bluuebunny/crossref_metadata_2025_split huggingface dataset:
P5-11-15: Should HER-2 Score 0/1+ Breast Cancer Cases Be Retested by In-Situ Hybridisation? Results of a Multicenter Retesting Study.
Authors: Reiner-Concin AM , Lax S , Regitnig P , Kronberger C , Jasarevic Z , Bogner S 
Published: June 2012

Abstract
Background: HER-2 status is vital for selection of appropriate therapy for breast cancer patients. Accuracy of immunohistochemistry (IHC) varies with a major problem of false negative testing. To assess the false negative rate retesting by in situ hybridisation was performed on a group of primary breast cancers in which according to guidelines routine retesting is not recommended.
Material and Methods: 570 breast cancers from 5 pathology departments scored 0/1+ by IHC (HercepTest or 4B5-antibody) were retested by HER2−Dual-SISH (BDISH) in a central laboratory. CAP/ASCO guidelines were applied. Cases showing ratios in the amplified or equivocal range by BDISH were further analysed by fluorescence in situ hybridisation (FISH) using Pathvysion® and ZytoLight® and retested centrally by IHC using 4B5 antibody (Ventana).
Results: 25/570 cases (4.38%) were amplified by BDISH, the majority with low level amplification (ratios ≤ 3.26). Only two cases showed high level ratios (6.35 and 6.48). 17/570 cases (2.98%) showed ratios by BDISH in the equivocal range (1.8 — 2.2). 24 amplified and 17 equivocal cases underwent further retesting. In one case no tumor tissue was available for further testing.
On further testing 17/24 (71%) BDISH-amplified cases showed IHC scores 2+/3+ and 7/24 (29%) cases showed IHC scores 0/1+. Subsequently 3/13 score 2+ cases were amplified by Pathvysion® and 9/13 by ZytoLight®. 3/4 score 3+ cases were amplified by both FISH assays. In case of amplification ratios of BDISH and both FISH assays appeared to be in the same range. Only 2/17 BDISH-equivocal carcinomas were confirmed equivocal by Pathvysion® and 6/17 were confirmed equivocal by ZytoLight®. All other BDISH-equivocal cases were non-amplified by both FISH assays. Discrepant results between different methods could partly be caused by interobserver variability. This question is currently under investigation. Overall, after multistep retesting amplification occurred in only 17 cases (2.98%).
Discussion: Amplification is rare in immunohistochemically HER-2 negative breast carcinomas and occurred predominantly at low level in our study. Low level amplification seemed to be diagnosed more frequently by BDISH compared with FISH. Since clinical data demonstrate a benefit of therapy even in carcinomas with low level amplification the identification of these carcinomas might be of interest.
Conflicts of Interest: The study was supported by Roche Austria GmbH.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-15.
P5-11-17: Evaluating Tumor Heterogeneity in Immunohistochemistry Stained Breast Cancer Tissue.
Authors: Potts SJ , Landis N , Eberhard DA , Schmechel SC , Young D , Lange H 
Published: June 2012

Abstract
Context: Quantitative clinical measurement of heterogeneity in immunohistochemistry staining would be useful in both evaluating patient therapeutic response and identifying underlying issues in histopathology laboratory quality control.
Objective: To create a heterogeneity scoring approach (HetMap) that allows the visualization of an individual patient's IHC heterogeneity in the context of a population.
Design: We combined HER2 semi-quantitative analysis with the use of ecology diversity statistics to evaluate cell-level heterogeneity (consistency of protein expression within neighboring cells in a tumor nest) and tumor-level heterogeneity (differences of protein expression across a tumor as represented by a tissue section). We evaluated the approach on HER2 immunohistochemistry stained breast cancer samples, using 200 specimens across two different CLIA laboratories, with three pathologists at each laboratory each outlining regions of tumor for scoring by automatic cell-based image analysis. HetMap was evaluated using three different scoring schemes: HER2 scoring according to ASCO/CAP guidelines, H-Score and a new continuous HER2 score (HER2cont).
Results: Two definitions of heterogeneity, cell-level and tumor-level, provided useful independent measures of heterogeneity. Cell-level heterogeneity, reported either as an average or the maximum area of heterogeneity across a slide, had low levels of dependency on the pathologist choice of region (coefficient of variation of 15%). Tumor-level heterogeneity measurements had more dependence on the pathologist choice of regions (coefficient of variation of 25%). Results were highly similar between the two laboratories, which is encouraging for HER2 standardization, as the labs involved different pathologists, different specimens, and different standardization procedures, although both complied with CLIA/CAP guidelines for HER2 testing.
Conclusions: HetMap is a measure of heterogeneity, by which pathologists, oncologists, and drug development organizations can view cell-level and tumor-level heterogeneity for a patient for a given marker in the context of an entire patient cohort. Heterogeneity analysis can be a useful means to identify tumors with higher degrees of heterogeneity, or to highlight slides that should be rechecked for QC issues.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-17.
P5-12-01: Aromatase Inhibitor Specific Metastasis Is Driven by the Steroid Receptor Coactivator SRC-1.
Authors: Theissen SM , McBryan J , Byrne C , Hughes E , Cocchiglia S , Hill AD , Young LS 
Published: June 2012

Abstract
Aromatase Inhibitors are currently one of the most promising therapies of estrogen-receptor positive breast cancer in postmenopausal women. Even though many women initially respond to the treatment, approximately 30–40% will acquire resistance and relapse within 5 years. The mechanisms involved in the development of resistance to AIs however are poorly understood as long term follow up is only now becoming available. To investigate the mechanisms involved in AI-specific tumour recurrence, we generated a cell line resistant to the AI Letrozole (LetR) and examined a cohort of endocrine treated breast cancer patients (n=150). In patients treated with a first-line AI (n=89), we found that hormone receptor switching between the primary tumour and the resistant metastasis was a common feature of disease recurrence. More so, this switch accompanied the development of a phenotype displaying an increase in migratory capacity and loss of organisation. Both the resistant cell model and AI resistant tumour samples expressed high levels of the steroid receptor coactivator SRC-1. We also found that the interaction between SRC-1 and the transcription factor Ets2 was involved in the regulation of Myc and MMP9 expression and that SRC-1 was required for the aggressive AI resistant phenotype. Expression of SRC-1 in the primary and/or recurrent tumour associated with poor disease free survival (p=0.01, n=89) in the AI treated population. A significant coassociation between SRC-1 and Ets2 in the nucleus of the recurrent tissue compared with the matched primary tumour was also observed (p=0.0004, n=3). These data describe a novel signaling mechanism of AI-specific metastatic progression where SRC-1 utilizes Ets2 to promote de-differentiation and migration to drive disease progression.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-12-01.
P5-13-14: Drug-Metabolizing Enzyme Polymorphisms and Clinical Outcome of Anthracycline-Based Chemotherapy in Chinese Han Breast Cancer Patients.
Authors: Tang J , Zhao J , Wu J , Ji M , Zhong S 
Published: June 2012

Abstract
Background
Anthracycline is one of the most effective drugs in the treatment of breast cancer and many of our most effective treatment regimens include anthracycline. Its efficacy can be influenced by cellular detoxification mechanisms involving drug metabolism and transport pathways. This study aimed to assess whether the functional polymorphisms in drug-metabolizing enzymes (MnSOD, CAT and GSTs) and transporter MDR1 may predict anthracycline treatment-related outcomes in Chinese Han breast cancer patients.
Material and methods: Genotyping was performed by allele-specific oligonucleotide ligation reaction (MnSOD T47C, CAT C-262T, GSTP1 A313G), multiplex PCR (GSTM1 null, GSTT1 null), and PCR-RFLP (MDR1 C3435T, G2677T/A and C1236T). Based on 153 evaluable patients received anthracycline-based neoadjuvant chemotherapy for breast cancer, the associations of these genotypes or their haplotypes with clinical response and recurrence-free survival (RFS) were analyzed.
Results: Of the 153 cases, the patients with GSTP1 313AA genotype had inferior response rates relative to those with AG or GG genotype (58.4% vs 77.8% or 100.0%; χ2=4.922, P=0.027). Moreover, the response rate of the combination of GSTP1 AA with both GSTT1 present and GSTM1 present was 44%, which was also lower comparing with the other groups (70.3%; χ2=6.454, P=0.011). A similar result was noticed for MDR1 3435 TT genotype, which had a significantly worse chemotherapy response compared with wild-type C allele carrier (33.3% vs 71.2%; χ2=11.586, P=0.001). Further, the response rate of the patients with 3435T-2677T, 3435T-1236T or 3435T-2677T-1236T haplotypes was lower than that of the patients with the other corresponding haplotypes (P=0.018, 0.011 and 0.019, respectively), too. Of note, the patients with both the adverse genotypes of GSTP1 314AA and MDR 3435TT shown the worst treatment efficacy in all (14.3%;χ2=26.33, P=0.000). Mean follow-up time of the 149 patients (4 patients lost) was 51 months. The recurrence rate in the patients with GSTP1 313AA or/and MDR 3435TT in the first three years was 39.0% (41/105), higher significantly than those with no adverse genotype [15.9% (7/44); OR=0.725, 95%Cl: 0.594−0.885, P=0.006]. Kaplan-Meier survival analysis showed that the patients with no adverse genotype were associated with reduced hazard of relapse (long-rank test, P&lt;0.01), compared to those with 1 or 2 adverse genotypes.
Conclusion: Polymorphisms in GSTs and MDR1 genes may help to predict clinical response and RFS of anthracycline-based chemotherapy in breast cancer, but further validation is required. These results provide support for a polygenic pathway approach for assessing the predictive potential of polymorphisms in treatment outcomes.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-14.
P5-13-21: Japanese Patients with Discordance in Estrogen Receptor between Primary Breast Cancer and Recurrent Tumor Have a Poorer Outcome.
Authors: Tanaka K , Kawaguchi H , Kuba S , Koga C , Nishimura S , Yoshiyama T , Ishida M , Nakamura Y , Ohno S 
Published: June 2012

Abstract
Background Decisions of systemic treatment for recurrent breast cancer are usually based on the estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor status of the primary tumor. Recently, discordance in receptor status between primary and recurrent tumors has been reported. The objective of this study was to compare receptor status between the primary and recurrent tumor, and to evaluate overall survival (OS) after the diagnosis of recurrence between patients with discordant and concordant receptor status.
Material and Methods Patients with recurrent breast cancer treated at National Kyushu Cancer Center between January 2004 and May 2011 were reviewed retrospectively. Primary and recurrent lesions were analyzed for ER and PR by immunohistochemistry (IHC) and HER2 by IHC or fluorescence in situ hybridization (FISH). OS in discordant and concordant groups for each receptor was estimated by Kaplan-Meier method and compared by log-rank test.
Results Among 283 recurrent breast cancer patients both primary and recurrent tumor information for ER, PR, and HER2 was available in 69. Among these, recurrent biopsy specimens were obtained from locoregional recurrence in 72.5% and from distant metastases in 27.5%. Discordant rate in receptor status between the primary and recurrent tumor was 36.2%. Discordant rate in ER, PR, and HER2 was 14.4%, 23.1%, and 4.3%, respectively. Two-year OS after the diagnosis of recurrence in discordant and concordant ER group was 66.7% and 84.7%, respectively. The discordant ER group had significantly worse OS than the concordant ER group (P = 0.040). There was no significant difference in OS between the discordant and concordant PR group (P = 0.950).
Conclusions Because discordance of receptor status between primary and recurrent tumors may exist, tissue confirmation of receptor status of recurrent tumor should be considered. Japanese patients with discordant ER between primary and recurrent tumor had a poorer outcome.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-21.
P5-14-09: Malignant Calcification Is an Important Prognostic Factor in Women with Invasive Breast Cancer – Suggestion for Regarding It as High-Risk Factor in Current Staging and Adjuvant Treatment Guidelines.
Authors: Ling H , Shao Z-M , Liu Z-B , Xu X-L , Yang W-T , Xu L-H , Gu Y-J 
Published: June 2012

Abstract
Purpose: To investigate whether calcification is a prognostic factor for breast cancer.
Methods: A total of 804 patients with invasive breast cancer diagnosed between 2001 and 2003 were recruited and divided into two groups based on whether they had malignant calcification on mammogram. The association of calcification with lymph node status, grade, tumor size, ER, PR and Her2 status, 8-year disease-free survival (DFS) and overall survival (OS) was evaluated. Survival difference was analyzed by Kaplan-Meier technique. The relative importance of each of the potentially prognostic variables was tested using Cox regression analysis.
Results: The incidence of malignant calcification in all breast cancer was 41.5%. Compared with tumor without calcification, those with calcification had a larger size (2.6cm vs 2.1cm, P=0.000), higher axillary lymph node (LN) positive rate (40.1% vs 31.5%, P=0.012), more LN involvement (14.8% vs 9.2%, P=0.000), lower ER (54.3% vs 65.1%, P=0.002) and PR (42.7% vs 60.6%, P=0.000) expression and higher Her2 expression (27.3% vs 14.7%, P=0.000).
The 8-year DFS was lower for patients with calcification than those without (89.9% vs. 76.8%, P=0.000). The 8-year OS for tumor with calcification was 82.2%, compared with 92.8% for those without (P=0.000).
Subgroup analysis showed that the shorter survival and higher relapse rate for tumors with calcification could be found in both LN- and LN+ patients, also could be found in T1, T2, Grade II, ER+, PR+ and Her2- patients.
The existence of calcification, LN stage, tumor size, ER status, and grade were significantly associated with survival in univariate analysis. Further Cox regression analysis demonstrated that calcification and LN stage maintained their prognostic significance in both DFS and OS. The hazard ratios of these factors are listed in Table 1.

Conclusions: The existence of calcification is a poor prognostic factor for patients with invasive breast cancer. Its prognostic value is only second to LN status and is higher than the other factors evaluated, including tumor size, grade, and ER, PR status. Thus, breast cancer with calcification should be regarded as a high-risk factor when determining cancer stage and selecting the adjuvant treatment.
Discussion: Given the strong prognostic value of calcification revealed in this research, the biological mechanism of its formation and related cell signal pathway should be investigated. Further adjuvant clinical trial should be done to select certain sensitive chemotherapeutic agent or regimen. Some biomarkers have been found to have a role in the formation of calcification and may be targets for treatment.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-09.
P5-14-21: Predicting the Status of the Axillary Lymph Nodes in 1300 Consecutive Patients with Early Breast Cancer Treated in a Single Institution.
Authors: Yoshihara E , Smeets A , Laenen A , Reynders A , Wildiers H , Soens J , Paridaens R , Van Ongeval C , Floris G , Moerman P , Neven P , Christiaens M-R 
Published: June 2012

Abstract
Purpose. Lymph node involvement is the most important prognostic factor in breast cancer. It is a multifactorial event determined by tumour and patient characteristics. Several predictors of axillary lymph node metastasis (ALNM) in breast cancer have been described. The purpose of this study was to determine clinical and pathological factors predictive for ALNM in patients with early breast cancer and to build a model to portend lymph node involvement.
Methods. We evaluated 1300 consecutive patients surgically treated in our institution (2007-2009) for cT1-T2 invasive breast cancer. The patient and tumour characteristics evaluated included: age at diagnosis, number of foci, histologic grade, location, tumour size, histologic subtype, lymphovascular invasion (LVI), estrogen-receptor (ER), progesterone-receptor (PR) and Her2 status. Univariate and multivariate analyses were performed. Factors significantly associated with lymph node metastasis by univariate analysis and histologic subtype were included in the multivariate model. We validated our model with the same 1300 patients on the basis of a multivariable logistic regression model containing the variables, using a correction factor.
Results. By univariate analysis, the incidence of ALNM was significantly higher in patients with a tumour with LVI (P &lt; 0.0001), larger tumours (P &lt; 0.0001), tumours with a higher histologic grade (P &lt; 0.0001), tumours located retroareolar or lateral in the breast (P &lt; 0.0001), tumours with multiple foci (P = 0.0002) and in patients who underwent an axillary lymph node dissection. We found no effect of ER/PR nor HER-2 status.

By multivariate analysis, lymph node involvement was significantly associated with the presence of lymphovascular invasion (P &lt; 0.0001), larger tumour size (P &lt; 0.0001), axillary lymph node dissection (P = 0.0003), retroareolar and lateral tumour location in the breast (P = 0.0019) and the presence of multiple foci (P = 0.0155).

The discrimination of the model, calculated by the area under the curve (AUC), was 0.778.
Conclusions. LVI and tumour size emerged as most powerful independent predictors of ALNM. A model with an AUC of 0.50 is equivalent to the toss of a coin, a model with an AUC &gt; 0.70 is considered as good. In conclusion, our result is not perfect in discrimination which raises further questions. It is clear that underlying mechanisms of ALNM remain to be elucidated.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-21.
P5-14-23: Clinical Outcomes of Different Subtypes Detected by Immunohistochemistry of Early Invasive Breast Cancers in a Monoinstitutional Series.
Authors: Ferro A , Eccher C , Caldara A , Triolo R , Barbareschi M , Cuorvo LV , Aldovini D , Dipasquale M , Galligioni E 
Published: June 2012

Abstract
Background
Early invasive breast cancer (EIBC) is an heterogeneous disease. Immunohistochemical (IHC) markers can be used to classify tumors in different biological subtypes with different clinical behavior.
Purpose: The aim of our study was to evaluate survival outcomes for patients (pts) with different subtypes of EIBC as classified using four ICH markers (ER, PR, HER2 and Ki67).
Methods: We evaluated data from 3403 consecutive cases of EIBC treated from 1995 to 2008 and classified as: luminal A (positive ER and PR, negative HER2 and Ki67&lt; 14%), luminal B (positive ER and/or PR, negative HER2 and Ki67&gt;14%), luminal C (positive ER and/or PR, positive HER2, any Ki67), HER2+ (negative ER and PR, positive HER2, any ki67), triple negative (negative ER and PR, negative HER2, any ki67). Log-rank test and Kaplan-Meyer estimator were performed to evaluate the impact of ICH subtypes on overall survival (OS), Event Free Survival (EFS) and their correlation with other known prognostic factors such as N, G, Size, Age.
Results: We identified 917 luminal A (26.9%), 1731 luminal B (50.9%), 279 (8.2%) luminal C, 183 HER2 + (5.4%) and 293 triple negative (8.6%). Median age was 61 years. Luminal A was more frequently (p&lt;0.001) associated with older age, smaller size, negative axilla involvement, low grading. Observed events (relapses, contralateral and second tumors) were: 54 in luminal A (6%), 215 in luminal B (16%), 40 in luminal C (14%), 42 in HER2+ (23%) and 59 in triple negative (20%). Disease free interval (DFI) was shorter in luminal C, HER2 and TN (median DFI: 30, 26 and 19 months) than in Luminal A and B (median DFI: 51 and 41 month). Luminal A and B presented more bony and less visceral recurrences than luminal C, HER2 and triple negative tumors. At median follow up of 51 months EFS was 94.1% in luminal A, 87.5% in luminal B, 85.5% in luminal C, 76.8% in HER2+ and 79.7% in triple negative. Corresponding OS was 95.3% in luminal A, 89% in luminal B, 89.2% in luminal C, 80.9% in HER2+, 81.9% in triple negative. Different subtypes EFS according to nodal status, grading, tumor size and age, was reported in table 1.

Considering only Luminal subtypes, Luminal B and C were significantly associated with poor EFS vs Luminal A EIBCs in both N0 (p=0.046) and N+ pts (p&lt;0.001), in T1 (p=0.013) and T2 (p=0.03) pts, in pts older than 40 years (p=0.002).
Conclusions: Luminal A showed better prognosis in term of EFS and OS than other subtypes regardless other prognostic factors as clinical features (age) and tumor extent (T and N).
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-23.
P5-18-01: No Effect of Adjuvant Chemotherapy in Postmenopausal Patients with Invasive Lobular (Mixed) Breast Cancer.
Authors: Truin W , Voogd A , Vreugdenhil G , Van der Heiden-van der Loo M , Siesling S , Roumen R 
Published: June 2012

Abstract
Background: Although the literature is clear concerning the lack of response of invasive lobular breast cancer to neoadjuvant chemotherapy, no studies exist on the effectiveness of the adjuvant use of chemotherapy in these patients, as compared to those with ductal and mixed type lobular cancer.
Methods: All women with primary non-metastatic invasive ductal or (mixed type) lobular breast cancer, aged 50 to 69 years, diagnosed in the period 1995 to 2008 and treated with surgery, were selected from the Netherlands Cancer Registry and followed until January 1, 2010. Patients were divided in two groups: those who received adjuvant hormonal therapy only versus those receiving hormonal therapy in combination with adjuvant chemotherapy. Cox proportional hazards analyses were carried out to determine the impact of chemotherapy in addition to hormonal treatment, for each histological entity separately. Results: In total 19,609 patients had ductal cancer, 3,685 had pure lobular cancer and 1,391 had mixed type lobular cancer. The patient groups were comparable with respect to the use of adjuvant systemic treatment. The 10-year survival of patients with ductal cancer treated with hormonal therapy alone was 69%, compared to 74% for those treated with hormonal therapy and chemotherapy (P&lt;.0001). For patients with lobular cancer, the 10-year survival rate was 68% after hormonal treatment alone and 66% after hormonal therapy with chemotherapy (P=.45). The hazard ratio for death among the patients with ductal cancer receiving chemotherapy in addition to hormonal treatment was 0.70 (95% CI, 0.64−0.76, p&lt;0.0001), as compared to those receiving hormonal treatment alone. In patients with pure or mixed type lobular cancer, however, the hazard ratio's were 1.00 (95% CI, 0.82−1.21, p=0.97) and 0.98 (95% CI, 0.70−1.33, p=0.83), respectively. A statistically significant interaction was observed between the use of adjuvant chemotherapy and histological tumor type.
Conclusions: Adjuvant chemotherapy confers no additional beneficial effects in postmenopausal patients with pure or mixed type lobular breast cancer receiving hormonal therapy.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-18-01.