[First results of a breast cancer risk assessment and management consultation]. / Consultation personnalisée d'évaluation du risque de cancer du sein : premiers résultats.

INTRODUCTION: In France, participation in the organized breast cancer screening program remains insufficient. A personalized approach adapted to the risk factors for breast cancer (RBC) should make screening more efficient. A RBC evaluation consultation would therefore make it possible to personalize this screening. Here we report our initial experience. MATERIAL AND METHOD: This is a prospective study on women who were seen at the RBC evaluation consultation and analyzing: their profile, their risk assessed according to Tyrer Cuzick model (TC)±Mammorisk© (MMR), the existence of an indication of oncogenetic consultation (Eisinger and Manchester score), their satisfaction and the recommended monitoring. RESULTS: Among the women who had had a TCS and/or MMR evaluation of SCR (n=153), 76 (50%) had a high risk (n=67) or a very high risk (n=9). Almost half (47%) had a possible (15%) or certain (32%) indication to an oncogenetic consultation. Regarding this consultation, 98% of women were satisfied or very satisfied. In total, 60% of women had a change in screening methods. CONCLUSION: This RBC evaluation consultation satisfies women and for a majority of them, modifies their methods of breast cancer screening.

B-type natriuretic peptide measurement for early diagnosis of acute pulmonary edema during pregnancy.

Calcium-channel blockers administered to pregnant women as tocolytic agents can cause acute pulmonary edema. The first signs of this severe complication can be atypical and so delay introduction of appropriate therapy. We describe three cases in whom B-type natriuretic peptide measurements proved to be relevant in early diagnosis and monitoring of pregnant women with acute pulmonary edema. B-type natriuretic peptide measurement in this setting could contribute to timely diagnosis and improve follow-up.

Prognostic value of isolated tumor cells and micrometastases of lymph nodes in early-stage breast cancer: a French sentinel node multicenter cohort study.

To define the prognostic value of isolated tumor cells (ITC), micrometastases (pN1mi) and macrometastases in early stage breast cancer (ESBC). We conducted a retrospective multicenter cohort study at 13 French sites. All the eligible patients who underwent SLNB from January 1999 to December 2008 were identified, and appropriate data were extracted from medical records and analyzed. Among 8001 patients, including 70% node-negative (n = 5588), 4% ITC (n = 305), 10% pN1mi (n = 794) and 16% macrometastases (n = 1314) with a median follow-up of 61.3 months, overall survival (OS) and recurrence-free survival (RFS) rates at 84 months were not statistically different in ITC or pN1mi compared to tumor-free nodes. Axillary recurrence (AR) was significantly more frequent in ITC (1.7%) and pN1mi (1.5%) compared to negative nodes (0.6%). Survival and AR rates of single macrometastases were not different from those of ITC or pN1mi. In case of 2 macrometastases or more, survival rates decreased and recurrence rates increased significantly. Micrometastases and ITC do not have a negative prognostic value. Single macrometastases might have an intermediate prognostic value while 2 macrometastases or more are associated with poorer prognosis.

Impact of immunohistochemical analysis of sentinel lymph node biopsy on breast cancer management.

BACKGROUND: Little evidence of the impact of immunohistochemical analysis (IHC) on the indications for adjuvant therapies is available. This study determined the modification rate of adjuvant chemotherapy and lymph node area radiotherapy using IHC and its impact on survival. PATIENTS AND METHODS: Between 2001 and 2005, 416 patients underwent surgery for invasive breast cancer with sentinel lymph node (SLN) biopsy. RESULTS: A total of 112 patients had positive SLNs: 12.5% isolated tumor cells, 35.7% micrometastasis and 51.8% macrometastasis. Only 4% of patients (14 out of 342 patients) had modified indications for chemotherapy and 7% of patients (25 out of 342) for lymph node area radiotherapy due to IHC findings. CONCLUSION: IHC analysis led to modifications in adjuvant chemotherapy and lymph node area radiotherapy in 4% and 7% of patients, respectively. The prognosis of patients with nodal metastasis discovered by ultrastaging was similar to that for conventional Haematoxylin-Eosin-Safran (HES) staining. Our data support the use of SLN ultrastaging.

Can the centrosome be a marker for DNA ploidy in breast cancer?

BACKGROUND: The role of DNA ploidy in genomic instability of cancer cells and prognosis has been described in a number of studies. The role of the centrosome in cell cycle has also been reported. AIM: In this study, we aimed to investigate the correlation between the centrosome and DNA ploidy in breast cancer in a search for a cytologic predictive and prognostic marker. MATERIALS AND METHODS: Cell prints were prepared from cell culture of mesothelial cells, fibroblast cell line MRC5 and breast cancer cell lines MCF7 and T47D. Indirect immunofluorescence was used with anti-γ-tubulin and centrosomes were quantified using a fluorescence microscope. DNA ploidy was scored with the DNA index analyzed by flow cytometry. RESULTS: The normal mesothelial cells (94% of the cells with one detected centrosome) and MRC5 diploid cells (68% with two centrosomes) were used as quality controls. A correlation between the number of centrosomes and DNA ploidy was found in MCF7 cell lines (64% of the cells with a number of centrosomes ≥ 3). It was not observed in invasive breast cancer samples; however, the frequency of cells with centrosomes ≥ 3 was found to be slightly higher in DNA aneuploid samples than in DNA diploid samples (15% vs 13.3%). CONCLUSION: Quantification of centrosome appears to be correlated to DNA ploidy in breast cancer cell lines and slightly associated to DNA aneuploidy in invasive breast cancer. Studies analyzing a larger number of samples as well as morphological abnormalities of the centrosome are needed.

Antibacterial-coated suture in reducing surgical site infection in breast surgery: a prospective study.

Background. To reduce the incidence of microbial colonization of suture material, Triclosan- (TC-)coated suture materials have been developed. The aim of this study was to assess the incidence of suture-related complications (SRC) in breast surgery with and without the use of TC-coated sutures. Methods. We performed a study on two consecutive periods: 92 patients underwent breast surgery with conventional sutures (Group 1) and 98 with TC-coated sutures (Group 2). We performed subgroups analyses and developed a model to predict SRC in Group 1 and tested its clinical efficacy in Group 2 using a nomogram-based approach. Results. The SRC rates were 13% in Group 1 and 8% in Group 2. We found that some subgroups may benefit from TC-coated sutures. The discrimination obtained from a logistic regression model developed in Group 1 and based on multifocality, age and axillary lymphadenectomy was 0.88 (95% CI 0.77-0.95) (P < 10(-4)). There was a significant difference in Group 2 between predicted probabilities and observed percentages (P < 10(-5)). The predicted and observed proportions of complications in the high-risk group were 38% and 13%, respectively. Conclusion. This study used individual predictions of SRC and showed that using TC-coated suture may prevent SRC. This was particularly significant in high-risk patients.

Predictive factors for complete excision and underestimation of one-pass en bloc excision of non-palpable breast lesions with the Intact(®) breast lesion excision system.

OBJECTIVE: Image-guided percutaneous biopsy is the recommended initial diagnostic procedure for suspicious mammographic lesions. This study was conducted to determine the accuracy of the Intact(®) breast lesion excision system (BLES) and to identify predictive factors for complete excision and underestimation. MATERIAL AND METHODS: A prospective study was conducted between January 28, 2008 and April 30, 2009 on 166 biopsy procedures using Intact(®) biopsy device. Diagnoses obtained from biopsy specimen were compared with to final diagnosis on surgical excision specimen. RESULTS: Of the 166 patients, 15 (9%) displayed lesions with cell atypia, 28 (17%) had an intra ductal carcinoma (IDC) and 9 (5%) had an invasive carcinoma. Eight of 15 patients with cell atypia had open surgical excision, and none showed underestimation. All patients with IDC underwent surgical excision: we found an invasive carcinoma in 6 cases (21.4% underestimation) and a complete removal of the lesion by the Intact(®) BLES in 11 cases (39%). All 9 patients with invasive carcinoma had a surgical excision, with 1 complete removal of the lesion by Intact(®) BLES. Multivariate analyses did not identify predictive factors for underestimation; clear margins ≥1mm on biopsy specimen was the only independent predictive factor of complete excision (OR=8.51, p=0.02). CONCLUSIONS: Intact(®) BLES provides a safe alternative to vacuum assisted core needle biopsy (VACNB) with an underestimation rate comparable to those previously reported for VACNB. The high rate of complete removal of the lesions, particularly ISC, offers an interesting perspective of avoiding subsequent excisional surgery for small lesions and thus requires further confirmational study.

A plea for the biopsy marker: how, why and why not clipping after breast biopsy?

In the last decade, percutaneous breast biopsies have become a standard for the management of breast diseases. Biopsy clips allow for precise lesion localization, thus minimizing the volume of breast to be resected at the time of surgery. With the development of many imaging techniques (including mammography, sonography, and breast magnetic resonance imaging), one of the challenges of the multidisciplinary became to synthesize all informations obtained from the various imaging procedures. The use of biopsy markers after percutaneous biopsy is one of the keys for optimal patient management, helping the radiologist to deal with multiple lesions, to insure correlation across different imaging modalities and to follow-up benign lesions, helping the oncologist by marking a tumor prior to neoadjuvant chemotherapy, helping the surgeon by facilitating preoperative needle localization, to precisely mark the margins of extensive disease and to guide intraoperative tumor resection, and helping the pathologist to insure the lesion of interest has been removed and to identify the region of interest in a mastectomy specimen. We believe biopsy clip markers should be deployed after all percutaneous interventions and present in this review the arguments to support this statement. Minimal indications for clip deployment will also be detailed.

Comparison of two nomograms to predict pathologic complete responses to neoadjuvant chemotherapy for breast cancer: evidence that HER2-positive tumors need specific predictors.

The aim of this study is to compare two published nomograms, the "Institut Gustave Roussy/M.D. Anderson Cancer Center" (IGR/MDACC) and the Colleoni nomograms, in predicting pathologic complete responses (pCR) to preoperative chemotherapy in an independent cohort and to assess the impact of HER2 status. Data from 200 patients with breast carcinoma treated with preoperative chemotherapy were collected. We calculated pCR rate predictions with the two nomograms and compared the predictions with the outcomes. Sixty percent of the patients with HER2-positive tumors received trastuzumab concomitantly with taxanes. Model performances were quantified with respect to discrimination and calibration. In the whole population, the area under the ROC curve (AUC) for the IGR/MDACC nomogram and the Colleoni nomogram were 0.74 and 0.75, respectively. Both of them underestimated the pCR rate (P = 0.026 and 0.0005). When patients treated with trastuzumab were excluded, the AUC were excellent: 0.78 for both nomograms with no significant difference between the predicted and the observed pCR (P = 0.14 and 0.15). When the specific population treated with trastuzumab preoperatively was analyzed, the AUC for the IGR/MDACC nomogram and the Colleoni nomogram were poor, 0.52 and 0.53, respectively. The IGR/MDACC and the Colleoni nomograms were accurate in predicting the probability of pCR after preoperative chemotherapy in the HER2-negative population but did not correctly predict pCR in the HER2-positive patients who received trastuzumab. This suggests that responses to preoperative chemotherapy, including trastuzumab, are biologically driven and that a specific nomogram or predictor for HER2-positive patients has to be developed.

Expression of MMP-2, -7, -9, MT1-MMP and TIMP-1 and -2 has no prognostic relevance in patients with advanced epithelial ovarian cancer.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in tumor invasion, but their prognostic significance is still under discussion. We set out to analyze the epithelial and stromal expression of MMP-2, MMP-7, MMP-9, MT1-MMP, TIMP-1 and TIMP-2 in advanced epithelial ovarian cancers and to assess their prognostic value. A tissue microarray of malignant ovarian tumors from 69 patients was constructed. Immunostaining results were scored using the HSCORE and assessed by univariate analysis with Bonferroni correction and classical multidimensional scaling (CMDS). Kaplan-Meier survival curves calculated with regard to patient and tumor characteristics were compared by the log-rank test. Patients treated by primary surgery (n=43) had a higher tumor size and a trend toward higher epithelial MMP and TIMP expression than those treated by interval surgery (n=26). Optimal cytoreduction (residue ≤ 1 cm) was obtained in 27 and 18 patients, respectively. Clinical and histological characteristics were not different in patients with optimal cytoreduction and those with suboptimal cytoreduction. The expression of epithelial MMP-9 (P=0.002) and TIMP-2 (P=0.026) were higher in the latter group. CMDS failed to demonstrate any influence of MMP and TIMP expression with regard to cytoreduction outcome. MMP and TIMP expression did not influence survival. Their prognostic values were outweighed by histological type, lymph node involvement and cytoreduction. Standard statistical analysis adjusted after Bonferroni correction and CMDS reduced the relevance of MMPs and TIMPs in the prognosis of patients with advanced ovarian cancer.

The usefulness of a preoperative compact imager, a hand-held gamma-camera for breast cancer sentinel node biopsy: final results of a prospective double-blind, clinical study.

UNLABELLED: The aim of this study was to compare the effectiveness of a hand-held preoperative compact imager (POCI) camera with conventional lymphoscintigraphy using a γ-camera for sentinel lymph node (SLN) detection in breast cancer. METHODS: The main objective was to demonstrate the noninferiority of the POCI relative to conventional lymphoscintigraphy and to compare the number of SLNs detected by the 2 imaging devices. Our study, a clinical prospective, double-blind, noninferiority study, planned to include 200 patients with early breast cancer and started in January 2006. A standard SLN protocol (4 periareolar injections of 37 MBq of (99m)Tc-nanocolloids, 2 h before lymphoscintigraphy) was performed preoperatively using a conventional γ-camera and then the POCI camera. Scans were obtained by 2 different nuclear medicine physicians unaware of each other's results. The day after, in the operating room, the surgeon, after receiving the previous results, used the counting probe for surgical SLN biopsy. The number and localization of axillary SLNs obtained by lymphoscintigraphy and the POCI and the duration of the whole procedure were determined. RESULTS: Among the 162 patients included, 138 were evaluable. The POCI detected more SLNs than did lymphoscintigraphy in 50 patients (36%), the same number of in 54 patients (39%), and fewer SLNs in 34 patients (25%), representing 84 (61%) discordant pairs. The noninferiority of preoperative compact imaging of axillary SLNs numbers was found to be statistically significant (95% confidence interval, 30%-52%, P = 0.025) using the McNemar test. The duration of acquisition was shorter using the POCI (<10 min in 84% [n = 117] of patients; mean, 7.5 ± 3.3 min) than lymphoscintigraphy (13% [n = 18] of patients; mean, 15.7 ± 3.4 min), with P < 0.001 using the McNemar test for paired proportions. CONCLUSION: Preoperative compact imaging using a hand-held camera was able to predict the number and localization of breast cancer SLNs and was not inferior to conventional lymphoscintigraphy in this study. Further studies will determine whether preoperative compact imaging could replace lymphoscintigraphy, especially in surgical centers without an on-site nuclear medicine department.

Nonmasslike enhancement at breast MR imaging: the added value of mammography and US for lesion categorization.

PURPOSE: To determine the value of adding conventional imaging (mammography and ultrasonography [US]) to nonmasslike enhancement (NMLE) analysis with breast magnetic resonance (MR) imaging for predicting malignancy and for building an interpretation model incorporating all imaging modalities. MATERIALS AND METHODS: The institutional ethics committees approved the study and granted a waiver of informed consent. In 115 women (mean age, 48.3 years; range, 21-76 years; 56 malignant, 12 high-risk, and 63 benign lesions), 131 NMLE lesions were analyzed. Two independent readers first classified MR images by using descriptive Breast Imaging Reporting and Data System (BI-RADS) criteria (BI-RADS classification with MR images alone [BI-RADS(MR)]) and later repeated this classification, adding information from conventional imaging (BI-RADS classification with combination of MR images and conventional images [BI-RADS(MR+Con)]). Lesion diagnosis was established with surgical histopathologic findings (n = 68), percutaneous biopsy results (n = 25), or 2 years of stability at MR imaging (n = 38). Receiver operating characteristic curves were built to compare BI-RADS(MR) with BI-RADS(MR+Con). A multivariate interpretation model was constructed and validated in a distinct cohort of 44 women. RESULTS: Values for inter- and intraobserver agreement, respectively, were better for BI-RADS(MR+Con) (κ = 0.847 and 0.937) than for BI-RADS(MR) (κ = 0.748 and 0.861). For both readers, the areas under the receiver operating characteristic curve (AUCs) for diagnosis of malignancy were also superior when BI-RADS(MR+Con) (AUC = 0.91 [reader 1] and 0.93 [reader 2]) was compared with BI-RADS(MR) (AUC = 0.84 [reader 1] and 0.87 [reader 2]) (P < .05). An interpretation model combining conventional imaging with MR imaging criteria showed very good discrimination (AUC = 0.89 [training set] and 0.90 [validating set]). CONCLUSION: Adding conventional imaging to NMLE lesion characterization at breast MR imaging improved the diagnostic performance of radiologists, and the interpretation model used offers good accuracy with the potential to optimize the reproducibility of NMLE analysis at MR imaging.

The molecular subtype classification is a determinant of sentinel node positivity in early breast carcinoma.

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.

[Are centrosomal abnormalities correlated to DNA ploidy in breast cancer?]. / Corrélation entre les anomalies centrosomiques et l'ADN-ploïdie dans le cancer du sein.

ADN ploidy was shown to play a role in genomic instability of cancer cells and prognosis. The implication of the centrosome in the cell cycle was also described. Therefore, new prognostic factors could be suggested for a better-tailored therapy. The purpose of this study is to search for correlation between centrosomal abnormality and ADN ploidy in breast cancer. Cell prints were prepared from cell culture of mesothelial ascitis, fibroblast cell line MRC5 and breast cancer cell lines MCF7 and T47D. Fresh cell prints were also obtained from cases with invasive carcinoma. The centrosome was labelled by an indirect immunofluorescence assay using anti-γ-tubulin antibody and F(ab')(2) FITC before quantification with fluorescence microscopy. ADN ploidy was scored with DNA index obtained by means of flux cytometry. The normal mesothelial cells (94% of cells with only one centrosome) and the diploid cell line MRC5 (68% of cells with two centrosomes) were used as controls. DNA ploidy was found to be correlated with centrosomal abnormality in MCF7 cell line (64% of cells had more than three centrosomes) but not in the 10 cases of invasive ductal carcinoma analysed in this study. The absence of correlation between DNA ploidy and centrosomal abnormality in breast cancer samples may be due to the small numbers of cases, the cell prints or tumorigenesis. Correlation analysis of a larger number of cases and types of breast lesions to numerical and morphological abnormalities of the centrosome are ongoing.

Discordance with local guidelines for adjuvant chemotherapy in breast cancer: reasons and effect on survival.

INTRODUCTION: Adjuvant treatments are usually decided according to guidelines. However, many individual factors, such as performance status, patient refusal, complex interactions between factors (eg, discrepancies between grade and Ki 67), and complex clinical features (borderline age or tumor size) may introduce discrepancies. The aim of this study was to quantify discrepancies between local guidelines and patient management. PATIENTS AND METHODS: From 2003 and 2005, 581 consecutive patients underwent surgery for invasive breast cancer. Patient, tumor characteristics, and outcome were recorded. We compared patient characteristics according to whether local guidelines had been followed. RESULTS: In 90% of cases local guidelines were followed. Patients who inadequately did not receive chemotherapy were older (P < .0001), with positive hormonal receptor status (P = .02), and less aggressive tumors (P < .05). Main reasons for not administering chemotherapy were age, patient refusal, and micrometastatic node involvement. Patients from the other discordant group (ie, those who inadequately received chemotherapy), had larger (P = .01) and more aggressive tumors (P < .0001). In these cases, the clinical decision was mainly based on multifocal tumors and limit lower age. For disease-free survival (DFS), we found a significant difference between groups (P = .001). The best overall survival and DFS was found for patients who adequately received no adjuvant treatment. Survival among groups were similar when stratified on treatment modality. CONCLUSION: The main reasons for discrepancy were age (advanced or lower limit), patient refusal, and multifocal tumors. In this series, deviations from recommendations had no affect on survival and raised the question of new indications for chemotherapy such as multifocal tumors.

Distinct p53 gene signatures are needed to predict prognosis and response to chemotherapy in ER-positive and ER-negative breast cancers.

PURPOSE: Estrogen receptor-positive (ER+) and -negative (ER) breast cancers are molecularly distinct diseases. We hypothesized that p53 mutations may lead to different transcriptional changes and carry different prognostic value in these two different types of cancers. EXPERIMENTAL DESIGN: We developed a 39-gene p53 signature derived from 213 ER+ and a separate 30-gene signature from 38 ER- cancers with known mutation status and tested their prognostic and chemotherapy response predictive values in ER+ and ER- cancers, respectively. RESULTS: External validation to predict p53 status (n = 103) showed sensitivity and specificity of 89% and 54% for the 39-gene signature, and 82% and 61% for the 30-gene signature. The 39-gene signature was predictive of worse distant metastasis free survival in ER+ cancers in two separate prognostic data sets (n = 255, HR: 2.3, P = 0.005 and n = 198, HR: 2.17, P = 0.09). It also predicted for poor prognosis even with adjuvant tamoxifen therapy (n = 277, HR = 2.43, P < 0.0001) but it was not prognostic in ER- cancers. It was also associated with higher chemotherapy sensitivity in ER+ but not in ER- cancers. The prognostic and predictive values remained significant in multivariate analysis. The 30-gene, ER-, p53 signature showed no prognostic or predictive values in ER+ cancers but it was associated with better prognosis in ER- cancers. It also had no chemotherapy response predictive value in ER- or ER+ cancers. CONCLUSIONS: P53 dysfunction is prognostically most relevant in ER+ cancers and supports the hypothesis that different predictive or prognostic markers will be needed for different molecular subsets of breast cancer.

Anaphylactic response to blue dye during sentinel lymph node biopsy.

The sentinel lymph node (SLN) procedure is now used routinely for the staging of clinically node-negative patients with early breast cancer. Two identification techniques exist: colorimetric and isotopic. These can be used alone or in combination. The combined method is associated with an increased identification rate. However, allergic and adverse reactions to blue dyes have been reported. The objective of this review was to determine the incidence of such events and to discuss alternative approaches. The authors conducted a search of the MEDLINE and EMBASE databases for reports of anaphylactic responses to isosulfan blue dye and patent blue V dye. Allergic reaction to the dyes isosulfan blue and patent blue V is rare and the reported incidence varies between 0.07% and 2.7%. Methylene blue dye appears to be safer, with no cases of allergic events having been reported. However, allergy tests in some patients have proven that there is cross-reactivity between isosulfan blue dye and methylene blue dye. Even though the risk of an anaphylactic response is low, this raises questions about the usefulness of colorimetric detection of SLN and whether alternatives to the use of the isosulfan and patent blue V dyes, such as methylene blue, exist.