Subgroup Of Breast Cancer Patients Research Articles

Pre-mir-27a rs895819 polymorphism and cancer risk: a meta-analysis

Aberrant expression of miRNAs plays critical roles in cancer development. Single nucleotide polymorphism (SNP) in miRNA precursors may affect miRNA expression levels. An important SNP in the pre-mir-27a with a A to G change (rs895819) was identified. Several original studies have explored the role of this SNP in cancer risk, but the results of these studies remain conflicting rather than conclusive. Therefore, we performed a meta-analysis of the published studies to derive a more precise estimation of the association between pre-mir-27a rs895819 polymorphism and cancer risk. In this meta-analysis, a total of 6 case-control studies (including 3,255 cases and 4,181 controls) were analyzed. The results of the overall meta-analysis did not suggest any associations between pre-mir-27a rs895819 polymorphism and cancer susceptibility. However, an decreased risk was observed in the subgroup of breast cancer patients (G vs A: OR = 0.90, 95 % CI = 0.83 ~ 0.97; P heterogeneity = 0.75) or in the subgroup of Caucasian race (G vs A: OR = 0.90, 95 % CI = 0.83 ~ 0.97, P heterogeneity = 0.78, I (2) = 0; AG vs AA: OR = 0.84, 95 % CI = 0.75 ~ 0.94, P heterogeneity = 0.35, I (2) = 3.7 %; GG+AG vs AA: OR = 0.85, 95 % CI = 0.76 ~ 0.94, P heterogeneity = 0.48, I (2) = 0). The findings suggest that pre-mir-27a rs895819 polymorphism may have some relation to breast cancer susceptibility or cancer development in Caucasian.

Abstract P2-10-23: Lymphovascular Invasion (LVI) and Overall Survival in Node-negative and Node-positive Breast Cancer Patients: A Meta-analysis.

Abstract Introduction: LVI is an important prognostic factor in patients with lymph node-negative invasive breast cancer. The prognostic value of LVI in lymph node-positive disease or in other subgroups remains unclear. Here we present a meta-analysis of studies assessing the impact of LVI on overall survival (OS) in different subgroups of breast cancer patients. Methods: A published data meta-analysis was conducted. Studies reporting hazard ratios (HR) for the association of LVI with OS in a multivariable model were included. Those not reporting HR or utilizing only univariable analyses were excluded. HR and 95% confidence intervals (CI) were extracted or computed and pooled using the DerSimonian and Laird random effects model. Subgroup analyses were conducted for the differential effect of lymph node involvement, estrogen receptor (ER) status, extent of LVI and decade in which the study was conducted (pre 1990, 1990–1999 and 2000 onwards). Results: Twenty studies comprising 40,417 patients were included in the analysis. There was marked heterogeneity in the effect size between studies (Cochran Q p < 0.001, I2=62%). When all studies were pooled, LVI was significantly associated with worse OS (HR:1.70 95% CI 1.49–1.95, p < 0.001). Among studies selecting patients by lymph node status, the association between LVI and OS was similar for lymph node positive and negative patients (HR:2.03 and 2.41 respectively, subgroup difference p = 0.56). There were no significant differences based on ER-status (subgroup difference p = 0.75) or decade of study (subgroup difference p = 0.21). Pooled assessment of the effect of extent of LVI was not possible as this parameter was not consistently reported. Conclusion: LVI is associated with similarly detrimental OS regardless of lymph-node or ER status. Improvements in adjuvant therapies over the past 20 years do not appear to have diluted the impact of LVI on OS. The marked heterogeneity in the effect size may result from differences in the extent of LVI. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-23.

Highlights of This Issue

The impact of pretransplantation iron overload on patient outcome after allogeneic stem cell transplantation is controversially discussed, because recent studies were retrospective in nature and relied on interference prone surrogate markers. Wermke and colleagues report prospective data based on liver MRI to quantify the extent of body iron in this context. In their cohort, surrogate parameters failed to accurately identify iron overloaded patients. Moreover, only liver iron as determined by MRI but not serum ferritin or transfusion burden predicted for survival. It will be important to understand the mechanisms by which excessive iron contributes to a worse outcome after transplantation.Measurement of HER family signaling is critically important in the clinical management of a significant number of breast cancer patients. Using a highly sensitive protein array, Wulfkuhle and colleagues identified a new subgroup of breast cancer patients with HER2 pathway activation in an otherwise HER2- negative cohort. These patients are not identified by current clinically approved or genomic tests for HER2, and are thus excluded from anti-HER2 therapies. Protein pathway activation mapping of receptor tyrosine kinases and linked signaling pathways may identify new patient cohorts that could benefit from existing FDA cleared and/or experimental molecular targeted inhibitors, if these measurements prove clinically useful.The novel magnetic resonance imaging method of vessel size imaging (VSI) provides in vivo images of blood volume and mean vessel radius. Using an intravascular contrast agent of the ultrasmall paramagnetic iron oxide class, Nielsen and colleagues utilized VSI for investigating the effect of the vascular disrupting agent combretastatin in a murine tumor model. Treatment with combretastatin reduced blood volume and indicated a change in the distribution of vessel sizes. VSI may be valuable in assessing tumor angiogenesis, prediction of response to vascular disrupting agents, and treatment monitoring.Adjuvant setting represents the optimal set to test the tumor vaccines because of the more conserved immune conditions of early cancer patients. In this phase II randomized trial, Filipazzi and colleagues used modified tumor peptides to immunize stage II–III melanoma patients. However, in spite of a prompt and persisting immune response, no evident clinical benefit was detected in vaccinated versus control patients. The limited number of true antitumor T cells induced by vaccination, unraveled by an extensive immunologic monitoring, shows that the choice of the immunization strategy is a critical step and that the use of modified peptides should be reconsidered.

Role of pharmacogenetics on adjuvant chemotherapy-induced neutropenia in Chinese breast cancer patients

Breast cancer patients regularly undergo adjuvant chemotherapies following surgery. However, these treatments are largely associated with chemotherapeutic toxicities ranging from nausea to severe myelosuppression. In this investigation, we examined the effects of four SNPs in NR1I2, CYP3A4 and CYP3A5 genes on chemotherapy-induced severe neutropenia in 311 female Chinese breast cancer patients undergoing a standard adjuvant chemotherapy regimen. Patients were monitored for adverse reactions throughout the treatment, then divided into "none or mild" (80 %) or "severe" (20 %) toxicity groups according to whether they suffered grade 4 neutropenia defined as having an absolute neutrophil counts (ANC) of less than 0.5 × 10(9)/L anytime during the treatment. DNA was extracted from patients' peripheral blood samples, then genotyped using allele-specific Tm-shift PCR and melting analysis. Logistic regression revealed that rs776746 or CYP3A5*3 strongly associated with grade 4 neutropenia (OR = 2.56, P = 0.023) after adjustment for covariates, one of which more significant factor was baseline ANC (OR = 0.68, P = 0.020). Although univariate analysis in all patients did not reveal any association at first, further analysis indicated that rs776746 is significantly associated with severe neutropenia in subgroup of breast cancer patients with normal baseline ANC (≥2.0 × 10(9)/L). These carriers of A-allele have 3.14-fold increased risk of developing severe neutropenia (P = 0.004). Our results suggested that polymorphisms in CYP3A5 might be useful pharmacogenetic markers for the prediction of severe neutropenia during chemotherapy, however, only after screening patients by their baseline ANC in the presence of gene-environmental interaction. We demonstrate an approach of pharmacogenetic analysis, in which the genetic data should be analyzed in the perspective of other clinical parameters.

IS10-2 - Personalized Treatment of Breast Cancer with Trastuzumab Can be Directed by Expression of the PDGFb-Receptor in Tumors

ABSTRACT Background Human epidermal growth factor receptor 2 (Her2/neu) have been found in ∼25–30% breast tumors and its overexpression is associated with a high risk of relapse, unfavourable prognosis and short survival. Trastuzumab has shown good clinical response in breast tumors overexpressing Her2/neu. Platelet-derived growth factor receptors (PDGFR) a and b are linked with advanced human breast cancers and PDGFRs produced in carcinomas are generally thought to act on the nonepithelial tumor stroma by promoting angiogenesis. Still it is unclear how expression of PDGFRs contributes to the resistance to trastuzumab. We therefore have assessed interactions between epithelial breast cancer cells and human fibroblasts upon trastuzumab treatment in a co-culture model. Methods Both human breast cancer-derived SKRB3 cells and human fibroblast-derived BJH-Tert cells were either mono-cell culture or co-culture in the current study. Upon co-cultured cells were treatment with trastuzumab and PDGF ligand bb, cell growth suppression assays, western blotting as well as PCGF-aa and PCGF-bb stimulations have been applied. In addition, tissue microarray was constructed and Immunohistochemistry was carried out. Results We found that Her2 overexpessing SKRB3 cells but not BJH-Tert cells derived from human fibroblasts respond to trastuzumab. This indicates that the effect of trastuzumab on these cells is Her2 dependent and this is in agreement with previously published data. Major finding of the present study is that the presence of PDGFRs can minimize the efficacy of trastuzumab in SKRB3 co-cultured with BJH-Tert cells. Furthermore, we found that AKT oncoprotein is a direct target of PDGF receptors to play role in mitigating sensitivity of trastuzumab in Her2-signaling pathway. Immunohiochemistry staining demonstrates that PDGF receptor beta is a crucial factor that can monitor disease relapse and patient survival. Conclusions We demonstrated that PDGFRs impair sensitivity to trastuzumab in a co-cultured breast cancer cell model through PIK3-AKT pathway. Expression of PDGF receptor beta in the tumor tightly related with disease relapse and patient survival. Our findings suggest that a more aggressive therapeutical protocol need to be setting up to improve the treatment of the subgroup of breast cancer patients with Her2-positive tumors which overexpress PDGFRs.

Accuracy validation of adjuvant! online in Taiwanese breast cancer patients - a 10-year analysis

BackgroundAdjuvant! Online ( http://www.adjuvantonline.com) is an Internet-based software program that allows clinicians to make predictions about the benefits of adjuvant therapy and 10-year survival probability for early-stage breast cancer patients. This model has been validated in Western countries such as the United States, United Kingdom, Canada, Germany, and Holland. The aim of our study was to investigate the performance and accuracy of Adjuvant! Online in a cohort of Taiwanese breast cancer patients.MethodsData on the prognostic factors and clinical outcomes of 559 breast cancer patients diagnosed at the National Cheng Kung University Hospital in Tainan between 1992 and 2001 were enrolled in the study. Comprehensive demographic, clinical outcome data, and adjuvant treatment data were entered into the Adjuvant! Online program. The outcome prediction at 10 years was compared with the observed and predicted outcomes using Adjuvant! Online.ResultsComparison between low- and high-risk breast cancer patient subgroups showed significant differences in tumor grading, tumor size, and lymph node status (p < 0.0001). The mean 10-year predicted death probability in 559 patients was 19.44%, and the observed death probability was 15.56%. Comparison with the Adjuvant! Online-predicted breast cancer-specific survival (BCSS) showed significant differences in the whole cohort (p < 0.001). In the low-risk subgroup, the predicted and observed outcomes did not differ significantly (3.69% and 3.85%, respectively). In high-risk patients, Adjuvant! Online overestimated breast cancer-specific survival (p = 0.016); the predicted and observed outcomes were 21.99% and 17.46%, respectively.ConclusionsAdjuvant! Online accurately predicted 10-year outcomes and assisted in decision making about adjuvant treatment in low-risk breast cancer patients in our study, although the results were less accurate in the high-risk subgroup. Development of a prognostic program based on a national database should be considered, especially for high-risk breast cancer patients in Taiwan.

Quantitative assessment of invasive mena isoforms (Menacalc) as an independent prognostic marker in breast cancer

IntroductionMena, an Ena/VASP protein family member, is a key actin regulatory protein. Mena is up-regulated in breast cancers and promotes invasion and motility of tumor cells. Mena has multiple splice variants, including Mena invasive (MenaINV) and Mena11a, which are expressed in invasive or non-invasive tumor cells, respectively. We developed a multiplex quantitative immunofluorescence (MQIF) approach to assess the fraction of Mena lacking 11a sequence as a method to infer the presence of invasive tumor cells represented as total Mena minus Mena11a (called Menacalc) and determined its association with metastasis in breast cancer.MethodsThe MQIF method was applied to two independent primary breast cancer cohorts (Cohort 1 with 501 and Cohort 2 with 296 patients) using antibodies against Mena and its isoform, Mena11a. Menacalc was determined for each patient and assessed for association with risk of disease-specific death.ResultsTotal Mena or Mena11a isoform expression failed to show any statistically significant association with outcome in either cohort. However, assessment of Menacalc showed that relatively high levels of this biomarker is associated with poor outcome in two independent breast cancer cohorts (log rank P = 0.0004 for Cohort 1 and 0.0321 for Cohort 2). Multivariate analysis on combined cohorts revealed that high Menacalc is associated with poor outcome, independent of age, node status, receptor status and tumor size.ConclusionsHigh Menacalc levels identify a subgroup of breast cancer patients with poor disease-specific survival, suggesting that Menacalc may serve as a biomarker for metastasis.

Association of mammographic density with the proliferation marker Ki-67 in a cohort of patients with invasive breast cancer

There is growing evidence that certain breast cancer (BC) risk factors specifically increase the risk for specific molecular tumor subtypes. Different molecular subtypes of BC can partly be described by analyzing proliferation in tumors. Very few data are available regarding the association of mammographic density (MD), as a BC risk factor, with proliferation. The aim of this study was to analyze the association between Ki-67 expression in BCs and MD. In this case-only study, data on BC risk factors, hormone receptor expression, and MD were available for 1,975 patients with incident BC. MD was assessed as percentage mammographic density (PMD) using a semiautomated method by two readers for every patient. The association of the Ki-67 proliferation index and PMD was studied using multifactorial analyses of covariance (ANCOVA), with PMD as the target variable and including well-known factors that are also associated with MD such as age, parity, use of hormone replacement therapy (HRT), and body mass index (BMI). There were no significant differences in PMD between women with BC who had low and high Ki-67 values (P = 0.31). However, there were relevant differences in women with low BMI (P = 0.07), and in women using postmenopausal HRT (P = 0.06) as well as in women with low PR values (P = 0.07). In these subgroups, the Ki-67 expression index increased with decreasing PMD. Likewise PMD is correlated with BMI, parity status, and menopausal status stronger in patients with low proliferating tumors, and with progesterone receptor expression in patients with high proliferating tumors. MD correlates inversely with Ki-67 proliferation in BC tumors only in some subgroups of BC patients, defined by commonly known BC risk factors that are usually associated with MD as well.

Combined analysis of vascular invasion, grade, HER2 and Ki67 expression identifies early breast cancer patients with questionable benefit of systemic adjuvant therapy

Introduction. Over-treatment of low-risk early breast cancer patients with adjuvant systemic therapies is an important clinical challenge. Better techniques are required which can be used to distinguish between the large group of patients with no residual disease after surgery and consequently no benefit of adjuvant treatment, from the smaller group with high relapse risk. A better integration of available prognostic factors might contribute to improved prediction of clinical outcome. Material and methods. The current study included 346 unselected pT1pN0 patients who did not receive adjuvant systemic treatment. In Norway, no patients with this stage were recommended systemic treatment at the time of the study (1995–1998). Histological type, tumour size, grade, vascular invasion (VI), hormone receptor (HR) status, HER2 and Ki67 (cut-off 10%) were analysed. Median follow-up was 86 months for relapse and 101 months for death. Results. Thirty-eight patients experienced relapse, 31 with distant metastasis. Twenty-one patients died of breast cancer. In univariate analysis grade, HER2, HR, VI and Ki67 had impact on clinical outcome (p < 0.005, log rank). In multivariate analysis, only grade 1–2 vs. grade 3, HER2, VI, and Ki67 status were significant for disease free survival, distant disease free survival, and/or breast cancer specific survival. These factors were used in combination, to separate patients into groups based on the number of unfavourable factors present [combined prognostic score (CPS) 0–4]. Close to 2/3 of the patients (61.4%) had no unfavourable factor (CPS0), whilst 18.4% had CPS ≥ 2. Only 3.6% of those with CPS0 developed metastasis (p < 0.001). The outcome was clearly worse for patients with CPS ≥ 2 (p < 0.001), systemic relapse was detected in approximately 40%. Conclusions. This study indicates that the combined use of grade, VI, HER2 and Ki67 identifies a subgroup of breast cancer patients with a relapse risk that may question the benefit of adjuvant systemic therapy.

CYP2D6 genotyping and use of antidepressants in breast cancer patients: test development for clinical application

Approximately 25 % of clinically important drugs and numerous environmental carcinogens are metabolised by CYP2D6. Variation in the CYP2D6 gene and concomitant use of tamoxifen (TAM) with certain antidepressants may increase recurrence risk in breast cancer patients due to reduced enzyme activity. In this study we determined the appropriateness of adding CYP2D6 genotyping to the breast cancer genetic testing options already available in South Africa, which include BRCA mutation screening and transcriptional profiling to assess estrogen receptor (ER) status. A total of 114 South African breast cancer patients, including 52 Caucasian and 62 Coloured (Mixed ancestry), and 63 Caucasian control individuals were genotyped for the most common inactivating allele (CYP2D6*4, rs3892097) previously identified in the CYP2D6 gene. In the initial validation data set consisting of 25 Caucasian and 62 Coloured patients, the CYP2D6*4 allele frequency was significantly higher in Caucasian compared to Coloured patients (24 % vs. 3 %, p < 0.001), similar to previous findings in the general South African population. Extended CYP2D6 genotyping was subsequently performed in an implementation data set of 27 Caucasian breast cancer patients, to determine the prevalence of depression and use of antidepressants in a clinical setting. A medical history of depression and/or use of antidepressants was reported in 37 % (10/27) of these breast cancer patients genotyped for CYP2D6*4. This translational research study has led to increased awareness among clinicians of the potential benefits of CYP2D6 genotyping to facilitate prevention of cumulative risk in a high-risk genetic subgroup of breast cancer patients considered for concomitant treatment of TAM and antidepressants that may reduce enzyme function.

Abstract 5584: Disregulation of phosphorelated Amplified In Breast Cancer3 (AIB3) contributes to poor prognosis and mediates trastuzumab efficacy in breast cancer patients

Abstract Trastuzumab (Herceptin) is the first line HER2 (ErbB2)/neu-directed therapy for the treatment of patients with metastatic breast cancer. Although the efficacy of trastuzumab depends on the HER2/neu status of the tumour, the single-agent response rate ranges from 12 to 30% and ew patients respond to trastuzumab monotherapy largely due to various resistance mechanisms. Amplifeid In Breast Cancer3 (AIB3) is a transcriptional coactivator. AIB3 plays an important role in embryonic development, adipocyte differentiation, metabolism. AIB3 was initially found to be amplified in subgroup of breast cancer patients. Our previous data using knockout mouse mode combined cell culture indicate that AIB3 plays important role in breast tumorigenesis. Here we report that AIB3 can be phosphorylated by MAPK at S884 site and phosphorylation at S884 of AIB3 dramatically reduced ligand-dependent AIB3 interactions with estrogen receptors when compared with the wild-type unphosphorylated form, although there was a significant increase of interactions with the unliganded receptor. Misexpression of phosphorylated AIB3 was observed in human breast cancer tissues and disregulation of phosphorylated AIB3 was associated with patients’ poor prognosis. Breast cancer is a heterogeneous disease and intrinsic subtypes play an extremely important role in improve on current standards for breast cancer prognosis and prediction of chemotherapy. Noticeably, phosphorylated AIB3 was highly expressed in Her2-enriched subtype of human breast cancer patients, as well as in the mammary tumor of MMTV-Her2 transgenic mice. Mechanism studies reveal that phosphorylated AIB3 alters trastuzumab efficacy in cultured breast cancer cells. The association between pAIB3 and important clinical outcomes confers pAIB3 a significant prognostic marker in breast cancer. Phosphorylated AIB3 as a modulator in ErbB2-MAPK regulating loop represents a potentially novel mechanism for trastuzumab (herceptin) efficacy. The implied interaction between pAIB3 and Her2 suggests the potential of dual targeting of Her2 and pAIB3 as a promising therapeutic approach for personalized breast cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5584. doi:1538-7445.AM2012-5584

Identification of distinct subgroups of breast cancer patients based on self-reported changes in sleep disturbance

The purposes of this study were to identify distinct subgroups of patients based on self-reported sleep disturbance prior to through 6 months after breast cancer surgery and evaluate for differences in demographic, clinical, and symptom characteristics among these latent classes. Women (n = 398) who underwent unilateral breast cancer surgery were enrolled prior to surgery. Patients completed measures of functional status, sleep disturbance (i.e., General Sleep Disturbance Scale (GSDS); higher scores indicate higher levels of sleep disturbance), fatigue, attentional fatigue, depressive symptoms, and anxiety prior to surgery and monthly for 6 months. Three distinct classes of sleep disturbance trajectories were identified using growth mixture modeling. The high sustained class (55.0%) had high and the low sustained class (39.7%) had low GSDS scores prior to surgery that persisted for 6 months. The decreasing class (5.3%) had high GSDS score prior to surgery that decreased over time. Women in the high sustained class were significantly younger, had more comorbidity and poorer function, and were more likely to report hot flashes compared to the low sustained class. More women who underwent mastectomy or breast reconstruction were in the decreasing class. Decreasing and high sustained classes reported higher levels of physical fatigue, attentional fatigue, depressive symptoms, and anxiety compared to the low sustained class. A high percentage of women has significant sleep disturbance prior to surgery that persists during subsequent treatments (i.e., radiation therapy and chemotherapy). Clinicians need to perform routine assessments and initiate appropriate interventions to improve sleep prior to and following surgery.

Hsa-mir-499 rs3746444 polymorphism and cancer risk: a meta-analysis

MicroRNAs (miRNAs) are gene regulators involved in numerous diseases including cancer, heart disease, neurological disorders, vascular abnormalities and autoimmune conditions. Although hsa-mir-499 rs3746444 polymorphism was shown to contribute to the susceptibility of multiple genes to cancer, the data have yielded conflicting results. Therefore, this meta-analysis was performed to provide a comprehensive assessment of po-tential association between hsa-mir-499 rs3746444 polymorphism and cancer risk. In this meta-analysis, a total of 9 articles regarding 10 eligible case-control studies in English (including 6134 cases and 7141 controls) were analyzed. No significant association between hsa-mir-499 rs3746444 polymorphism and overall cancer risk was demonstrated. However, an increased risk was observed in the subgroup of breast cancer patients (G allele vs A allele: OR = 1.10, 95% CI = 1.00-1.20; Pheterogeneity = 0.114; I2 = 53.9%) and population-based studies (G allele vs A allele: OR = 1.12, 95% CI = 1.00-1.25; Pheterogeneity = 0.062; I2 = 64.0%). The findings suggested an association be-tween hsa-mir-499 rs3746444 polymorphism and increased risk to breast cancer.

Identification of distinct depressive symptom trajectories in women following surgery for breast cancer.

Depressive symptoms, common in breast cancer patients, may increase, decrease, or remain stable over the course of treatment. Most longitudinal studies have reported mean symptom scores that tend to obscure interindividual heterogeneity in the symptom experience. The identification of different trajectories of depressive symptoms may help identify patients who require an intervention. This study aimed to identify distinct subgroups of breast cancer patients with different trajectories of depressive symptoms in the first six months after surgery. Among 398 patients with breast cancer, growth mixture modeling was used to identify latent classes of patients with distinct depressive symptom profiles. These profiles were identified based on Center for Epidemiological Studies-Depression (CES-D) scale scores completed just prior to surgery, and 1, 2, 3, 4, 5, and 6 months after surgery. Four latent classes of breast cancer patients with distinct depressive symptom trajectories were identified: Low Decelerating (38.9%), Intermediate (45.2%), Late Accelerating (11.3%), and Parabolic (4.5%) classes. Patients in the Intermediate class were younger, on average, than those in the Low Decelerating class. The Intermediate, Late Accelerating, and Parabolic classes had higher mean baseline anxiety scores compared to the Low Decelerating class. Breast cancer patients experience different trajectories of depressive symptoms after surgery. Of note, over 60% of these women were classified into one of three distinct subgroups with clinically significant levels of depressive symptoms. Identification of phenotypic and genotypic predictors of these depressive symptom trajectories after cancer treatment warrants additional investigation.

Clinical utility of the combination of lapatinib and letrozole in the management of hormone receptor-positive and HER2-positive advanced breast cancer

Breast cancers that overexpress human epidermal growth factor receptor-2 (HER2-positive [HER2+]) tend to be biologically aggressive and associated with a poor prognosis, even those that coexpress receptors for estrogen and/or progesterone (hormone receptor-positive [HR+]). Optimal therapy for patients with "double-positive" (HR+/HER2+) breast cancers is still being defined. In this subset of patients, the efficacy of targeted endocrine therapies appears to be diminished by cross-activation or "crosstalk" between estrogen receptor-mediated gene transcription and pathways activated by other growth factor receptors, including HER2. Lapatinib is a tyrosine kinase inhibitor which binds reversibly to the intracellular domains of the epidermal growth factor receptor and HER2, interfering with their ability to initiate signal transduction cascades that promote cancer cell proliferation, survival, and metastasis. In a recently published randomized, placebo-controlled Phase III study in postmenopausal HR+ metastatic breast cancer, the addition of lapatinib to the aromatase inhibitor letrozole significantly improved progression-free survival solely in women who were also HER2+. This article reviews the biology of "double-positive" breast cancers and the rationale underlying combining endocrine and HER2-targeted therapies, including the lapatinib/letrozole combination, for these tumors. Results from the Phase III trial are examined, as well as available data on other combinations of HR and HER2-targeted therapies. Ongoing trials and potential future applications of these combinations in both HR+/HER2+ and other subgroups of breast cancer patients are also discussed.

MTOR in breast cancer: Differential expression in triple-negative and non-triple-negative tumors

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptors (ER), progesterone receptors (PR) and overexpression of HER2. Targeted therapy is currently unavailable for this subgroup of breast cancer patients. mTOR controls cancer cell growth, survival and invasion and is thus a potential target for the treatment of patients with TNBC. Using immunohistochemistry, mTOR and p-mTOR were measured in 89 TNBCs and 99 non-TNBCs. While mTOR expression was confined to tumor cell cytoplasm, p-mTOR staining was located in the nucleus, perinuclear area and in the cytoplasm. Potentially important, was our finding that nuclear p-mTOR was found more frequently in triple-negative than non triple-negative cancers (p < 0.001). These results suggest that mTOR may play a more important role in the progression of TNBC compared to non-TNBC. Based on these findings, we conclude that mTOR may be a new target for the treatment of triple-negative breast cancer.

Mortality Rates Among Early-Stage Hormone Receptor-Positive Breast Cancer Patients: A Population-Based Cohort Study in Denmark

Indications for adjuvant endocrine treatment of breast cancer have gradually increased over the past several years. We aimed to define subgroups of patients who may or may not benefit from adjuvant endocrine therapy. A population-based cohort of systemically untreated breast cancer patients (N = 3197) were identified within the registry of the Danish Breast Cancer Cooperative Group (DBCG). The patients were node negative and had estrogen receptor-positive and/or progesterone receptor-positive tumors (except medullary tumors) and were further characterized by the following risk factors: aged 35-74 years (grouped into 5-year categories) at surgery, tumor size (≤20 mm), and histopathology (grade 1 ductal carcinoma, grade 1 or 2 invasive lobular carcinoma, other or unknown histopathology). Standardized mortality ratios (SMRs) were calculated based on the mortality rate (observed number of deaths per 100,000 person-years) among patients relative to the mortality rate in the general population of women (expected number of deaths per 100,000 person-years). The association between standardized mortality ratio and risk factors were analyzed in univariate and multivariable Poisson regression models. All findings were validated in a subsequent DBCG cohort of breast cancer patients (N = 2710). The median follow-up after surgery was 14.8 years. In the study population there were 970 deaths compared with expected death of 737 women, which was an excess mortality of 233 deaths (SMR = 1.32, 95% CI = 1.24 to 1.40). Mortality rates were 2356 per 100,000 person-years in the study population and 1790 per 100,000 person-years in the general population of women. The mortality rate was associated with larger tumor size (11-20 mm tumors vs 1-10 mm tumors, SMR = 1.42, 95% confidence interval [CI] = 1.31 to 1.53 vs. SMR = 1.12, 95% CI = 1.00 to 1.26). The mortality rate was also associated with age (35-59 years, SMR > 1) compared with that in the general population of age-matched women, except for a small subgroup of patients (aged 60-74 years, tumors ≤10 mm, grade 1 ductal carcinoma, and grade 1 or 2 lobular carcinoma: adjusted relative risk = 1.02, 95% CI = 0.89 to 1.16.). A small subgroup of breast cancer patients who were 60 years or older and had hormone-responsive early-stage tumors up to 10 mm, and received no systemic adjuvant therapy, were not at increased risk of mortality compared with women in this age-group in the general population.

Prognostic significance of tumor/stromal caveolin‐1 expression in breast cancer patients

Caveolin-1 (Cav-1) has been extensively characterized in cancer biological research. However, the role of Cav-1 in the interaction between tumor and stromal cells remains unclear. In the present study, we examined Cav-1 expression in tumor cells and stromal cells in breast cancer tissue by immunohistochemical analysis and evaluated its prognostic value in a training cohort. Immunohistochemical analysis of Cav-1 expression was scored as (++), (+) or (-) according to the proportion of positively stained tumor cells (T) and stromal cells (S). Correlation analysis between tumor/stromal Cav-1 expression and clinicopathological parameters revealed that only T(++) Cav-1 status was positively associated with tumor size and histological nodal status (P = 0.019 and 0.021, respectively). Univariate analysis revealed that combined T(++)/S(-) status was significantly correlated with unfavorable prognostic outcomes (P < 0.001). Multivariate analysis demonstrated that this combined status is an independent prognostic factor for primary breast cancer (P = 0.002). Clinical outcomes in different subgroups of breast cancer patients were also strictly dependent on this combined status (P < 0.05). The prognostic value of T(++)/S(-) Cav-1 status was also validated in the testing cohort. Collectively, our data indicate that high Cav-1 expression in tumor cells and lack of this expression in stromal cells could help identify a particular subgroup of breast cancer patients with potentially poor survival. Further studies are required to understand the regulatory mechanism of Cav-1 in the tumor microenvironment.

Abstract 429: The value of Tenascin-C expression in neoadjuvant breast cancer therapy

Abstract Introduction: The extra cellular matrix molecule Tenascin-C (TNC) in its many isoforms is highly expressed during tissue repair and pathological conditions such as cancer and stress. Utilising the selective pressure of neoadjuvant chemotherapy on carcinoma cells we screened for a subgroup of breast cancer patients with elevated TNC expression and a bad therapy response. TNC expression was correlated with biomarkers, histopathological (stage) and clinical data. Breast cancer cell lines were tested on TNC levels and their expression behaviour under competitive conditions. Methods: Paraffin sections from 68 preoperatively treated breast cancer patients were used for automated immunohistochemistry (IHC) with antibodies targeting TNC, AE1/AE3, Ki67, CD3 and p53. In addition F-18 FDG PET-CT was performed to evaluate therapy response. Protein- and gene expression experiments performed onto six breast cancer cell lines (MCF-7, MDA-MB231, MDA-MB453, SK-BR3, SUM-159, T47-D) showed TNC-expression in MDA-MB453 breast cancer cell line. Gene expression of TNC in hedgehog positive cells (MCF-7) was evaluated after co-cultivation with TNC positive cells (MDA-MB453) by qRT-PCR. The qRT-PCR results confirmed the protein expression results on in vitro stained cell-slides after cell-cell interactions and different growth times. Growth and migration behaviour was studied in 3D-matrigels. Results: We demonstrate that TNC expression in breast cancer is immensely reduced after neoadjuvant chemotherapy (43% of patients lost TNC expression) and that expression profiles after treatment correlate with tumor grade, lymph node status and estrogen receptor status, indicating prognostic value, probably for endocrine treatment. Post-therapeutical correlation and co-localisation of the proliferation marker Ki67 in cancer cells and TNC in the surrounding tumor-stroma of patients having a less beneficial response to chemotherapy. The evaluation of expression levels revealed a linear correlation of TNC and Ki67. Submitting cell lines to selective environmental pressure on cell chamber slides, we observed differentiated staining patterns and cellular localization for TNC. After co-cultivation with MDA-MB453, the hedgehog positive cell line MCF-7 expressed highly elevated levels of TNC. Conclusions: These findings concur with the role of TNC in tissue reorganisation, wound healing and it's growth promoting properties in cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 429. doi:10.1158/1538-7445.AM2011-429

Abstract 4827: Loss of 11p in primary breast cancer and brain metastases

Abstract Metastatic breast cancer remains essentially incurable, with mortality being especially high in patients who develop brain metastases. Approximately 15% of all epithelial tumors metastasize to the brain, with incidence rates highly dependent on the primary tumor type. Apparently, the brain microenvironment is specifically permissive for the out-growth of tumor cells from some carcinomas but not others. In a previous study we screened by array CGH primary breast tumors and brain metastases. A 10MBp loss at 11pter-p15.4 was found in 70 % of the brain metastases whereas only 15% of the early stage primary tumors showed loss of 11p. In this study the aberration pattern of 11p was verified by microsatellite analysis in primary breast tumors and brain metastases. Six markers with an average spacing of 2 MBp were analyzed at 11p15.5-p15.4. Allelic imbalance (AI) at 11p was found in 26% (11/42) of the primary tumors whereas 71.4% (15/21) of brain metastases showed AI (p=0.001). In primary tumors the occurrence of AI was associated with high grade (p=0.03) and positive lymph node status (p=0.02). Interestingly, primary tumors with a brain relapse showed an equally high AI rate (75%) as the brain metastases (71%) in contrast to primary tumors without a relapse (26%). Furthermore, two matched pairs of primary tumors and brain metastases showed equal aberrations patterns and the third matched pair showed an enlarged AI of 11p, indicating that loss of 11p is defining a specific subgroup of breast cancer patients with a high risk of brain relapse. In summary, these results indicate an accumulation of chromosomal imbalances during the carcinoma-metastasis sequence and the possible involvement of loss of 11p in brain metastasis formation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4827. doi:10.1158/1538-7445.AM2011-4827