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Introduction: Several authors have underscored a strong relation between the molecular subtypes and the axillary status of breast cancer patients. The aim of our work was to decipher the interaction between this classification and the probability of a positive sentinel node biopsy., Materials and Methods: Our dataset consisted of a total number of 2654 early-stage breast cancer patients. Patients treated at first by conservative breast surgery plus sentinel node biopsies were selected. A multivariate logistic regression model was trained and validated. Interaction covariate between ER and HER2 markers was a forced input of this model. The performance of the multivariate model in the training and the two validation sets was analyzed in terms of discrimination and calibration. Probability of axillary metastasis was detailed for each molecular subtype., Results: The interaction covariate between ER and HER2 status was a stronger predictor (p = 0.0031) of positive sentinel node biopsy than the ER status by itself (p = 0.016). A multivariate model to determine the probability of sentinel node positivity was defined with the following variables; tumour size, lympho-vascular invasion, molecular subtypes and age at diagnosis. This model showed similar results in terms of discrimination (AUC = 0.72/0.73/0.72) and calibration (HL p = 0.28/0.05/0.11) in the training and validation sets. The interaction between molecular subtypes, tumour size and sentinel nodes status was approximated., Discussion: We showed that biologically-driven analyses are able to build new models with higher performance in terms of breast cancer axillary status prediction. The molecular subtype classification strongly interacts with the axillary and distant metastasis process.

Purpose: To evaluate the accuracy of a boost technique., Methods and Materials: Twenty-two patients underwent tumorectomy with placement of two or more clips in the surgical cavity before breast remodeling. Preoperative and postoperative computed tomography scans, with match-point registration, were performed on all patients. The relationship between the location of the gross tumor volume (GTV), defined on the preoperative scan, and clip clinical target volume (CTV) (clips with a 5-mm margin on the postoperative scan) was then studied, by use of commercial volume analysis software., Results: Of the patients, 4 had two clips, 2 had three clips, 8 had four clips, and 8 had five clips. The median GTV was 1.06 mL (range, 0.2-5.3 mL); clip CTV ranged from 2.4 to 21.5 mL. Volumetric analysis showed that in 7 cases (32%), there was no intersection between the GTV and the clip CTV, with the following distribution: 4 patients with two clips, 1 patient with three clips, 1 patient with four clips, and 1 patient with five clips. The common contoured volume was defined as the percent ratio between the intersection of the GTV and clip CTV and the GTV. It was found to be significantly increased if three or more clips were used vs. only two clips (common contoured volume, 35.45% vs. 0.73%; p = 0.028). Finally, the GTV and clip CTV volume relationship can be presented as follows: 12.5% to 33% overlap in 8 patients (36.4%), 50% to 75% in 5 patients (22.7%), and greater than 90% in 2 patients (9%)., Conclusions: The use of three or more clips during tumorectomy increases the accuracy of tumor bed delineation., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: The BRCA2 gene is responsible for a high number of hereditary breast and ovarian cancers, and studies of the BRCA2 biological functions are limited by the lack of models that resemble the patient's tumour features. The aim of this study was to establish and characterise a new human breast carcinoma xenograft obtained from a woman carrying a germline BRCA2 mutation., Methods: A transplantable xenograft was obtained by grafting a breast cancer sample into nude mice. The biological and genetic profiles of the xenograft were compared with that of the patient's tumour using histology, immunohistochemistry (IHC), BRCA2 sequencing, comparative genomic hybridisation (CGH), and qRT-PCR. Tumour response to standard chemotherapies was evaluated., Results: Histological profile identified the tumour as a basal-like triple-negative breast cancer. Targeted BRCA2 DNA sequencing of the xenograft showed the presence of the mutation previously identified in the carrier. Comparative genomic hybridisation array profiles of the primary tumour and the xenograft revealed a high number of similar genetic alterations. The therapeutic assessment of the xenograft showed sensitivity to anthracyclin-based chemotherapy and resistance to docetaxel. The xenograft was also highly sensitive to radiotherapy and cisplatin-based treatments., Conclusions: This study describes a new human breast cancer xenograft obtained from a BRCA2-mutated patient. This xenograft provides a new model for the pre-clinical drug development and for the exploration of the drug response biological basis.

Purpose: To determine the appearance of breast lesions at quantitative ultrasonographic (US) elastography by using supersonic shear imaging (SSI) and to assess the correlation between quantitative values of lesion stiffness and pathologic results, which were used as the reference standard., Materials and Methods: This study was approved by the French National Committee for the Protection of Patients Participating in Biomedical Research Programs. All patients provided written informed consent. Conventional US and SSI quantitative elastography were performed in 46 women (mean age, 57.6 years; age range, 38-71 years) with 48 breast lesions (28 benign, 20 malignant; mean size, 14.7 mm); pathologic results were available in all cases. Quantitative lesion elasticity was measured in terms of the Young modulus (in kilopascals). Sensitivity, specificity, and area under the curve were obtained by using a receiver operating characteristic curve analysis to assess diagnostic performance., Results: All breast lesions were detected at SSI. Malignant lesions exhibited a mean elasticity value of 146.6 kPa +/- 40.05 (standard deviation), whereas benign ones had an elasticity value of 45.3 kPa +/- 41.1 (P < .001). Complicated cysts were differentiated from solid lesions because they had elasticity values of 0 kPa (no signal was retrieved from liquid areas)., Conclusion: SSI provides quantitative elasticity measurements, thus adding complementary information that potentially could help in breast lesion characterization with B-mode US.

To assess anti-tumor activity of sequential epirubicin/cyclophosphamide followed by docetaxel with the randomized addition of celecoxib in HER2 negative patients or trastuzumab in HER2 positive patients. From May 2004 till October 2007, 340 patients with stage II and III breast adenocarcinoma, ineligible for breast conserving surgery, received eight sequential three weekly cycles of EC-D [epirubicin (75 mg/m(2))-cyclophosphamide (750 mg/m(2)) for four cycles followed by docetaxel (100 mg/m(2)) for four cycles]. HER2-negative patients (N = 220) were randomized to receive concomitantly with docetaxel celecoxib 800 mg/day during cycles 5-8 or no additional treatment, while HER2-positive patients confirmed by FISH (N = 120) were randomized to trastuzumab concomitant to docetaxel (8 mg/kg then 6 mg/kg IV every 3 weeks) or no additional preoperative treatment. In the HER2 negative group, pCR (grade 1 and 2 of Chevallier's classification) was observed in 11.5 and 13% of patients treated without and with neoadjuvant Celecoxib, respectively. In the HER2 positive group, pCR rate reached 26% in those who received neoadjuvant trastuzumab versus 19% in the others. There was no unexpected toxicity, no cardiac toxicity, and no toxic death. Triple negative breast cancers experience the highest pCR rate of 30%. Celecoxib is not likely to improve pCR rates in addition to EC-D in patients with HER2-negative tumor. In HER2-positive tumor patients, trastuzumab added to ECD leads to increased pCR rates. It was the only combination to deserve further study according to the two-stage Fleming's design used in this trial.

Background: The treatment of choice for elderly women with breast cancer remains controversial. This retrospective analysis of a cohort from a single institution was designed to evaluate whether such patients are really undertreated because of their age and to reappraise their usual management., Methods: The characteristics of 538 patients aged > or = 70 years with operable breast cancer, treated between 1995 and 1999, were retrospectively analyzed comparing patients aged 70 to 75 years (group I, n = 288), 75 to 80 years (group II, n = 156), and > or = 80 years (group III, n = 94). Cause-specific survival, distant recurrence-free interval, and local control were estimated by the Kaplan-Meier method and compared by log rank test. Multivariate analysis used Cox regression., Results: In group III, tumors were more frequently T2 than T1 (P < 0.0001) and estrogen receptor negative (P = 0.045) than in groups I and II. Surgery was performed in 94.6% of patients, breast-conserving in 72.1% (62% in group III; P = 0.0015) with axillary dissection in 89.2% (77% in group III; P = 0.0015); 100% received radiotherapy after lumpectomy (hypofractionated in 63% of group III; P < 0.0001). Adjuvant hormone therapy and chemotherapy were administered to 57 and 3.7% of patients, respectively. At 7 years, no difference in the three groups was observed for cause-specific survival (91% for group I, 89% for group II, 86% for group III) distant recurrence-free interval, and local control (>90%)., Conclusions: Elderly patients with operable breast cancer who are completely and correctly treated with realistic treatment options that are based on surgery and adjuvant radiotherapy have a similar chance of being cured as younger patients.

As tumours in BRCA1/2 mutation carriers might be more sensitive to radiation, we investigated after long-term follow-up whether mutation status influenced the rate of ipsilateral and contralateral breast cancers after breast-conserving treatment (BCT). BRCA1 and BRCA2 genes were screened for germline mutations in 131 patients with a family history of breast and/or ovarian cancer who had undergone BCT and radiotherapy. Patients were matched to 261 controls with sporadic breast cancer according to age at diagnosis and year of treatment. Controls were followed up for at least as long as the interval between diagnosis and genetic screening in familial cases. Rates of ipsilateral and contralateral cancer between groups were compared by the log-rank test. The BRCA1/2 mutations occurred in 20.6% of tested patients. Tumours in mutation carriers were more likely to be grade III (P < 10(-4)) and oestrogen receptor negative (P = 0.005) than in non-carriers and controls. Overall median follow-up was 161 months. There was no significant difference in ipsilateral tumours between mutation carriers, non-carriers and controls (P = 0.13). On multivariate analysis, age was the most significant predictor for ipsilateral recurrence (P < 10(-3)). The rate of contralateral cancer was significantly higher in familial cases: 40.7% (mutation carriers), 20% (non-carriers), and 11% (controls) (P < 10(-4)). After 13.4 years of follow-up, the rate of ipsilateral tumours was no higher in mutation carriers than in non-carriers or controls. As tumours in BRCA1/2 mutation carriers might be more sensitive to radiation, BCT is a possible treatment option.

Purpose: Following breast-conserving surgery for DCIS, reexcision before radiotherapy is recommended when margins are close or involved. We investigated whether an additional radiation dose could replace reexcision., Methods: We selected 208 women with DCIS of the breast treated with breast-conserving surgery between 1992 and 2002 who had either close margins (< 2 mm) (89 pts) or focally (< 1 mm) or minimally (1-15 mm) involved margins (119 pts). Sixty-one patients (29%) underwent reexcision before irradiation and 147 patients (71%) received breast irradiation with boost, without reexcision., Results: Median follow-up was 89 months. Median age was 53 years with 7 patients less than 41. Involved margins were less frequent in the non reexcision group than in the reexcised group (50% vs. 74%, p = 0.0019). All other clinical and histological features were comparable. Median whole-breast radiation dose was 50 Gy. Median total doses to the tumour bed were 67 Gy (range, 45-77) and 60 Gy (range, 46-74), respectively (p < 0.0001). Of the 61 reexcised patients, 56% had residual DCIS and 6% had invasive cancer. Six underwent a mastectomy for persistent margin involvement. Seven-year locoregional failure rates were 9.3% without, and 9.6% with reexcision (ns). No differences were observed when adjusting for margin status., Conclusion: In carefully selected patients with close (< 2 mm) or focally/minimally involved margins, reexcision may be avoided and satisfactory local control achieved by increasing the radiation dose to the tumour bed to at least 66 Gy. These results only apply to patients older than 40 and would need confirmation in independent series.

Background: In early breast cancer patients, bone marrow (BM)-disseminated tumor cells (DTCs) were associated with distant metastasis and locoregional recurrence. Our aim was to determine whether BM DTC detection could be related to specific locoregional dissemination of cancer cells, according to radiotherapy volumes., Patients and Methods: The relationship between locoregional recurrence-free survival (LRFS) and DTC detection was evaluated according to the various locoregional volumes irradiated after surgery., Results: BM DTCs were detected in 94 of 621 stage I-III breast cancer patients (15%) and were not associated with axillary node status. Eighteen patients (2.9%) experienced locoregional recurrence (median follow-up 56 months), of whom eight (44%) were initially BM DTC positive. BM DTC detection was the only prognostic factor for LRFS [P = 0.0005, odds ratio = 5.2 (2.0-13.1), multivariate analysis]. In BM DTC-positive patients, a longer LRFS was observed in those who were given adjuvant hormone therapy (P = 0.03) and radiotherapy to supraclavicular nodes (SCNs)/internal mammary nodes (IMNs) (P = 0.055) (multivariate analysis; interaction test: P = 0.028)., Conclusions: The presence of DTC in BM may be associated with a different pattern of locoregional cancer cell dissemination and influences LRFS. The possible reseeding of the primary cancer area by DTC could be prevented by systemic hormone therapy but also by SCN/IMN irradiation.

Background: Breast cancer is a heterogeneous disease that is not totally eradicated by current therapies. The classification of breast tumors into distinct molecular subtypes by gene profiling and immunodetection of surrogate markers has proven useful for tumor prognosis and prediction of effective targeted treatments. The challenge now is to identify molecular biomarkers that may be of functional relevance for personalized therapy of breast tumors with poor outcome that do not respond to available treatments. The Mitochondrial Tumor Suppressor (MTUS1) gene is an interesting candidate whose expression is reduced in colon, pancreas, ovary and oral cancers. The present study investigates the expression and functional effects of MTUS1 gene products in breast cancer., Methods and Findings: By means of gene array analysis, real-time RT-PCR and immunohistochemistry, we show here that MTUS1/ATIP3 is significantly down-regulated in a series of 151 infiltrating breast cancer carcinomas as compared to normal breast tissue. Low levels of ATIP3 correlate with high grade of the tumor and the occurrence of distant metastasis. ATIP3 levels are also significantly reduced in triple negative (ER- PR- HER2-) breast carcinomas, a subgroup of highly proliferative tumors with poor outcome and no available targeted therapy. Functional studies indicate that silencing ATIP3 expression by siRNA increases breast cancer cell proliferation. Conversely, restoring endogenous levels of ATIP3 expression leads to reduced cancer cell proliferation, clonogenicity, anchorage-independent growth, and reduces the incidence and size of xenografts grown in vivo. We provide evidence that ATIP3 associates with the microtubule cytoskeleton and localizes at the centrosomes, mitotic spindle and intercellular bridge during cell division. Accordingly, live cell imaging indicates that ATIP3 expression alters the progression of cell division by promoting prolonged metaphase, thereby leading to a reduced number of cells ungergoing active mitosis., Conclusions: Our results identify for the first time ATIP3 as a novel microtubule-associated protein whose expression is significantly reduced in highly proliferative breast carcinomas of poor clinical outcome. ATIP3 re-expression limits tumor cell proliferation in vitro and in vivo, suggesting that this protein may represent a novel useful biomarker and an interesting candidate for future targeted therapies of aggressive breast cancer.

To determine whether any histological trait was associated with regional and/or systemic spread of occult tumour cells (OTCs) in small size invasive breast cancer, we compared tumour characteristics, axillary sentinel lymph node (SN) and bone marrow (BM) status in a series of 287 pT1T2 cases. Surgery was the first step of treatment, associated with SN procedure and with BM aspiration for the detection of OTC. SN was histologically classified as negative, metastatic (>2mm), micro-metastatic (>0.2mm and 2mm) or involved by OTC detected by immunohistochemistry (Ni+, 0.2mm). BM specimens were analysed after immunocytochemistry and classified as negative or positive with atypical cytokeratin-positive OTC. Metastasis and micro-metastasis in the SN were correlated with size, grade and vascular invasion. In contrast, presence of OTC in both SN and BM was independent of these parameters but positively associated with lobular type. This correlation was also observed for BM status, which was similarly independent of the tumour characteristics. No association was found between SN status and BM status. Our data indicate that, in the course of breast cancer, OTC spreading is frequent and could be an early event, related to lobular histological type but independent of classical histoprognostic parameters, and that the loco-regional metastatic spread of OTC is not a prerequisite for systemic involvement.

Unlabelled: This retrospective analysis was designed to confirm the predictive role of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type I (PAI-1) in the outcome of early stage, node-negative breast cancer patients., Patients and Methods: Node-negative patients having not received adjuvant chemotherapy, and for whom frozen samples were available, were selected., Results: Among the 169 patients included, 56.8% presented with uPA >3 ng/mg of proteins and/or PAI-1 >14 ng/mg of proteins. The median follow-up was 73 months. Significant correlations were found between uPA and disease-free survival (p [univariate]=0.003; p [multivariate]=0.01), and between uPA, PAI-1, and uPA plus PAI-1 and distant relapses (p=0.002). No significant correlation was found between uPA/PAI-1 and the risk of locoregional recurrence., Conclusion: This study demonstrated that uPA and PAI-1 are useful predictors of distant metastases in a subset of early stage, node-negative breast cancer patients.

Purpose: BRCA1/2 germline mutations are associated with impaired DNA double-strand break repair. We tested whether breast cancers in BRCA1/2 mutation carriers were more responsive to induction treatments than in noncarriers., Patients and Methods: The BRCA1 and BRCA2 genes were screened for germline mutation in a retrospective cohort of 90 patients (with 93 tumors) with a family history of breast and/or ovarian cancer, treated with induction anthracycline-containing chemotherapy and/or radiotherapy. Median tumor size was 40 mm. Clinical responses and breast preservation rates were correlated to BRCA1/2 mutation status, and to other clinical and pathologic factors., Results: A complete clinical response was achieved in 15/39 (46%) BRCA1/2-mutated tumors and in 7/54 (17%) nonmutated tumors (P = 0.008). Complete or major clinical response rate was observed in 55 of the 74 tumors treated with induction chemotherapy (74.3%). The overall complete or major clinical response rate in the tumors treated with induction radiotherapy was 68% (13/19 tumors). Following induction treatment by either chemotherapy or radiotherapy, more breast-conserving treatments could be performed in mutation carriers than in noncarriers: the rates of breast preservation were 82% in BRCA1/2-mutated tumors and 63% in nonmutated tumors, respectively (P = 0.045). BRCA1 mutation was the sole predictor of breast conservation., Conclusion: Breast conservation after induction treatment was higher in BRmut+ tumors, and clinical response was related to aggressive tumor features correlated with BRCA1/2 mutations. This suggests that impaired repair mechanisms related to the BRCA1/2 mutations increased the chemosensitivity and radiosensitivity of large breast cancers. Further studies will need to determine the long-term outcome in these patients.

Secretory breast carcinomas (<0.15% of breast tumors) are associated with a characteristic morphology and a favorable prognosis. Remarkably, this entity is the only epithelial tumor of the breast with a balanced translocation, t(12;15), that creates an ETV6-NTRK3 gene fusion encoding chimeric tyrosine kinase also encountered in cellular mesoblastic nephroma and infantile fibrosarcoma. The aim of this study was to determine the phenotypic class (ie luminal A/B, ERBB2, basal-like) of secretory breast carcinoma. A series of six secretory breast carcinomas were identified in our files. The ETV6 rearrangement was confirmed in all cases by fluorescence in situ hybridization. Immunophenotype was assessed with anti-ER, PR, ERBB2, KIT, EGFR, E-cadherin, vimentin, PS100, smooth muscle actin, basal (CK5/6 and 14), luminal cytokeratins (CK8/18) and p63 antibodies. In situ and invasive components shared the same immunoprofile and were ER, PR, ERBB2 negative with expression of basal cytokeratins. ETV6 gene alterations were present in both in situ and invasive components, highlighting their genetic similarities. The immunoprofile data (triple-negative with expression of basal markers) showed that secretory breast carcinomas with ETV6-NTRK3 fusion gene belong to the phenotypic basal-like spectrum of breast carcinomas. These results support the hypothesis that secretory breast carcinomas have immunohistochemical and genetic features that distinguish them from other basal-like tumors of the breast.

Introduction: We sought to determine whether the levels of expression of 17 candidate genes were associated with locoregional control after breast-conserving treatments of early-stage breast cancers in young, premenopausal women., Methods: Gene expression was measured by using RT-PCR in the breast tumors of a series of 53 young (younger than 40 years), premenopausal patients. All treatments consisted of primary breast-conserving surgery followed by whole-breast radiotherapy (+/- regional lymph nodes) with or without systemic treatments (chemotherapy +/- hormone therapy). The median follow-up was 10 years., Results: The 10-year locoregional control rate was 70% (95% CI, 57% to 87%). In univariate analysis, no clinical/pathologic prognostic factors were found to be significantly associated with decreased locoregional control. Expression of three genes was found to be significantly associated with an increased locoregional recurrence rate: low estrogen-receptor beta, low aromatase, and high GATA3. Two others were associated with only a trend (P < 0.10): low HER1 and SKP2. In multivariate analysis, only the absence of aromatase was significantly associated with an increased locoregional recurrence rate (P = 0.003; relative risk = 0.49; 95% CI 0.29 to 0.82)., Conclusions: Recent data give credit to the fact that breast cancer in young women is a distinct biologic entity driven by special oncogenic pathways. Our results highlight the role of estrogen-signaling pathways (mainly CYP19/aromatase, GATA3, and ER-beta) in the risk of locoregional recurrence of breast cancer in young women. Confirmation in larger prospective studies is needed.

Routine follow-up of breast cancer patients in specialist clinics is standard practice. This follow-up involves regularly scheduled breast cancer check-ups during the disease-free period, in order to detect recurrence. However, demands on specialist resources rise with the increase in the prevalence of diagnosed breast cancer. Since September 2004, it was proposed in our Institut an alternative routine follow-up schedule. Some patients who are in remission for more than 5 years will be deferred to their general practitioner or gynaecologist for follow-up schedule, alternatively with their referent practitioner from the institut (oncologist, radiation oncologist, or surgeon). We herein present the preliminary results of this strategy, and demonstrate that partially transferring primary responsibility for follow-up does not compromise its quality.

Purpose: Clinical significance of disseminated tumor cells (DTC) in bone marrow of early breast cancer patients has been reported, but improvements in detection methods are needed., Experimental Design: Bone marrow aspirates from 621 patients with stage I to III breast cancer were screened for cytokeratin-positive (CK+) cells. CK+ cells were categorized into DTC only if they had specific morphologic features of tumor cells. Bone marrow status and clinical and pathologic variables of the patients were correlated with clinical outcome after a median follow-up of 56 months., Results: DTC and non-DTC CK+ cells were detected in 15% and 34% of patients, respectively, with no correlation with clinical and pathologic variables. On univariate analysis, DTC detection was associated with a poorer distant metastasis-free survival (DMFS; P = 0.0013) and overall survival (OS; P = 0.005). Moreover, DTC detection was also associated with local relapse-free survival (P = 0.0009). On multivariate analysis, DTC detection was an independent prognostic factor for DMFS, local relapse-free survival, and OS. There was no significant interaction between DTC detection and hormonal receptors status (P = 0.34). Non-DTC CK+ cells had no clinical significance., Conclusion: DTC detection is a powerful prognostic marker for DMFS and OS in early breast cancer patients and can be individualized from irrelevant non-DTC CK+ cells by morphologic criteria. Biologically, despite high rates of systemic adjuvant therapy and locoregional irradiation in this series, DTC detection remains a prognostic factor of distant and, more strikingly, of local relapse, in favor of resistance to treatment of locally or distant disseminated cancer cells in DTC-positive patients.

Breast cancer is one of the most frequently diagnosed cancers in women in France, but its aetiology remains unknown. Viruses including Epstein-Barr virus (EBV), a human equivalent of murine mammary tumour virus (MMTV) and human papillomavirus (HPV) have been detected in benign breast tissues and breast tumours and are considered to be involved in the aetiology of breast cancer. The aim of this study was to determine the prevalence of high-risk oncogenic HPVs in breast carcinoma from French patients. Fifty unselected DNA samples extracted from invasive breast carcinoma tissues were analysed. Polymerase chain reaction (PCR) was performed to amplify both consensus GP5+/GP6+HPV sequences and specific sequences for HPV types 16, 18, 33, 45 and 6-11. No HPV-DNA sequences were detected in our series of 50 samples. These data argue against the role of oncogenic HPV in the pathogenesis of breast cancer.

Aims: To evaluate the surgical management of patients who underwent VLNB for breast microcalcifications., Methods: This retrospective study compared the histological results and the surgical procedures in two groups of patients, group 1: large-core needle biopsy n=1009, and group 2: surgical biopsy n=270., Results: After VLNB, 54% patients were not operated on after stereotactic large-core needle biopsy, 42% underwent one operation, 4% underwent two operations and 0.2% underwent three operations. No surgery was performed for 95% of benign lesions. Multiples operations were necessary in 12% of patients with malignant lesions of VLNB group compared to 45% in the surgical biopsy group. The rate of underdiagnosis of borderline lesions and ductal carcinomas in situ was 16% by the large-core biopsy technique., Conclusion: VLNB constitutes an alternative to surgical biopsy. This procedure avoids surgery for most benign lesions and reduces the number of surgical procedures in malignant lesions.

Purpose: To gain insight into genomic and transcriptomic subtypes of ductal carcinomas in situ of the breast (DCIS)., Experimental Design: We did a combined phenotypic and genomic analysis of a series of 57 DCIS integrated with gene expression profile analysis for 26 of the 57 cases., Results: Thirty-two DCIS exhibited a luminal phenotype; 21 were ERBB2 positive, and 4 were ERBB2/estrogen receptor (ER) negative with 1 harboring a bona fide basal-like phenotype. Based on a CGH analysis, genomic types were identified in this series of DCIS with the 1q gain/16q loss combination observed in 3 luminal DCIS, the mixed amplifier pattern including all ERBB2, 12 luminal and 2 ERBB2(-)/ER(-) DCIS, and the complex copy number alteration profile encompassing 14 luminal and 1 ERBB2(-)/ER(-) DCIS. Eight cases (8 of 57; 14%) presented a TP53 mutation, all being amplifiers. Unsupervised analysis of gene expression profiles of 26 of the 57 DCIS showed that luminal and ERBB2-amplified, ER-negative cases clustered separately. We further investigated the effect of high and low copy number changes on gene expression. Strikingly, amplicons but also low copy number changes especially on 1q, 8q, and 16q in DCIS regulated the expression of a subset of genes in a very similar way to that recently described in invasive ductal carcinomas., Conclusions: These combined approaches show that the molecular heterogeneity of breast ductal carcinomas exists already in in situ lesions and further indicate that DCIS and invasive ductal carcinomas share genomic alterations with a similar effect on gene expression profile.

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.

The literature reports low rates of breast conservation after neoadjuvant chemotherapy for operable breast cancers not amenable to initial breast-conserving surgery. This study aims to compare the outcome of lobular vs ductal carcinomas after neoadjuvant chemotherapy. Between 1989 and 1999, 750 patients with clinical stage II/IIIA ductal (672) or lobular (78) invasive breast carcinomas were treated at the Institut Curie with primary anthracycline-based polychemotherapy followed by either breast conservation (surgery and/or radiotherapy) or mastectomy. Median follow-up was 10 years. Clinical response to primary chemotherapy was significantly worse for lobular than for ductal carcinomas (47 vs 60%; P=0.04), but only histological grade remained predictive in multivariate analysis. Breast conservation was high for both ductal and lobular carcinomas (65 and 54%; P=0.07), due, in part, to the use of radiotherapy, either exclusive or preoperative, for respectively 26 and 40% of patients. The lobular type had no adverse effect, neither on locoregional control nor on overall survival, even in the group of patients treated with breast conservation.

Background: To distinguish new primary breast cancers from true recurrences, pangenomic analyses of DNA copy number alterations (CNAs) using single-nucleotide polymorphism arrays have proven useful., Methods: The pangenomic profiles of 22 pairs of primary breast carcinoma (ductal or lobular) and ipsilateral breast cancers from the same patients were analyzed. Hierarchical clustering was performed using CNAs and DNA breakpoint information. A partial identity score developed using DNA breakpoint information was used to quantify partial identities between two tumors. The nature of ipsilateral breast cancers (true recurrence vs new primary tumor) as defined using the clustering methods and the partial identity score was compared with that based on clinical characteristics. Metastasis-free survival was compared among patients with primary tumors and true recurrences as defined using the partial identity score and by clinical characteristics. All statistical tests were two-sided., Results: All methods agreed on the nature of ipsilateral breast cancers for 14 pairs of samples. For five pairs, the clinical definition disagreed with both clustering methods. For three pairs, the two clustering methods were discordant and the one using DNA breakpoints agreed with the clinical definition. The partial identity score confirmed the nature of ipsilateral breast cancers as defined by clustering of DNA breakpoints in 21 of 22 pairs. The difference in metastasis-free survival of patients with new primary tumors and those with true recurrences was not statistically significant when tumors were defined based on clinical and histologic characteristics (5-year metastasis-free survival: 76%, 95% confidence interval [CI] = 52% to 100% for new primary tumors and 38%, 95% CI = 17% to 83% for true recurrences; P = .18; new primary tumor vs true recurrence, hazard ratio = 2.8, 95% CI = 0.6 to 13.7), but the difference was statistically significant when tumors were defined using the partial identity score (5-year metastasis-free survival: 100% for new primary tumors and 29%, 95% CI = 11% to 78% for true recurrences; P = .01)., Conclusions: DNA breakpoint information more often agreed with the clinical determination than CNAs in this population. The partial identity score, which was calculated based on DNA breakpoints, allows statistical discrimination between new primary tumors and true recurrences that could outperform the clinical determination in terms of prognosis.

Breast cancer dissemination can be monitored in patients by detecting circulating and/or disseminated tumor cells. However, bone marrow disseminated tumor cells (BM DTC) may undergo a dormancy during several years before growing (or not) into clinically detectable metastases. We therefore hypothesized that breast cancers which have formed BM DTC in the course of their metastatic growth might exhibit a longer interval before metastatic relapse. We examined the association of DTC detection (cytokeratin 8, 18 or 19 positive epithelial cells with cancerous morphological features), at metastatic relapse, with the metastasis-free interval in breast cancer patients. In the 110 metastatic patients studied, 42% (n = 64/110) were classified as BM DTC-negative. These patients had a significantly shorter metastasis-free interval than BM DTC-positive patients (P = 0.02). In multivariate logistic regression analysis, the metastasis-free interval was an independent predictor of DTC detection (P = 0.02), together with bone metastasis (P = 0.0003) and low tumor grade (grade I or II, P = 0.05). We finally suggest that a faster metastatic process might skip in some patients the BM DTC-associated dormancy step. Dissemination of DTC in other host organ and/or epithelial-mesenchymal transition from cytokeratin-positive to cytokeratin-negative DTC may explain this observation.

Introduction: This study aimed to evaluate responses and outcome of hormone-therapy (HT) and radiotherapy (RT) given concurrently for large breast cancers in post-menopausal women., Material and Methods: Forty-two breast carcinomas in 41 women were treated with HT and concurrent RT to the breast +/- lymph node bearing areas. For 30 tumours this was followed by breast surgery (with axillary lymph node dissection when the axilla had not been irradiated). RT delivered a median dose to the tumour of 50 Gy (48-66) and 75 Gy (65-84) for, respectively, preoperative and exclusive RT-HT. Median follow-up was 64 months., Results: Out of 42 clinically assessable tumours (after a mean dose of 50 Gy), 9 tumours (21%) had complete clinical responses, 24 (57%) partial responses, 9 (21%) stable disease. Breast-conserving surgery or exclusive RT-HT was possible in 74% of tumours. For 29 patients who underwent breast surgery, the rate of pathological complete responses was 17%. At 50 Gy no skin toxicity higher than grade 2 occurred. Five year OS, RFS and local control were, respectively, 85%, 84% and 97%. Lymphoedema occurred in one patient., Conclusion: Concurrent association of RT-HT demonstrated good efficacy, both in terms of clinical and pathological complete responses. It allowed breast conservation with acceptable tolerance and good 5-year local control.

The characteristics of ipsilateral breast tumour recurrences (IBTRs) relative to those of their primary tumours (PTs) remain scarcely studied. Of 70 young (< or =40 years) premenopausal women with IBTRs, we studied a series of 63 with paired histological data. Median follow-up since IBTR was 10 years. Rates of histological types, grades or hormonal receptors were not significantly different in PTs and in IBTRs. The concordance between IBTRs and their PTs was good for histological types. IBTRs with conserved histological types tended to occur more locally, but not significantly sooner than others. These IBTRs had good concordance for hormone receptors. In discordant cases there were as many losses as appearances of the receptors. The concordance was weak for grades, with equivalent numbers of IBTRs graded lower as higher than their PTs. The 10-year overall survival rate was 70%. Neither the conservation of histological type, location, nor of the two combined were associated with deaths. Early (<2 years) IBTRs, tended to be associated with poorer survival (HR=2.24 (0.92-5.41); P=0.08). IBTRs did not display features of higher aggressiveness than PTs. Neither clinical nor histological definition of a true recurrence could be established other than the conservation of the histological type.

Purpose: To evaluate the accuracy of clinical examination and of three imaging modalities (ultrasound [US] scan, mammography, and magnetic resonance imaging [MRI]) to assess the tumor response of breast cancer to a preoperative regimen of concurrent radiochemotherapy for large breast cancers, using pathologic data as the reference., Methods and Materials: Sixty women were accrued. Treatment consisted of 4 cycles of (5-fluorouracil-vinorelbine) chemotherapy with, starting with the second cycle of chemotherapy, locoregional radiotherapy to the breast and the internal mammary and supraclavicular and infraclavicular lymph nodes. Breast surgery and axillary lymph node dissection were subsequently performed. Breast imaging assessments were performed both before chemotherapy and preoperatively., Results: The correlation coefficients between tumor dimension at imaging and pathology were statistically significant for US scan (r = 0.4; p = 0.006) and MRI (r = 0.4; p = 0.004) but not for clinical examination (r = 0.2; p = 0.16) or mammography (r = -0.15; p = 0.31). Furthermore, the area under the receiver operating characteristic curve for MRI was 0.81, compared with 0.67 for US scan. At the optimal threshold score, MRI performed with 81% sensitivity and 75% specificity., Conclusion: Compared with clinical examination, US scan, or mammography, MRI substantially improved the prediction of pathologic tumor response to preoperative concurrent radiochemotherapy for large breast cancers.

Background: Axillary lymph node dissection (ALND) for patients with positive sentinel lymph nodes (SLNs) is currently under discussion in the literature. The breast cancer nomogram (BCN), an online tool developed by the Memorial Sloan-Kettering Cancer Center (MSKCC), aims to predict the risk of positive non-SLN in SLN-positive patients. The purpose of this study was to test the accuracy of the nomogram on patients with macrometastatic and micrometastatic SLN-positive biopsy findings., Methods: Patient characteristics, tumor pathology, and positive SLN characteristics were collected on 588 consecutive patients who underwent completion ALND. The MSKCC BCN tool was used to calculate risk of metastases for all 588 cases that included a subgroup of the 213 patients with SLN micrometastases. The BCN was performed for positive SLN biopsy findings regardless of the method of metastasis detection. Evaluation of the BCN was performed by the area under the curve method., Results: The BCN applied to all 588 patients achieved an area under the receiver operating characteristic curve (ROC) of .724 (range, .677-.771) compared with .76 in the MSKCC study. When the tool was applied solely to micrometastases found by hematoxylin and eosin staining and metastases found by immunohistochemistry, the area under the ROC was .538 (range, .423-.653)., Conclusions: The MSKCC nomogram has been validated for all the patients having a metastatic SLN at the Institut Curie. However, this model was not reliably predictive for positive non-SLN in cases with micrometastic positive SLN.

Purpose: To establish a panel of human breast cancer (HBC) xenografts in immunodeficient mice suitable for pharmacologic preclinical assays., Experimental Design: 200 samples of HBCs were grafted into Swiss nude mice. Twenty-five transplantable xenografts were established (12.5%). Their characterization included histology, p53 status, genetic analysis by array comparative genomic hybridization, gene expression by Western blotting, and quantitative reverse transcription-PCR. Biological profiles of nine xenografts were compared with those of the corresponding patient's tumor. Chemosensitivities of 17 xenografts to a combination of Adriamycin and cyclophosphamide (AC), docetaxel, trastuzumab, and Degarelix were evaluated., Results: Almost all patient tumors established as xenografts displayed an aggressive phenotype, i.e., high-grade, triple-negative status. The histology of the xenografts recapitulated the features of the original tumors. Mutation of p53 and inactivation of Rb and PTEN proteins were found in 83%, 30%, and 42% of HBC xenografts, respectively. Two HBCx had an ERBB2 (HER2) amplification. Large variations were observed in the expression of HER family receptors and in genomic profiles. Genomic alterations were close to those of original samples in paired tumors. Three xenografts formed lung metastases. A total of 15 of the 17 HBCx (88%) responded to AC, and 8 (47%) responded to docetaxel. One ERBB2-amplified xenograft responded to trastuzumab, whereas the other did not. The drug response of HBC xenografts was concordant with that of the patient's tumor in five of seven analyzable cases., Conclusions: This panel of breast cancer xenografts includes 15 triple-negative, one ER positive and 2 ERBB2 positive. This panel represents a useful preclinical tool for testing new agents and protocols and for further exploration of the biological basis of drug responses.

Several recent papers have suggested the role of HRT in the development of breast cancers. From the data base of the Institut Curie we compared the clinical characteristics, histoprognosis factors and survival of a cohort of 6737 patients recorded between 1988 and 1999 in which 1482 declared having receive HRT for more than 6 months. Surgical procedure, locoregional recurrence, metastasis, disease free and global survival were compared bet the patient who received an HRT versus the patients who didn't receive this treatment Mammographic diagnosis was more frequent in the HRT group and the age at diagnosis was smaller (p < 10(-4)). Cancers diagnosed in the HRT group were smaller and had a more favourable biologic profile as well as there were more lobular carcinomas and the conservative treatment was more frequent (p < 10(-4)). Mean follow up was 97 months. Recurrence free survival was not different in the two groups but the metastasis free and global survival were better in the HRT group. HRT remained an independent prognostic factor in a multivariate analysis. In western countries the increasing incidence of breast cancer concerns pre as well as post menopausal women. HRT cannot be considered as the only responsible of this augmentation.

Phyllodes tumors are rare fibroepithelial tumors of the breast. The pathologic grading of phyllodes tumors based on the aspect of the stromal component, is divided into 2 or 3 grades according to the system used. To determine whether genetic markers could be of use for improving the classification of phyllodes tumors and to provide a better knowledge of the genetic alterations in these tumors, we analyzed chromosomal changes detected by comparative genomic hybridization (CGH) in comparison with histological data, in a series of 30 cases. Recurrent chromosome imbalances were observed in 55, 91 and 100% of benign, borderline and malignant phyllodes tumors, respectively. The mean number of chromosome changes was one in benign, six in borderline, and six in malignant phyllodes tumors. Most frequent genetic imbalances were +1q (12/30), -13q (7/30), -6q (9/30), +5 (9/30) and -10p (8/30). Gains of 1q, present in only one of nine benign tumors, were found in 11/21 (51%) borderline or malignant tumors. Losses of 13q have 13q14.2 as smallest region of overlap, suggesting that the RB1 gene could be the target of deletions. Amplifications of 12q14, involving the MDM2 locus, and of 8p24, involving the MYC gene, were observed in one case each. Borderline and malignant phyllodes tumors could not be differentiated on the basis of their genomic imbalances (presence and number of chromosomal changes, presence of 1q gain and/or 13q loss). Conversely, benign tumors could be significantly differentiated from the group composed of borderline and malignant tumors (P<0.01). This study reveals two distinct patterns of genomic imbalance in phyllodes tumors: benign, with none or a few chromosome changes and malignant, with numerous recurrent chromosomal changes, in particular 1q gain and 13q loss. Helpful additional pathological criteria for differentiating the two genetic groups of phyllodes tumors are the nuclear size and the mitotic rate.

Purpose: To ascertain the loco-regional recurrence (LRR) rate and its major prognostic factors in patients younger than 40 and to determine the influence of age on the features of breast cancer and its treatment in two age groups: 35 years and [36-39] years., Methods and Materials: Between 1985 and 1995, 209 premenopausal women, younger than 40, were treated for early breast cancers with primary breast conserving surgery followed by radiotherapy+/-chemotherapy. Median age was 37 years with 66 patients (32%) 35 years and 143 older (68%). Median follow-up was 12 years. Tumours' characteristics were: cT1 in 75%, pN0 in 60%., Results: LRR rate was 38% at 10 years, contralateral breast cancer rate 12%. Age was the only prognostic factor for LRR. The relative risk of LRR increased by 7% for every decreasing year of age. The annual risk of local recurrence peaked between 2 and 3 years after the initial diagnosis and returned to the level of contra-lateral breast cancer at 10 years. The younger population had infiltrating carcinomas that were significantly more commonly ductal, less commonly lobular, and of higher grade - they received chemotherapy more often., Conclusion: Using conventional methods we could find no explanation as to why age remained the most important prognostic factor for breast cancer LRR. Known prognostic factors such as involved surgical margins seemed erased by adequate radiotherapy doses.

Discrepancies have been reported between HER2 status in primary breast cancer and micrometastatic cells in bone marrow. The aim of this study was to assess HER2 gene status in micrometastatic cells in bone marrow and corresponding primary tumour. Micrometastatic cells were detected in bone marrow aspirations in a prospective series of 27 breast cancer patients by immunocytochemistry (pancytokeratin antibody). HER2 status of micrometastatic cells was assessed by fluorescence in situ hybridisation (FISH), respectively in 24 out of 27. Primary tumour HER2 status was assessed by immunohistochemistry (CB11 antibody) and by FISH in 20 out of 27 of the cases. HER2 was amplified or overexpressed in five out of 27 (18.5%) primary tumours and in four out of 27 (15%) micrometastatic cells. In two cases, HER2 was overexpressed and amplified in primary tumour, but not in micrometastatic cells, whereas, in one case, HER2 presented a low amplification rate (six copies) in micrometastatic cells not found in the primary tumour. We demonstrated that negative and positive HER2 status remained, in the majority of the cases, stable between the bone marrow micrometastasis and the primary tumour. Therefore, the efficiency of anti-HER2 adjuvant therapy could be evaluated, in a clinical trial, by sequential detection of HER2-positive micrometastatic cells within the bone marrow, before and after treatment.

Introduction: Typical medullary breast carcinoma (MBC) has recently been recognized to be part of the basal-like carcinoma spectrum, a feature in agreement with the high rate of TP53 mutations previously reported in MBCs. The present study was therefore designed to identify phenotypic and genetic alterations that distinguish MBCs from basal-like carcinomas (BLC)., Methods: Expression levels of estrogen receptor (ER), progesterone receptor (PR), ERBB2, TP53, cytokeratins (KRTs) 5/6, 14, 8/18, epidermal growth factor receptor and KIT, as well as TP53 gene sequence and high-density array comparative genomic hybridization (CGH) profiles, were assessed and compared in a series of 33 MBCs and 26 BLCs., Results: All tumors were negative for ER, PR and ERBB2. KRTs 5/6 were more frequently expressed in MBCs (94%) than in BLCs (56%) (p = 0.0004). TP53 mutations were disclosed in 20/26 MBCs (77%) and 20/24 BLCs (83%). Array CGH analysis showed that a higher number of gains (95 regions) and losses (34 regions) was observed in MBCs than in BLCs (36 regions of gain; 13 regions of losses). In addition, gains of 1q and 8q, and losses of X were found to be common to the two groups, whereas gains of 10p (53% of the cases), 9p (30.8% of the cases) and 16q (25.8% of the cases), and losses of 4p (34.8% of the cases), and amplicons of 1q, 8p, 10p and 12p were the genetic alterations found to characterize MBC., Conclusion: Our study has revealed that MBCs are part of the basal-like group and share common genomic alterations with BLCs, the most frequent being 1q and 8q gains and X losses; however, MBCs are a distinct entity within the basal-like spectrum, characterized by a higher rate of KRT 5/6 expression, a higher rate of gains and losses than BLCs, recurrent 10p, 9p and 16q gains, 4p losses, and 1q, 8p, 10p and 12p amplicons. Our results thus contribute to a better understanding of the heterogeneity in basal-like breast tumors and provide potential diagnostic tools.

This study evaluated, in terms of pathological complete response (pCR) and acute toxicity, preoperative concurrent (5-fluorouracil (5-FU)-vinorelbine) chemoradiotherapy for large breast cancers. A total of 60 women were included in the study. Chemotherapy consisted of 4 cycles of 5-FU, 500 mg/m2/d, continuous infusion (d1-d5) and vinorelbine, 25 mg/m2 (d1; d6). Starting with the second cycle, radiotherapy delivered 50 Gy to the breast and 46 Gy to the internal mammary and supra/infra-clavicular lymph nodes. Breast surgery and axillary lymph node dissection were then performed. Four patients did not complete their chemotherapy. Breast conservation was possible in 69% of patients. The rate of pCR was 27%. Three factors were associated with pCR: histological grade 3, absence of hormonal receptors and high mitotic index. Grade 4 haematological toxicity occurred in 22% of patients. In conclusion, chemoradiotherapy demonstrated good efficacy, both in terms of pCR and in allowing breast conservation with acceptable tolerance.

Unlabelled: In France, 20% of breast cancers occur in women over the age of 70 and 10% in women over the age of 80. As these women are not included in screening programs, breast cancer is often diagnosed later, at the stage of a large tumor., Purpose: To analyze clinical response, possibilities of conservative treatment and course of hormonal receptors in patients receiving neoadjuvant aromatase inhibitor (AI) therapy for at least 6 months., Patients and Methods: There were 75 patients, with a mean age of 75 +/- 8 years (range, 58-91 years) received AI for 6 months after the diagnosis of invasive breast cancer with positive hormonal receptors. Clinical and radiologic tumor reduction, the number of conservative treatments and the course of estrogens receptor-labeled cells were determined for each patient., Results: All but 1 of these patients obtained clinical reduction of their tumor. Of these, 86% patients received conservative treatment. In the majority of patients, estrogen receptor (ER) level did not vary between the initial assay and analysis of the operative specimen., Discussion and Conclusion: Aromatase inhibitors are effective as neoadjuvant therapy in ER positive elderly patients with large tumors, as is tamoxifen. Changes in hormone receptor expression during treatment do not predict clinical response. In our experience, neoadjuvant AI therapy should be administered for at least 6 months to optimize clinical response before deciding upon surgery. Discrepancy observed in the literature could be explained by the duration of the treatment.

Tumor infiltrating lymphocytes (TIL) display activation markers and their presence is often associated with a favorable outcome. The role of tumor antigens in T cell recruitment into tumors is unclear. In an attempt to address this issue, we purified lymphocytes from breast tumor or nontumor, mammary tissue from patients, and normal mammary tissue from healthy individuals. In all groups, including healthy individuals, the majority of cells displayed an effector/memory (CD45RA(lo)/CD27(+/-)) phenotype and quite surprisingly the early and transient activation marker CD69, thus, questioning the tumor antigen specificity of TIL. Because the human repertoire is diverse, the T cells found in the tumors could recognize both self/tumor and environmental antigens through cross-reactivity. To test this hypothesis, we used two anti-male HY monospecific TCR transgenic mouse models. We found an infiltration of HY negative tumors by the CD4(+) and CD8(+) monoclonal T cells after priming with HY positive cells in the periphery. Thus, the presence of activated effector/memory T lymphocytes in tumors can be independent of reactivity against tumor antigens. These results suggest that to find activated effector T cells in a tissue does not always mean that a specific immune response is taking place., ((c) 2005 Wiley-Liss, Inc.)

Recent biological studies have classified breast carcinomas into HER2-overexpressing, estrogen receptor-positive/luminal, basal- and normal-like groups. According to this new biological classification, the objectives of our study were to assess the clinical, morphologic and immunophenotypic characteristics of adenoid cystic carcinoma of the breast in order to classify this subtype of breast carcinoma. A total of 18 cases of adenoid cystic carcinoma were identified from the Institut Curie files. Clinical information was available for 16 patients with a median follow-up of 6.5 years. Morphologically, all tumors were graded according to the system defined by Kleer and Oberman (histologic and nuclear grade). Immunophenotype was assessed with anti-ER, PR, HER-2, KIT, basal (CK5/6) and luminal cytokeratins (CK8/18) and p63 antibodies. One out of 18 tumors was nuclear grade 1 (16%), nine were nuclear grade 2 (50%) and eight were nuclear grade 3 (44%). All cases were estrogen receptor, progesterone receptor and HER-2 negative. Epithelial cells were strongly positive around glandular lumina with one or both cytokeratins, identifying the coexistence of CK5/6+ cells, CK5/6 and CK8/18+ cells, CK8/18+ cells and p63+ cells. All cases (100%) were also KIT positive. In all, 15 patients were treated by surgery. Nine of them received adjuvant radiotherapy. Follow-up was available for 16 patients. In all, 14 patients were alive. Two of them, initially treated by surgery only, presented a local recurrence. Two patients died (one of them treated by radiation therapy only died from her disease). Our study shows that adenoid cystic carcinoma of the breast is a special, estrogen receptor, progesterone receptor, HER-2 negative and highly KIT-positive, basal-like breast carcinoma, associated with an excellent prognosis. This highly specific immunophenotype could be useful to differentiate adenoid cystic carcinoma of the breast from other subtypes of breast carcinoma such as cribriform carcinoma.

BRCA1 and BRCA2 germline mutations are associated with a strong risk of breast cancer, which may preclude breast-conserving treatment in carriers. This study examined whether mutation status influenced the rate of breast cancer recurrence following breast-conserving treatment. BRCA1 and BRCA2 genes were screened for germline mutations in 131 patients with a family history of breast and/or ovarian cancer, who had been treated with breast-conserving surgery and radiotherapy. The 131 patients with familial history were matched to 261 patients without, according to age at diagnosis and year of treatment. The follow-up of controls was at least equal to the time-interval between diagnosis and genetic testing in familial cases. Matched cohorts were compared according to rates of breast cancer recurrence as first event and contralateral breast cancer using log-rank tests. BRCA1/2 mutations were found in 20.6% patients with a family history. Nineteen patients had a BRCA1 mutation and 8 had a BRCA2 mutation. Breast cancers in mutation carriers were more often grade III (p<10-4) and oestrogen receptor negative (p=0.005) than tumours in both non-carriers and controls. Median follow-up for all 392 patients was 8.75 years. No significant differences in breast cancer recurrence as first event were seen between BRCA1/2 tumours and controls (p=0.47), carriers and non-carriers with a family history (p=0.96), or non-carriers and controls (p=0.10). On multivariate analysis, age was the most important factor significantly predicting for breast cancer recurrence. The rate of contralateral breast cancer was significantly increased in all patients with a family history: BRCA1/2 carriers versus controls (p=0.0003), non-carriers versus controls (p=0.0034) and carriers versus non-carriers (p=0.02). At a 9-year median follow-up, the rate of ipsilateral breast cancer recurrence was not higher in BRCA1 and BRCA2 mutation carriers than in non-carriers with a family history or sporadic cases. These results support the hypothesis that breast tumours in BRCA carriers are more sensitive to radiation. Therefore, breast-conserving treatment can be offered to these patients. However, longer follow-up is needed to ensure that the rate of new primary cancer in the treated breast does not increase in the long-term.

Benign breast diseases have always been neglected in comparison to cancer, despite the fact that there are many more patients with such diseases than patients presenting to a breast clinic for cancer. Like normal breast tissues, benign breast diseases are under a complex system of controls by both systemic hormonal and local factors. In this review, we attempt to present an overview of the latest knowledge concerning the epidemiology, classification, clinical presentation, management, and physiopathology of these disorders.

Context: Localized breast lesions have been described in lupic or diabetic patients. However, the description of breast gigantomastia in women presenting with autoimmune diseases has not been reported., Setting: The study took place within the Department of Endocrinology and Reproductive Medicine, Necker Hospital, Paris, France., Patients: We describe eight patients with inflammatory gigantomastia, occurring in a context of immune-mediated diseases: myasthenia, chronic arthritis, or thyroiditis., Main Outcome Measures: Together with hormonal, immunological, and breast magnetic resonance imaging (MRI) evaluation, breast histology enabled us to perform immunocytochemical and indirect immunofluorescence studies. Control sera were obtained from patients with (n = 10) and without (n = 7) antinuclear antibodies., Results: Six of the eight patients developed gigantomastia either at puberty or during pregnancy. Neither a hormonal oversecretion nor a specific immunological pattern was observed. All patients except one presented antinuclear antibodies. Histological study revealed a diffuse, stromal hyperplasia and a severe atrophy of the lobules. A rarefaction of adipocytes was also noted, as previously suggested on MRI. There was a perilobular lymphocytic infiltrate made of CD3+ lymphocytes. Study of sera from five of six cases of gigantomastia showed a nuclear immunofluorescence pattern in normal mammary ductal and lobular glandular epithelium, as well as in kidney and intestine epithelial cells. In control sera, a nuclear signal was observed only when antinuclear antibodies were present., Conclusions: We suggest that breast tissue may be a target tissue in autoimmune diseases, this process being favored by the hormonal milieu. However, the precise mechanism of such association is not individualized. The fact that stromal hyperplasia is the main histological feature justifies the search for the involvement of growth factors in such a process.

In a previous study that used comparative genomic hybridization (CGH) to analyze 43 ductal breast carcinomas selected for hyperdiploidy, we proposed the existence of two distinct pathways of chromosomal evolution. In the present study, in which we reassessed our cytogenetic findings on 158 ductal breast carcinomas selected for having a modal number of chromosomes of fewer than 60, we confirmed the existence of two subtypes of tumors. Along with the great majority of tumors (142 of 158) that evolved through structural rearrangements with no or very few whole-chromosome gains, we found that a minor subset (16 of 158) evolved through progressive gains of whole chromosomes with no or only a few associated rearrangements. In this article, we describe the karyotypes of these 16 tumors together with data from CGH, which was performed for 10 of them. Chromosomes 5, 7, 8, and 20 were the most frequently gained. Our findings support the evidence of a new pathway of chromosomal evolution in a small subset of ductal breast carcinomas characterized by numerical chromosome aberrations., (Copyright 2005 Wiley-Liss, Inc.)

Completion of the working draft of the human genome has made it possible to analyze the expression of genes according to their position on the chromosomes. Here, we used a transcriptome data analysis approach involving for each gene the calculation of the correlation between its expression profile and those of its neighbors. We used the U133 Affymetrix transcriptome data set for a series of 130 invasive ductal breast carcinomas to construct chromosomal maps of gene expression correlation (transcriptome correlation map). This highlighted nonrandom clusters of genes along the genome with correlated expression in tumors. Some of the gene clusters identified by this method probably arose because of genetic alterations, as most of the chromosomes with the highest percentage of correlated genes (1q, 8p, 8q, 16p, 16q, 17q, and 20q) were also the most frequent sites of genomic alterations in breast cancer. Our analysis showed that several known breast tumor amplicons (at 8p11-p12, 11q13, and 17q12) are located within clusters of genes with correlated expression. Using hierarchical clustering on samples and a Treeview representation of whole chromosome arms, we observed a higher-order organization of correlated genes, sometimes involving very large chromosomal domains that could extend to a whole chromosome arm. Transcription correlation maps are a new way of visualizing transcriptome data. They will help to identify new genes involved in tumor progression and new mechanisms of gene regulation in tumors.

Background: We defined the indications for and evaluated the results of a new technique for radioguided surgery, the SiteSelect system. The procedure allows en-bloc resection of the breast parenchyma under local anesthesia., Methods: This prospective study was based on 167 patients operated on between December 2000 and October 2003 with 2 phases. The first step was an evaluation of the feasibility of the procedure with the 15-mm cannula, and the second was therapeutic with the 22-mm cannula., Results: The mean duration of the procedure was 42 minutes. In 96.9% of procedures, the lesion was excised successfully. Only one complication (hematoma) and two failures and were observed. Histological examination revealed benign disease in 65.8% of cases and cancer in 34.2% of cases. In the latter cases, the specimen margins were histologically involved in 86.2% of cases with the 15-mm procedure and in 41% with the 22-mm procedure. During the first evaluation, all patients with a cancer underwent systematic surgical re-excision: residual tumor was present in 18 cases (64.2%). The biopsy was painless for 88 patients, and the cosmetic result was good in all cases., Conclusions: This study shows that the SiteSelect procedure allows resection of the lesion in 96.9% of cases. Combined with complementary surgical lumpectomy during the same operation, this procedure achieved a success rate of 98.7%. In the case of cancer, the 15-mm cannula is not wide enough to allow free margins. The use of a new 22-mm cannula, currently under evaluation, might solve this problem.

The " Standards, Options and Recommendations " (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centres (FNCLCC), the 20 French cancer centres, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. Objectives : To update the Standards, Options and Recommendations clinical practice guidelines for the management of ductal carcinoma in situ of the breast (DCIS). Methods : The working group identified the questions requiring up-dating from the previous guideline. Medline(r) and Embase(r) were searched using specific search strategies from year 1996 to year 2003. In addition several Internet sites were searched in October 2002. Results : Clinical guidelines have been defined for the management of diagnosis, treatment, follow-up, and treatment of recurrence of DCIS. The issue of hormone replacement therapy has also been addressed in the context of DCIS.

Estrogen is the main hormone involved in the development and growth of hormone-dependent breast cancer. Endocrine adjuvant treatment in recent years focused primarily on the use of SERMs, mainly tamoxifen. Tamoxifen actions are complex. It acts by competitive antagonism of estrogen at its receptor site. It has beneficial agonistic effects in preventing bone demineralization in postmenopausal women, but a detrimental agonistic effect by increasing the risk of uterine cancer and of thrombo-embolism. However, the situation is changing rapidly with the introduction of recent aromatase inhibitors, which display high specificity towards aromatase. They suppress plasma estrogen levels in postmenopausal women by inhibiting or inactivating aromatase, the enzyme responsible of the synthesis of estrogens from androgenic substrates. A complete estrogen deprivation in target tissues may eventually induce osteoporosis. Unlike tamoxifen, aromatase inhibitors have no partial agonistic action. During the last 20 years, adjuvant tamoxifen treatment for 5 years was the "gold standard" endocrine treatment in postmenopausal women with hormone-receptor-positive breast cancers. A 25% reduction risk of deaths was observed. Recently, the results of clinical trials comparing aromatase inhibitors to tamoxifen in post menopausal women with hormone-dependent breast cancer showed a benefit in favor of aromatase inhibitors in reducing the risk of recurrence. These trials were either comparative (for anastrozole) or sequential (for anastrozole, letrozole and exemestane). The issues of long term adverse effects (bone) and hormone treatment sequence remain to be addressed.