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BACKGROUND:Hormone receptor status and HER2 status are of critical interest in determining the prognosis of breast cancer patients. Their status is routinely assessed by immunohistochemistry (IHC). However, it is subject to intra-laboratory and inter-laboratory variability. The aim of our study was to compare the estrogen receptor, progesterone receptor and HER2 status as determined by the MapQuant™ test to the routine immuno-histochemical tests in early stage invasive breast cancer in a large comprehensive cancer center. PATIENTS AND METHODS:We retrospectively studied 163 invasive early-stage breast carcinoma with standard IHC status. The genomic status was determined using the MapQuant™ test providing the genomic grade index. RESULTS:We found only 4 tumours out of 161 (2.5%) with discrepant IHC and genomic results concerning ER status. The concordance rate between the two methods was 97.5% and the Cohen's Kappa coefficient was 0.89. Comparison between the MapQuant™ PR status and the PR IHC status gave more discrepancies. The concordance rate between the two methods was 91.4% and the Cohen's Kappa coefficient was 0.74. The HER2 MapQuant™ test was classified as « undetermined » in 2 out of 163 cases (1.2%). One HER2 IHC-negative tumour was found positive with a high HER2 MapQuant™ genomic score. The concordance rate between the two methods was 99.3% and the Cohen's Kappa coefficient was 0.86. CONCLUSION:Our results show that the MapQuant™ assay, based on mRNA expression assay, provides an objective and quantitative assessment of Estrogen receptor, Progesterone receptor and HER2 status in invasive breast cancer.

Background: At metastatic relapse, detection of circulating tumor cells (CTC) in peripheral blood is predictive of poor survival of breast cancer patients. Detection of disseminated tumor cells (DTC) in bone marrow (BM) is an independent prognostic factor in early breast cancer. We evaluated the prognostic value of DTC detection in the BM of metastatic breast cancer patients. Materials and methods: BM aspirates from 138 patients were screened for DTC with the pancytokeratin mAb A45-B/B3, according to the ISHAGE classification. One hundred and ten patients (80%) were enrolled before first-line treatment. Thirty-seven patients were simultaneously screened for CTC in the blood. Results: DTC detection rate in the BM was 59%. DTC were associated with bone metastasis (P = 0.0001), but not with a poorer overall survival. Adverse significant prognostic factors were hormone receptor negativity (P = 0.0004) and more than one line of chemotherapy (P = 0.002). CTC detection in the subgroup of 37 metastatic patients was associated with shorter survival (P = 0.01). Conclusions: Detection of CTC but not BM DTC had a prognostic significance in stage IV breast cancer patients. CTC in blood are a more reliable and a less invasive tool to evaluate prognostic and monitor tumor response in this metastatic setting. [ABSTRACT FROM AUTHOR]

Background: The REMAGUS-02 multicenter randomised phase II trial showed that the addition to neoadjuvant chemotherapy (NAC) of trastuzumab in patients with localised HER2-positive breast cancer (BC) increased the pathological complete response (pCR) rate and that the addition of celecoxib in HER2-negative cases did not increase the pCR rate. We report here the long-term follow-up results for disease-free survival (DFS) and overall survival (OS)., Patients and Methods: From 2004 to 2007, 340 stage II-III BC patients were randomly assigned to receive neoadjuvant EC-T (four cycles of epirubicin-cyclophosphamide followed by four cycles of docetaxel) +/- celecoxib in HER2-negative cases (n = 220) and ± trastuzumab in HER2-positive cases (n = 120). From September 2005, all patients with HER2-positive BC received adjuvant T (n = 106)., Results: Median follow-up was nearly 8 years (94.4 months, 20-127 m). In the HER2-negative subgroup, addition of celecoxib was not associated with a DFS benefit. Favourable factors were smaller tumour size, expression of progesterone receptor status (PgR) and pCR. In the HER2-positive population, neoadjuvant trastuzumab was not associated with a DFS benefit. Axillary pCR was the only prognostic factor associated with DFS in this group [HR = 0.44, 95% CI = 0.2-0.97], p = 0.035]. To note, DFS and OS were significantly higher in the HER2-positive than in HER2-negative BC patients (HR = 0.58 [0.36-0.92], p = 0.021)., Conclusion: Celecoxib combined with NAC provided neither pCR nor survival benefit in patients with HER2-negative BC. Absence of PgR is a major prognostic factor. Neoadjuvant trastuzumab increased pCR rates without translation into a DFS or OS benefit compared with adjuvant trastuzumab only. Axillary pCR could be a more relevant surrogate of survival than in the breast in HER2-positive population. A retrospective comparison shows that patients with HER2-positive tumours have a better outcome than HER2-negative BC patients showing the impact of trastuzumab on the natural history of BC., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Avoiding axillary lymph node dissection (ALND) for invasive breast cancers with isolated tumor cells or micrometastatic sentinel node biopsy (SNB) could decrease morbidity with minimal clinical significance., Purpose: The aim of this study is to simulate the medico-economic impact of the routine use of the MSKCC non-sentinel node (NSN) prediction nomogram for ER+ HER2- breast cancer patients., Methods: We studied 1036 ER+ HER2- breast cancer patients with a metastatic SNB. All had a complementary ALND. For each patient, we calculated the probability of the NSN positivity using the MSKCC nomogram. After validation of this nomogram in the population, we described how the patients' characteristics spread as the threshold value changed. Then, we performed an economic simulation study to estimate the total cost of caring for patients treated according to the MSKCC predictive nomogram results., Results: A 0.3 threshold discriminate the type of sentinel node (SN) metastases: 98.8% of patients with pN0(i+) and 91.6% of patients with pN1(mic) had a MSKCC score under 0.3 (false negative rate = 6.4%). If we use the 0.3 threshold for economic simulation, 43% of ALND could be avoided, reducing the costs of caring by 1 051 980 EUROS among the 1036 patients., Conclusion: We demonstrated the cost-effectiveness of using the MSKCC NSN prediction nomogram by avoiding ALND for the pN0(i+) or pN1(mic) ER+ HER2- breast cancer patients with a MSKCC score of less than or equal to 0.3.

Context: In a cohort of 95 women with multiple breast fibroadenomas (MFAs), we recently identified patients harboring germline heterozygous variants of the prolactin receptor (PRLR) exhibiting constitutive activity (PRLR I146L and PRLR I176V )., Objective: This study sought to better delineate the potential role of PRLR gain-of-function variants in benign and malignant mammary tumorigenesis., Design: This was an observational study and transgenic mouse model analysis., Setting: The study took place at the Department of Endocrinology, Reproductive Disorders and Rare Gynecologic Diseases, Pitié Salpêtrière, Paris, and Inserm Unit 1151, Paris., Patients or Other Participants: We generated a second MFA cohort (n = 71) as well as a group of control subjects (n = 496) and a cohort of women with breast cancer (n = 119). We also generated two transgenic mouse models carrying the coding sequences of human PRLR I146L or PRLR WT ., Intervention: We aimed to determine the prevalence of PRLR variants in these three populations and to uncover any association of the latter with specific tumor pattern, especially in patients with breast cancer., Results: This study did not highlight a higher prevalence of PRLR variants in the MFA group and in the breast cancer group compared with control subjects. Transgenic mice expressing PRLR I146L exhibited very mild histological mammary phenotype but tumors were never observed., Conclusion: PRLR I146L and PRLR I176V variants are not associated with breast cancer or MFA risk. However, one cannot exclude that low but sustained PRLR signaling may facilitate or contribute to pathological development driven by oncogenic pathways. Long-term patient follow-up should help to address this issue.

Purpose: Neoadjuvant systemic therapy (NAC) is currently used in the treatment of stage II/III breast cancer. Pathological complete response as a surrogate endpoint for clinical outcomes is not completely validated for all subgroups of breast cancers. Therefore, there is a need for reliable predictive tests of the most effective treatment., Methods: We used a combination of predictive clinical, pathological, and gene expression-based markers of response to NAC in a prospective phase II multicentre randomized clinical trial in breast cancer patients, with a long follow-up (8 years). This study concerned the subpopulation of 188 patients with similar levels of pathological response rates to sequential epirubicin/cyclophosphamide and docetaxel to determine predictive marker of pCR and DFS. We used a set of 45 genes selected from high throughput analysis and a standardized RT-qPCR. We analyzed the predictive markers of pathological complete response (pCR) and DFS in the overall population and DFS the subpopulation of 159 patients with no pCR., Results: In the overall population, combining both clinical and genomic variables, large tumor size, low TFF1, and MYBL2 overexpression were significantly associated with pCR. T4 Stage, lymphovascular invasion, negative PR status, histological type, and high values of CCNB1 were associated with DFS. In the no pCR population, only lymphovascular invasion and high values of BIRC5 were associated with DFS., Conclusions: We confirm the importance of ER-related and proliferation genes in the prediction of pCR in NAC-treated breast cancer patients. Furthermore, we identified BIRC5 (survivin) as a main pejorative prognostic factor in patients with breast cancers with no pCR. These results also open perspective for predictive markers of new targeted therapies.

Drug discovery efforts have focused on the tumor microenvironment in recent years. However, few studies have characterized the stroma component in patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMs). In this study, we characterized the stroma in various models of breast cancer tumors in mice. We performed transcriptomic and flow cytometry analyses on murine populations for a series of 25 PDXs and the two most commonly used GEMs (MMTV-PyMT and MMTV-erBb2). We sorted macrophages from five models. We then profiled gene expression in these cells, which were also subjected to flow cytometry for phenotypic characterization. Hematopoietic cell composition, mostly macrophages and granulocytes, differed between tumors. Macrophages had a specific polarization phenotype related to their M1/M2 classification and associated with the expression of genes involved in the recruitment, invasion and metastasis processes. The heterogeneity of the stroma component of the models studied suggests that tumor cells modify their microenvironment to satisfy their needs. Our observations suggest that such models are of relevance for preclinical studies.

Therapeutic strategies targeting Homologous Recombination Deficiency (HRD) in breast cancer requires patient stratification. The LST (Large-scale State Transitions) genomic signature previously validated for triple-negative breast carcinomas (TNBC) was evaluated as biomarker of HRD in luminal (hormone receptor positive) and HER2-overexpressing (HER2+) tumors. The LST genomic signature related to the number of large-scale chromosomal breakpoints in SNP-array tumor profile was applied to identify HRD in in-house and TCGA sets of breast tumors, in which the status of BRCA1/2 and other genes was also investigated. In the in-house dataset, HRD was predicted in 5% (20/385) of sporadic tumors luminal or HER2+ by the LST genomic signature and the inactivation of BRCA1, BRCA2 or RAD51C confirmed this prediction in 75% (12/16) of the tested cases. In 14% (6/43) of tumors occurring in BRCA1/2 mutant carriers, the corresponding wild-type allele was retained emphasizing the importance of determining the tumor status. In the TCGA luminal and HER2+ subtypes HRD incidence was estimated at 5% (18/329, 95%CI: 5-8%) and 2% (1/59, 95%CI: 2-9%), respectively. In TNBC cisplatin-based neo-adjuvant clinical trials, HRD is shown to be a necessary condition for cisplatin sensitivity. This analysis demonstrates the high performance of the LST genomic signature for HRD detection in breast cancers, which suggests its potential as a biomarker for genetic testing and patient stratification for clinical trials evaluating platinum salts and PARP inhibitors., (© 2015 UICC.)

Background: Hormone receptor status and HER2 status are of critical interest in determining the prognosis of breast cancer patients. Their status is routinely assessed by immunohistochemistry (IHC). However, it is subject to intra-laboratory and inter-laboratory variability. The aim of our study was to compare the estrogen receptor, progesterone receptor and HER2 status as determined by the MapQuant™ test to the routine immuno-histochemical tests in early stage invasive breast cancer in a large comprehensive cancer center., Patients and Methods: We retrospectively studied 163 invasive early-stage breast carcinoma with standard IHC status. The genomic status was determined using the MapQuant™ test providing the genomic grade index., Results: We found only 4 tumours out of 161 (2.5%) with discrepant IHC and genomic results concerning ER status. The concordance rate between the two methods was 97.5% and the Cohen's Kappa coefficient was 0.89. Comparison between the MapQuant™ PR status and the PR IHC status gave more discrepancies. The concordance rate between the two methods was 91.4% and the Cohen's Kappa coefficient was 0.74. The HER2 MapQuant™ test was classified as « undetermined » in 2 out of 163 cases (1.2%). One HER2 IHC-negative tumour was found positive with a high HER2 MapQuant™ genomic score. The concordance rate between the two methods was 99.3% and the Cohen's Kappa coefficient was 0.86., Conclusion: Our results show that the MapQuant™ assay, based on mRNA expression assay, provides an objective and quantitative assessment of Estrogen receptor, Progesterone receptor and HER2 status in invasive breast cancer.

Purpose: This study aimed to chart patterns of simultaneous trajectories over 8 months in breast cancer survivors' (BCS) supportive care needs, psychological distress, social support, and posttraumatic growth. Clusters of BCS among these trajectories were identified and characterized., Methods: Of 426 BCS study participants, 277 (65%) provided full assessments in the last week of primary cancer treatment and 4 and 8 months later. Latent trajectories were obtained using growth mixture modeling for patients who responded to all scores for at least one time point (n = 348). Then, classification of BCS was performed by hierarchical agglomerative clustering on axes derived from a multiple factor analysis of trajectory assignments. Self-esteem, attachment security, and satisfaction with care were assessed at baseline., Results: Four trajectory clusters were identified, including two BCS subgroups (63%) with low needs and low psychological distress. Two others (37%) exhibited high or increasing needs and concerning levels of psychological distress. These latter clusters were characterized by higher insecure attachment, lower satisfaction with care, and either lower education or younger age, and having undergone chemotherapy., Conclusion: More than a third of BCS present unfavorable patterns in supportive care needs over 8 months after primary cancer treatment. Identified psychosocial and cancer care characteristics point to targets for enhanced BCS supportive care.

Background: Information is a care priority in most breast cancer survivors (BCS). We assessed whether BCS information needs at 8 months after hospital cancer treatment could be related to their age, education level, perceived medical communication competence, satisfaction with care, attachment style, and self-esteem., Methods: Of 426 BCS approached during the last week of treatment (T1), 85% completed the Medical Communication Competence Scale, European Organisation for Research and Treatment of Cancer Satisfaction with Care Questionnaire, Rosenberg's Self-Esteem Scale and Experiences in Close Relationships Scale. The Hospital Anxiety and Depression Scale and the Supportive Care Needs Survey were completed at T1 and again 8 months later (T2) with a 66% (n = 283) response rate., Results: Baseline respondents' median (range) age was 56 years (23-86 years). Information needs decreased over time, although some persisted. Multivariate regression analyses evidenced overall higher information needs at T2 in younger BCS and in those dissatisfied with the information provided at T1. Specifically, in younger BCS, higher information needs were related to lower satisfaction with doctors' availability, and in older BCS, they were related to higher self-perceived competence in information giving, lower self-perceived competence in information seeking, and lower satisfaction with doctors' information provision. Psychological distress was strongly related to information needs. Education, BCS attachment style, and self-esteem were not associated with information needs., Conclusions: In order to enhance supportive care for BCS, younger BCS should be provided with more time to address all their concerns and older BCS should be encouraged to express their specific desires for information., (Copyright © 2015 John Wiley & Sons, Ltd.)

Reciprocal interactions between tumor cells and their microenvironment vitally impact tumor progression. In this study, we show that GM-CSF produced by primary breast tumor cells induced the activation of plasmacytoid predendritic cells (pDC), a cell type critical to anti-viral immunity. pDC that expressed the GM-CSF receptor were increased in breast tumors compared with noninvolved adjacent breast tissue. Tumor-activated pDC acquired naïve CD4(+) T-cell stimulatory capacity and promoted a regulatory Th2 response. Finally, the concomitant increase of GM-CSF and pDC was significantly associated with relatively more aggressive breast cancer subtypes. Our results characterize the first tumor-derived factor that can activate pDC to promote a regulatory Th2 response, with implications for therapeutic targeting of a tumor-immune axis of growing recognition in its significance to cancer., (©2015 American Association for Cancer Research.)

We present a benchmark pilot study in which high-resolution Full-Field Optical Coherence Tomography (FF-OCT) was used to image human breast tissue and is evaluated to assess its ability to aid the pathologist's management of intra-operative diagnoses. FF-OCT imaging safety was investigated and agreement between FF-OCT and routinely prepared histopathological images was evaluated. The compact setup used for this study provides 1 mm3 resolution and 200 mm imaging depth, and a 2.25 cm2 specimen is scanned in about 7 minutes. 75 breast specimens were imaged from 22 patients (21 women, 1 man) with a mean age of 58 (range: 25-83). Pathologists blind diagnosed normal/benign or malignant tissue based on FF-OCT images alone, diagnosis from histopathology followed for comparison. The contrast in the FF-OCT images is generated by intrinsic tissue scattering properties, meaning that no tissue staining or preparation is required. Major architectural features and tissue structures of benign breast tissue, including adipocytes, fibrous stroma, lobules and ducts were characterized. Subsequently, features resulting from pathological modification were characterized and a diagnosis decision tree was developed. Using FF-OCT images, two breast pathologists were able to distinguish normal/benign tissue from lesional with a sensitivity of 94% and 90%, and specificity of 75% and 79% respectively.

Introduction: Epigenetic modifications such as aberrant DNA methylation has long been associated with tumorogenesis. Little is known, however, about how these modifications appear in cancer progression. Comparing the methylome of breast carcinomas and locoregional evolutions could shed light on this process., Methods: The methylome profiles of 48 primary breast carcinomas (PT) and their matched axillary metastases (PT/AM pairs, 20 cases), local recurrences (PT/LR pairs, 17 cases) or contralateral breast carcinomas (PT/CL pairs, 11 cases) were analyzed. Univariate and multivariate analyzes were performed to determine differentially methylated probes (DMPs), and a similarity score was defined to compare methylation profiles. Correlation with copy-number based score was calculated and metastatic-free survival was compared between methods., Results: 49 DMPs were found for the PT/AM set, but none for the others (FDR < 5%). Hierarchical clustering clustered 75% of the PT/AM, 47% of the PT/LR, and none of the PT/CL pairs together. A methylation-based score (MS) was defined as a clonality measure. The PT/AM set contained a high proportion of clonal pairs while PT/LR pairs were evenly split between high and low MS score, suggesting two groups: true recurrences (TR) and new primary tumors (NP). CL were classified as new tumors. MS score was significantly correlated with copy-number based scores. There was no significant difference between the metastatic-free survival of groups of patients based on different classifications., Conclusion: Epigenomic alterations are well suited to study clonality and track cancer progression. Methylation-based classification of TR and NP performed as well as clinical and copy-number based methods suggesting that these phenomenons are tightly linked.

Background: The identification and validation of suitable predictive and prognostic factors are a challenge to improve the treatment scheme selection. Discordances in histological grade can be established between core biopsy and surgical specimens. This is important in HR-positive/HER2-negative subgroup where histological grade identifies patients at high risk and is a strong determinant for treatment scheme., Methods: A total of 350 consecutive invasive breast carcinoma biopsies were assessed and compared with surgical specimens in Institut Curie, Paris, France. Clinical, radiological and pathological data were recorded., Results: Histological grade concordance rate in the HR+/HER2- group was 75%. A grade underestimation was mainly due to mitotic index misgrading (23%). Large tumours (P<0.05), premenopausal patients (P=0.005) and non-ultrasound-guided biopsies (P=0.04) were risk factors for misgrading. The highest discordance was found in tumours that required chemotherapy (39%, P<0.05), and it was related to an underestimation of histological grade on core biopsies (94%)., Conclusions: Histological grade in HR+/HER2- group is important to identify patients with poor prognosis and start a systemic therapy. Histological grade discordance was correlated with an underestimation of mitotic index and factors probably associated with intratumor heterogeneity (premenopausal status, tumour size and the type of core biopsy performed). But such discordance did not appear to modify the therapeutic decision, because systemic treatment decision-making also integrates other variables. Determining histological grade in core biopsy can be especially important in HR-positive/HER2-negative subgroup where it identifies patients at high risk and is a strong determinant of the treatment scheme.

Aim: To identify predictors for infiltrating carcinoma and lymph node involvement, before immediate breast reconstructive surgery, in patients with an initial diagnosis of extensive pure ductal carcinoma in situ of the breast (DCIS)., Patients and Methods: Between January 2000 and December 2009, 241 patients with pure extensive DCIS in preoperative biopsy had underwent mastectomy. Axillary staging (sentinel node and/or axillary dissection) was performed in 92% (n = 221) of patients. Patients with micro-invasive lesions at initial diagnosis, recurrence or contralateral breast cancer were excluded., Results: Respectively 14% and 21% of patients had a final diagnosis of micro-invasive carcinoma (MIC) and invasive ductal carcinoma (IDC). Univariate analysis showed that the following variables at diagnosis were significantly correlated with the presence of either MIC or IDC in the mastectomy specimen: palpable tumor (p = 0.002), high grade DCIS (p = 0.002) and detection of an opacity by mammography (p = 0.019). Axillary lymph node (ALN) involvement was reported in 9% of patients. Univariate analysis suggested that a body mass index higher than 25 (p = 0.007), a palpable tumor (p = 0.012) and the detection of an opacity by mammography (p = 0.044) were associated with an increased rate of ALN involvement., Conclusion: Skin-sparing mastectomy and immediate breast reconstruction (IBRS) has become increasingly popular, especially for patients with extended DCIS of the breast. This study confirmed that extended DCIS is associated with a substantial risk of finding MIC or IDC on the surgical specimen but also ALN involvement. Adjuvant systemic treatment and/or radiotherapy could be indicated for some of these patients after the surgery. Patients should be informed of the rate of 1) complications associated to IBRS that will potentially delay the introduction of systemic or local therapy 2) complications associated to radiotherapy after IBRS., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

BRCA2 is the major high-penetrance predisposition gene for luminal (estrogen receptor [ER] positive) breast cancers. However, many BRCA2 mutant carriers lack family history of breast/ovarian cancers and do not benefit from genetic testing. Specific genomic features associated with BRCA2 inactivation in tumors could help identify patients for whom a genetic test for BRCA2 may be proposed. A series of ER-positive invasive ductal carcinomas (IDCs) including 30 carriers of BRCA2 mutations and 215 control cases was studied by single-nucleotide polymorphism (SNP) arrays. Cases and controls were stratified by grade and HER2 status. Independently, 7 BRCA2 and 51 control cases were used for validation. Absolute copy number and Loss of heterozygosity (LOH) profiles were obtained from SNP arrays by the genome alteration print (GAP) method. BRCA2 tumors were observed to display a discriminatively greater number of chromosomal breaks calculated after filtering out and smoothing <3 Mb variations. This argues for a BRCA2-associated genomic instability responsible for long-segment aberrations. Co-occurrence of two genomic features-LOH of 13q13 and 14q32-was found to predict BRCA2 status with 90% of sensitivity and 87% of specificity in discovery series of high-grade HER2-negative IDCs and 100% of sensitivity and 88% of specificity in an independent series of 58 IDCs. Estimated positive predictive value was 17.2% (confidence interval: 6.7-33.5) in the whole series. In conclusion, the simplified BRCA2 classifier based on the co-occurrence of LOH at 13q13 and 14q32 could provide an indication to test for BRCA2 mutation in patients with ER-positive IDC., (Copyright © 2013 UICC.)

This study was designed to identify predictive signatures of pathological complete response (pCR) in breast cancer treated by taxane-based regimen, using clinicopathological variables and transcriptomic data (Affymetrix Hgu133 Plus 2.0 devices). The REMAGUS 02 trial (n = 153,training set) and the publicly available M.D. Anderson data set (n = 133, validation set) were used. A re-sampling method was applied. All predictive models were defined using logistic regression and their classification performances were tested through Area Under the Curve (AUC) estimation. A stable set of 42 probesets (31 genes) differentiate pCR or no pCR samples. Single-or 2-probesets signatures, mainly related to ER pathway, were equally predictive of pCR with AUC greater then 0.80. Models including probesets associated with ESR1, MAPT, CA12 or PIGH presented good classification performances. When clinical variables were entered into the model, only CA12 and PIGH, remained informative (p = 0.05 and p = 0.005) showing that a combination of a few genes provided robust and reliable prediction of pCR., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Metastasis, a fatal complication of breast cancer, does not fully benefit from available therapies. In this study, we investigated whether ATIP3, the major product of 8p22 MTUS1 gene, may be a novel biomarker and therapeutic target for metastatic breast tumors. We show that ATIP3 is a prognostic marker for overall survival among patients with breast cancer. Notably, among metastatic tumors, low ATIP3 levels associate with decreased survival of the patients. By using a well-defined experimental mouse model of cancer metastasis, we show that ATIP3 expression delays the time-course of metastatic progression and limits the number and size of metastases in vivo. In functional studies, ATIP3 silencing increases breast cancer cell migration, whereas ATIP3 expression significantly reduces cell motility and directionality. We report here that ATIP3 is a potent microtubule-stabilizing protein whose depletion increases microtubule dynamics. Our data support the notion that by decreasing microtubule dynamics, ATIP3 controls the ability of microtubule tips to reach the cell cortex during migration, a mechanism that may account for reduced cancer cell motility and metastasis. Of interest, we identify a functional ATIP3 domain that associates with microtubules and recapitulates the effects of ATIP3 on microtubule dynamics, cell proliferation, and migration. Our study is a major step toward the development of new personalized treatments against metastatic breast tumors that have lost ATIP3 expression.

Background: To evaluate whether predictive factors of axillary lymph node metastasis in female breast cancer (BC) are similar in male BC., Patients and Methods: From January 1994 to May 2011, we recorded 80 non-metastatic male BC treated at Institut Curie (IC). We analysed the calibration and discrimination performance of two nomograms [IC, Memorian Sloan-Kettering Cancer Center (MSKCC)] originally designed to predict axillary lymph node metastases in female BC., Results: About 55% and 24% of the tumours were pT1 and pT4, respectively. Nearly 46% demonstrated axillary lymph node metastasis. About 99% were oestrogen receptor positive and 94% HER2 negative. Lymph node status was the only significant prognostic factor of overall survival (P = 0.012). The area under curve (AUC) of IC and MSKCC nomograms were 0.66 (95% CI 0.54-0.79) and 0.64 (95% CI 0.52-0.76), respectively. The calibration of these two models was inadequate., Conclusions: Multi-variate models designed to predict axillary lymph node metastases for female BC were not effective in our male BC series. Our results may be explained by (i) small sample size (ii) different biological determinants influencing axillary metastasis in male BC compared with female BC.

Background: Molecular signatures may become of use in clinical practice to assess the prognosis of breast cancers. However, although international consensus conferences sustain the use of these new markers in the near future, concerns remain about their degree of discordance and cost-effectiveness in different international settings. The present study aims to validate Ki67 as prognostic factor in a large cohort of early-stage (pT1-pT2, pN0) breast cancer patients., Methods: 456 patients treated in 1995-1996 were identified in the Institut Curie database. Ki67 (MIB1) was retrospectively assessed by immunohistochemistry for all cases. The prognostic value of this index was compared to that of histological grade (HG), Estrogen receptor (ER) and HER2 status. Distant disease free interval, loco-regional recurrence, time-lapse from first metastatic diagnosis to death were analyzed., Results: All 456 patients were treated by lumpectomy plus axillary dissection and radiotherapy. 27 patients (5.9%) received systemic treatment. Tumors were classified as HG1 in 35%, HG2 in 42% and HG3 in 23% of cases. ER was expressed in 86% of the tumors, HER2 in 5% and 14% were triple negative. The median follow-up was 151 [5-191] months. Distant and loco-regional disease recurrences were observed in 16% and 18%, respectively. High (>20%) Ki67 rate [HR = 3 (1.8-4.8), p<10e-06] and HG3 [HR = 4.4 (2.2-8.6), p = 0.00002] were associated with an increased rate of distant relapse. In multivariate analysis, the Ki67 remained the only significant prognostic factor in the subgroups of ER positive HER2 negative [HR = 2.6 (1.5-4.6), p = 0.0006] and ER positive HER2 negative HG2 tumors [HR = 2.2 (1.01-4.8), p = 0.04]., Conclusions: We validate the prognosis value of the Ki67 rate in small size node negative breast cancer. We conclude that Ki67 is a potential cost-effective decision marker for adjuvant therapy in early-stage HG2, pT1-pT2, pN0, breast cancers.

BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signature of BRCA1-associated genomic instability. Large-scale state transitions (LST), defined as chromosomal break between adjacent regions of at least 10 Mb, were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer., (©2012 AACR.)

Description of the various modalities of breast and ovarian cancer risk management, patient choices and their outcome in a single-center cohort of 158 unaffected women carrying a BRCA1 or BRCA2 germline mutation. Between 1998 and 2009, 158 unaffected women carrying a BRCA1 or BRCA2 gene mutation were prospectively followed. The following variables were studied: general and gynecological characteristics, data concerning any prophylactic procedures, and data concerning the outcome of these patients. Median age at inclusion was 37 years and median follow-up was 54 months. Among the 156 women who received systematic information about prophylactic mastectomy, 5.3 % decided to undergo surgery within 36 months after disclosure of genetic results. Prophylactic salpingo-oophorectomy was performed in 68 women. Among women in whom follow-up started between the ages of 40 and 50 years, prophylactic salpingo-oophorectomy was performed, within 24 months after start of follow-up, in 83.7 and 52 % of women with BRCA1 and BRCA2 mutations, respectively. Twenty four women developed breast cancer. Ovarian cancer was detected during prophylactic salpingo-oophorectomy in two women (2.9 %). In this cohort of French women carrying BRCA1/2 mutations, prophylactic mastectomy was a rarely used option. However, good compliance with prophylactic salpingo-oophorectomy was observed. This study confirms the high breast cancer risk in these women.

The goal of the present study was to evaluate the role of the tyrosine kinase receptor fibroblast growth factor-1 (FGFR1) and its ligand, the fibroblast growth factor 2 (FGF2) in determining the response to chemoradiotherapy of breast cancers. S14 was a phase II neoadjuvant study carried out at the Institut Curie that recruited 59 patients between November 2001 and September 2003. This prospective study aimed to assess the pathological response after preoperative radiochemotherapy (5FU-Navelbine-radiotherapy) for large breast cancers. The expression of FGFR1 and FGF2 in tumor cells were assessed by immunohistochemistry. Tumors in which no staining was seen, were considered as negative for that protein. We used the Khi-2 test or the Fisher test to compare the qualitative variables and the Student t test or the non-parametric Wilcoxon test for the quantitative variables. We included in the present study all the 32 patients from the S14 cohort for whom the tissue blocks from the biopsy specimens were available with sufficient tumoral tissue. FGFR1 and FGF2 staining were observed respectively in 17 (56%) and 22 (68%) of the 32 tumoral biopsies. The expression of FGFR1 was associated with the hormone receptor positive status (p=0.0191). Only 11% (1/9) of the high grade tumors failed to respond to chemoradiotherapy compared to 68 % resistant tumors (15/22) among the low/intermediate grade tumors (p=0.0199). Among the low/intermediate grade tumors, FGFR1 negative tumors did not respond to chemoradiotherapy (0/9), compared with tumors expressing FGFR1 among which, almost one half had a good response (6/13) (p=0.0167). Among the low and intermediate grade breast cancers, the FGFR1 negative tumors were resistant to chemoradiotherapy. The expression of FGFR1 in patients' biopsies may serve as a marker of response to chemoradiotherapy.

Objectives: Breast cancer treatment relies on 3 major phenotypical subtypes, including the triple-negative (TN), HER2-positive, and hormone receptor-positive (estrogen receptor/progesterone receptor) ones. We retrospectively determined the clinical and pathologic response rates to intensified taxane-free neoadjuvant chemotherapy according to these phenotypical classes in a series of patients with highly proliferative operable breast cancer, and examined the patterns of recurrence., Methods: Patients with early breast cancer with highly proliferative (S-phase fraction >4%) operable tumors of >3 cm received 4 cycles of intensified neoadjuvant chemotherapy with high-dose cyclophosphamide (doxorubicin 70 mg/m d1, cyclophosphamide 700 mg/m d1/d8, and 5 FU 700 mg/m d1-d5) every 3 weeks., Results: Fifty-five patients were included in the analysis. Patients with TN phenotype experienced a high pathologic complete response (pCR) rate to intensified chemotherapy in comparison with patients with HER2-positive and estrogen receptor/progesterone receptor tumors (47%, 0%, and 12%, respectively). Forty percent of patients with TN breast cancer recurred after a median follow-up of nearly 11 years, but only 22% of those achieving a pCR., Conclusions: A high pCR rate to short intensified neoadjuvant chemotherapy with high-dose cyclophosphamide was achieved in patients with operable highly proliferative TN breast cancer, and pCR was associated with a low rate of recurrence.

Background: The clinical management of lobular carcinoma in situ lesions remains challenging. Our aim was to evaluate the risk of relapse for lobular carcinoma in situ (LCIS) patients, diagnosed on mammography performed for microcalcifications and according to proliferation assessed by Ki67 staining., Methods: A series of 47 patient's files with LCIS and followed in our institution were retrospectively selected. All patients underwent lumpectomy without radiation therapy. The expression of E-cadherin, estrogen receptor (ER), progesterone receptor (PR), EGFR and Ki67 were determined. Four different classes were then defined with the following criteria: ER+ and Ki67 ≤ 10%; ER+, Ki67 >10%; ER-; ER-PR- and EGFR+., Results: Patient's mean age was 51.3 yrs. The majority of the lesions were classical LCIS (97%). All cases were E-cadherin either negative (71%) or weak and incomplete (29%). Among the 44 evaluable cases, 34 cases were ER or PR positive with KI67 ≤ 10% (79%), 9 cases ER positive with KI67 > 10% (21%), 1 case was ER and PR negative and expressed EGFR. At five years, all patients were alive, 1/34 ER positive and Ki67 low experienced a relapse contrasting with 3 out of 9 ER positive and Ki67 high (3 invasive carcinomas including 2 ductal and 1 lobular) (p = 0.0054)., Conclusion: In this retrospective study, we observed a higher risk of relapse associated with a high proliferative activity of classical LCIS. If confirmed in larger series, this observation suggests that radiation therapy or hormonotherapy could be discussed for patients with Ki67 high classical LCIS in order to decrease their risk of relapse., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Our objective was to assess the global cost of the sentinel lymph node detection [axillary sentinel lymph node detection (ASLND)] compared with standard axillary lymphadenectomy [axillary lymph node dissection (ALND)] for early breast cancer patients., Patients and Methods: We conducted a prospective, multi-institutional, observational, cost comparative analysis. Cost calculations were realized with the micro-costing method from the diagnosis until 1 month after the last surgery., Results: Eight hundred and thirty nine patients were included in the ASLND group and 146 in the ALND group. The cost generated for a patient with an ASLND, with one preoperative scintigraphy, a combined method for sentinel node detection, an intraoperative pathological analysis without lymphadenectomy, was lower than the cost generated for a patient with lymphadenectomy [€ 2947 (σ = 580) versus € 3331 (σ = 902); P = 0.0001]., Conclusion: ASLND, involving expensive techniques, was finally less expensive than ALND. The length of hospital stay was the cost driver of these procedures. The current observational study points the heterogeneous practices for this validated and largely diffused technique. Several technical choices have an impact on the cost of ASLND, as intraoperative analysis allowing to reduce rehospitalization rate for secondary lymphadenectomy or preoperative scintigraphy, suggesting possible savings on hospital resources.

Clinicians can use biomarkers to guide therapeutic decisions in estrogen receptor positive (ER+) breast cancer. One such biomarker is cellular proliferation as evaluated by Ki-67. This biomarker has been extensively studied and is easily assayed by histopathologists but it is not currently accepted as a standard. This review focuses on its prognostic and predictive value, and on methodological considerations for its measurement and the cut-points used for treatment decision. Data describing study design, patients' characteristics, methods used and results were extracted from papers published between January 1990 and July 2010. In addition, the studies were assessed using the REMARK tool. Ki-67 is an independent prognostic factor for disease-free survival (HR 1.05-1.72) in multivariate analyses studies using samples from randomized clinical trials with secondary central analysis of the biomarker. The level of evidence (LOE) was judged to be I-B with the recently revised definition of Simon. However, standardization of the techniques and scoring methods are needed for the integration of this biomarker in everyday practice. Ki-67 was not found to be predictive for long-term follow-up after chemotherapy. Nevertheless, high KI-67 was found to be associated with immediate pathological complete response in the neoadjuvant setting, with an LOE of II-B. The REMARK score improved over time (with a range of 6-13/20 vs. 10-18/20, before and after 2005, respectively). KI-67 could be considered as a prognostic biomarker for therapeutic decision. It is assessed with a simple assay that could be standardized. However, international guidelines are needed for routine clinical use.

Purpose: A gene expression signature, predictive for local recurrence after breast-conserving treatment, has previously been identified from a series of 165 young patients with breast cancer. We evaluated this signature on both another platform and an independent series, compared its performance with other published gene-sets, and investigated the gene expression profile of a larger data set., Experimental Design: Gene expression tumor profiles were obtained on 148 of the initial 165 Dutch patients and on an independent validation series of 195 French patients. Both unsupervised and supervised classifications were used to study the gene expression profile of the 343 breast cancers and to identify subgroups that differ for their risk of local recurrence., Results: The previous local recurrence signature was validated across platforms. However, when applied to the French patients, the signature did not reproduce its reported performance and did not better classify the patients than other published gene sets. Hierarchical clustering of all 343 breast cancers did not show any grouping reflecting local recurrence status. Genes related to proliferation were found differentially expressed between patients with or without local recurrence only in triple-negative tumors. Supervised classification revealed no significant gene set predictive for local recurrence or able to outperform classification based on clinical variables., Conclusions: Although the previously identified local recurrence signature was robust on another platform, we were neither able to validate it on an independent data set, nor able to define a strong gene expression classifier for local recurrence using a larger data set. We conclude that there are no significant differences in gene expression pattern in tumors from patients with and without local recurrence after breast-conserving treatment.

Introduction: To decipher the interaction between the molecular subtype classification and the probability of a non-sentinel node metastasis in breast cancer patients with a metastatic sentinel lymph-node, we applied two validated predictors (Tenon Score and MSKCC Nomogram) on two large independent datasets., Materials and Methods: Our datasets consisted of 656 and 574 early-stage breast cancer patients with a metastatic sentinel lymph-node biopsy treated at first by surgery. We applied both predictors on the whole dataset and on each molecular immune-phenotype subgroups. The performances of the two predictors were analyzed in terms of discrimination and calibration. Probability of non-sentinel lymph node metastasis was detailed for each molecular subtype., Results: Similar results were obtained with both predictors. We showed that the performance in terms of discrimination was as expected in ER Positive HER2 negative subgroup in both datasets (MSKCC AUC Dataset 1 = 0.73 [0.69-0.78], MSKCC AUC Dataset 2 = 0.71 (0.65-0.76), Tenon Score AUC Dataset 1 = 0.7 (0.65-0.75), Tenon Score AUC Dataset 2 = 0.72 (0.66-0.76)). Probability of non-sentinel node metastatic involvement was slightly under-estimated. Contradictory results were obtained in other subgroups (ER negative HER2 negative, HER2 positive subgroups) in both datasets probably due to a small sample size issue. We showed that merging the two datasets shifted the performance close to the ER positive HER2 negative subgroup., Discussion: We showed that validated predictors like the Tenon Score or the MSKCC nomogram built on heterogeneous population of breast cancer performed equally on the different subgroups analyzed. Our present study re-enforce the idea that performing subgroup analysis of such predictors within less than 200 samples subgroup is at major risk of misleading conclusions.

Purpose: This phase II trial aimed to investigate the efficacy of concurrent radio- (RT) and chemotherapy (CT) in the preoperative setting for operable, non-metastatic breast cancer (BC) not amenable to initial breast-conserving surgery (BCS)., Patients and Methods: From 2001 to 2003, 59 women were included. CT consisted of four cycles of 5-FU, 500 mg/m(2)/d, continuous infusion (d1-d5) and vinorelbine, 25 mg/m(2) (d1 and d6). Starting concurrently with the second cycle, RT delivered 50 Gy to the breast and 46 Gy to the internal mammary and supra/infra-clavicular areas. Breast surgery and lymph node dissection were then performed. Adjuvant treatment consisted of a 16 Gy boost to the tumor bed after BCS, FEC (four cycles of fluorouracil 500 mg/m(2), cyclophosphamide 500 mg/m(2), and epirubicin 100 mg/m(2), d1; d21) for pN1-3 and hormone-therapy for positive hormone receptors BC., Results: The in-breast pathological complete response rate was 27%. BCS was performed in 41 (69%) pts. Overall and distant-disease free survivals at 5 years were respectively 88% [95% CI 80-98] and 83% [95% CI 74-93] whereas locoregional and local controls were 90% [95% CI 82-97] and 97% [95% CI 92-100]. Late toxicity (CTCAE-V3) was assessed in 51 pts (86%) with a median follow-up of 7 years [5-8]. Four (8%) experienced at least one grade III toxicities (one telangectasia and three fibroses). Cosmetic results, assessed in 35 of the 41 pts (85%) who retained their breasts, were poor in four pts (11%)., Conclusion: Preoperative concurrent administration of RT and CT is an effective regimen. Long-term toxicity is moderate. This association deserves further evaluations in prospective trials., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Genomic grade (GG) is a 97-gene signature which improves the accuracy and prognostic value of histological grade (HG) in invasive breast carcinoma. Since most of the genes included in the GG are involved in cell proliferation, we performed a retrospective study to compare the prognostic value of GG, Mitotic Index and Ki67 score., Methods: A series of 163 consecutive breast cancers was retained (pT1-2, pN0, pM0, 10-yr follow-up). GG was computed using MapQuant Dx(R)., Results: GG was low (GG-1) in 48%, high (GG-3) in 31% and equivocal in 21% of cases. For HG-2 tumors, 50% were classified as GG-1, 18% as GG-3 whereas 31% remained equivocal. In a subgroup of 132 ER+/HER2- tumors GG was the most significant prognostic factor in multivariate Cox regression analysis adjusted for age and tumor size (HR = 5.23, p = 0.02)., Conclusions: In a reference comprehensive cancer center setting, compared to histological grade, GG added significant information on cell proliferation in breast cancers. In patients with HG-2 carcinoma, applying the GG to guide the treatment scheme could lead to a reduction in adjuvant therapy prescription. However, based on the results observed and considering (i) the relatively close prognostic values of GG and Ki67, (ii) the reclassification of about 30% of HG-2 tumors as Equivocal GG and (iii) the economical and technical requirements of the MapQuant micro-array GG test, the availability in the near future of a PCR-based Genomic Grade test with improved performances may lead to an introduction in clinical routine of this test for histological grade 2, ER positive, HER2 negative breast carcinoma.

Background: Identification of predictive markers of response to treatment is a major objective in breast cancer. A major problem in clinical sampling is the variability of RNA templates, requiring accurate management of tumour material and subsequent analyses for future translation in clinical practice. Our aim was to establish the feasibility and reliability of high throughput RNA analysis in a prospective trial., Methods: This study was conducted on RNA from initial biopsies, in a prospective trial of neoadjuvant chemotherapy in 327 patients with inoperable breast cancer. Four independent centres included patients and samples. Human U133 GeneChips plus 2.0 arrays for transcriptome analysis and quantitative RT-qPCR of 45 target genes and 6 reference genes were analysed on total RNA., Results: Thirty seven samples were excluded because i) they contained less than 30% malignant cells, or ii) they provided RNA Integrity Number (RIN) of poor quality. Among the 290 remaining cases, taking into account strict quality control criteria initially defined to ensure good quality of sampling, 78% and 82% samples were eligible for transcriptome and RT-qPCR analyses, respectively. For RT-qPCR, efficiency was corrected by using standard curves for each gene and each plate. It was greater than 90% for all genes. Clustering analysis highlighted relevant breast cancer phenotypes for both techniques (ER+, PR+, HER2+, triple negative). Interestingly, clustering on trancriptome data also demonstrated a "centre effect", probably due to the sampling or extraction methods used in on of the centres. Conversely, the calibration of RT-qPCR analysis led to the centre effect withdrawing, allowing multicentre analysis of gene transcripts with high accuracy., Conclusions: Our data showed that strict quality criteria for RNA integrity assessment and well calibrated and standardized RT-qPCR allows multicentre analysis of genes transcripts with high accuracy in the clinical context. More stringent criteria are needed for transcriptome analysis for clinical applications., (© 2011 de Cremoux et al; licensee BioMed Central Ltd.)

Background: Adjuvant! Online is a web-based application designed to provide 10 years survival probability of patients with breast cancer. Several predictors have not been assessed in the original Adjuvant! Online study. We provide the validation of Adjuvant! Online algorithm on two breast cancer datasets, and we determined whether the accuracy of Adjuvant! Online is improved with other well-known prognostic factors., Patients and Methods: The French data set is composed of 456 women with early breast cancer. The Dutch data set is composed of 295 women less than 52 years of age. Agreement between observation and Adjuvant! Online prediction was checked, and logistic models were performed to estimate the prognostic information added by risk factors to Adjuvant! Online prediction., Results: Adjuvant! Online prediction was overall well-calibrated in the French data set but failed in some subgroups of such high grade and HER2 positive patients. HER2 status, Mitotic Index and Ki67 added significant information to Adjuvant! Online prediction. In the Dutch data set, the overall 10-year survival was overestimated by Adjuvant! Online, particularly in patients less than 40 years old., Conclusion: Adjuvant! Online needs to be updated to adjust overoptimistic results in young and high grade patients, and should consider new predictors such as Ki67, HER2 and Mitotic Index.