 531 cases with IHC marker data, 333 (62.7%) were classified as luminal A, 85 (16.0%) were luminal B, 43 (8.1%) were Her2-type, and the remaining 70 cases (13.2%) were TN. The distribution of patient demographics (age at diagnosis, menopausal status, and BMI) did not differ significantly by breast cancer tumor subtype. Case-only ORs comparing each subtype to luminal A were caluculated. Of the TN cases, postmenopausal TN cases were more likely to be underweight (OR = 3.14, 95% CI = 1.19 to 8.01). Although some epidemiological studies have reported that higher BMI was associated with premenopausal TN cases compared with luminal A cases, this association was not found among premenopausal TN cases analyzed using BMI 18.5 to 24.9 kg/m2 as the reference in this analysis. However, there were no underweight cases (BMI < 18.5 kg/m2) among the premenopausal TN cases in the present study. Therefore, the association between BMI and the TN subtype was also analyzed using BMI < 25 kg/m2 as the reference. Compared to luminal A cases, premenopausal TN cases were more likely to be obese (OR = 4.11, 95% CI = 1.10 to 14.40), similar to reports from Western countries. Compared to luminal A cases, premenopausal luminal B cases were likely to be underweight (OR = 3.27, 95% CI = 0.88 to 11.39) or obese (≥ 25 kg/m2) (OR = 3.32, 95% CI = 0.98 to 10.81), yet this association was of borderline significance. Compared to luminal A cases, luminal B and Her2-type cases were likely to be underweight (BMI < 18.5 kg/m2), yet this association was of borderline significance (luminal B: OR = 2.12, 95% CI = 0.97 to 4.46; Her2-type: OR = 2.53, 95% CI = 0.92 to 6.36).

Conclusions: In the present study, significant heterogeneity of associations between BMI and tumor subtypes was observed. Breast cancer subtypes may have different etiologies associated with each subtype.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-09-04.
Abstract P3-10-04: Regulation of inflammatory breast cancer cell invasion through Akt1/PKBα phosphorylation of RhoC GTPase
Authors: Lehman HL , Van Laere SJ , van Golen CM , Vermeulen PB , Dirix LY , van Golen KL
Published: August 2014

With a 42% and 18% 5- and 10-year respective disease-free survival rate, inflammatory breast cancer (IBC) is arguably the deadliest form of breast cancer. IBC invades the dermal lymphatic vessels of the skin overlying the breast and as a consequence nearly all women have lymph node involvement and ∼1/3 have gross distant metastases at the time of diagnosis. One year after diagnosis ∼90% of patients have detectable metastases, making IBC a paradigm for lymphovascular invasion. Understanding the underlying mechanisms of the IBC metastatic phenotype is essential for new therapies. Work from our laboratory and others show distinct molecular differences between IBC and non-inflammatory breast cancers. Previously we demonstrated that RhoC GTPase is a metastatic switch responsible for the invasive phenotype of IBC. In the current study we integrate observations made in IBC patients with in vitro analysis. We demonstrate that the PI3K/Akt signaling pathway is crucial in IBC invasion. Key molecules involved in cytoskeletal control and cell motility are specifically upregulated in IBC patients compared with stage and cell-type-of-origin matched non-inflammatory breast cancer patients. Distinctively, RhoC GTPase is a substrate for Akt1 and its phosphorylation is absolutely essential for IBC cell invasion. Further our data show that Akt3, not Akt1 has a role in IBC cell survival. Together our data demonstrate a unique and targetable pathway for IBC invasion and survival.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-10-04.
Abstract P3-10-06: Patterns of failure in patients with inflammatory breast cancer: the case for aggressive local/regional treatment
Authors: Warren LE , Regan MM , Nakhlis F , Yeh ED , Jacene HA , Hirshfield-Bartek J , Overmoyer BA , Bellon JR
Published: August 2014

Background: While the survival of patients with inflammatory breast cancer (IBC) is dictated by the status of their distant metastases, local/regional control remains an important component of quality of life. We have sought to determine patterns of local/regional recurrence (LRR) in patients presenting with inflammatory breast cancer.

Methods: The medical records of 92 patients (pts) diagnosed with IBC from 1997 until 2007 were reviewed. Pt cohorts were stratified by disease burden at presentation (metastatic or local/regional) and their tumor, treatment, and disease course were analyzed. Primary outcomes were time from diagnosis to LRR, time to distant recurrence, and overall survival (OS). Median follow-up (MFU) for the entire cohort was 6 years (yrs) (range 0.1 to 12.7 yrs); for those patients who presented with metastatic disease versus only local/regional disease, MFU is 2 yrs and 6 yrs, respectively. This study was approved by the hospital institutional review board.

Results: Median age at diagnosis was 49 yrs (range 24 to 72). 68 (74%) patients were without evidence of metastatic disease on presentation. With 6yr MFU, 40/68 (59%) had disease recurrence at either local or distant sites, and 15/68 (22%) had documented LRR, either as the first or subsequent site of recurrence. Estimated 5yr OS is 64%.

24 (26%) pts presented with metastatic disease (lung, liver, distant lymph nodes, pleura). All of the 24 pts presenting with metastatic disease developed systemic disease progression; 12/24 (50%) also developed LRR, and for 9/12 pts the LRR was first progression or concurrent with distant progression. Eleven of the 24 pts did not receive radiation or surgery; and within this cohort, 7 (64%) pts developed LLR at a median time of 9 months after diagnosis. Six pts received radiation therapy without surgery; 3/6 (50%) developed LRR. One pt had surgery alone; this patient was not known to have LRR, although had limited follow-up. Six pts received radiation therapy and surgery; 1 for palliation and 5 to prevent LRR. Of these 5 pts, 1/5 (20%) developed LRR that extended to the contralateral breast at 1.2y after diagnosis. Among the 24 patients, the cumulative incidence of LRR was 29%, 37%, and 43% at 1yr, 2yr, and 3yr (accounting for competing risk of death). The median OS was 2.9 yrs and estimated 5yr OS was 36%.

Conclusions: Pts with inflammatory breast carcinoma presenting with metastatic disease are at high risk for local/regional disease progression. Aggressive local therapy should be considered to prevent symptoms of uncontrolled local disease, despite an uncertain impact upon OS.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-10-06.
Abstract P3-10-08: A new in vitro method of growing and studying inflammatory breast cancer emboli
Authors: Lehman HL , Daasner EJ , Vermeulen PB , Dirix LY , Van Laere S , van Golen KL
Published: August 2014

Inflammatory breast cancer (IBC) is the deadliest form of breast cancer, presenting as intralymphatic emboli. Emboli within the dermal lymphatic vessels are thought to contribute to rapid metastasis. The lack of appropriate in vitro models has made it difficult to accurately study how IBC emboli metastasize. To date, attempts at creating IBC tumor emboli in vitro have used 3-dimensional culture on a solid layer of MatrigelTM, which does not resemble the physical properties of the lymphatic system. Dermal lymphatic fluid produces oscillatory fluid shear forces and is 1.5–1.7-fold more viscous than water with a pH range of 7.5–7.7. We have established a method for forming tumor emboli by culturing the IBC cell lines in suspension with either polyethylene glycol- or hyaluronic acid-containing medium and oscillatory fluid shear forces. Non-IBC cells do not form emboli under identical conditions. In vitro IBC emboli were analyzed for expression of markers associated with patient emboli and their ability to undergo amoeboid movement. In a direct comparison, the in vitro IBC emboli closely resemble IBC patient emboli with respect to size, composition and E-cadherin expression. Further, cells from the emboli are able to invade in clusters via RhoC GTPase-dependent amoeboid movement. Invasion by clusters of IBC cells is disrupted by exposure to TGFβ. This study provides a biologically relevant in vitro model to accurately grow and study inflammatory breast cancer biology and metastasis.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-10-08.
Abstract P3-12-07: Voyagers and their aids: The role of interactions between tumor and endothelial cells in brain metastasis
Authors: Shah KN , Faridi JS
Published: August 2014

Clinically, brain metastases are most commonly observed in breast, lung, and melanoma cancers. When a tumor cell leaves its site of origin, it enters a nearby blood vessel on a voyage to find a new tissue to invade. These circulating tumor cells will act as voyagers and they interact with a endothelial cell. For example, in the case of brain metastasis, tumor cells need to adhere to brain endothelial cells before they can invade into the surrounding brain tissue. Thus, investigating the mechanisms of tumor and endothelial cell interactions can serve as a very powerful tool to inhibit the voyage of these tumor cells and prevent the formation of metastases. In this study, we performed trans-endothelial migration assay using HBMVEC cells to study tumor-endothelial interactions. In general, HBMVEC cells were seeded to BD-Falcon cell culture inserts at a density of 2 × 105 cells and allowed to grow for 24 hours to form a confluent monolayer and GFP expressing tumor cells (MCF-7, Akt3 overexpressing MCF7, MDA-MB-231 and MDA-MB-231-BR) were incubated at suitable interval at 37°C. At the end of incubation period, cells were fixed and number of tumor cells that will penetrate the monolayer of HBMEC were counted using Phase-contrast microscope in 12 different visual fields. Transmigrating tumor cells are thought to be able to overcome the endothelial barrier by inducing changes within endothelial cells. We identified the molecular changes responsible for such adhesion and invasion by cell sorting for gene expression analysis. After co-culturing the HBMEC (after transfecting with Mcherry protein) with GFP expressing tumor cells and Mcherry labeled HBMEC, we used cell sorting to separate tumor and HBMEC cells. After sorting the tumor cells and endothelial cells from co-culture, (MCF-7 monolayer vs MCF-7 co-cultured, MDA-MB-231 monolayer vs MDA-MB-231 co-cultured, HBMEC monolayer vs HBMEC co-cultured) gene expression analysis was performed using SABiosciences cell adhesion assay kit to accurately capture the genetic changes that occured in the tumor and endothelial cells upon co-culture.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-12-07.
Abstract P3-12-08: Incidence, predictive factors and outcome of brain metastases (BM) in a single institution cohort of breast cancer patients.
Authors: Perelló A , Alarcon J , Garcias C , Duran J , Colom B , Clemente G , Avella A , Canet R , Torrecabota J , Rifa J
Published: August 2014

Background: The aim of the study was to determine the cumulative incidence of BM, predictive factors of BM, and survival from diagnosis of BM in a cohort of breast cancer patients in a single institution.

Patients and Methods: We collected data from a cohort of 793 breast cancer patients between January 2000 and December 2005 in our institution. Variables recorded include age at diagnosis, hormonal receptor status (HRS), human epidermal growth factor receptor 2 status (HER2), histological grade, T stage and N stage. We analyzed the 5 and 10-year cumulative incidence of BM. Time to detection of BM and survival from BM were estimated using Kaplan-Meier method. Cox regression model was used to analyze the variables associated with time to BM

Results: With a median follow-up of 100 months, 49 patients went on to develop BM. The overall 5 and 10 year cumulative incidence of BM were 4.9% and 8.2% respectively. The table shows the 5 and 10 year cumulative incidence and hazard ratio (HR) of the predictive factors for the development of BM in the univariable analysis.

Including all significant variables in the model, HER2 positive and node positive patients had an increase risk of BM, HR 2.46 (95% CI: 1.22–4.95) and 2.51 (95% CI: 1.19–5.29) respectively. HRS positive patients had a decreased risk of developing BM, HR 0.44 (95% CI: 0.21–0.89).

Median survival from BM of HER2 positive and HER2 negative patients was 9 and 3 months respectively (p = 0.015), and 6 and 1 month for HRS positive and negative respectively (p = 0.02)

Conclusion: Predictive factors independently associated with a high risk of BM in our cohort are HER2 positivity and positive nodes. Patients with positive HRS have a decreased risk of BM. Survival time following BM is poor. HER2 positive and HRS positive patients have a better survival than HER2 negative and HRS negative patients.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-12-08.
Abstract P3-12-09: The risk of brain metastases according to expression of selected immunohistochemical markers in primary breast cancers
Authors: Sosinska-Mielcarek K , Winczura P , Duchnowska R , Badzio A , Majewska H , Lakomy J , Peksa R , Pieczynska B , Radecka B , Debska S , Zok J , Rogowski W , Strzelecka M , Kulma-Kreft M , Blaszczyk P , Litwiniuk M , Jesien-Lewandowicz E , Rutkowski T , Jaworska-Jankowska M , Adamowicz K , Foszczynska-Kloda M , Biernat W , Jassem J
Published: August 2014

Background: About 10–30% of breast cancer patients will develop brain metastases.

In untreated patients with brain metastases the median survival is 1–2 months, and in those undergoing palliative radiotherapy — 3–6 months. The mechanism of brain metastases remains largely unknown. The identification of molecular markers might help in selecting high risk patients, and enable active surveillance, prevention and early treatment. The aim of this study was to analyze predictive value of expression of selected tumor proteins for the risk of brain metastases in breast cancer patients.

Material and methods: This study included 198 advanced breast cancer patients treated between 2001 and 2007 in 11 oncology centers in Poland, including 96 woman with and 102 without overt brain metastases, respectively. The median age at diagnosis in these two groups was 52 and 60 years, respectively, with 52% and 32% of patients being premenopausal. Stage at diagnosis was similar in both groups and ductal carcinoma was a dominant histological type (76% and 86% of cases, respectively). Immunohistochemistry was performed on formalin-fixed paraffin embedded microarray cores derived from the primary tumor. Expression analysis included ER, PR, HER2, Ki67, CK5/6, EGFR, HER3, CXCR4, RAD51, E-cadherin, and claudin 3 and 4. Cox regression model was used to estimate the relative risk of brain metastases.

Results: Expression of HER2, CK5/6, EGFR, RAD51 (both cytoplasmatic and nuclear staining), CXCR4 (cytoplasmatic staining) and Ki67 ≥14%, as well as ER or PR negativity was associated with increased risk of brain metastases in the univariate analysis (Table 1). Of those, Ki67 ≥14% (HR 2.76 [95%CI 1.70–4.48]; p < 0.001), cytoplasmatic expression of double strand DNA repair gene RAD51 (HR 1.87 [95%CI 1.14–3.08]; p = 0.014) and ER negativity (HR 1.72 [95%CI 0.36–0.94]; p = 0.029) were found to be significantly related to the risk of brain relapse in the multivariate analysis. Four molecular profiles composed of the latter three markers were created, of which a profile including ER, Ki67 and RAD51 was associated with the highest risk of brain metastases (HR 4.43 [95%CI 2.69–7.27]; p < 0.001). Molecular subtype analysis showed the highest risk of BM in the ER/PR/ HER2-negative (triple negative) subset (HR 1.21 [95%CI 1.11–1.32]; p < 0.001).

Conclusion: Expression of proteins related to high tumor proliferation, DNA repair and ER negativity is associated with increased risk of brain metastases in breast cancer patients.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-12-09.
Abstract P3-12-10: Age, breast cancer subtype approximation and the risk of the development of brain metastasis in breast cancer patients
Authors: Hung M-H , Liu C-Y , Chao T-C , Wang Y-L , Tsai Y-F , King K-L , Chiu J-H , Shiau C-Y , Shyr Y-M , Tzeng C-H , Tseng L-M
Published: August 2014

Purpose: Biological subtypes and age were well-known risk factors associated with the development of brain metastasis in breast cancer patients. However the impact of each biological subtype in different age group was less discussed.

Patient and methods: Patients with invasive ductal carcinoma of breast diagnosed from January 2000 to December 2009 were divided by age of diagnosis into three groups: age below 35, age from 36–59 and age above 60. Four biological subtypes of breast cancer subtype were approximated as luminal A, luminal B, HER2 enriched and triple negative breast cancer by intergrading status of estrogen receptor, progesterone receptor and HER2 and grade.

Result: With a median follow-up time of 54.2 months, there were 164 patients (7.3%) among the 2248 enrolled patients developed brain metastasis. Patients with HER2 enriched [hazard ratio (HR) 2.53; 95% confidence interval (CI): 1.57–4.07, p < 0.0001)], triple negative breast cancer (HR 4.42; 95% CI: 2.86–6.85, p < 0.0001) and diagnosed age younger than 35 years-old (HR 2.09; 95% CI: 1.15–3.81, p = 0.016) were strongly associated with higher incidence of brain metastasis. Table 1 showed the important characteritics according to different age group.

Furthermore the influence of each biological subtype amoung different age group were investigated. For patient younger than 35 years-old, risk of the developement of brain metastasis was independent to biological subtype (p = 0.507); while the risk of brain metastasis was influenced by biological subtype in older age groups. For patients older than 35, patients with triple negative and HER2 enriched disease had significantly increased risk for brain metastasis compared to luminal A; but for patients with luminal B disease, such incremental risk for the development brain metastasis was only observed in patients older than 60 years-old.

Conclusion: Our study found that each biological subtypes of breast cancer had distinct impact on the development of brain metastasis among different age group. Further studies were needed to disclose the biology underneath. Also the findings should be taken into consideration when developing strategy for brain metastasis prevention.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-12-10.
Abstract P3-13-02: Safety and Efficacy of Zoledronic Acid Beyond 24 Months in Breast Cancer Patients
Authors: Suzuki Y , Saito Y , Ogiya R , Oshitanai R , Terao M , Terada M , Morioka T , Tsuda B , Niikura N , Okamura T , Tokuda Y
Published: August 2014

Background: Bisphosphonate therapy has decreased the risk of skeletal complications associated with osteolytic bone lesions in patients with breast cancer and multiple myeloma. The large prospective studies have used 21 to 24 months of treatment. We studied the safety and efficacy of Zoledronic acid in a subset of patients who received therapy for more than 24 months.

Patients and Methods: Patients who received Zoledronic acid were identified. Data on skeletal events and laboratory parameters were gathered by chart review. The treatment regimen is 4 mg of Zolendronic acid at 3- to 4-week intervals, and concurrent chemotherapy, hormonal therapy, and radiation therapy was included. Before approval of Zoledronic acid, we were using Pamidronate and Incadronate.

Results: We used the Zoledronic acid in 221 patients from June 2006 until December 2011 (range, 1–69 times of administration). We analyzed 71 cases in which the treatment could be continued for more than 24 months (range, 24–69 times of administration). No significant calcium, phosphorus, electrolyte abnormalities were encountered. There were no significant differences between the long-term treatment patients with Zoledronic acid and all the other patients in the range of pain felt at the time of the bone metastasis diagnosis, or the bone metastases sites. In addition, by March 2012, more than 50% patients of long-term usage of Zoledronic acid had continued receiving treatment. And in all of the patients, as well, the most cited reason for discontinuing treatment was a disease progression, adverse effect was few. In long-term treatment patients, 4 cases of fractures and 2 cases of spinal compression were encountered. The median time until an SRE occurred was 37 months. There were fewer occurrences of SREs in our investigation than in the 12 months of a clinical trial conducted in Japan with Zoledronic acid and a placebo. As for adverse effects, BRONJ appeared in 4 (1.8%) out of a total of 221 cases, and in 3 (4.2%) at prolonged treatment patients. The other adverse effects were fever in 4 cases and fatigue in 2 cases.

Conclusion: Prolonged treatment with Zoledronic acid seems to be well tolerated and should be studied in prospective, randomized studies to document prolonged skeletal efficacy and survival.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-13-02.
Abstract P3-13-06: Osteocytic Connexin 43 Hemichannels in Prevention of Bone Metastasis
Authors: Zhou JZ , Jiang JX
Published: August 2014

Bone metastases are major, potentially fatal complications in patients with advanced cancers including breast, prostate and lung cancers. The gap junction-forming protein connexin 43 (Cx43) has been known to inhibit primary tumor cell growth. In addition to gap junctions, Cx43 also forms halves of gap junctions known as hemichannels which allow communication between the intracellular and extracellular environments. Cx43 hemichannels in osteocytes have been shown to open when induced by mechanical stimulation as well as by treatment with alendronate (AD), an efficacious and commonly used bisphosphonate drug. The opening of hemichannels is known to release small molecules important for bone formation and remodeling. To confirm the opening of Cx43 hemichannels in the presence of AD, we measured uptake of ethidium bromide (EtBr) in MLO-Y4 cells after the addition of AD. As expected, an increase in Cx43 hemichannels EtBr uptake was observed after AD treatment. To elucidate the effect(s) of osteocyte Cx43 hemichannels on cancer cell growth and migration, we treated MLO-Y4 osteocytes with AD. Conditioned media (CM) was collected after treatment and were used to incubate with metastatic MDA-MB-231 breast cancer cells and PC3 prostate cancer cells. Cell migration was measured using wound healing and transwell migration assays, and cell proliferation was measured using the soft agarose anchorage-independent growth assay. The CM collected from MLO-Y4 osteocytes treated with AD reduced cancer cell migration and proliferation in a dose-dependent manner. However, direct treatment with AD had no effect on the cell migration or proliferation of the MDA-MB-231 cells. These data validated that the decrease in migration and proliferation was not a result of direct action by AD on the cancer cells. In order to elucidate the direct functional involvement of Cx43 hemichannels in cell migration, we treated the MLO-Y4 cells with Cx43 (E2) antibody, a specific antibody which blocks hemichannel activity but not gap junction channels formed by Cx43. The inhibitory effect of the CM on the migration and proliferation of MDA-MB-231 and PC3 cells was diminished. Interestingly, the inhibitory effects of osteocytes on cancer cell migration were not observed when using osteoblasts. Together, these results suggest the functional importance of osteocytic Cx43 hemichannels in attenuating cancer cell migration and growth.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-13-06.
Abstract P3-14-02: Should patients with comedo ductal carcinoma in situ (DCIS) be managed as if they have locally invasive breast cancer?
Authors: Dillman Robert O , McClure Stephanie E , Heinemann Francis S
Published: August 2014

Withdrawn by Author

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-14-02.
Abstract P3-14-04: Symptomatic DCIS is a risk factor for invasion and should be managed accordingly
Authors: Dimopoulos N , Williams K , Kirwan CC , Johnson R , Howe M , Bundred NJ
Published: August 2014

Background: The National ABS Guidelines indicate axillary surgery is unwarranted in DCIS but should be offered to patients undergoing mastectomy. Up to 30% of pre-operatively diagnosed DCIS lesions harbour occult invasive cancers at mastectomy.

Methods: To determine if DCIS mode of presentation, size (or other clinical factors such as Grade or HER2 status) predict invasion or nodal involvement, 380 patients undergoing surgery with a DCIS pre-operative (B5) diagnosis were studied. In total 162 patients underwent mastectomy +/− axillary staging for DCIS and 216 conservation surgery between 2008–2011 in one unit.

HER2, oestrogen receptor (ER) and progesterone receptor (PR) expression within primary DCIS were established using immunohistochemistry. HER2 was scored 0 (absent) to 3 (maximum). Scores ≥2 were taken as positive if amplified on FISH testing. ER and PR scored positive if ≥5% of cells stained.

Results: In total 216 had Breast Conservation and 162 Mastectomy with 127 undergoing sentinel lymph node biopsy (111) or subsequent axillary surgery (16).

Of 162 patients undergoing mastectomy for DCIS, 121 (75%) underwent axillary staging, with 9 (7%) having involved nodes.

Screening mammography detected 117 (72%) but 45 (28%) presented symptomatically with a breast mass. Median age at diagnosis was 57.8 years (range 29–94). Women less than 35 years of age had tumours sized greater than 4 cm in 72.3% compared to 59% in older women (p < 0.05).

In total 50 (31%) women with DCIS had occult invasive disease, with an additional 9 (6%) having microinvasion. Young age (p 0.003), - symptomatic presentation (p < 0.001), presence of a palpable mass (p <0.001), ultrasound visibility (p <0.01) and Her2 negativity (p < 0.05) were associated with invasion, however size of DCIS, grade, oestrogen and progesterone receptor status were not.

Sentinel node involvement was associated with symptomatic presentation (p = 0.03) and presence of a palpable mass (p = 0.04) but not DCIS size, grade, age or receptor status.

Conclusion: Symptomatic DCIS presents more frequently with an occult invasive component and nodal invasion. In symptomatic DCIS presenting with a mass lesion.

Ultrasound of the axilla and breasts should be a requisite preoperative assessment for all women. Moreover, sentinel node biopsy should be considered in patients with DCIS and a mass lesion.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-14-04.
Abstract P3-14-05: Recurrence in Patients Diagnosed with Ductal Carcinoma in Situ: Predictors and Prognostic Significance
Authors: Sue GR , Killelea B , Horowitz NR , Lannin DR , Chagpar AB
Published: August 2014

Background: While patients diagnosed with ductal carcinoma in situ (DCIS) enjoy a favorable prognosis, recurrence after definitive management does occur in a subset of these patients. Factors influencing the development of recurrence, and the ultimate impact of this event on overall survival, remain poorly understood. We sought to determine clinicopathologic factors affecting recurrence and the prognostic role this plays in patients with DCIS.

Methods: A retrospective chart review of 205 consecutive patients who presented to an academic breast center with DCIS from 2000 to 2003 was conducted under an IRB-approved protocol. Non-parametric statistical analyses comparing patients who recurred to those who did not were then performed using SPSS Statistical Software.

Results: With a median follow-up of 8.5 years, 14 (6.8%) of the 205 patients who presented with DCIS between 2000–2003 had an invasive or in situ recurrence. The median age of all patients at the time of diagnosis of their initial DCIS was 55.5 years (range; 35.8–88.9). 51 (24.9%) had possible (albeit not definitive) microinvasion on their initial specimen. The majority were grade 2 (91; 44.4%), and 99 (48.3%) had comedo histology. The median size of DCIS on the initial excision was 10 mm (range; 0.1–80). All patients underwent definitive surgery to negative margins. The mean time to recurrence was 4.7 years (range; 1.1–10.6). On bivariate analysis, histologic grade of DCIS was the only factor that was significantly correlated with the risk of recurrence. Patients with grade 3 DCIS were more likely to develop a recurrence compared to those with grade 2 or grade 1 DCIS (12.3% vs. 3.3% vs. 0%, respectively, p = 0.032). Patient age, race, extent of DCIS, and histologic subtype were not associated with recurrence (see table below). 5-year actuarial overall survival was no different between those who developed a recurrence and those who did not (92.9 vs. 95.7%, p = 0.171).

Conclusions: Approximately 7% of patients diagnosed with DCIS will recur within 10 years. Patients with high grade DCIS are more likely to recur, and this seems to be more predictive of recurrence than other clinicopathologic markers. Irrespective of whether or not patients with DCIS recur, overall survival is not significantly different between these two groups, and patients with DCIS enjoy an outstanding prognosis regardless.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-14-05.
Abstract P4-01-05: Utility of Preoperative Routine MRI and PET/CT in Breast Cancer Staging vs. Surgical Staging
Authors: Higaki K , Kochi M , Ito M , Otani S
Published: August 2014

Background: Staging of breast cancer is one of the most important factors in determining treatment options. The aim of this study is to assess the utility of routine magnetic resonance imaging (MRI) and positron emission tomography and computed tomography (PET/CT) in preoperative breast cancer staging.

Patients and methods: We examined 616 consecutive patients, who were newly-diagnosed with operable primary breast cancer less than 3 cm, at our institution between 2009 and 2011. They all underwent MRI and PET/CT to assign the clinical stage by TNM classification. Tumor size was measured by contrast MRI examinations and node status and metastases were evaluated on PET/CT. We examined their clinical and pathological T and N status retrospectively to assess the utility and concordance rate of preoperative imaging studies. Patients with tumors more than 3 cm were excluded from this study, since preoperative systemic therapy is the standard therapeutic strategy for those patients.

Results: The concordance rate of T status was 79.9% in clinical T1 patients (366/458) and 55.6% in clinical T2 patients (88/158). The concordance rate of N status was 83.8% in clinical N0 patients (495/591) and 60.0% in clinical N1 patients (15/25). As a result, the concordance rate of clinical stage was 66.5% in clinical stage I patients (296/445) and 55.0% in clinical stage II patients (94/171). In addition, 43 patients were diagnosed as contrary breast cancer by MRI (7.5%) and 31 contrary breast cancer (5.4%) and 12 other malignant disease (1.9%) were found by PET/CT.

Conclusions: MRI and PET/CT are valuable tools to provide information on tumor size, lymph node involvement, distant metastases and other occult primary disease. Preoperative routine MRI and PET/CT studies have a substantial impact on patients with operable primary breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-01-05.
Abstract P4-01-08: Effect of bilateral salpingo-oophrectomy on breast MRI fibroglandular volume and background parenchymal enhancement for BRCA 1/2 mutation carriers.
Authors: De Leo MJ , Domchek S , Kontos D , Conant E , Weinstein S
Published: August 2014

PURPOSE: Bilateral salpingo-oophrectomy (BSO) reduces breast cancer risk in women with BRCA1/2 mutations by approximately 50%. Annual screening for these high-risk women includes breast MRI and mammography. It is unknown whether BSO affects fibroglandular volume (FG) and background enhancement (BG) on breast MRI in this population. The purpose of this study is to assess the difference in FG and BG in BRCA1/2 mutation carriers before and after BSO on breast MRI.

METHOD AND MATERIALS: We compared FG and BG on contrast-enhanced breast MRI before and after BSO. Two readers blinded to both clinical and imaging history scored FG according to the BI-RADS criteria from 1–4: fatty, scattered, heterogeneously dense, or extremely dense. BG was graded based on the MRI BI-RADS scale from 1–4: minimal, mild, moderate, and marked. Average BIRADS scores of each reader were used to calculate mean FG and BG (±SD) before and after BSO, and compared using a paired t-test for significance.

RESULTS: We examined 60 women with BRCA1/2 mutations who underwent breast MRI before and after BSO from 2001–2011 at our institution. Five patients were excluded from the final analysis as they underwent mastectomy or bilateral radiation therapy before post-BSO MRI. Mean time to post-BSO MRI was 8.3 months ± 7 months. Mean pre- and post-operative FG were 2.64±0.78 and 2.58±0.75, respectively (p = 0.622). Mean pre- and post-operative BG were 2.46±0.93 and 1.87±0.81, respectively (p = 0.0001). Breast cancer was detected in 8 women at a median time of 3.4 years following BSO. In these 8 women, mean pre- and post-operative FG were 3.10±0.57 and 2.55±0.69, respectively. Mean pre- and post-operative BG were 3.20±0.67 and 2.35±0.71, respectively.

CONCLUSION: In this population of 55 BRCA1/2 mutation carriers who underwent breast MRI before and after BSO, there was a significant reduction in BG following BSO. There was no difference in FG on MRI following BSO. For the 8 patients in this cohort who were diagnosed with breast cancer after BSO, there was a trend toward higher FG and BG both before and after BSO, in comparison to the patients who were not diagnosed with breast cancer, suggesting that rates of higher FG and BG may be associated with increased risk for developing breast cancer.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-01-08.
Abstract P4-01-11: Clinical Findings and Outcomes from MRI Staging of Breast Cancer in a Diverse Population
Authors: Raghavendra A , Ji L , Ricker C , Tang S , Church TD , Larsen L , Sheth P , Sposto R , Sener S , Tripathy D
Published: August 2014

Background: Staging breast MRI can detect occult breast cancers in 1–10% of newly diagnosed patients. The performance of MRI, impact of patient factors, and resulting surgical management in underserved and diverse populations has not been well studied.

Methods We performed a retrospective analysis of consecutive patients with newly diagnosed in situ or invasive breast cancer (2006–2011) who had a preoperative staging MRI seen at our Centers that cares for an underserved and minority population. IRB approval was obtained to extract demographic and clinicopathological data, imaging studies and surgical treatment. Non-index lesions (NIL) were defined as those in breast or axillary nodes not known to be malignant or presenting with clinical, mammographic or ultrasound findings, in a different quadrant and given an MRI BIRADS score of 4 or 5. Occult cancers (OC) were those lesions found by biopsy or surgery to be invasive or in situ cancer. Logistic regression was used to examine the association between the probability of a NIL or OC and patients characteristics. Statistical computation was performed using STATA.

Results: Among 678 patients, 144 (21%) had a total of 171 NIL identified by MRI; 67 (9.8%) were ipsilateral, 44 (6.5%) contralateral and 24(3.5%)axillary nodes. 57 patients (8.4%) had a total of 62 OCs detected −34 (5%) ipsilateral, 8(1.2%) contralateral, and 9(1.3%) axillary nodes of which 49 (7.2%) were invasive and 8 (1.2%) in situ. 40% of patients with NILs were confirmed as OCs.

Analyses showed that age was marginally significantly associated with the probability of having OC(OR = 1.5 for each 10 years increase, p = 0.080). Patients with no BRCA mutation had significantly higher chance of having NILs tested with MRI (p = 0.003), but the probability of having OC did not significantly differ between those tested. Ipsilateral compared to contralateral NILs had a 4-fold higher chance of being OCs(p < 0.001). For NILs (n = 157), 59 (37.6%) underwent biopsy, 11 (7%) biopsy followed by lumpectomy, 10(6.4%) had lumpectomy, 24 (15.3%) mastectomy, 15 (9.6%) biopsy followed by mastectomy and (15)9.6% node dissection. Amongst OCs (n = 62) 6 (3.8%) underwent biopsy, 6 (3.8%) biopsy followed by lumpectomy, 6 (3.8%) lumpectomy, 20(12.7%) mastectomy, 12 (7.6%) had biopsy followed by mastectomy and 10 (6.4 %) node dissection.

Conclusions: In this diverse population, staging MRI detected NILs and OC in 21% and 8.4% of patients, respectively. Laterality and age seemed to be associated with chance of having OC. Interestingly, none of the OCs detected were among the known 32 mutation carriers. MRI staging appears to identify OC to an equal extent in a largely Hispanic and younger underserved population as reported in the literature for populations of mostly insured patients.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-01-11.
Abstract P4-01-15: Impact of Preoperative MRI on the Surgical Treatment of Breast Cancer: A SEER-Medicare Analysis
Authors: Thorsen CM , Weiss JE , Kerlikowske K , Ozanne EM , Buist DS , Hubbard RA , Tosteson AN , Henderson LM , Virnig BA , Goodrich ME , Onega TL
Published: August 2014

Background: Preoperative magnetic resonance imaging (MRI) use has increased for women with invasive breast cancer and ductal carcinoma in situ (DCIS). Prior studies have disputed whether preoperative MRI is associated with increased rates of mastectomy. We evaluated the rates of mastectomy versus breast conserving surgery (BCS) and their association with preoperative MRI in older women.

Methods: We identified women in SEER-Medicare 66 years or older diagnosed with DCIS or invasive breast cancer between 2002 and 2007 treated within 6 months of diagnosis with mastectomy or breast conserving surgery (BCS) with or without radiotherapy (RT). Preoperative MRI was defined as MRI occurring before a woman's first surgery after her initial diagnosis. We looked for surgical treatment (BCS or mastectomy) and radiotherapy, age at diagnosis, year of diagnosis and cancer type, overall and separately by receipt of MRI. We examined the association of surgical treatment with MRI using multivariable logistic regression adjusting for age at diagnosis, year of diagnosis, cancer type and radiotherapy.

Results: Among the 70,758 women identified, 5,126 (7.2%) had a preoperative MRI. The overall use of MRI increased from 1.2% in 2002 to 18.0% in 2007 (p < 0.0001). Women with MRI were more likely to undergo mastectomy than those without MRI (331 per 1000 vs. 314 per 1000; respectively, p < 0.0001) and more likely to undergo BCS RT (432 per 1000 vs. 354 per 1000; respectively, p < 0.0001).

Conclusion: The use of preoperative MRI has increased in recent years and is significantly associated with increased rates of BCS RT and mastectomy. Limitations of this study include that it is an observational analysis and that selection bias may exist for MRI and aggressive treatment that is not related to what is observed on MRI. Further studies are needed to understand how patient characteristics and information obtained from MRI influence treatment choices.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-01-15.