bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression levels of histone deacetylases and acetylation of histone H4 and tubulin associated with breast cancer progression.
Authors: Suzuki J , Chen Y , DeVries S , Chan L , Baehner FL , Benz CC , Waldman FM , Hwang E
Published: December 2010

Abstract #2051

Background: Excess histone deacetylase (HDAC) activity can induce global hypoacetylation of histone and non-histone protein substrates, altering gene expression patterns and cell behavior potentially associated with malignant transformation. However, HDAC expression and protein acetylation have not previously been studied in the context of breast cancer progression.  Materials and Methods: We performed immunohistochemistry (IHC) to assess expression levels of acetylated histone H4 (acH4), acH4K12, acTubulin, HDAC1, HDAC2 and HDAC6 in formalin fixed paraffin embedded sections with synchronous normal epithelium (N), ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) components from 58 archived samples at UCSF. Staining was assessed on the basis of H-score, defined as the sum of the intensity of staining (0-3) multiplied by % of stained cells for each intensity (score range 0-300). H-score differences between groups were tested for significance using either the Mann-Whitney test or the Wilcoxon signed rank test for paired samples.  Results: From N to DCIS, there was a marked reduction in histone acetylation (acH4, acH4K12). Tubulin acetylation, a marker of non-histone protein acetylation, showed a smaller reduction. Expression of all three HDACs was also reduced, but to a lesser extent than histone acetylation. Moreover, from DCIS to IDC, the same pattern of changes in acetylation and HDAC expression was seen, although these differences were of smaller magnitude than between N and DCIS. All markers were significantly different between N and DCIS (all p<0.0001) and between DCIS and IDC (all p<0.03). ER-negative tumors exhibited greater changes from N to DCIS than did ER-positive tumors, particularly for acH4 and HDAC1 (p=0.05 and 0.0001 respectively). High-grade invasive tumors showed more significant changes from N to DCIS than low/intermediate grade tumors for acH4, acH4K12, acTubulin, and HDAC1 (p=0.0009, 0.006, 0.05, and <0.0001 respectively). The change in protein acetylation and HDAC expression with cancer progression did not differ by HER2 status or age (≤50 or >50).    Conclusions: Overall there was a pattern of hypoacetylation associated with malignant progression, with normal epithelium exhibiting the highest acH4, acH4K12, and acTubulin levels and IDC exhibiting the lowest levels. Paradoxically, expression of HDAC 1, 2 and 6 was not increased; thus, our data support that histone hypoacetylation is not regulated by HDAC expression but rather by modulation of HDAC activity. Outcome studies and clinical trials are needed to assess the prognostic significance of these findings and to determine how effectively HDAC inhibitors could reverse the hypoacetylation observed in progression from N to DCIS and IDC.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2051.
RANKL plays a role in migration and invasion of the bone-seeking cell line MDA-MB-231-BO2 through human type I collagen by up-regulating MMP1.
Authors: Casimiro S , Alho I , Fernandes A , Lipton A , Guise T , Costa L
Published: December 2010

Abstract #2052

Background: Cancer-induced bone destruction is associated with increased osteoclastogenic activity induced by tumor cells, and an unbalanced bone remodelling cycle that favours bone osteolysis. In this proccess the RANK-RANKL signaling is crucial for both osteoclastogenesis and osteoclastic activity. Furthermore, breast cancer cells have been shown to also express the RANK receptor and to increase migration towards RANKL stimuli, however it is not known if RANK - RANKL interaction stimulates breast cancer cell to invade and degrade bone collagen. Objective: To determine if RANKL increases the ability of breast cancer cells to invade a type I collagen matrix and degrade bone collagen. Material and Methods: The influence of sRANKL on MDA-MB-231-BO2 cell migration or cell invasion (type I collagen) were assessed by Boyden-chamber chemotaxis assay. Binding of RANKL to BO2 cells, levels of RANK expression and levels of matrix metalloproteinases secreted during invasion were determined by RT-PCR and WB analysis. The activation of AKT signaling pathway was determined by WB against the phosphorylated form pAKT1/2/3(Ser473). Results: sRANKL influences the migration and invasion of RANK-expressing BO2 cells in a dose-dependent manner (dose range 0.75-2.5 ug/mL), while the neutralization of sRANKL with a specific antibody abrogated this effect. sRANKL stimuli activates AKT pathway downstream of RANK, while the pre-treatment of cells with 100 nM of wortmannin (a PI(3)K inhibitor) blocked this effect and impaired invasion. During invasion of type I collagen the levels MMP1 expression and of secreted MMP1 increase and are positively correlated with the increase in sRANKL concentration. Conclusions: Our data suggest that RANKL can trigger an increase in expression of MMP1 by breast cancer cells expressing RANK, contributing to invasion via degradation of matrix proteins directly by the cancer cells.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2052.
Receptor activator of NF-kB (RANK) and RANK ligand protein expression in invasive ductal carcinoma.
Authors: Roudier-Meyer M , Jacob A , Tometsko M , Erwert R , Woody L , Soriano R , Huang L , Hawkins J , Branstetter D , Dougall W
Published: December 2010

Abstract #2057

Purpose: Bone metastases are commonly observed in patients with advanced breast cancer. Tumor cells interact with the bone microenvironment to induce osteoclastogenesis via local bone stromal expression of receptor activator of NF-kB ligand (RANKL), leading to bone destruction and release of growth factors. In addition to its critical role in tumor-induced osteolysis, RANKL has been demonstrated to enhance the invasive behavior of epithelial tumor cells that express RANK, and RANK over-expression in transgenic mice using the breast-specific MMTV promoter results in increased mammary carcinoma. This study assessed the expression of human RANK and its ligand (RANKL) in invasive ductal carcinoma (IDC).  Methods: We studied a total of 57 IDC specimens. Antibodies against human RANK (AF683) and human RANKL (M366; Amgen) were used for immunohistochemistry (IHC) cell staining along with an isotype control. The specificity of the 2 antibodies was substantiated by IHC, flow cytometry and Western blot analysis of positive and negative control cells. In addition, for RANK, mass spectrometry/protein sequencing of immunoprecipitated proteins was performed. The intensity of IHC staining was scored on a semiquantitative scale (1=weak, 2=moderate, 3=intense) or a complex scale (sum of percentages of stained tumor cells x staining intensity (0-3)).  Results: Using a complex score with a threshold of 10, 20/57 IDC (35%) expressed minimal level of RANK (range 0 to <10, median 1) while 37/57 IDC (65%) expressed RANK protein with a score ranging from 10 to 100 (median 50). The expression in the tumor was heterogeneous, with cells having no expression and cells having intense expression. In addition, RANK was intensely expressed in the basal layer of all normal ducts and lobules. RANKL was observed in rare tumors (7/57; 11%), in rare lymphocytes of most tumor stroma (42/62; 68%), and in rare fibroblast-like cells in the stroma of rare tumors (3/62; 4.8%).  Conclusion: In this study, RANK expression was observed by IHC in the majority (65%) of IDC. RANKL expression was observed in the epithelial carcinoma element of some tumors (11%) and was detected in 68% of tumors in rare lymphocytes infiltrating the tumor stroma. Correlation studies between prognosis markers ER, PR, Her2, and CK5/6 expression and RANK or RANKL expression in those IDC have been initiated.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2057.
Upregulation of Fra-1 and Fra-2 in breast cancer cells results in changes in adhesion, migration, invasion and stem cell markers.
Authors: Schroeder C , Janke S , Krenkel S , Streichert T , Jaenicke F , Milde-Langosch K
Published: December 2010

Abstract #2058

Background: Fra-1 and Fra-2 (Fos-related antigen1 and 2) are members of the Fos family of AP-1 transcription factors which are often up-regulated in human mammary carcinomas. The results of previous studies with clinical tumor tissues and experimental studies of breast cancer cell-lines suggested that they might be involved in the regulation of tumor invasion and metastasis in breast cancer.  Materials and Methods: In order to analyze the impact of Fra-1 and Fra-2 on the aggressive behavior of breast cancer cells, we established stable transfectants of the weakly invasive MCF-7 cells and as well in the highly invasive MDA-MB231 breast cancer cells with Fra-1 and Fra-2 overexpression. Additionally we generated MCF-7 stable transfectants with inducible Fra-2 transcription controlled by the tetracycline-inducible tetON-system. The consequences of Fra-1 and Fra-2 upregulation on the biology of the breast cancer cells were analysed by MTT assays (proliferation) and Matrigel invasion assays (invasion and motility). In addition, possible target genes which were differentially regulated in stable transfectants with Fra-1 and Fra-2 overexpression were identified by microarray analysis and, partly Western blots.  Results: Cell proliferation was not influenced by Fra-1 and Fra-2. In contrast, the invasive potential of the cells was increased by Fra-1 and Fra-2 in MDA-MB231 and MCF7 cells. In addition, there was a similar effect on cell motility. By using the GeneChip Human Genome U133A 2.0 array (Affymetrix), we identified several genes which are known to be involved in cell adhesion, migration or invasion and which were up- or downregulated in stable transfectants, i.e. ICAM, L1CAM, ALCAM, CX43 etc. Moreover, Fra-2 overexpression in MDA-MB231 cells resulted in CD44 upregulation and CD24 downregulation, which is characteristic of breast cancer stem cells.  Discussion: In clinical breast cancer tissues, up-regulation of Fra-2 and Fra1 protein expression has been observed and was shown to be associated with a more aggressive phenotype. Our data of the experimental studies with breast cancer cell-lines indicates that Fra-2 as well as Fra-1 may play an important role in tumor progression by transcriptional regulation of genes which are involved in cell adhesion, invasion and motility.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2058.
Do isolated cells (pN0i+) in the sentinel lymph node change the post-operative management in breast cancer?.
Authors: Charles C , Alran S , De Rycke Y , Malka I , Fourchotte V , Falcou M , Berry M , Benamor M , Kirova Y , Pierga J , Sastre X , Sigal-Zafrani B , Salmon RJ
Published: December 2010

Abstract #206

Background: immunohistochemical (IHC) analysis of the sentinel lymph node (SLN) allows detection of occult metastases not routinely diagnosed by conventional techniques. There is, however, no consensus concerning the post-operative management of those patients with IHC-positive (pN0i+) nodes: should one re-operate, change the medical treatment or alter the irradiation fields?  Patients and methods: 2692 patients with early invasive breast cancer underwent conservative treatment with SLN biopsy between 2000 and 2006. SLN were evaluated with frozen section followed by serial-section HES and IHC if HES showed no tumour cells. Lymph node staging followed the accepted pTNM classification: pN0, pN0i+ (≤ 0.2mm, IHC+), pNmi (0.2-2mm) and pN1a (> 2mm). In 1506 patients with T1pN0 tumours : 143 were pN0i+, that is 10%. We compared the post-operative management of pN0 patients, who had no completion axillary dissection (CAD), to those pN0i+ who did. All positive SLNs underwent CAD according to our institutional protocol.  Results: 15 of 143 (10.5%) pN0i+ patients showed metastases in their CAD; a single node in 10 cases, 2-3 in 4 and > 3 in one patient. Univariate analysis showed chemo- and hormono-therapy to be more frequently administered in pN0i+ (24.5% vs. 77.6%) compared to pN0 (9.1% vs. 55.8%) patients; p < 0.0001. Irrespective of the result of CAD, pN0i+ patients had significant modifications in their fields of lymphatic irradiation at the internal mammary (43.6% vs. 23.5%), supra-clavicular (40.9% vs. 21.5%) and sub-clavicular (13.5% vs. 3.7%) areas; p < 0.0001. Other predictive factors showed a similar pattern including age < 50 years (31.5% vs. 18.6%), tumour size bigger (1.51cm vs. 1.16 cm) and lymphovascular invasion (27.5% vs. 11.6%); p < 0,0001. After multivariate analysis, the sole decisive factor for chemotherapy between the two groups was the presence of nodal metastasis in CAD. The duration of this study is, however, insufficient to comment on the long-term implications for pN0i+ patients.  Discussion: immunohistochemistry alone plays a decisive role in favour of chemotherapy in N+ supplementary AD in only 10% of pN0i+ (15/143) patients. However, this concerns only 1% (15/1506) of those undergoing IHC so may have significant resource implications and other factors were found to be more influential. Moreover, pN0i+ patients underwent additional lymphatic irradiation, to all 3 fields, more frequently.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 206.
Expression of MDA7/IL-24 human breast cancer and the molecular impact.
Authors: Jiang WG , Douglas-Jones A , Mokbel K , Mansel RE
Published: December 2010

Abstract #2060

INTRODUCTION. MDA-7 (melanoma differentiation associated gene-7), also known as IL-24, was initially identified from cancer cells and was found to be up-regulated in melanoma cells. Forced expression of MDA7 in cancer cells was found to be growth inhibitory. MDA7/IL-24 operates in cells via its receptor, MDA7R/IL-24R, which includes at least the IL-20Rα and IL-20Rβ complex and the IL-22R and IL20Rβ complex. The present study investigated the impact of MDA7 on the growth and motility of breast cancer cells and the clinical relevance of MDA7 expression in mammary tumour tissues.  MATERIALS AND METHODS. Human breast cancer cell lines MDA MB-231 and MCF-7 were used for in vitro testing. The response of cancer cells to rhMDA7 in growth and cellular motility was determined using growth assay and ECIS (electric cell impedance sensing, and confirmed by wounding assay). Localisation of MDA7 in mammary issues was assessed using conventional immunohistochemical method. Levels of MDA7 transcript in fresh frozen breast tissues were determined using quantitative PCR analysis and analysed against clinical and pathological information.  RESULTS. Recombinant human MDA-7 only had a marginal effect on the in vitro growth of the breast cancer cell lines used. However, rhMDA had a significant effect on the migration of breast cancer cells. Cells treated with rhMDA-7 showed a slower rate of migration (electrical resistance 80.1±24.3Ω), when compared with control cells (130±24.3Ω) (p=0.024). Normal mammary epithelial cells showed a good degree of staining of MDA-7, a staining greatly reduced in cancer cells. Using the Nottingham Prognostic Index as a predictor of prognosis, tumours from patients with poor prognosis showed a significantly lower level of MDA-7 transcript compared with tumours from those with good prognosis (p=0.049). A significant difference was seen between tumours from patients who died of breast cancer and tumours from patients who remained disease free (p=0.035), the later showing a higher levels of MDA7 transcript. Using the Kaplan-Meier survival analysis, it was revealed that low levels of MDA-7 were significantly correlated with a shorter disease free survival (mean survival for low level group 121.7 (108.5-134.9) months compared with high levels 140.4 (133.7 – 147.1, 95% CI) months, p=0.0287. ER positive tumours showed a lower but levels of MDA-7 expression compared with ER-negative tumours, although this was not statistically significant (p=0.094).  CONCLUSIONS. MDA-7 is a potential regulator of cellular motility of breast cancer cells. The aberrant expression of the molecule is linked to the prognosis and long term survival of patients, indicating the potential clinical implication of MDA-7 in cancer therapies.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2060.
Sentinel lymph node biopsy in pure tubular carcinoma of the breast: a retrospective multicentric study of 234 cases.
Authors: Dejode M , Dravet F , Sagan C , Giard S , Mignotte H , Houvenaeghel G , Ferron G , Leveque J , Tunon de Lara C , Rodier J , Marchal F , Classe J
Published: December 2010

Abstract #207

BACKGROUND. Pure tubular carcinoma (PTC) is a favourable histologic subtype of breast cancer with a low rate of lymph node involvement. This study was initiated to assess the sentinel lymph node (SLN) detection rate and the rate of axillary involvement.  METHODS. Inclusion criteria were a PTC (tubular component >90%) core biopsy diagnosed breast cancer smaller than 20 mm, and a homolateral clinically axilla free of nodal involvement. Patients underwent a SLND alone or with an Axillary level I-II Lymphadenectomy (AL). An AL was performed in the case of the learning curve, or in the case of SLN involvement – macrometastases, micrometastases or isolated cells - or in the case of mapping failure.  RESULTS. From January 1999 to December 2006, 234 patients were selected from 9 French Comprehensive Cancer Centers. Median tumour size was 9.59 mm (1-22) . The SLN detection rate was 97.9% (229/234). The median number of SLN harvested was 2.15 (range 0-8). Respectively the frequency of macrometastasis - >2mm - was 2.6% (6/229), micrometastasis was 6.5% (15/229) and isolated cells was 0.8% (2/229). There were no false negative cases among the 24 patients with a systematic complementary axillary lymphadenectomy performed in the case of a learning curve. Axillary macrometastasis were found in non sentinel lymph nodes after completed axillary lymphadenectomy in 3 / 6 patients with macrometastasis, in 1/15 patients with micrometastasis and in 0/2 patients with isolated cells. There was no lymph node involvement for tumour size < 10mm. Pathological tumor size >10 mm was statistically correlated to the risk of axillary involvement (p=0.0223).  CONCLUSIONS. This study confirms that in the case of PTC ≤ 20mm SLN detection is feasible and the risk of lymph node involvement very low. In the case of PTC<10 mm our series suggests that a surgical axillary evaluation, even with the SLN technique, is not warranted.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 207.
Rapid screening of tissue microarrays for Her-2 FISH testing is a safe, accurate, efficient and economic method enabling provision of an entirely FISH-based Her-2 testing service.
Authors: Faratian D , Graham AD , Rae F , Thomas JS
Published: December 2010

Abstract #2070

Introduction: FISH (fluorescence in situ hybridisation) testing is the gold standard method for Her-2 status assessment in breast cancer yet is only employed in about 30% of tests carried out partly due to cost and labour considerations. Previously we described TMA-based (tissue microarray) testing1 to reducing cost constraints and now describe a rapid screening approach to eliminate unequivocally negative and positive cases and reduce time spent testing.  Materials and methods: We examined TMAs (6 cores per case) from 89 cases of invasive breast cancer comparing formal FISH scoring with a rapid screening method using systematic examination of the entire core at x100 magnification without formal counting. Each core was screened by two observers and results recorded for each core as positive (P), equivocal (E) or negative (N). Formal counting and rapid screening methods were timed.  Results: The results are given in Table 1. Where both observers agreed that every core in a particular case was negative (43 cases) or positive (10 cases) the predictive value was 100%. The three “Mixed” Groups were constituted as follows: (1) a predominance of positive observations, (2) a predominance of negative observations and (3) a predominance of equivocal observations. Comparison of the FISH scores for the five observational groups using Student's T Test showed significant or highly significant differences (Range: p=0.02-p=0.0001). Screening each 6 TMA core case at x100 magnification took 2 minutes and formal counting of each case took 12 minutes.    Conclusion: Using stringent criteria we show that rapid screening of TMAs for routine Her-2 FISH testing provides a safe, economical and time-efficient method for the assessment of Her-2 status in breast cancer. The technique ensures that all patients receive gold standard testing. 65% of Her-2 negative cases can be rapid screened and eliminated from formal counting with 100% confidence. Unanimous positive cases can also be appropriately categorised. The remaining cases require formal counting which takes no longer than is normally the case with whole section techniques. The TMAs also provide a valuable resource for future analyses.  Reference: 1. Graham AD, Faratian D, Rae F, Thomas J St J. Tissue microarray technology in the routine assessment of Her-2 status in invasive breast cancer: a prospective study of the use of immunohistochemistry and fluorescence in situ hybridization. Histopathology 2008; 52: 847-855.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2070.
Multicentric/-focal vs. unifocal breast cancer: is the TNM-classification justified.
Authors: Weissenbacher TM , Zschage M , Janni W , Scholz C , Sommer H
Published: December 2010

Abstract #2075

Background:  For classification of breast cancer, the TNM-staging is standard since more than fifty years and the prognostic relevance of the T-category is well established. However, tumor size in multicentric and multifocal tumors is assessed by the largest tumor focus only, and does not reflect the cumulative tumor volume. Aim of this study was to compare the prognosis of multicentric/-focal tumors vs unifocal tumors with identical tumor sizes according to TNM-Staging.  Methods:  Overall, 576 patients between 1963 and 2007 were examined. Based on a consecutive patient cohort (n=5.691 pts), two equivalent groups of 288 early breast cancer patients with multicentric/-focal vs unifocal tumors were selected by matched-paired analysis. Match criterias were tumor size, histopathologic grading as well as hormone receptor status, which were equally distributed in both groups (p=1,0, each). Disease free survival and breast cancer specific survival were evaluated. For the multivariate analysis the Cox regression system was used. The median follow-up was 70 month (5,8 years, range 19 - 312 mts)  Results:  The Kaplan-Meier estimate for mean breast cancer specific survival was 221.6 mon (206.7 – 236.4 95%CI) in patients with unifocal and 203.3 mon (184.1 – 222.5, 95% CI, p< .0001, log rank test) in patients with multicentric/-focal tumors. Furthermore, in patients with a unifocal tumor the relapse-free survival was 205.9 mon (190.7 – 221.2 95%CI) and 169.6 mon (150.8 – 188.5, 95% CI, p< .0001, log rank test) in patients with multicentric/-focal disease. In multivariate Cox regression analysis, allowing for tumor size, grading and nodal status, multicentricity/-focality was an independent significant predictor for reduced breast cancer specific survival (p< .0001) as well as reduced relapse-free survival.  Conclusion:  In breast cancer, multicentric/-focal disease is associated with a worse prognosis compared to unifocal disease with identical tumor size. The authors conclude that the tumor biology of multicentric/-focal tumors is not reflected adequately by the current TNM-classification.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2075.
Clinical outcomes of patients with T1N0 breast cancers: how important are biological risk factors?.
Authors: De Boer RH , Chan A
Published: December 2010

Abstract #2078

Background: Tumour size (T) and nodal status (N) have traditionally been regarded as the most important prognostic factors which determine individual recommendations for adjuvant treatment. Early trials of adjuvant systemic therapy relied on nodal status as the key determinant of recurrence risk, with node negative patients (pts) often excluded due to their 'low risk' classification. With greater understanding that predominant growth signalling pathways in a given tumour may be of greater importance than size and nodal spread, current clinical practice places greater emphasis on high risk biological factors. Factors include young age (<35y), HER2 positivity (pos), grade III status, absence of hormone receptors (HR), and triple negative (TN) phenotype. Presence of these features will likely influence systemic treatment recommendations. With this in mind we examined data which has been prospectively collected to determine the outcomes of pts with high risk T1N0 tumours and compared them to pts with lower risk biological profiles.  Methods: Data on 2285 pts with early breast cancer were analysed. Comparisons were made between T1N0 high risk pts (defined as having one or more of the following features: age<35, grade III, HER2 pos, or TN) and pts with good biological prognostic features (defined as the absence of all the above factors) in the following subgroups: 1) T1N0, 2) T1N1-2, and 3) T2-3N0. In addition outcomes were specifically assessed in T1N0 pts with Her2 pos vs negative disease; TN vs non-TN.  Results: 401 pts with T1N0 high risk tumours were identified (T1N0HR). In the low risk group there were 330 pts with T0 tumours (T1N0LR), 286 pts with T1Npositive tumours (T1NposLR) and 154 pts with T2/T3N0 tumours (T2/3N0LR). There were 137 pts T1N0 Her2 pos (T1N0H2). The median follow up for all pts was 3.4 yrs (0.5-36). Treatment given and clinical outcome for each pt group are shown in the table.    The majority of DFS events in the T1N0H2 pts occurred in those not receiving adjuvant trastuzumab (12.4% vs 2.2%). TN tumours were seen in 12.5% of pts studied. Despite the use of systemic therapy in 97.5% of TN pts (vs 64% in non-TN) , there was a higher DFS event and death rate (18% vs 15%; and 13% vs 6% respectively)  Conclusions: Outcomes for T1N0HR pts were similar to that of T1N0LR and T2/3N0LR pts, possibly related to the greater use of systemic therapies in the T1N0HR pts (89% vs 50% vs 79%). Despite the high rate of adjuvant systemic therapy, the outcomes for the T1N0HR group were inferior to the outcomes for pts in the T1NposLR group (DFS 15.7% vs 9.8%) supporting the view that biological factors may be a more important determinant of outcome than nodal status. Similarly, even in pts with small tumour size, triple negative phenotype had worse outcome.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2078.
Outcome of breast cancer in young women stratified by age at diagnosis: the younger, the worse? The Korean Breast Cancer Society registry program data.
Authors: Han W
Published: December 2010

Abstract #2079

Introduction: In the previous studies investigating the relation between age of onset of breast cancer and disease outcome, the age cut-off for very young onset was usually under 35 or under 40. However, these cut-offs were set arbitrarily or empirically without sufficient outcome data on the detailed age strata. Hence we tried to compare breast cancer outcomes of premenopausal women (age ≤50)according to age groups of 5 year interval.  Patients and Methods: We analyzed data of 9,885 breast cancer patients aged ≤50 years registered in the Korean Breast Cancer Society Registration Program between 1992 and 2001. The overall survivals were compared between age groups. The median follow-up for this cohort of patients was 74.4 months.  Results: 351 patients were aged <30 years (Group I), 1,092 patients were 31-34 (Group II), 2,087 patients were 35-39 (Group III), and 6,354 patients were 40-50 years old (Group IV). Younger patients had significantly higher T-stage, higher lymph-node positivity, and lower hormone-receptor positiviy than older patients. In Univariate analysis, Group I patients showed worse outcome than Group II patients (p=0.03). Also, Group II patients showed worse outcome that Group III patients (p<0.0001). Interestingly, there was no significant difference in survival of Group III and Group IV patients. This survival trend according to age group was found only in hormone receptor positive or unknown patients, and not in hormone receptor negative patients. Multivariate analysis was performed using a Cox regression model including age groups, tumor size (2cm), lymph node involvement, hormone receptor, chemotherapy, and hormone therapy. Compared to the Group IV patients (reference), Group III patients had similar survival (hazard ratio (HR) = 1.06, 95% confidence interval (CI): 0.94-1.20). But, Group II and I patients had significantly worse survival (HR = 1.43 (95%CI: 1.24-1.64), HR = 2.09 (95%CI: 1.69-2.58), respectively). The HR was even higher in patients young than 25 (HR = 2.35, 95%CI: 1.35-4.06).  Conclusions: Patients aged 35 to 39 showed similar overall survival compared to patients aged 40 to 50, whereas patients aged <35 showed significantly worse outcome than patients aged 35 to 39. Moreover, patients aged <30 showed significantly worse outcome than patients aged 31 to 34.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2079.
Biology and prognosis by age of primary operable breast cancer.
Authors: Brouckaert O , Camerlynck E , Van Belle V , Van Huffel S , Pintens S , Amant F , Leunen K , Smeets A , Berteloot P , Van Limbergen E , Weltens C , Van den Bogaert W , Paridaens R , Moerman P , Vergote I , Christiaens M , Wildiers H , Neven P
Published: December 2010

Abstract #2082

Introduction Breast cancer (BC) biology and prognosis are age dependent. We studied the effect of age on BC biology, treatment and prognosis.  Methods Data from 2059 consecutive patients, primary operated for invasive BC in UZ Leuven (01/01/00–01/06/05), were used. Patients with ≥ 3.5 yrs follow-up were included (n=1064) to study relapse in relation to age (logistic regression).  Results Early relapse in BC is age-related, decreasing 3.2% each yr for patients < 60 yrs at diagnosis (p=0.0132, 95% CI OR: 0.943-0.993). This relation is reversed >60 yrs: early relapse increases 5.5% each yr (p=0.0007, 95% CI OR: 1.021-1.082). The positive lymph node status is decreasing 3.5% each yr <65 yrs (p<0.0001, 95% CI OR: 0.950-0.980) and increasing 3.8% each yr ≥65 yrs (p=0.0259, 95% CI OR: 1.004-1.072) (Fig 1). The chance on a positive estrogen receptor (ER) increases with increasing age until 60 yrs (p=0.0071, 95% CI OR=1.009-1.059) with no significant effect >60 years. For the progesterone receptor (PR), this depends quadratically on the age at diagnosis (p=0.0108, 95% CI OR=0.999-1.000), decreasing <50 years and increasing above. With increasing age, the chance on HER-2 positivity decreased (p=0.0414, 95% CI OR: 0.970-0.999). Grade 3 tumors dropped significantly until 50 yrs (p<0.0001 CI OR=0.900 (0.869-0.933) whereafter we observed a non significant upward trend (Fig 2). The chance to receive any adjuvant therapy decreased with age (p=0.0023, 95% CI OR: 0.958-0.991). Above 70 yrs, systemic adjuvant therapy was absent in 12.95% of non-relapsing -, but in 28.95% of relapsing patients. Radiotherapy was not taken into account.  Conclusion Early relapse was higher with increasing/decreasing age, starting from age 60. This goes in parallel with the U-shape curve of lymph node involvement (Fig1). Increased relapse and lymph node positivity in elderly might partially be a reflection of the fact that BC is diagnosed in a later stage in elderly patients but might also be related to different biological behavior or to decreased use of adjuvant systemic treatment. HER-2 overexpression decreases with age and age related differences in ER and PR expression as well as tumor grading are observed (Fig 2).       

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2082.
Triple negative breast cancers: comparative study of clinical features and overall survival in an Irish population.
Authors: O'Kane G , Quinn L , Boyle T , Dunne B , Griffin M , Kennedy J , Connolly EM
Published: December 2010

Abstract #2083

Introduction   Triple negative breast cancers (TNBC) are defined by a lack of estrogen, progesterone and Her2 receptors and account for 15% of breast cancers. They present at an earlier age and a higher stage and are associated with a poorer survival compared to non-TNBC's. There is a paucity of information available on outcomes of TNBCs managed with up to date oncology treatment.  Aims  To investigate TNBCs in an Irish cohort of patients and to compare their clinicopathological features and survival outcomes with non TNBCs.  Methods  Using a prospectively gathered database all patients treated for invasive breast cancer in our unit between 2001 and 2007 were included. The median age and pathological stage at presentation, histological features and overall survival in the TNBC and non-TNBC groups were compared.  Results  Between 2001 and 2007 1081 patients were treated for breast cancer at St. James's Hospital. Follow up and full clinical data was available on 934 patients. 121(13%) patients were identified as having TNBCs, 625 (67%) were Her2-ve, hormone receptor +ve and 187 (20%) were Her2 +ve.  Age, stage, tumour size and histological grade were similar in the TNBC and the Her2+ groups with the Her2-ve, hormone receptor +ve group having a more favourable pathological profile. Overall survival in TNBC group was significantly worse at 5 yrs compared with the non-TNBC groups.    Conclusions:  In our patients TNBC's present at a similar age and stage as Her2 + patients. The 5 year survival is worse in the TNBC group. The survival in the Her2+ group is similar to the Her2 – group suggesting that targeted therapy with herceptin is effective. These results highlight the need for a targeted therapy to treat TNBCs.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2083.
Triple negative breast cancer phenotypes: a comparison between symptomatic and screening patients.
Authors: Johnson RK , Winstanley JH , Corcoran F , Pearson M
Published: December 2010

Abstract #2085

Body: Background: Triple-negative breast cancers are defined by a lack of expression of oestrogen, progesterone, and HER-2 receptors. Prognostically, they are associated with a poor clinical outcome. It is uncertain whether during growth and maturation of a breast cancer its phenotype may drift from one which over-expresses ER, PR and HER-2 towards a tumor type that loses this expression. In the UK women are screened for breast cancer between the ages of 50 and 70 years, which provides us with a cohort of patients whose breast cancers are at a much earlier stage than those presenting symptomatically. Thus if phenotypic drift occurred the screening population might have a lower incidence of triple negative tumors compared to those presenting symptomatically.  Aim: To compare the incidence of triple negative tumors in a screening and symptomatic population. Materials and Methods: Pathology reports for 2002 to 2004 inclusive were scrutinized for ER PR and HER-2 expression. A list of screening patients was retrieved from our screening database and cross-referenced with pathology reports. Immunohistochemistry (IHC) was used to quantify ER and PR expression, a quick score of 4 or less was negative for over-expression. Similarly IHC was used to quantify HER-2 expression, and a score of 0 or 1+ was negative for over-expression. clinical data, such as patient age, lymphovascular invasion, lymph node status, tumor size, and grade were available for statistical analysis. Results: There were 213 screening patients of which, 31 (14.5%) had triple negative phenotypes and 443 symptomatic patients of which, 73 (16.4%) were triple negative. This difference was not statistically different. Discussion: The incidence of Basal-like breast tumors is similar in the screening group compared to the symptomatic population suggesting that this aspect of tumor biology is determined at a very early stage in the development of tumors and is not subject to phenotypic drift.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2085.
The black to white breast cancer incidence rate crossover.
Authors: Anderson WF , Rosenberg PS , Jatoi I , Pfeiffer RM
Published: December 2010

Abstract #2086

Background: Although breast cancer incidence rates are higher among Blacks than Whites prior to age 40 years, the reverse is true after age 40 years. This so-called Black to White ethnic crossover has been described but never systematically studied.  Materials and Methods: To further assess the Black to White incidence rate crossover, we obtained data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Invasive female breast cancers were stratified by Black and White race and estrogen receptor (ER) expression. Standard descriptive epidemiology was supplemented with “comparative” age-period-cohort (APC) models.  Results:]We observed “qualitative” (reversing or crossing) age-interactions by race, stratified by birth-cohort and adjusted for calendar-period. For example, APC fitted age-at-onset curves were higher among Blacks than Whites prior to age 40 years, and then rates crossed, after which age-specific rates were higher for Whites (p ∼ 0 for difference). In contrast to age-related differences, secular trends were similar for Blacks and Whites (net drifts, p = 0.85 for difference). For all time periods and age groups, ER negative incidence rates were higher among Blacks, whereas ER positive rates were higher among Whites.  Conclusion: When viewed as a qualitative (crossing) age-interaction, the Black to White ethnic crossover reflects the reversal of incidence rate ratios for early-onset/poor prognosis and late-onset/good prognosis breast cancer types. Blacks have more early-onset and ER-negative tumors, even after adjustment for calendar-period (screening) and birth-cohort (exposure) effects.   

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2086.
Molecular differences between the triple negative tumors of African-American women and white women.
Authors: Lund M , Eley JW , O'Regan RM , Gabram SS , Saavedra HI , Liff JM , Brawley OW , Porter PL
Published: December 2010

Abstract #2087

Purpose. We recently reported associations between triple negative tumors (TNTs) and several key cell-cycle proteins. TNTs have also been associated with: 1) younger age and African-American (AA) race, 2) a relative lack of therapeutic targets, and 3) higher recurrence and poorer survival relative to other tumor subtypes. Furthermore, AA women diagnosed with TNTs experience worse outcomes than white women. TNTs are a mixed group of tumors that includes both basal and non-basal types. Markers that could help differentiate tumors with the poorest outcome would be of great use in determing how to effectively treat women with TNT. This study examines whether there are racial differences in key cell-cycle and apoptotic proteins among women with TNTs and could help to identify potential molecular mechanisms underlying racial disparities in these aggressive tumors.  Methods. Invasive TNTs from a population-based cohort of 136 Atlanta women (56 AA and 79 white) aged 20–54, diagnosed between 1990 and 1992, were centrally reviewed and immuno-histochemically analyzed for ER, PR, HER2, Bcl2, Cyclins D1 and E, pRb, p16, p21, p27, p53, p130, Ki67, and apoptotic index (AI). Weighted frequency distributions, Chi-square tests, and logistic regression were used to assess racial differences. Age and stage-adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated.  Results. Among the 136 women diagnosed with TNTs, AA women were significantly more likely than white women to present at a later stage, with larger tumors, and increased grade, mitotic activity, tumor necrosis, and apoptotic index. AA women were also significantly younger, poorer, and obese. Cell cycle protein differences between AA and white women diagnosed with TNTs included higher expression of Cyclin E [OR = 4.0 (95% CI=1.9, 8.5)], pRB [OR = 2.8 (95% CI=1.6, 4.9)], p16 [OR = 2.2 (95% CI=1.3,3.8)], p21 [OR = 2.0 (95% CI=1.1, 3.5)], AI [OR = 2.1 (95% CI=1.3, 3.9)], and lower expression of p130 [OR = 0.6 (95% CI=0.3, 1.0)].  Conclusions. Exclusively among triple negative tumors, we identified racial differences in expression levels of several key cell-cycle and apoptotic related proteins. Combined with other poor prognostic factors, these differences may account for racial disparities in outcome. Future etiologic studies and clinical trials dedicated to TNTs should consider underlying molecular differences.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2087.
Differences in breast cancer subtype distribution exist among ethnic subgroups of Asian women in California.
Authors: Telli ML , Kurian AW , Chang ET , Keegan TH , McClure LA , Ford JM , Gomez SL
Published: December 2010

Abstract #2088

Background: Distinct breast cancer subtypes have been identified by gene expression analysis. Little is known about the distribution of these subtypes among Asian women. We previously reported an increased frequency of HER2-positive breast cancers among certain ethnic subgroups of Asian women in California. To follow up on that finding in detail, we undertook the current analysis to explore factors associated with differences in breast cancer subtype distribution among Asian women in California.  Methods: We defined immunohistochemical surrogates for each breast cancer subtype among Chinese, Japanese, Filipina, Korean, Vietnamese and South Asian patients in the population-based California Cancer Registry diagnosed in the period 1999-2005. Subtypes were defined using combinations of immunohistochemical markers: luminal A (ER+ and/or PR+, HER2-), luminal B (ER+ and/or PR+, HER2+), basal-like (ER-, PR-, HER2-) and HER2+/ER- (ER-, PR-, HER2+). Polytomous logistic regression was used to evaluate associations between breast cancer subtype and age, race, AJCC stage, tumor grade, tumor histology, socioeconomic status, nativity and hospital ownership (private vs. public). Models were used to compare differences in these characteristics simultaneously across the four breast cancer subtypes.  Results: Of 12,245 Asian women diagnosed with invasive breast cancer, 7,217 (59%) women had data for all three immunohistochemical markers. The majority of breast cancers among Japanese women were of the luminal A subtype (67%), with a low frequency of basal-like (10%) and HER2+ (22%) cancers. Korean, Filipina and Vietnamese women had a high frequency of HER2+ cancers (35%, 31% and 31%, respectively) compared to Non-Hispanic White women diagnosed during this period (n=12,996, 21%). In regression analyses among Asian women, the four subtypes varied significantly in their associations with age group (p=0.01), detailed Asian ethnicity (p<0.0001), stage (p<0.0001), grade (p<0.0001), histology (p<0.0001), year of diagnosis (continuous; p=0.03) and hospital ownership (p<0.0001). However, there was no significant variation among the subtypes in their relationships with socioeconomic status (p=0.94) or nativity (p=0.29).  Conclusions: Differences in the distribution of breast cancer subtypes exist among Asian women according to ethnicity, as well as other demographic and disease characteristics. These differences were not associated with place of birth or socioeconomic status. Breast cancers among Japanese women had the most favorable subtype distribution, while Korean women had the least favorable distribution. Further study may identify genetic and environmental risk factors responsible for these differences, with implications for prevention and treatment.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2088.
Disparate racial benefits of chemotherapy in breast cancer.
Authors: May KA , Hair BY , Zaky SS , Gabram-Mendola SG , Rizzo M , Bumpers HL , Oprea G , O'Regan RM , Lund M
Published: December 2010

Abstract #2091

Purpose: Patients with triple negative breast tumors (TNTs) have high recurrence and poor survival rates. African-American (AA) women have a higher prevalence of TNTs and worse outcomes than Caucasian (CA) women. The addition of a taxane to anthracycline-based chemotherapy in the adjuvant setting appears to improve outcome to a greater extent in estrogen receptor (ER)- compared to ER+ cancers. There is insufficient data examining currently approved adjuvant chemotherapy regimens in AA. We evaluated the outcomes associated with different chemotherapy regimens in a largely AA group with early stage breast cancer. Methods: The Surveillance Epidemiology End Results (SEER) registry identified 509 AA or CA female breast cancer patients (Stages I-III) diagnosed during 2003-2004 at 3 Atlanta-based hospitals who were residents of Fulton/DeKalb counties. SEER data was augmented by medical record abstraction. Frequency distributions, chi-square tests of independence, logistic regression, and Cox models were used to assess recurrence and mortality by tumor subtype and chemotherapy regimen. Results: The mean follow-up was 3.2 years. Of 509 patients, 66.2% were AA. TNTs represented 17.1% (N=87), with a higher proportion in AA (20.2%) than CA (11.0%) women. Compared to ER+PR+HER2- tumors, patients with TNTs were more likely to experience a recurrence (HR=3.1, 95% CI 1.3, 7.0) and to die (HR=2.9, 95% CI 1.3, 6.3) after adjusting for receipt of chemotherapy, age, race, socioeconomic status, stage, and grade. Among chemotherapy-treated women with ER+PR+HER2- cancers, AA had higher recurrence (27.1% v. 8.3%) and death (21.3% v. 3.7%) rates than CA women; however, similar recurrence (42.2% v. 33.3%) and death (28.0% v. 35.7%) rates were found in the chemotherapy-treated AA and CA patients with TNTs. Among women treated with adriamycin-based regimens, the addition of a taxane did not appear to impact recurrence or survival in the ER+PR+HER2- or TNT subgroups. Conclusions: This data supports prior data demonstrating a two-fold increase in TNTs in AA compared to CA women. TNTs in this majority AA population were associated with a higher likelihood of short-term recurrence and mortality than other subtypes. Chemotherapy was not as beneficial for AA women with ER+PR+HER2- tumors compared to CA women. No statistically significant differences in outcome were noted for AA or CA women with TNT treated with chemotherapy. The addition of a taxane to adriamycin-based chemotherapy did not improve recurrence or survival rates for women with ER+PR+HER2- or TNTs. Clinical trials with consideration of racial diversity are needed to further assess the effectiveness of chemotherapy regimens on reducing recurrence and mortality in breast cancer patients.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2091.