bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic implications of isolated tumour cells and micrometastasis in lymph nodes in non-adjuvant treated breast cancer patients.
Authors: Park D , Kåresen R , Naume B , Sauer T 
Published: December 2010

Abstract
Abstract #205
Introduction : The status of axillary lymph nodes (ALNs) is the most powerful predictor of survival and has clinical implications for adjuvant treatment of breast cancer patients. Occult metastases in ALNs of patients initially staged as negative have been detected up to 40%, using the various methods with serial sectioning and/or immunohistochemical (IHC) staining. However, there is no consensus concerning the prognostic significance for occult metastases. The aim of this study was to estimate the prognostic value of isolated tumor cells (ITC, ≤0.2 mm) and micrometastases (MM, 0.2-2.0 mm) in invasive breast cancer.&#x2028; Materials and Methods: The ALNs of 295 patients with axillary node-negative invasive breast cancer treated from 1995 to 1998 was evaluated with serial sectioning and cytokeratin IHC (a single section from each of 10 levels) and hematoxylin-eosin (one section from 3rd and 10th level). Disseminated tumor cell status in bone marrow was also known. Of 295 patients, 232 were offered no systemic adjuvant therapy. Patients were categorized by largest cluster size (≤0,2mm, 0.2-2.0mm), and then their survival rates, i.e. disease-free survival (DFS), distant disease-free survival (DDFS) and breast cancer specific survival (BCSS) were compared with those of node-negative patients. We also investigated the correlation between occult metastases in ALNs and bone marrow (BM).&#x2028; Results: The median patient age was 59 years and the median tumour size was 1.5 cm. At a median observation time of 98 months (9-127 months), 33 patients had developed relapse,2 local and 31 systemic. 17 patients had died of breast cancer. Occult metastases were found in 92 of 295 patients (31%); ITC – 58% (53/92), MM -34% (31/92) and macrometastases (&gt;2.0mm)- 8% (8/92). The cases with macrometastases were excluded from survival analysis. The results presented in the table below demonstrate significant prognostic impact of MM on BCSS, borderline significance on DFS and DDFS. This was not shown for ITC. No significant correlation was found between occult metastases in ALN and BM in both total patients (Χ2-test, p=0.680).&#x2028; &#x2028; Conclusions: Our observation of a prognostic impact of MM in non-adjuvant treated patients indicates that adjuvant therapy might be warranted in this group. Lack of a similar finding in patients with ITC questions the need of adjuvant therapy in this group. The lack of correlation between occult metastases in ALN and BM indicates different “homing” mechanisms for the two compartments.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 205.
JNK2 enhances mammary carcinoma cell migration by regulating EPS8 expression and localization.
Authors: Mitra S , Van Den Berg C 
Published: December 2010

Abstract
Abstract #2050
Cell migration is a tightly regulated event critical for normal development and adult wound healing, but it is also a key step in the tumor metastasis cascade. Growth factors initiate intra-cellular signaling pathways that stimulate cell movement by virtue of remodeling the actin cytoskeleton. Fine regulation of this process renders a degree of polarity to the cells, altering their cytoskeleton and providing the requisite mechanical torsion to move forward. Breast cancer cells extravasate from their primary site and travel to other organs forming metastatic colonies.Various signaling molecules including members of the Mitogen Activated Protein Kinase (MAPK) such as c-Jun N-Terminal Kinase (JNK) have been implicated in regulating cancer cell migration. How growth factors transmit signals to form dorsal ruffles and filopodia for cell migration is not precisely understood. Additionally, JNK is encoded by three genes, resulting in 10 isoforms, hence its role in metastasis is complicated. Here, we used the Polyoma Virus Middle T Antigen (PyVMT) transgenic mouse model where wildtype jnk2 was expressed or knocked out. In tumors we found that PyVMT jnk2-/- tumors express higher Epidermal Growth Factor Receptor Substrate 8 (EPS8) mRNA and protein. EPS8 was originally identified as a substrate for Epidermal Growth Factor Receptor (EGFR), and was recently reported to have an actin capping function. Hence, EPS8 is a prime candidate for connecting the EGFR signaling to actin cytoskeletion remodeling, and therefore mediate cell migration. In vitro using Boyden Chamber based migration assays, we found that the PyV MT jnk2+/+ cells migrated fivefold more than the PyV MT/jnk2-/- cells. Pan inhibition of JNK using a small peptide inhibitor TAT-JIP VII significantly reduced migration of the PyV MT/jnk2+/+ cells but was ineffective at further reducing PyVMT jnk2-/- cell migration, suggesting that the JNK2 is the major isoform to convey this function. Furthermore, shRNA mediated knock down of EPS8 in the PYVMT jnk2-/- cells, increased migration of these cells to levels comparable with the wild type counterparts. We subsequently undertook immunocytochemistry studies to evaluate EPS8 localization and cytoskeletal changes upon serum stimulation. Cells expressing JNK2 showed more dorsal ruffles upon serum stimulation, and EPS8 localized to the plasma membrane and in dorsal ruffles. In contrast, EPS8 was predominantly localized in focal adhesions in the PyVMT jnk2-/- cells, which may explain their reduced migration potential. Together our model supports an integral role for JNK2 regulation of EPS8 expression and localization to facilitate cell migration. Our current studies are aimed at further deciphering the JNK/EPS8 pathway to understand the exact molecular mechanism by which these proteins regulate a critical step in mammary cancer cell metastasis.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2050.
Identification of non-catalytic matrix metalloproteinase 1 residues that participate in collagenolysis.
Authors: Lauer-Fields JL , Fields GB 
Published: December 2010

Abstract
Abstract #2063
Collagen serves as a structural scaffold and a barrier between tissues, and thus collagen catabolism (collagenolysis) is required to be a tightly regulated process in normal physiology. In turn, the destruction or damage of collagen during pathological states plays a role in tumor growth and invasion, cartilage degradation, or atherosclerotic plaque formation. Only a small number of proteases have been identified capable of efficient processing of triple-helical regions of collagens. Several members of the zinc metalloenzyme family, specifically matrix metalloproteinases (MMPs), possess collagenolytic activity, and at least one of these (MMP-1) has been strongly implicated in the progression of breast cancer. The present study has utilized triple-helical peptide (THP) substrates and inhibitors to dissect MMP-1 collagenolytic behavior. Analysis of MMP-1/THP interactions by hydrogen/deuterium exchange mass spectrometry (HDX MS) in combination with site-specific mutagenesis and enzyme kinetic assays have allowed us to identify non-catalytic sites in MMP-1 that participate in collagenolysis. As we have recently demonstrated [J. Am. Chem. Soc. 129, 10408 (2007)], non-catalytic sites can be utilized to create THP inhibitors that target proteases implicated in cancer progression while sparing proteases with host-beneficial functions.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2063.
STAT1 and STAT3 synergistically suppress EGF-induced MMP-9 activity in SKBR3 human breast cancer cell line.
Authors: Kim S , Choi J , Lim H , Lee S , Kim W , Yang J , Nam S , Lee J 
Published: December 2010

Abstract
Abstract #2064
Background: EGF is a cytokine associated with cell proliferation, migration, and tumor invasion through EGFR activation in various cancer cells. EGFR activates its downstream molecules such as protein kinase C-δ, ERK, PI3-kinase, STAT-3. It has been shown that EGFR induces matrix metalloproteinase-9 (MMP-9), leading to invasion and migration of cancer cells. However, it has not been fully elucidated the roles of STAT-1 and STAT-3 in breast cancer cells. We investigated the regulatory mechanism of STAT-1 and STAT-3 on EGF-induced MMP-9 activity in SKBR3 cells.&#x2028; Material and Methods: EGF-induced MMP-9 activity regarding to ERK, JNK, PI-3 kinase and STAT-3 were evaluated by Western blot. Then, we transfected SKBR-3 cells with adenoviral vectors containing STAT-1 and STAT-3 to make SKBR-3 cells overexpressing each gene. We also treated SKBR-3 cells with STAT-3 siRNA. Overexpression and silencing of genes were identified with Western blot. With the treatment of EGF, MMP-9 activity was measured with gelatinase Zymography.&#x2028; Results: We confirmed that EGF increases MMP-9 activity and induces the phosphorylation of ERK, JNK, PI-3 kinase and STAT-3 in dose-dependent manner. We found that EGF-induced MMP-9 activity was significantly decreased by MEK1/2 inhibitor, UO126, and PI3-kinase inhibitor, LY294002, respectively, but not by JNK inhibitor, SP600125. In contrast to previous study, EGF-induced MMP-9 activity was inhibited by STAT-3 overexpression. We also found that it was increased by STAT-3 siRNA transfection. Moreover, we found that STAT-1 and STAT-3 co-overexpression synergistically decreased EGF-induced MMP-9 activity in STAT-1 and STAT-3 co-overexpressing SKBR-3 cells.&#x2028; Discussion: We demonstrated that EGF-induced STAT-3 activation suppresses tumor invasion through down-regulation of MMP-9 in SKBR-3 cells. Moreover, we found that there is a synergistic relationship between STAT-1 and STAT-3, inhibiting EGF-induced MMP-9 activity.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2064.
The use of proximity ligation assay to identify HER2:HER3 heterodimers in early breast cancers.
Authors: Spears M , Munro AF , Taylor KJ , Mallon EA , Bartlett JM 
Published: December 2010

Abstract
Abstract #2068
Background: The HER receptor family includes four members: HER1, HER2, HER3 and HER4. Expression of these proteins is linked to breast cancer development and progression. HER2 gene amplification is found in 20-30% of breast cancers. Overexpression of HER2 has been linked with high grade tumours and poor prognosis. Clinical studies have demonstrated a strong relationship between HER2 and HER3 with 70% of HER3-positive tumours also being positive for HER2. Co-expression of HER2/HER3 has been suggested to drive endocrine and chemotherapy resistance. However such resistance is driven not by co-expression but by signalling via HER2/HER3 dimers which have previously been impossible to detect in situ. Proximity ligation assays (PLAs) can detect homo- and heterodimers in situ at a single-molecule level and allow study of signalling pathways. Paired antibodies are used to detect protein complexes in tissues.&#x2028; Methods: Using tissue microarrays containing 100 breast cancer samples, we analysed HER2 homodimers and HER2:HER3 heterodimers by PLA. HER2 amplification was detected using FISH analysis.&#x2028; Results: PLA was used to detect HER2 homo and heterodimers in vivo and in vitro. HER2 homodimers were detected in amplified and non-amplified cases. A significant association (p&lt;0.00001) was identified between HER2 homodimerisation and amplification. HER2 homodimerisation was not associated with any clinicopathological data.&#x2028; HER2:HER3 heterodimers were detected in vivo and in vitro through PLA and western blot analysis. The median number of HER2:HER3 heterodimers (7.8 signals per cell) was greater than HER2:HER2 homodimers (2.0 signals per cell) in this series indicating HER2:HER3 may be the preferred dimer. HER2:HER3 was significantly associated with nodal status (p=0.003) and grade (p=0.02).&#x2028; Conclusions: Using an in situ PLA we demonstrated the in vivo expression of HER2 homodimers in human breast cancer and increased HER2 homodimerisation linked to HER2 gene amplification. We have demonstrated HER2:HER3 heterodimers to be linked to nodal status and grade. Our observations suggest that PLA is an invaluable method to detect homo and heterodimers in situ and could potentially be used a diagnostic tool in the future.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2068.
Prognosis in BRCA1, BRCA2 associated breast cancer (BC): a prospective Breast Cancer Family Registry (BCFR) international population-based cohort study.
Authors: Goodwin P , Phillips K , West D , Ennis M , Hopper J , John EM , O'Malley F , Milne R , Andrulis I , Friedlander M , Longacre T 
Published: December 2010

Abstract
Abstract #2072
Hereditary BC occurs at a younger age and is associated with more adverse tumor-related features than sporadic breast cancer (BC) (defined here as BC in those with no 1st or 2nd degree family history of breast or ovarian cancer). Using pre-specified criteria, we assembled a population-based cohort of newly diagnosed BC at 3 centers: Ontario, Canada (1996-98), San Francisco Bay area, USA (1995-2000), Melbourne/Sydney, Australia (1991-1998). Medical information was obtained from medical records; women were followed prospectively for recurrence, new cancers and death. Pathology data were obtained from central review or pathology reports. BRCA1 and BRCA2 mutation testing was performed on 77% and 70% of cases, respectively (sporadic BC cases were not tested at 2 centers). Hereditary and sporadic BC cases were compared using Cox proportional hazards (stratified by center). 3215 eligible cases were enrolled in the BCFR, with a mean age at diagnosis of 46.9 years. Median follow-up was 7.61 years; 565 women had distant recurrences and 547 died. There were 92 cases with BRCA1 and 72 with BRCA2 mutations; 1549 (48.2%) had sporadic BC; the remainder had familial BC as defined above. BRCA1 mutations were associated with young age, estrogen and progesterone receptor (ER and PgR) negativity and high grade; BRCA2 mutations were associated with node positivity and high grade. Distant disease-free survival (DDFS) and overall survival (OS) did not differ significantly between BRCA1 carriers and sporadic cases in univariate or multivariate analyses. DDFS and OS were worse in BRCA2 carriers than in sporadic cases (HR 1.6, p=0.04 and HR 1.8, p=0.01, respectively) in univariate analyses but not in multivariate analyses (DDFS HR 1.0, p=0.98; OS HR 1.13, p=0.61). The small group of BRCA2 carriers who did not receive adjuvant chemotherapy had a significantly worse OS (multivariate HR 3.63, p = 0.005). Furthermore, BRCA2 carriers who received adjuvant tamoxifen had significantly worse OS than women with sporadic BC (HR=2.0, p=0.03). We conclude that BRCA1 and BRCA2 mutations do not independently impact DDFS or OS. Significantly worse outcomes were seen in BRCA2 carrier subgroups defined by adjuvant treatment; this requires further investigation and may have implications for clinical practice.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2072.
Pharmacokinetics and tolerability of lapatinib administered once daily in combination with tamoxifen.
Authors: Cardoso F , Koch KM , Awada A , Lokiec F , Brain E , Bogaerts J , Marreaud S , Chung S , Campello V , Fumoleau P 
Published: December 2010

Abstract
Abstract #2073
Background: The pharmacokinetics (PK) and tolerability of daily oral dosing with lapatinib (LAP) and tamoxifen (TAM) in patients (pts) with advanced or metastatic breast cancer (MBC) are examined in this study. Optimal dose selection requires characterization of PK to accommodate the potential for a bi-directional PK interaction involving LAP inhibition and TAM induction of CYP3A4 and P-glycoprotein (Pgp).&#x2028; Methods: Twenty three previously treated pts with ER and/or PR positive MBC, not ErbB selected, were randomly assigned to one of two groups, to separately assess each direction of the potential PK interaction at steady state during daily dosing of 1250mg LAP and 20mg TAM. In one group, the PK of LAP is assessed on the 14th day of dosing LAP alone, and again on the 28th day dosing of LAP and TAM together. In the other group, the PK of TAM is assessed on the 28th day of dosing TAM alone, and on the 7th day of dosing TAM and LAP together. LAP and TAM are dosed together throughout subsequent 28 day cycles.&#x2028; Results: To date 23 pts have been enrolled with a median age of 58 (38-83) and a median PS of 1. Preliminary PK data for LAP from six patients summarized in the table below showing geometric median (95% confidence limits) parameters indicate that LAP plasma concentrations are decreased by TAM. Final PK analysis will be presented at the meeting. To date, the most common adverse events at cycle 1 were: fatigue gr1/2 (100%), diarrhoea gr 1/2 (53%), rash gr 1 (40%), anorexia gr 1 (40 %) and nausea gr1/2 (40 %). Transaminase elevation (SGPT/ALT) increased from 3 pts at baseline to 6 pts at cycle 1 including one gr3.&#x2028; &#x2028; Conclusions: The preliminary PK results are consistent with data indicating TAM induces hepatic CYP3A, the primary route of LAP elimination. This important information may impact in ongoing adjuvant lapatinib studies.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2073.
Survival differences among women with newly diagnosed stage IV and recurrent breast cancer.
Authors: Dawood S , Kristine B , Hortobagyi GN , Giordano S 
Published: December 2010

Abstract
Abstract #2077
Background &#x2028; The objective of this retrospective study was to determine whether differences in survival exist between women with newly diagnosed stage IV disease and those with recurrent breast cancer.&#x2028; Methods&#x2028; Women with newly diagnosed stage IV disease or recurrent breast cancer with distant metastases diagnosed between 1992 and 2007 were identified from the Breast Cancer Management System Database at UTMDACC. Among women with recurrent breast cancer, distant disease-free interval (DDFI) was defined as the time from diagnosis of primary breast cancer to the date of the first distant metastases. For all patients, overall survival (OS) was measured from the date of first distant metastases to the date of death from any cause or last follow-up. The Kaplan-Meier product limit method was used to estimate OS, and OS was compared across groups using log-rank statistic. Cox-proportional hazards models were fit to determine the association between stage IV breast cancer (recurrent versus newly diagnosed) and OS after controlling for other patient and tumor characteristics.&#x2028; Results&#x2028; The analysis included 3524 patients of whom 643 (18.2%) had newly diagnosed disease and 2881 (81.8%) had recurrent disease. Median follow-up was 19 months. Median OS among patients with newly diagnosed stage IV disease and recurrent disease was 39.2 and 27.2 months, respectively (p&lt;0.0001). Patients with recurrent disease with DDFI &lt; 5 years had worse OS compared to those with newly diagnosed disease (p&lt;0.0001). Patients with DDFS &gt;5years had better OS compared to those with newly diagnosed stage IV disease (p&lt;0.005). In the multivariable model patients with recurrent disease had an increased risk of death compared to patients with newly diagnosed stage IV disease (HR=1.75, 95% CI 1.47-2.08, p&lt;0.0001). When the multivariable model was stratified by DDFI, patients with recurrent disease with DDFI &lt;5 years had 1.74 times the risk of death compare to those with newly diagnosed stage IV disease (95% CI 1.44-2.10, p&lt;0.0001). The risk of death was not statistically different among patients with recurrent disease with DDFI &gt;5 years compared to those with newly diagnosed stage IV disease (HR=1.11, 95% CI 0.88-1.41, p=0.38).&#x2028; ConclusionThis large cohort study provides further insight into the natural history of recurrent and newly diagnosed stage IV breast cancer. Compared to women with newly diagnosed stage IV disease, those with recurrent disease whose DDFI was &gt;5 years and &lt;5 years had similar and worse OS respectively.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2077.
Male breast cancer in Chinese population – a ten year review.
Authors: Kwong A , Suen DT 
Published: December 2010

Abstract
Abstract #2094
Objective: Breast cancer is uncommon in men, occurring in 1% of the male population based on Western data. There is limited knowledge about the natural history and prognosis of male breast cancer in Chinese population. This study aims to be the first to perform a 10 year review of the clinical presentation and outcome of Chinese male breast patients.&#x2028; Methods: A retrospective study of patients with male breast cancer treated in Hong Kong from January 1995 to December 2005 was performed.&#x2028; Results: A total of 83/124 medical records of male breast cancers treated in 16 hospitals during this 10 year study period were available and reviewed. The mean age at diagnosis was 65 years old. Of those where family history was known, only 3% had a family history of breast cancer. Only 7 patients had gynaecomastia. The mean time of presentation from time of symptoms occurrence was 23.2 months (range 0.06- 216). The most common presentation was presence of a breast lump. 75 (97%) of these patients underwent mastectomy, half of whom also had axillary dissection. 4 patients had LD flap reconstruction in addition to the mastectomy. 67 (87%) of these were invasive carcinoma of which 1 was invasive lobular carcinoma, 2 were mucinous carcinoma, 8 were invasive papillary carcinoma and the rest were invasive ductal carcinoma. 9 (11.7%) were in-situ carcinomas, where 6 were intraductal papillary carcinoma and the rest were ductal carcinoma in-situ. One patient had breast sarcoma. Of the invasive tumors, 74% were classified as Grade II and above. 29.8% of the patients had nodal involvement and the most common stage of presentation were either Stage 1 (33) or Stage 2 (27%). Majority of the tumors were oestrogen (95.8%) and progesterone (81%) receptor positive and 50% were cerbB2 positive. Where treatment data was available, all patients with ER positive tumors except for 6 patients received tamoxifen. 2.7% received neoadjuvant chemotherapy, 19.2% adjuvant chemotherapy and 47.3% received radiation therapy. The mean follow up was 54.5 months (1-178) months. The 5-year disease free and overall survival were 88% and 71.2% respectively. Interestingly 15 patients also had a second primary cancer not of breast origin.&#x2028; Discussions: Male breast cancer in Chinese men is rare and present at an older age but at an early stage. Disease free survival was better than overall survival likely due to death cause by disease other than breast cancer due to the older age of presentation. Although a majority of our cohort did not have family history of breast cancer, there was a high incidence of second primary cancer not of breast origin. Further investigation with genetic study in this group of patients is likely to be of relevance.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2094.