bluuebunny/crossref_metadata_2025 huggingface dataset:
P4-12-14: Pilot Study Utilizing Fluorine-18 Fluorodeoxyglucose (F-18 FDG) Positron Emission Tomography–Computed Tomography Scan (PET-CT Scan) To Investigate Brain Metabolic Changes during Treatment in Women with Breast Cancer.
Authors: Virani S , Lagos R , Hobbs G , Marano G , Nagaiah G , Abraham J
Published: June 2012

BACKGROUND: Approximately 25% of the patients undergoing chemotherapy develop cognitive changes. Similarly, significant neurocognitive changes in verbal memory and executive functioning have been reported in patients undergoing endocrine therapy. Though extensively studied, specific changes in the brain associated with cognitive dysfunction are still not clear. We performed an IRB-approved retrospective pilot study utilizing brain images from standard PET-CT scans in patients being treated for breast cancer. Comparison was made between patients initial and follow-up scans to look for metabolic changes.

MATERIALS AND METHODS: Thirty nine patients with a diagnosis of breast cancer were identified from radiology database of West Virginia University Hospitals, who underwent at least two PET-CT scans during their treatment for breast cancer from 2004–2009. Patients with brain metastasis were excluded. NeuroMIM® software analysis program was used to compare a comprehensive database of physiologic brain anatomy and metabolism with F-18 FDG perfusion brain images from the patients. Comparison was made in sixty-three defined brain regions. For each patient, two scans at approximately twelve month intervals were analyzed. The data sets from initial scans were compared with the follow up.

RESULTS: A total of 37 patients received cytotoxic chemotherapy, 2 patients received only endocrine therapy. Data analysis using the signed-rank test shows that the collective Z-score values change between the initial and follow up scans. When data analysis is applied to the individual brain regions, the Lingual Gyrus (p=0.012) and the Angular Gyrus (p=0.056)show statistically significant and near significant decreases in brain metabolism respectively. These regions are attributed with language, mathematics and cognition. Several additional regions such as the fusiform gyrus and the primary visual cortex show p-values between 0.05 and 0.10, which indicate “trending”. These regions may demonstrate statistically significant decrease in metabolism if the sample size is increased.

DISCUSSION: The Lingual and the Angular Gyrus show a statistically significant and near significant decrease in glucose metabolism respectively, in patients receiving treatment for breast cancer. Limitations of this study include lack of baseline brain imaging and its clinical correlation with cognitive function. Based upon these preliminary findings prospective studies are being planned.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-12-14.
P4-14-01: Weight-Adjusted Change of Unilateral Arm Volumes for Quantification of Lymphedema after Bilateral Breast Surgery.
Authors: Miller CL , Specht MC , Ancukiewicz M , Skolny MN , O ‘Toole J , Taghian AG
Published: June 2012

Background: Accurate quantification of breast cancer-related lymphedema (BCRL) is important for early detection and successful management. Arm volume changes after unilateral breast surgery can be calculated through relative volume change (RVC) of the affected arm using the contralateral arm as a control (Ancukiewicz et al Int J Radiat Oncol Biol Phys 79(5):1436–43 2011). However there currently exists no accurate method for quantifying arm volume changes in patients after bilateral breast surgery. As the number of women undergoing bilateral mastectomies continues to increase, it is critical to develop a method to quantify arm volume changes in this population for detection of lymphedema. Our aim was to develop a weight-adjusted formula for unilateral arm volume changes independent of the contralateral arm for application in the setting of bilateral breast surgery.

Materials and Methods: We analyzed longitudinal measurements of arm volumes in 141 unilaterally affected patients undergoing screening for BCRL with a perometer at our institution (71 with left affected and 70 with right affected arms). Each patient had a baseline measurement prior to surgery and at least one post-surgical measurement. Median time of follow-up was 27.5 months and median standard deviation of longitudinal weight changes within patients during follow-up was 3%.

Results: Unilateral arm volume changes of the unaffected arm were correlated with weight changes at the last follow-up point (Kendall's tau=.58 and P<.0001). Estimates of slope and intercept for median regression line between percent weight change and percent arm volume change evaluated for the unaffected arm at last follow-up are, respectively, .90 [95% CI] and .009 [95% CI]. Thus, percent weight change and percent arm volume change in the unaffected arm have an approximately linear relationship, such that the weight adjusted change (WAC) of affected unilateral arm volumes can be calculated according to the formula WAC=(A2*W1)/(W2*A1) — 1, where A1 is pre-surgical baseline arm volume on the affected side and A2 is post-surgical arm volume on the affected side, and W1, W2 are the patient's weights at these time points. Weight-adjusted change showed a strong correlation with RVC (RVC=(A2*U1)/(U2*A1) — 1), where A1, A2 are arm volumes on the side of the affected breast, and U1, U2 are volumes on the contralateral side at these time points (Kendall's tau=.41, P<.0001).

Discussion: Unilateral arm volume changes can be quantified by adjusting for weight changes. We propose the weight-adjusted change (WAC) formula to calculate unilateral arm volume changes for detection and monitoring of BCRL in patients who undergo bilateral breast surgery. The validity of such a formula needs to be assessed in conjunction with clinically reported lymphedema.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-14-01.
P4-19-05: A Population-Based Study of Guideline-Based BRCA Screening in Male Breast Carcinoma.
Authors: Bradley KL , Nuk JE , Chia SK , Villa D , Speers CH , Woods R , Young S , Tyldesley S
Published: June 2012

Purpose: The British Columbia Cancer Agency (BCCA) Hereditary Cancer Program (HCP) is a publicly funded, centralized program that provides BRCA testing to patients with male breast cancer (MBC) who meet specified referral criteria (aimed at detecting a mutation in > 10% of those tested). Criteria include: MBC with Ashkenazi heritage, MBC with one other family member with breast or ovarian cancer, MBC diagnosed at < 35 years, Bilateral MBC with first diagnosed at < 50 year. In this context, the purpose was to study referral patterns for hereditary counselling and outcomes of BRCA testing within a population-based study of male breast carcinoma.

Patients and Methods

Records of consecutive cases of invasive MBC diagnosed from 2000 to 2010 were reviewed. We documented any recorded personal and family history of cancer. For those meeting the HCP referral criteria we recorded whether a referral was made and the outcome of any genetic testing.

Results: Of 158 cases of MBC, 23 (14.6%) patients (21 met referral criteria; 2 did not) were seen for genetic counselling, of whom 21 were offered BRCA1/2 testing, and 19 accepted testing. Of 19 patients with BRCA1/2 genetic test results, 3 (16%) had a pathogenic mutation identified; one in the BRCA1 gene (c.1387_1390delinsGAAAG) and two in the BRCA2 gene (***c.755_758delACAG; c.1813dupA). In a further 4 cases (21%) an unclassified variant in BRCA1 was identified. In the remaining 12 cases (63%), testing was uninformative.

Conclusions: The BRCA1/2 mutation detection rate of 16% is in line with the expected rate of >10% using established selection criteria. Expanding the criteria at this time to include all male breast cancers would be expected to decrease the detection rate below 10% with the potential to negatively impact on the publicly-funded and finite resources of the Hereditary Cancer Program and Cancer Genetics Laboratory.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-19-05.
P5-01-08: Immunocytochemistry Staining of Estrogen Receptor in Circulating Tumor Cells as Compared to Primary Tumor.
Authors: Mayer JA , Pham T , Wong KL , Bischoff FZ
Published: June 2012

Introduction: Estrogen receptor (ER) status in all breast cancer patients is recommended by immunohistochemistry (IHC) and is considered standard practice for selection of treatment options. However, the analytical sensitivity of IHC in detecting low levels of ER is often poor and likely due to methodological variation. Because biopsy is not often feasible in all patients presenting with recurrent and/or metastatic breast disease, circulating tumor cells (CTCs) offer an attractive alternative source of tumor tissue for determining ER status and can be monitored more readily to enable a more effective course of treatment.

Experimental Design: Twenty ml of peripheral blood was collected prospectively from # patients diagnosed with late stage metastatic/recurrent breast cancer. CTCs were isolated using the microfluidic OncoCEE™ platform. A cocktail of antibodies was utilized for CTC capture and detection with an expanded anti-cytokeratin (CK) cocktail mixture and anti-CD45. ER protein expression was assessed by immunocytochemistry (ICC) on the cells captured within the microchannels and compared to IHC performed on the primary tumor.

Results: CK+/CD45- cells were detected in 23 of 27 cases (85%). Among the 23 cases in which CK+ cells were detected, only moderate concordance (16/23; 70%) in ER status between primary tumor and CTCs was observed.

Conclusions: There is significant heterogeneity between ER protein expression in CTCs and primary tumor. ER ICC on CTCs from peripheral blood using the OncoCEE™ platform is shown to be feasible but the comparison likely compromised by lack of tumor staging at the time of blood draw. Given that IHC was in some cases performed 5–10 years pre-blood draw and that tumors have the potential to convert, ER status only moderately correlates to the IHC status in the primary tumor. The significance of heterogeneity at the ER protein level in CTCs ascertaining to the prognosis and predictive response to anti-estrogen therapy needs further evaluation in larger prospective clinical trials.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-01-08.
P5-06-05: Switching Addictions between HER2 and FGFR2 in HER2−Positive Breast Tumor Cells: FGFR2 as a Potential Target for Salvage after Lapatinib Failure.
Authors: Tsurutani J , Azuma K , Sakai K , Aaro T , Nishio K , Nakagawa K
Published: June 2012

Agents that target HER2 have improved the prognosis of patients with HER2−amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC50 of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2−targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2−positive breast cancer.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-06-05.
P5-06-08: Mesenchymal Stem Cells and Carcinoma-Associated Fibroblasts Sensitize Breast Cancer Cells in 3D Cultures to Kinase Inhibitors.
Authors: Dittmer J , Dittmer A , Oerlecke I , Leyh B , Martens JWM , Thomssen C
Published: June 2012

Background: Bone-derived mesenchymal stem cells (MSCs) are attracted to cancer lesions and may differentiate to CAFs. By interacting with cancer cells, MSCs and CAFs may promote cancer progression and modulate drug sensitivity.

Material and Methods: To analyze ability of MSCs and CAFs to modulate drug response, we generated spheroids of MCF-7 or MDA-MB-231 breast cancer cells in the absence or presence of human (h) MSCs or hCAFs and tested the susceptibility of the breast cancer cells to three different kinase inhibitors (TKI258, RAD001 and RAF265) as used in cancer therapy.

Results: While MSCs and CAFs did not affect the response of either breast cancer cell line to PDGFR/FGFR/VEGFR inhibitor TKI258, they sensitized breast cancer cells to the mTOR inhibitor RAD001. In MCF-7 cells, this was accompanied by increased apoptosis. hMSCs and to a lesser extent hCAFs also enhanced the cytotoxic effect of RAF inhibitor RAF265 on MDA-MB-231 cells. Searching for the mechanism that underlies the effect of stromal cells on RAF265 response we found that stromal cells inhibited RAF265-induced increase in ERK1/2 phosphorylation, supported RAF265-dependent downregulation of PKCalpha (protein kinase Calpha) and prevented RAF265-induced conversion of LC3B, a marker of autophagy. To mimic the changes in ERK1/2 phosphorylation and PKCalpha expression in response to the stromal cells, we treated cells with MEK1 inhibitor U0126 or PKCalpha inhibitor Gö6976, respectively. U0126, but not Gö6976, was as effective as hMSCs in sensitizing MDA-MB-231 cells to RAF265.

Discussion: Our data suggest that hMSCs and hCAFs increased the cytotoxic effect of RAF265 on MDA-MB-231 cells by downregulating ERK1/2 phosphorylation. In summary, this study shows that hMSCs are able to render breast cancer cells more susceptible to kinase inhibitors and that, to the most part, hCAFs to which hMSCs can differentiate are able to mimic the drug-sensitizing effects of hMSCs.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-06-08.
P5-07-03: Modulation of Autophagic Activity by Extracellular pH.
Authors: Xu T , Su H , Ganapathy S , Yuan Z-M
Published: June 2012

Reprogramming energy metabolism from oxidative phosphorylation to aerobic glycolysis, a common feature of human cancer, results in a relative acidic tumor microenvironment which is further accentuated by hypoxia operating within most tumors. We report that alteration of extracellular pH induces marked and rapid changes of autophagic activity in a variety of cell lines including mammary non-transformed cells and breast cancer cells. Interestingly, acidic and basic conditions induce completely opposite effect on autophagy, with its activity suppressed at lower pH whereas stimulated at higher pH. Gene knockdown experiments indicate that pH induced-autophagy requires Beclin 1, Vps34 and ATG5, key components of the autophagy pathway. Of note, acidic condition not only inhibits the basal but also blocks starvation-induced autophagy activity. Significantly, examination of different areas of tumor mass reveals a lower autophagic activity within the inner region than the outer region. These findings have important implications on the connections between autophagy and cancer as well as a wide range of other physiological and pathological processes.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-07-03.
P5-08-03: How Reader's Training, Software, and Image Formats Impact Percent Dense Area Measures.
Authors: Fan B , Duewer F , Wu FF , Kerlikowske K , Vachon C , Shepherd JA
Published: June 2012

BACKGROUND: Mammographic percent dense area, the percent ratio of dense to total breast area in a mammogram, is one of the strongest measures of a woman's risk of breast cancer. However, systematic differences have been observed between readers and mammography technologies (film and digital) that could cause clinically inconsistent associations with risk. The purpose of this study was to evaluate inter- and intra-reproducibility of percent dense area between readers and between film and digital technologies.

METHODS: One hundred digitized film mammograms were randomly selected with 25 films in each of quartile of percent density and read by two readers at two different sites (Mayo Clinic and UCSF). The readers had extensive experience and were also jointly trained at university of Toronto using Cumulus software. After training, all films were read twice with at least one year between duplicate readings. The Mayo clinic reading used Cumulus while UCSF used custom semiautomatic software to estimate total and dense tissue area. In addition, digitized films and unprocessed full field digital mammograms of the same women were assessed by one reader. The time between the film and digital acquisitions ranged from nine to twenty-four months. Interclass correlation coefficient (ICC) was calculated for each comparison.

RESULTS: The intra- and inter-observer ICCs, consistency for film images, were 0.96 (UCSF) and 0.97 (Mayo), and 0.96 (UCSF vs. Mayo). We found ICC between film and digital mammograms for percent dense area was 0.88. The digital mammogram had 9% significantly higher total breast area and 5% significantly lower percent density area compared to film.

CONCLUSIONS: Similarly trained readers had a high reproducibility regardless of the software used. Our results suggest centralized reader training should enable pooling of film breast density results from different clinics. However, pooling film and digital results would need careful calibration due to lower measured percent dense areas than on film.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-08-03.
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

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

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

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

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<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

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

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

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 < 0.0001), larger tumours (P < 0.0001), tumours with a higher histologic grade (P < 0.0001), tumours located retroareolar or lateral in the breast (P < 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 < 0.0001), larger tumour size (P < 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 > 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

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< 14%), luminal B (positive ER and/or PR, negative HER2 and Ki67>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<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<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

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<.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<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.
P5-19-10: Correlation of Response of Weekly Paclitaxel and Paraplatin as First Line Treatment of Metastatic Breast Cancer with p53 Status.
Authors: El-Sadda W , Magdy M , Abdel-Halim I , Abdel-Wahab A
Published: June 2012

Background Paclitaxel is one of the most active drugs in metastatic breast cancer. Weekly paclitaxel seems less toxic & more efficient compared with paclitaxel every 3 weeks (possibly because of the proapoptotic and antiangiogenic activity), the dose intensity is quiet higher with tolerable toxicity. The sensitivity of tumors overexpressing p53 to paclitaxel is a matter of debate.

The purpose of study is to evaluate weekly paclitaxel and paraplatin in patients with metastatic breast cancer in terms of response rate, toxicity profile, relation of response to p53 status, progression free survival & overall survival.

Patients & Methods: Between September 2006 & September 2008, 60 patients with measurable metastatic breast cancer after adjuvant anthracycline treatment, WHO PS <2, adequate renal, liver & bone marrow function. Patients received no prior chemotherapy for metastasis. Pathology specimens were evaluated for p53 status by immunohistochemistry (IHC). All patients received weekly paclitaxel 80 mg/m2 D1, D8, D15 (one hour IV infusion) and paraplatin AUC 5 D1 (IV infusion over half an hour) every 4 weeks for six cycles. Response was assessed every 2 cycles, patients showed an objective response (CR, PR or SD) had continued to 8 cycles.

Results: All patients were evaluable for response, toxicity & survival. Median age was 50 years range (42-64 years), median WHO PS 0. Main metastatic sites were lung 40%, liver 30%, LN 20%, Skin 12% & bone 50%. Forty percent of patients had one metastatic site, 40% had 2 metastatic sites and 20% had > 2 metastatic sites.

The total number of cycles delivered was 466 with a median of 7 cycles / patient with no dose reduction. The overall response rate was 65% (CR 25%, PR 40%), SD 27% & PD 8%. Overexpression of p53 was found in 18 (30%) of the 60 studied patients, four of them showed only PR, compared to 30 patients having normal p53 status responded to treatment including 15 CRs. Overexpression of p53 had a significant negative impact on response to treatment (p=0.01). No grade 4 toxicity G2 anemia 15%, G3 neutropenia observed in 13.3%, G2 neuropathy occurred in 15%. Median time to progression & median survival were 18.5 & 28 months respectively.

Conclusion: The overall response rate achieved with weekly paclitaxel plus paraplatin is among the highest in metastatic breast cancer. However, the poor response rate seen in patients with p53 overexpression suggests the use of other combinations that may help to improve the outcome.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-10.
P5-20-02: N-Terminal Pro-Brain B-Type Natriuretic Peptide (nt-pro-BNP) before and during Treatment with Trastuzumab Allows Early Detection of Cardiotoxicity in Breast Cancer Patients.
Authors: Blancas I , Carrillo J , Legerén M , Delgado M , Jurado JM , Zarcos I , Villaescusa A , Gómez FJ , Moreno E , García-Puche JL
Published: June 2012

Background: The treatment with Trastuzumab (T) is associated with a certain degree of cardiotoxicity. This study sought to evaluate the level of nt-pro-BNP as a possible marker of cardiotoxicity so accurate as the value of left ventricular ejection fraction (LVEF)

Patients and methods: Forty patients with breast cancer treated with T were prospectively measured LVFE with echocardiography and nt-pro-BNP level before and every 3 months during T treatment. Median age: 50years(27;70). Received T as adjuvant treatment: 82.5% of the patients and 17.5% for metastatic disease.Patients with previous chemotherapy: 13(32.5%)neoadjuvant, 23(57.5%)adjuvant and 7(17.5%) for metastastic disease. Patients with previous treatment with anthracyclines: 12(30%)neoadjuvant, 21(52.5%)adjuvant and 2(5%)for metastatic disease(one patient had received anthracyclines too during adjuvant treatment).None received anthracyclines and T concomitant. Chi-square analyzed the correlation of high pathological level of nt-pro-BNP (values over the normal ***range, adjusted by the patient age) and a significative decrease of LVEF (more than 10% when LVEF >50% or more than 5% when LVEF< 50%)

Results: A decrease in LVEF was observed in 6 patients(15%) and pathological high levels of nt-pro-BNP in 7(17.5%).Two patients(5%) presented cardiac insufficiency with clinical symptoms, in both nt-pro-BNP was higher than 600pg/ml and LVEF lower than 40%. In the other patients the decreases of LVEF(never were<40%) or high levels of nt-proBNP(never were>600pg/ml)were not related to any clinical symptoms. Chi-square analysis showed a correlation between pathological high levels of nt-pro-BNP and significative decrease of LVEF (p=0.001), The estimated risk of a false negative nt-pro-BNP result (nt-pro-BNP normal value and significative LVEF decrease) was 2.735% (95 % confidence interval: 0.878 to 8.522 %) and the estimated risk of a false positive nt-pro-BNP result (nt-pro-BNP pathological value and no significative LVEF decrease) was 0.132%(95% confidence interval: 0.39 to 0.448%) Conclusion:The level of nt-pro-BNP is a possible marker of cardiotoxicity so accurate as the value of LVEF in patients with breast cancer treated with T.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-20-02.