bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-10-11: Clinical Significance of Progesterone Receptor and HER2 Status in Estrogen Receptor-Positive, Operable Breast Cancer with Adjuvant Tamoxifen: Consistent Prognostic Impact of HER2 Status Over Time
Authors: Moon YW , Park S , Sohn JH , Kang DR , Koo JS , Park HS , Chung HC , Park B-W
Published: April 2011

Purpose: To evaluate prognostic factors in estrogen receptor (ER)-positive, operable breast cancer, focusing on the progesterone receptor (PR) and HER2 over time.

Patients and Methods: A total of 819 patients with ER-positive, operable breast cancer were enrolled. All received adjuvant tamoxifen. Prognostic value of the PR status and HER2 status was evaluated using Cox regression before and after 5 years post-surgery.

Results: PR and HER2 status were inversely correlated (P = .014). PR-negativity was a time-dependent poor prognostic factor for recurrence before 5 years post-surgery (P = .049), but not after 5 years post-surgery (P = .566).

However, HER2 overexpression and younger age (35 years or less) were consistent prognostic factors for recurrence over all time periods, whereas N stage and histologic grade, which are known prognostic factors, were no longer informative after 5 years post-surgery, except for N3 disease. Conclusion: In ER-positive, operable breast cancer, the prognostic impact of PR status along with N stage and histologic grade were strong for the first 5 years post-surgery, but disappeared thereafter. However, HER2 overexpression was a consistent poor prognostic factor, suggesting that an alternative adjuvant strategy, possibly involving incorporation of prolonged HER2-targeted therapy should be evaluated for HER2-overexpressing tumors.

Figure available in online version.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-11.
Abstract P3-10-13: Prognostic Value of Genomic Analysis after Neoadjuvant Chemotherapy for Breast Cancer
Authors: Mayer EL , Shak S , Miller K , Rugo H , Carey L , Ryabin N , Pomeroy C , Yoshizawa C , Winer EP , Burstein HJ
Published: April 2011

Background

Oncotype DX® Recurrence Score® (RS) provides both predictive and prognostic information for estrogen receptor positive (ER+) breast cancer. Whether RS evolves after exposure to chemotherapy (C), or if RS post-neoadjuvant C has prognostic capacity for outcomes after bevacizumab, is not known. Methods

DFCI 05-055 treated patients (pts) with residual invasive disease following neoadjuvant C with sequential bevacizumab-containing regimens. Archival FFPE tissue was obtained from participants at 3 potential timepoints: pre-C core biopsy, post-C surgical residual disease, and core biopsy at time of systemic recurrence. Standard RS testing was performed on all samples.

Results

A total of 162 pts were enrolled on the parent study; of that, 118 samples from 80 pts were available for testing, including 48 pre-C core biopsies, 68 post-C surgical samples, and 34 paired samples before and after C. Comparison of ER/PR/HER2 testing by local IHC vs RT-PCR for the pre-C core biopsies showed excellent concordance. For the entire cohort of 80, 20 pts (25%) experienced distant recurrence (9 ER+, 11 ER-by IHC). RS risk distribution in this group included 14 high, 3 intermediate (int), and 3 low. High RS was positively associated with distant recurrence for the entire cohort (t-test p=0.04); this association remained consistent whether RS was tested pre-C (t-test p=0.07) or post-C (t-test p=0.02). Specimen characteristics of the 34 paired pre-C/post-C samples are described below. Of the 34 paired samples, RS was highly correlated before and after exposure to neoadjuvant C, (r=0.85, 95% CI 0.72-0.92), suggesting little, if any, change in RS from C exposure. Specific changes over time included 24 without change in RS group, 3 high to int, 1 high to low, 1 int to low, and 5 low to int. Testing by RT-PCR remained consistent for ER (r=0.91, 95% CI 0.82-0.95), PR (r=0.79, 95% CI 0.62-0.89) and HER2 (r=0.88, 95% CI 0.76-0.94) before and after neoadjuvant C. Two pts had biopsy samples from systemic recurrence; testing showed RS, ER, PR, HER remained in similar range from core biopsy to surgery to disease recurrence.

Conclusions

In this evaluation of samples pre-and post-neoadjuvant C, high RS determined either before or after neoadjuvant C predicted for disease recurrence after adjuvant bevacizumab treatment. RT-PCR and IHC values for ER/PR/HER2 were concordant. Paired RS and RT-PCR ER/PR/HER2 remained correlated despite interval exposure to neoadjuvant C. Post neoadjuvant C RS may provide valid prognostic information for breast cancer disease recurrence and warrants further study.

Specimen Characteristics for Paired Samples (n=34)

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-13.
Abstract P3-10-15: Quantitative Gene Expression by RT-PCR in Classic and Variant Forms of Lobular Carcinoma in Estrogen Receptor Positive Invasive Breast Cancer
Authors: Anderson JM , Yoshizawa C , Winer EP , Watson D , Millward C , Tan V , Shak S , Baehner FL
Published: April 2011

Background: Classic lobular carcinoma is characterized by a distinctive morphology, loss of E-cadherin commonly due to mutation or deletion of CDH1 on chromosome 16q, and a variable clinical course (Pestalozzi J Clin Oncol. 2008 26:3006). Variants (pleomorphic, solid and alveolar) with distinct morphologies and potential differences in outcome have been described (Rosen 2009). Herein we explore the patterns of quantitative gene expression as measured by the 21 gene Oncotype DX® assay observed between ductal NOS (DC) and classic and variant lobular carcinomas. Material and Methods: All tumors analyzed in the Genomic Health laboratory from 6/1/04-3/31/10 were included. Central path used WHO criteria for classification of classic lobular (CL), solid & alveolar lobular (SAL), and pleomorphic lobular (PL) carcinomas. Quantitative expression of 16 cancer related genes was measured on a scale from 0 to 15 (relative to reference genes) where a 1 unit increment is associated with an ∼2-fold change in expression. Descriptive statistics for RS & individual genes [ER, PR, invasion gene group (IGG) & proliferation gene group (PGG)] among the different subtypes were obtained. Comparisons of means among the subtypes were adjusted to control the overall error rate under any complete or partial null hypothesis.

Results: DC accounted for 90.4% of 133,234 cases, CL 8.2%, SAL 0.7% and PL 0.8%. For all types a continuous range of RS was observed. DC had the greatest percentage of high risk RS followed by SAL, PL and CL. DC had the highest RS and CL had the lowest RS. SAL had the highest ER expression and CL had the lowest expression, but these results may refect a submission bias and are not population based. The proportion with the ER+/PR-phenotype was slightly different among the subtypes: SAL (24.2%) and PL (19.5%) had a higher incidence compared to DC (15%) and CL (15.6%). SAL had the highest PGG expression; CL had the lowest. DC had the highest IGG; CL had the lowest.

Discussion: Classic lobular carcinoma and the lobular carcinoma variants are characterized by differential patterns of gene expression. Outlier cases are not infrequent within each of the special subtypes in this large observational cohort. The variation in gene expression, noted by histologic subtype, will be presented in detail.

RS Distributions in Ductal NOS, Lobular and Lobular Variants

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-15.
Abstract P3-10-17: The Fractal Analysis of Tumor Histology Is an Independent Prognostic Factor in Breast Cancer Patients
Authors: Magliocco A , Eliasziw M , Tambasco M
Published: April 2011

Background: Despite the usefulness of standard clinical prognosticators for breast cancer patients, recommendations for systemic adjuvant therapy are not entirely straightforward. Hence, there is a need for a more accurate independent prognosticator that provides additional information to improve risk assessment and associated therapeutic decisions. Methods: We used fractal dimension analysis to quantitatively assess the morphologic complexity of breast epithelium. To investigate the relationship between fractal dimension and patient survival we applied fractal analysis to pan-cytokeratin stained tissue microarray (TMA) cores derived from a series of 408 patients with over 10 years follow up, and analyzed three TMA cores for each patient. A data-oriented approach was used to stratify patients according to low (<1.56), intermediate (1.56-1.75), and high (>1.75) fractal dimension. Univariate statistical analyses were performed to show the relationship between outcome and fractal dimension, tumour size, tumour grade, lymph node status, estrogen receptor status, and HER-2/neu status. Multivariate analysis was performed to assess the relative effect of these prognosticators on disease-specific and overall survival.

Results: Patients with higher fractal score had significantly lower disease-specific 10-year survival (69.4%, 56.4%, and 25.0%, for low, intermediate, and high fractal dimension, respectively, P<0.001). Overall 10-year survival showed a similar association with fractal dimension. Cox regression analysis showed fractal dimension, lymph node status, and grade to be the only significant (P<0.05) independent predictors for both disease-specific and overall survival. Fractal dimension had the highest hazard ratio for overall survival 2.7(95% confidence interval (CI)=1.6-4.7); P<0.001), and the second highest for disease-specific survival 2.6(95% CI=1.4-4.8; P=0.002) versus 3.1(95% CI=1.9-5.1; P<0.001) for lymph node status. Discussion: Except for lymph node status, morphologic complexity of breast epithelium as measured by fractal dimension is more strongly and significantly associated with disease-specific and overall survival than standard clinical prognosticators. Furthermore, it is independent of standard prognosticators, and unlike tumour grade, it provides prognostic information that can be objectively assessed from TMA cores.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-17.
Abstract P3-10-20: The Prognostic Relevance of Serum CA27.29 level in Primary Breast Cancer Patients before Adjuvant Chemotherapy — Results of the German SUCCESS Trial
Authors: Neugebauer JK , Rack BK , Schindlbeck C , Schrader I , Tesch H , Schneeweiss A , Zwingers T , Lichtenegger W , Beckmann MW , Sommer HL , Friese K , Janni W
Published: April 2011

Background: While tumor markers are frequently used to assess treatment efficacy in metastatic breast cancer, there is lack of evidence regarding the role of MUC-1 markers in primary disease. The value of CA27.29 in the adjuvant setting was prospectively evaluated in the German multicenter SUCCESS study.

Material and Methods: The German SUCCESS trial is a multicenter phase III study comparing FEC-Docetaxel (Doc) vs. FEC-Docetaxel-Gemcitabine (Doc-G) and 5 versus 2 years of Zoledronate as adjuvant treatment in patients with node positive or high risk node negative primary breast cancer. In this trial serum CA27.29 level has been prospectively evaluated in 3202 patients before and immediately after adjuvant chemotherapy as well as 2 and 5 years thereafter. CA27.29 was measured with the ST AIA-PACK CA27.29 reagent using MUC-1 for AIA-600II (Tosoh Bioscience, Tessenderlo, Belgium). The cutoff for positivity was >31 U/ml. Results: Mean CA27.29 serum level before adjuvant chemotherapy was 19,3 U/ml (SD +/− 15,5) in both arms. 8,0% (n=127) of patients in the FEC-Doc-G arm and 7,4% (n= 120) in the FEC-Doc arm had marker levels of more than 31 U/ml. Mean CA27.29 serum levels were significantly higher in patients with lobular carcinoma (p=0.001), with positive lymph nodes (p=0.02) and post-menopausal patients (P<0.001). After a median follow-up period of 34 months 233 patients relapsed and 108 patients died. CA27.29 before chemotherapy was a significant prognostic marker for disease-free survival (DFS) (P<0.0001) and overall survival (OAS) (P<0.0001) in univariate and multivariate analysis. Conclusion: These findings indicate the independent prognostic relevance of serum CA27.29 levels in primary breast cancer patients before adjuvant treatment. Further follow-up within the SUCCESS trial will show whether initial CA27.29 level could serve as a tool for adjuvant treatment monitoring.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-20.
Abstract P3-10-24: Fibroblast Growth Factor Receptor 1 Amplification and Overexpression in Breast Cancer Tissue Microarrays Using Chromogenic In Situ Hybridization and Immunohistochemistry
Authors: Nuciforo P , Burzykowski T , Lambertini C , Gardner H , Liu WH , Lee B , Barzaghi-Rinaudo P , Rheinhardt J , Barrett C , Linnartz R , Dugan M , Hackl W , Eiermann W , Pienkowski T , Crown J , Robert N , Pawlicki M , Martin M , Finn R , Lindsay M-A , Slamon D , Press M
Published: April 2011

Fibroblast growth factor receptors 1 (FGFR1) belongs to a subfamily of receptor tyrosine kinases (RTKs), which are involved in proliferation and apoptosis. FGFR1 amplification and mRNA overexpression occurs in ∼10% of breast cancers and has been associated with poor outcome. However, studies assessing FGFR1 amplification and protein overexpression in a large collection of breast tumors are lacking. In this prospective, we examined a series of primary breast cancers samples derived from the BCIRG trials assembled into 15 tissue microarrays. FGFR1 gene amplification was studied using chromogenic in situ hybridization (CISH) and evaluated with respect to association with level of protein expression and clinicopathological parameters. FGFR1 gene amplification was significantly associated with high protein levels as determined by immunohistochemistry (P<0.0001, 3294 pts with available matched CISH and IHC records). Overall, the incidence of FGFR1 amplification found was 9.7% (160 out of 1646 pts. with available clinicopathological records) without a statistically significant difference between Her2- (78 out 720 pts., 11%) and Her2+ (82 out of 926 pts., 9%) cancers. In both cohorts, the hormone receptor-positive (ER+/PR+) cancers showed statistically significant higher levels of FGFR1 amplification compared to hormone receptor-negative tumors. In the analysis of the association of FGFR1 and the presence of PIK3CA mutations, the incidence of FGFR1 amplificationwas greatly reduced in mutant vs. wt PI3KCA tumors. In these cohorts, a clear relationship between FGFR1 amplification status and clinical outcome was not detected. Data from this large study confirms recently reported incidences of FGFR1 amplification in breast cancer and shows for the first time an association between FGFR1 gene amplification and protein overexpression. Moreover, the lower incidence of FGFR1 amplification in PIK3CA mutated cancers suggests that these are largely exclusive molecular events that could benefit from different targeted therapies.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-24.
Abstract P3-10-25: The Prognosis of Metaplastic Breast Cancer Patients Compare to Triple-Negative Breast Cancer Patients
Authors: Cho DH , Jang JH , Lee SK , Choi M-Y , Koo MY , Hur SM , Bae SY , Kim SM , Choe J-H , Lee JE , Kim J-H , Kim JS , Nam SJ , Yang J-H
Published: April 2011

Background: Metaplastic breeast cancer (MBC) is a rare, heterogenous cancer characterized by admixture of adenocarcinoma with metaplastic elements, low hormone receptor expression and poor outcome. This study was planned to assess the clinicopathological chacteristics and immunohistochemical findings of MBC compared to invasive ductal carcinoma (IDC) including the triple-negative subtype (TN-IDC). Material and Methods: We retrospectively reviewed the medical records of 47 MBC and 1,346 IDC patients. Two hundred eighteen TN-IDC patients were included in the 1,346 IDC patients. Between 2005 and 2009, these patients were undergone surgical treatment at the Samsung Medical Center. Patients were reviewed clinicopathologic factors, immunohistochemistry of biologic factors such as ER, PR, HER-2, p53, Ki67, cytokeratine (CK) 5/6, epidermal growth factor receptor (EGFR), and treatment modalities (type of operation, use of chemotherapy, radiotherapy and hormone therapy). Result: The MBC patients presented with a larger tumor size (>T1, 66.0% vs. 44.3.%, P = 0.008), lower lymph node involvement (N0, 73.3% vs. 55.6%, P = 0.03), higher histologic (HG) and nuclear grade (NG) (HG3, 70.0% vs. 41.5%, P = 0.001; NG3,82.6% vs. 46.9%, P < 0.001), fewer estrogen receptor (ER), progesterone receptor (PR) and HER2 positivity (ER+, 4.3% vs. 69.2%, P < 0.001; PR+, 6.4% vs. 63.5%, P < 0.001; HER2+, 0% vs. 27.6%, P < 0.001), higher p53, CK5/6 and EGFR expression (p53+, 63.8% vs.38.8%, P < 0.001; CK5/6+, 71.9% vs.21.5%, P < 0.001; EGFR+, 93.9% vs.21.6%, P <0.001) and more TN subtypes (93.6% vs. 16.2%, P < 0.001) compared to the IDC group. There was no significant difference in clinicopathological characteristics with MBC and TN-IDC except EGFR over expression (EGFR+, 93.9% vs.69.0%, P = 0.017). In follow-up duration (median 30 months, range 2-56 months), seven (14.9%) MBC patients and 98 (7.2%) IDC patients recurred. The 3-year disease-free survival (DFS) rate was 78.1% in the MBC group and 91.1% in IDC group (P <0.001). The 3-year DFS rate was not significantly difference between MBC group and TN-IDC group (78.1% vs. 84.9%, P = 0.114). However, in patients with lymph node metastasis who underwent adjuvant chemotherapy, the 3-year DFS rate was 44.4% in MBC group and 72.5% in TN-IDC group (P = 0.025).

Discussion: In our result, MBC show poorer clinical outcome than IDC. It is not shown significant difference between MBC and TN-IDC. However, MBC patients with nodal metastasis have poorer prognosis than TN-IDC patients with metastasis despite adjuvant chemotherapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-25.
Abstract P3-10-31: Epithelial Proliferation (Ki67) Is Not an Independent Variable for Breast Cancer Relapse in Symptomatic or Screen Detected Breast Cancers (SDBC)
Authors: Bundred NJ , Knox WF , Cramer A , Wilson M , Prasad R , Morris J
Published: April 2011

Background: UK screen detected breast cancers (SDBC) (aged 50-65 years) have an overall 97.2% 5 year relative survival compared to 77.6% for symptomatic cancers. Epithelial proliferation has been used to determine therapy in the St. Gallen guidelines (Ki67 ≥30% indicates the need for chemotherapy).

Methods: To determine the value of Ki67 in post-menopausal breast cancer in women aged 50-65 years, we have studied Ki67 in 1270 women aged 50-65 years (mean 57 years) with either symptomatic cancers (n=412) or SDBC (n=858) with a 10 year follow up.

Results: Ki67 predicted relapse and death in both symptomatic and SDBC. Mode of detection, size, grade, node status and oestrogen receptor (ER) were independently predictive of breast cancer mortality and Ki67 was not an independent variable. In small size ≤15mm ER positive SDBC (n=248) or symptomatic cancers (n=146), Ki67 was not prognostic (p=0.13 and 0.59 respectively). Twelve per cent of symptomatic and 2% of SDBC had died within 5 years. Mean Ki67 in SDBC was 21.4 (SD 10.3) and 34.2 (SD 16.2) in symptomatic cancers (p=≤0.001). ER positive cancers had lower Ki67 levels (p=0.002). For each 10 unit increase in Ki67, increases in distant relapse occurred (RR 1.43:95%CI;1.32-1.55).

Ten Year Survival According to Ki67 and Mode of Presentation

Discussion: Epithelial proliferation is prognostic in breast cancer but its value is predominantly in large size (≥15mm) symptomatic tumours and Ki67 alone cannot be used to determine therapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-31.
Abstract P3-10-37: Molecular Analysis of Single Circulating Tumor Cells for Characterization of the Targets of Systemic Breast Cancer Therapy as Chance to Individualize Therapy
Authors: Carl S , Camara O , Plaschke-Schluetter A , Kroll T , Pachmann K.
Published: April 2011

Background: In breast cancer therapy predictive and prognostic markers are derived from the primary tumor but systemic therapy aims at eliminating the remnant tumor cells left in the body after surgery which the cells circulating in peripheral blood are part of. For individualized therapy, therefore, it would be advantageous to better characterize this remnant disease for more targeted therapeutic approaches. Materials and Methods: 10 to 20 single live epithelial antigen positive cells were isolated from peripheral blood of 50 newly diagnosed breast cancer patients using the automated capillary cell isolation system of the MMI CellEctor and individually deposited under visual control onto Ampli Grid slides (Advalytics). The mRNA was the reverse transcribed and amplified using primers for 6 different tumor associated targets among them EpCAM and Her2/neu.

Results: Expression profiling could be successfully performed from more than 80% of all individually deposited isolated cells demonstrating the epithelial nature of these cells but also heterogeneity among the cells of in individual patients with respect to other genes. Thus we show that circulating epithelial cells from breast cancer patients can be individually deposited and these single celsl can subsequently be subject to expression profiling.

Discussion: Further analysis by high through-put profiling of the remnant tumor burden in breast cancer patients after surgery comprising the cells circulating in peripheral blood may contribute to better characterize the targets of systemic therapy in order to individualize cancer therapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-37.
Abstract P3-10-38: Histopathological Subclassification of Triple Negative Breast Carcinoma Using Prognostic Scoring System
Authors: Miyashita M , Ishida T , Tamaki K , Amari M , Ohuchi N , Sasano H.
Published: April 2011

Purpose: Triple negative breast carcinoma (TNBC) is currently being required to be classified pluralistically in order to provide the most appropriate therapy to the patients. We attempted to subclassify TNBC cases into subgroups based on clinical outcome or prognosis of the patients with TNBC using archival specimens. Materials and Methods: We analyzed 102 Japanese cases of invasive TNBC who underwent surgery between January 1998 and December 2007. The clinicopathological factors and clinical information of these patients were retrospectively retrieved from charts of the patients. Immunohistochemical staining was performed for estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor 1 (EGFR1), CK5/6, Ki-67 and CD31 for microvessel density (MVD). Results: Median follow-up time of the patients was 68.5 months. Multivariable analysis demonstrated that the pathologic node status was the most significantly associated with relapse-free survival (RFS) and breast cancer-specific survival (BCSS) of the patients. Pathological tumor size, basal-like type, Ki-67 labeling index (LI) and MVD were also independently associated with RFS and BCSS. Based on these results, we devised the Risk Score system reflecting Hazard ratios (HRs) of these prognostic factors above.

Multivariate analysis and the Risk Score for TNBC patients.

With this system, TNBC patients in this study were classified into three subgroups; patients with score 0-3 are in low risk group, score 4-7 in intermediate risk group and score 8- in high risk group. These three groups had statistically significant differences for risk of relapse and breast cancer-specific death, respectively.

Conclusions: We propose the Risk Score system, which incorporated pathologic nodal status, size of the primary tumor, the presence or absence of basal-like features, Ki67 LI and MVD of the patients in order to predict postoperative clinical course of the Japanese patients with TNBC. Such a classification which can be performed in diagnostic pathology laboratory can be useful as a decision-making tool for triple negative patients.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-38.
Abstract P3-11-02: Aspirin Use in the Community and the Risk of Breast Cancer
Authors: McCowan C , Carroll S , Makubate B , Dewar JA , Schweiger S , Thompson AM.
Published: April 2011

Introduction: Breast cancer is the most common cancer in women with incidence rates increasing annually. Laboratory work at Dundee had suggested aspirin may be a chemo-preventive agent for breast cancer, although a recent US study has shown no effect of aspirin use in reducing breast cancer in premenopausal women.1 Using routine population datasets in Tayside, this study examined the use of aspirin and the development of breast cancer.

Methods: From the cancer registry all women in Tayside with an incident breast cancer from 1998 onwards were identified. Prescribing records for all women aged 30 and over were extracted for the period 1993 to 2003. Women with a breast cancer diagnosis prior to 1998 were excluded. Use of aspirin was examined with dosing and duration of use calculated. Cox proportional hazards models were used to determine if drug use reduced the risk of breast cancer

Results: There were 117,948 women aged 30 or over on the 1st January 1998 who were resident throughout the study period or until their death. 1,761 had a diagnosis of breast cancer prior to 1st January 1998 and so were excluded from further analysis. There were 23,970 (20%) women who encashed a prescription for aspirin between 1st January 1993 and 31st December 2003.

The median duration of aspirin use was 3.1 years (IQR 0.6-6.2) and patients took aspirin for a median 6 days (IQR 5-7) per week over that period. There were a total of 1,420 (1.2%) cancers recorded during the study period.

Ever use of aspirin was associated with a reduced risk of breast cancer (HR=0.635, 95% CI 0.550-0.733, P<0.001) after allowing for age and social. Increasing duration of aspirin was associated with reducing risk of cancer compared to never users and higher aspirin usage was also associated with a decreasing risk.

Conclusions: Aspirin would seem to be an effective chemo-preventive agent from this population based study. However further research is required to determine its effectiveness and to identify the groups of patients who may benefit the most from its use.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-11-02.
Abstract P3-11-08: Incidence and Outcome of Male and Female Breast Cancer: A Multinational Population Based Study
Authors: Miao H , Verkooijen HM , Chia KS , Pukkala E , Larønningen S , Mellemkjær L , Czene K , Hartman M.
Published: April 2011

Background: Male breast cancer is a rare disease as its incidence rate is about 0.5% to 1% of that of female breast cancer. Given its scarcity, few studies have assessed the risk and prognosis.

Methods: We performed a multi-national population based study of 569,771 female breast cancer patients and 3,615 male breast cancer patients diagnosed in Denmark, Finland, Switzerland, Norway, Singapore and Sweden from 1943 to 2007. We calculated incidence and mortality as well as overall survival for both sexes. Life table analysis and Cox proportional hazard model were used to analyze the survival.

Results: The overall incidence rates, adjusted to the World Standard Population, of breast cancer were 60.2 per 100,000 in women and 0.4 per 100,000 in men. Women were diagnosed with breast cancer at a younger median age (61.4 years) than men (68.9 years). Among the 203,093 patients (35%) with information on TNM stage, 50% of the women and 47% of men were classified as stage I whilst stage III and stage IV cases accounted for 11% and 20% for women and men respectively. The 5-year cumulative survival was 66.2% for women and 53.0% for men. The adjusted relative risk of death was 24% higher in men [HR 1.24 (95% CI, 1.19-1.28)] as compared to women after controlling for age and time at diagnosis. Men had an 18% higher relative risk of death [HR 1.18 (95% CI, 1.09-1.27)] compared to women after further adjustment for TNM stage. Conclusion: Male breast cancer patients have later onset and worse prognosis than female patients. This may be due to the difference in tumour characteristics and treatment.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-11-08.
Abstract P3-11-12: Influence of Hormone Therapy Prior to Breast Cancer Diagnosis on Prognosis of Postmenopausal and Perimenopausal Breast Cancer Patients
Authors: Baumgaertner AK , Haeusler A , Seifert-Klauss VR , Schuster T , Schwarz-Boeger U , Kiechle M. Klinikum
Published: April 2011

Introduction: Use of hormone therapy (HT) has been associated with higher incidence of hormone receptor positive breast cancer in postmenopausal women. However, it is unclear if breast cancers developing after HT use are different in course of disease and prognosis from tumors growing without prior exogenous hormone use.

Methods:

Women with hormone receptor positive breast cancer diagnosed between 1984 and 2006 at our university breast cancer center (n=1247) were analyzed in a single-center retrospective trial. Outcome data comparing overall survival, local and distant recurrence were extracted from the hospital cancer data base and the local breast cancer registry, as well as from primary care-giving gynecologists and by review of patient charts. Cases were stratified according to hormone therapy use before breast cancer diagnosis. This is the first analysis differentiating between perimenopausal and postmenopausal patients.

Results:

1053 patients with hormone receptor positive non-metastasized invasive breast cancer were included in the final analysis. 198 (18.8%) women were premenopausal, 126 (12.0%) were perimenopausal and 729 (69.2%) were postmenopausal. Information on former HT use was available for 933 (88.6%) patients. 542 (51.4%) patients had never used HT, including 194 premenopausal patients. 324 (44.4%) postmenopausal and 67 (53.2%) perimenopausal women had used HT before breast cancer diagnosis. At time of first diagnosis there was a significantly higher rate of early stage and nodal negative disease in postmenopausal HT users versus non users (P<0.01 and p=0.02 respectively).

In multivariate analysis, HT use prior to diagnosis in postmenopausal patients resulted in longer time to progression and longer overall survival (RR 0.84 and RR 0.70 with p=0.34 and p=0.07 respectively). In perimenopausal patients however, HT use prior to breast cancer diagnosis was associated with shorter time to progression and overall survival (RR 2.41 and RR 3.32 with p=0.99 and p=0.05 respectively). Higher BMI in perimenopausal women had a significant influence on prognosis with RR=1.14 for TTP and RR=1.23 for OS, whereas it had no effect in the postmenopausal group.

Conclusion: According to this retrospective analysis, hormone therapy prior to breast cancer diagnosis has different effects on outcome parameters depending on patients’ menopausal state. Whereas in postmenopausal patients HT was associated with better prognosis, in perimenopausal women it might have detrimental effect.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-11-12.
Abstract P3-12-02: Polymorphisms, Endogenous Hormone Levels and Breast Cancer Risk in Premenopausal Women
Authors: Walker K , Johnson N , Palles C , Folkerd E , Hillier SG , Moss S , Gibson L , Dowsett M , Peto J , dos Santos Silva I , Fletcher O.
Published: April 2011

Background: Endogenous sex hormone levels are widely believed to be implicated in the etiology of breast cancer through indirect evidence such as early menarche and late menopause, and from direct evidence of an association between circulating levels and breast cancer risk in postmenopausal women. Epidemiological studies suggest that levels may be partly genetically determined, particularly in premenopausal women. Few studies have attempted to identify polymorphisms associated with endogenous hormone levels in premenopausal women, and their findings have been limited.

Quantification of hormone levels in premenopausal women is difficult because of their cyclical nature. In particular, estrogen has a marked peak in the follicular phase and a further wider peak in the luteal phase. Methods: 789 healthy premenopausal women from the Mammography Oestrogens and Growth Factors (MOG) study and the British Breast Cancer (BBC-NCRN) study each provided a single blood sample and up to 7 urine samples. We developed a protocol designed to capture peak follicular phase urinary estrone glucuronide (E1G), and luteal phase E1G. Repeated measurements of creatinine-adjusted E1G levels were used to describe features of the E1G curve such as mean and peak follicular E1G, and luteal E1G. Endogenous sex hormone binding globulin (SHBG) and the androgens testosterone, androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate were measured on single plasma samples. 691 tagging SNPs capturing common variation in genes within the estrogen synthesis and metabolism pathways were successfully genotyped. Linear regression was used to evaluate the effect of each polymorphism on (log-transformed) measures of urinary E1G levels, SHBG levels and plasma androgen levels.

Results: We identified a SNP with minor allele frequency of 7%, in which the minor allele was associated with a 20% reduction in circulating levels of E1G (P<10-8) in healthy premenopausal women. We are currently genotyping this SNP in 12,000 breast cancer cases and 12,000 controls to test whether the reduction in circulating estrogen levels affects breast cancer risk.

Conclusions: Circulating hormone levels in premenopausal women may provide a useful intermediate phenotype in the search for low-penetrance breast cancer risk alleles.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-12-02.
Abstract P3-12-09: Numb Expression Varies by Hormone Receptor Status among Danish Breast Cancer Patients
Authors: Zhou W , Rasmussen B , Busch-Sørensen M , Demuth T , Reilly J , Bergstrom D , Pearson J , Møller S , Ejlertsen B.
Published: April 2011

Background: Numb-mediated regulation of Notch signaling pathway might play a causative role in early breast cancer. Little information is available on whether Numb expression differs according to tumor characteristics including hormone receptor status. We investigated Numb expression status in archival tissue from primary tumor of 197 breast cancer patients identified within the 2004 cohort of the Registry of the Danish Breast Cancer Cooperative Group's (DBCG), where patients were treated according to the guidelines of the DBCG.

Materials and Methods: Numb expression was measured by immunohistochemistry method, and Numb(-) was defined as Numb immunoreactivity present in less than 10% of the invasive tumor cells. Chi-square test was used to assess the correlation between Numb(-) and hormone receptor status.

Results: The median age was 57 years (range, 26-98), 32% were premenopausal. 82% were ductal, 9% lobular, 9% others. 10% were grade I, 41% grade II, 47% grade III, 2% non-graded. 70% were node positive. 60% were ER+, 41% PR+, and 24% were HER2+ by IHC and FISH. 58% were operated by mastectomy, 42% by lumpectomy. The adjuvant treatment comprised Tamoxifen (36%), cyclophosphamide/methotrexate/fluorouracil (CEF, 19%), CEF+Tamoxifen (11%), and 22% were missing treatment information. 49% relapsed and 3% metastasized during 10 year of follow up. Overall, 10% (19 out of 197) of patients were Numb(-). Numb expression was significantly associated with hormone status, with a Numb(-) frequency of 24% (9/37) among ER+/PR-/HER2-, 9% (6/65) among ER+/PR+/HER2-, 6% (3/47) among HER+ (1/16 among ER+/PR+/HER2+ and 2/31 among ER-/PR-/HER2+), and 2% (1/47) among ER-/PR-/HER2- patients (P<0.01). Similar differences were observed using the H-score matrix where the IHC intensity was summarized with a range of 0-300.

Discussion: Our results suggested Numb(-) is correlated with hormone status, with the higher frequency of Numb(-) among ER+/PR-/HER2- patients, and lower frequency among other groups, particularly the triple negative group.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-12-09.
Abstract P3-13-01: Delayed Chemotherapy-Induced Nausea and Vomiting in Asian Women with Breast Cancer
Authors: Bourdeanu L , Mortimer J , Somlo G , Hurria A , Chung C , Frankel P , Luu TH.
Published: April 2011

Background: Chemotherapy-induced nausea and vomiting (CINV) remain among the most frequently reported distressing side effects associated with a doxorubicin-based chemotherapy regimen, and it can significantly affect patients’ quality of life and compliance with therapy. Despite the significant advances in antiemetic management in preventing and controlling CINV, as many as 50% of patients still experience some degree of nausea and vomiting. The main risk factor for the degree of CINV is the emetogenic potential of the chemotherapeutic agents. However, several patient-related risk factors have been identified, including individuals’ genetic makeup. Although several studies have noted that ethnicity influences nausea and vomiting related to motion sickness, fluorescein dye, and pregnancy, no studies have evaluated the relationship between ethnicity and CINV; specifically, if there is a higher incidence of severe CINV in patients of Asian descent.

Methods: A retrospective, comparative, correlational chart review was performed to abstract all relevant variables. The association between CINV and ethnicity was examined through chi square analysis.

Results: Data from a convenience sample of 300 women with breast cancer who received chemotherapy that includes doxorubicin between 2004 and 2008 at City of Hope in Duarte, CA, were evaluated. The sample consisted of Caucasians (46.3%), African Americans (3.7%), Asians (24.0%), and Hispanics (26.0%). The results of this study indicate that Asian women with breast cancer undergoing treatment with chemotherapy that includes doxorubicin experienced statistically significantly more severe CINV (grade ≥ 2) than their non-Asian counterparts (X2 = 10.601, p = .001). Conclusion: This study provides strong but preliminary evidence that Asian ethnicity plays a role in the development of severe CINV. When managing chemotherapy toxicities in women with breast cancer, healthcare providers are advised to optimize their patients’ outcomes by ensuring that therapy is tailored according to each patient's individual risk profile. Consideration of the antiemetic therapy should accommodate patient characteristics, specifically being of Asian descent. In this way, effective prevention of CINV can be maximized during a patient's initial treatment.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-13-01.
Abstract P3-13-03: Association between Ethnicity and Survival after Breast Cancer in a Multi-Ethnic Asian Setting: Results from the Singapore-Malaysia Hospital-Based Breast Cancer Registry
Authors: Bhoo Pathy N , Verkooijen HM , Taib NA , Saxena N , Iau P , Bulgiba AM , Lee S-C , Yip C-H , Hartman M.
Published: April 2011

Background: Little is known on the impact of ethnicity on survival after breast cancer in the multi-ethnic Asian setting. Material and Methods: Using the multi-institutional Singapore-Malaysia hospital-based breast cancer registry, we investigated the association between ethnicity and risk of mortality after breast cancer in 3,366 patients diagnosed between 1990 and 2007 (Chinese: 77%, Malay: 15%, Indian: 8%). Kaplan-Meier analysis was used to estimate overall cumulative survival (OS). Multivariable hazard ratios (HR) adjusted for tumor and treatment characteristics were computed using Cox regression analysis after splitting follow-up time along the age-axis and calendar-time axis. Results: Malay patients presented at younger age compared to Chinese and Indians (47years vs 52years vs 53years, respectively, P<0.001) with larger tumors (35mm vs 24mm vs 30mm, respectively, P<0.001), and at later stages (TNM stage III or IV) (37% vs 23% vs 25%, respectively, P<0.001). Malay women were least likely to have undergone surgery, and most likely to receive chemotherapy. Five-year OS was 71.9% (95% CI: 69.7%-74.1%) in Chinese, 47.2% (95%CI: 41.9%-52.5%) in Malays and 62.7% (56.0%- 69.4%) in Indians.

After adjustment for tumor and treatment characteristics, Malay patients had approximately 60% higher risk of death than the Chinese (HR:1.57; 95%CI:1.40-1.77). Indian ethnicity was not significantly associated with risk of mortality after breast cancer compared to Chinese (HR:1.12; 95%CI: 0.98-1.30).

Conclusion: In the Asian setting, Malay ethnicity seems to be associated with significantly poorer survival after breast cancer, independent of tumor and treatment profile. The underlying reasons for this association are unclear but may be explained by variations in susceptibility to treatment, co-morbidity and lifestyle after diagnosis of breast cancer.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-13-03.
Abstract P3-13-07: Clinicopathologic and Biologic Recurrence Risk in African-American Versus Caucasian Women with Early-Stage Hormone Receptor Positive Breast Cancer, a Single Institution Experience
Authors: Allen AD , Allen JW , Sachdev JC.
Published: April 2011

Background: African-American women with hormone receptor positive breast cancer have an inferior survival compared to Caucasians (Sparano, et al (SABCS, 2009, Abstract #37) and Albain, et al (ASCO, 2010, Abstract #511)). It is not clear whether this difference is a result of disparities in access to care and stage at presentation or biological factors. We sought to examine whether African-American women with early-stage hormonereceptor positive breast cancer had a higher risk of recurrence than similarly staged Caucasians using a standard clinicopathologic risk prediction algorithm (AdjuvantOnline!) and a biologic risk prediction algorithm (Oncotype DX).

Materials and Methods: Women with early stage, hormone receptor positive, Her2 normal, lymph node negative breast cancer seen at the University of Tennessee Cancer Institute between 2007-2009 were retrospectively reviewed. All patients had an AdjuvantOnline! recurrence risk calculated. For patients in whom an Oncotype DX was available, differences in risk of recurrence between clinicopathologic and biologic algorithms were evaluated with respect to race (African-American versus Caucasian).

Results: 96 women were identified, 38 of whom were African-American and 58 of whom were Caucasian. 50 women had an Oncotype DX available. Clinicopathologic factors were well-balanced between the groups (see Table 1). Using AdjuvantOnline!, there was no significant difference between African-American and Caucasian patients in their average risk of recurrence (25% versus 23%, P=0.15). Using Oncotype DX, there was similarly no significant difference in the average risk of recurrence by race (18.6% for African-American versus 18.9% for Caucasian, P=0.55).

Patient Characteristics

Grade was not available for 1 Caucasian patient.

Discussion: When matched for stage and general clinicopathologic factors (hormone receptor positivity, Her2 normal, lymph node negative), African-American and Caucasian patients have similar risk of recurrence using AdjuvantOnline! and Oncotype DX, though the expected risk was somewhat lower with Oncotype DX in both groups. This would suggest that there may be little biologic difference between African-American and Caucasian women with early stage hormone receptor positive breast cancer and that any difference in survival is likely related to non-biological factors.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-13-07.
Abstract P3-14-09: Preclinical Safety and Activity of MM-302, a HER2-Targeted Liposomal Doxorubicin Designed To Have an Improved Safety and Efficacy Profile over Approved Anthracyclines
Authors: Wickham TJ , Reynolds J , Drummond DC , Kirpotin DB , Lahdenranta J , Leonard SC , Geretti E , Lee H , Klinz S , Hendriks BS , Olivier K , Eckelhofer I , Park JW , Benz CC , Moyo VM , Niyikiza C , Nielsen UB.
Published: April 2011

Background: Anthracyclines have been an effective backbone of breast cancer therapies for decades. However, cardiotoxicity issues associated with free anthracyclines have limited their effective use in the clinic and ledto the exploration of anthracycline-free regimens, particularly with HER2- positive cancers that require treatment with another cardiotoxic agent, trastuzumab. While liposomal doxorubicin formulations have succeeded in reducing cardiotoxicity, they have failed to demonstrate clearcut efficacy advantages and can involve other toxicities. To address the safety and efficacy limitations of currently available anthracyclines, we have designed a new liposomal formulation, MM-302, that targets doxorubicin to HER2- overexpressing tumor cells. Antibody fragments that bind to HER2 without blocking HER2-mediated signaling are coupled to the outer surface of pegylated liposomal doxorubicin. MM-302 specifically binds and enters tumor cells overexpressing HER2 with minimal uptake into normal cells such as cardiomyocytes which express low levels of HER2. Materials and methods: MM-302, untargeted pegylated liposomal doxorubicin (PLD), and free doxorubicin were compared for their uptake into target and nontarget cells, pharmacokinetics, biodistribution, tumor microdistribution using FACS and confocal microscopy, and anti-tumor activity in BT-474 and NCI-N87 xenograft models. Results: Cellular uptake studies in tumor cell lines expressing various levels of HER2 demonstrate that MM-302 delivers significantly higher doxorubicin levels to HER2 over-expressing tumor cells compared to PLD as well as similar or higher levels than highly permeable free doxorubicin. However, in human cardiomyocytes, while free doxorubicin was again taken up at high levels, doxorubicin uptake was dramatically lower with both MM-302 and PLD. Pharmacokinetic studies in mice demonstrate that MM-302 has a similar half life, clearance, and organ distribution compared to PLD. In HER2-overexpressing BT-474 breast and NCI-N87 gastric tumor xenografts, MM-302 exhibits superior anti-tumor activity to both free anthracyclines and PLD. Tumor microdistribution studies further suggest that differences in the localization of doxorubicin in the tumor may be responsible for the enhanced activity of MM-302 compared to free doxorubicin and PLD.

Discussion: These preclinical data suggest that MM-302 may provide in clinical practice a new opportunity to specifically deliver an anthracycline to HER2-overexpressing tumors with a potentially cleaner safety profile and improved efficacy over currently available free or liposomal doxorubicin.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-09.