Quality of life in a randomized control trial? Comments concerning MA 17.
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Antineoplastic Agents, Hormonal↗
Biomedical subjects
Brigitte Sigal-Zafrani
Publications and source records attributed to Brigitte Sigal-Zafrani.
Pathological response to preoperative concurrent chemo-radiotherapy for breast cancer: results of a phase II study.
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.
Adult↗
Antigen-independent accumulation of activated effector/memory T lymphocytes into human and murine tumors.
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.
Adult↗
Risk of breast cancer recurrence and contralateral breast cancer in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy.
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.
Adult↗
Visualizing chromosomes as transcriptome correlation maps: evidence of chromosomal domains containing co-expressed genes--a study of 130 invasive ductal breast carcinomas.
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.
Breast Neoplasms↗
Stereotactic radioguided surgery by siteSelect for subclinical mammographic lesions.
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.
Adult↗
Ductal breast carcinoma develops through different patterns of chromosomal evolution.
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.
Aged↗
Benign breast diseases.
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.
Adolescent↗
KIT is highly expressed in adenoid cystic carcinoma of the breast, a basal-like carcinoma associated with a favorable outcome.
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.
Adult↗
[Standards, Options and Recommendations for the management of ductal carcinoma in situ of the breast (DCIS): update 2004].
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.
Breast Neoplasms↗
Enrichment methods to detect bone marrow micrometastases in breast carcinoma patients: clinical relevance.
INTRODUCTION: Improving technologies for the detection and purification of bone marrow (BM) micrometastatic cells in breast cancer patients should lead to earlier prognosis of the risk of relapse and should make it possible to design more appropriate therapies. The technique used has to overcome the challenges resulting from the small number of target cells (one per million hematopoietic cells) and the heterogeneous expression of micrometastatic cell markers. In the present study, we have assessed the clinical relevance of current methods aimed at detecting rare disseminated carcinoma cells. METHODS: BM aspirates from 32 carcinoma patients were screened for the presence of micrometastatic cells positive for epithelial cell adhesion molecule and positive for cytokeratins, using optimized immunodetection methods. A comparison with data obtained for 46 control BM aspirates and a correlation with the clinical status of patients were performed. RESULTS: We developed a sensitive and efficient immunomagnetic protocol for the enrichment of BM micrometastases. This method was used to divide 32 breast carcinoma patients into three categories according to their epithelial cell adhesion molecule status. These categories were highly correlated with the recently revised American Joint Committee on Cancer staging system for breast cancer, demonstrating the clinical relevance of this simple and reliable immunomagnetic technique. We also evaluated immunocytochemical detection of cytokeratin-positive cells and cytomorphological parameters. Immunocytochemistry-based methods for the detection of BM micrometastases did not provide any information about the clinical status of patients, but helped to refine the immunomagnetic data by confirming the presence of micrometastases in some cases. We also tested a new density gradient centrifugation system, able to enrich the tumor fraction of BM specimens by twofold to threefold as compared with standard Ficoll methods. CONCLUSION: These improved methods for the detection of micrometastatic cells in patient BM should help clinicians to predict the clinical status of breast cancer patients at the time of surgery or treatment.
Adult↗
Proliferation markers predictive of the pathological response and disease outcome of patients with breast carcinomas treated by anthracycline-based preoperative chemotherapy.
The cell proliferation rate has been correlated to the response of breast carcinomas to preoperative chemotherapy (CT) and to disease outcome. However, this parameter is not yet used to select which tumours should be treated with preoperative CT. Furthermore, there is no consensus in the method used to evaluate cell proliferation. In poor prognosis breast carcinomas (PPBCs) treated by intensive preoperative CT, we compared the predictive value of S phase fraction (SPF), mitotic index (MI) and Ki67. We also evaluated the prognostic significance of the variation of the MI after CT. A series of 55 T2-T4N0N1M0 breast carcinomas were treated with 4 cycles of cyclophosphamide, 5-fluorouracil (5-FU) and doxorubicin. SPF was determined by flow cytometry on pre-therapeutic needle aspiration products. MI and Ki67 were evaluated on pre-therapeutic biopsy samples and on the tumours after CT. Fifteen patients (27%) had a pathological complete response (pCR), whereas 40 (73%) had residual disease. All three proliferative markers were found to have predictive value, but this value was higher for MI than for SPF (P = 0.04) and Ki67 (P = 0.03): the rate of pCR was 50% in cases with MI > 17/3.3 mm2, but was only 7% in cases with MI under this threshold (P = 0.0003). A significant decrease of MI (mean 10.97) was observed after CT (P = 0.001). Furthermore, we observed that even for patients with residual tumour, the variation of MI after CT was a prognostic parameter and overall survival. The sequential analysis of MI in breast cancers treated by preoperative CT thus provides a surrogate for predicting long-term outcome.
Adult↗
Histological margin assessment for breast ductal carcinoma in situ: precision and implications.
Local recurrence after lumpectomy for ductal carcinoma in situ (DCIS) is a major concern and is related to residual disease in the breast. We studied the predictive value of lumpectomy margins for residual DCIS and compared our results and pathological processing techniques with those published in the literature. Margin status was determined for 89 patients with screen-detected DCIS who had lumpectomy and re-excision, for the presence and extent of residual disease. Margin width was defined as the narrowest distance between tumor and any inked margin or, where margins were positive, classified into focal involvement (<1 mm of the inked surface involved), minimal (>or=1<15 mm) and extensive (>or=15 mm). The amount of residual tumor was quantified according to the number of ducts involved with tumor: small (fewer than 10 ducts) or large (10 or more ducts) residuum. The initial margin status was a significant predictor for the presence of residual tumor in re-excision specimens (P=0.006). There was residual tumor in 44 and 45% of close non-involved (>1 and 25 mm,respectively, showing residual disease. The presence of residual tumor was not significantly related to age, mammographic appearance, nuclear grade or intraductal necrosis. The initial margin status was found to predict for the amount of residual tumor. With careful margin assessment, margin status after lumpectomy for DCIS can be used to predict for the presence and amount of residual tumor in the breast and is a guide to further management decisions. A standard for margin status reporting and pathological processing of screen-detected DCIS in situ lesions will help in the interpretation of data from different institutions.
Adult↗
Overexpression/amplification of HER-2/neu is uncommon in invasive carcinoma of the uterine cervix.
The aim of this study was to investigate HER-2/neu (c-erbB2) overexpression/amplification in carcinoma of the uterine cervix using immunohistochemistry and fluorescent in situ hybridization (FISH) to assess whether anti-p185c-erbB2 therapy might have potential benefits in patients with advanced invasive cervical carcinoma. The authors used a protocol for p185c-erbB2 immunohistochemistry (clone CB11) that has been previously calibrated using FISH as the gold standard, showing a 98% accuracy rate in a large series of breast carcinomas. Immunolabeling for p185c-erbB2 was present in 24 of 82 (29%) of the tumors, but only 2 tumors (2%) with a labeling of more than 60% of the cells were considered positive for overexpression. FISH analysis did not find HER-2/neu gene amplification in these cases, although five other tumors showed weak and/or focal immunolabeling. There was no correlation between the presence of immunolabeling and age, histologic type, or clinical stage. Overexpression/amplification of HER-2/neu is uncommon in invasive cervical carcinoma, suggesting that there is little indication for using anti-p185c-erbB2 therapy in the treatment of these patients.
Adenocarcinoma↗
MRI for surgical planning in patients with breast cancer who undergo preoperative chemotherapy.
OBJECTIVE: Accurate presurgical evaluation of residual disease appears essential for successful clinical outcome in patients with breast cancer who are undergoing chemotherapy. Our objective was to study the impact on surgical planning of adding serial MRI evaluations of the tumor to standard non-MRI assessments. MATERIALS AND METHODS: MR images of breast tumors obtained before, during, and after preoperative chemotherapy were reviewed in 30 patients. Tumor response was assessed using both size and morphologic MRI criteria. We compared the actual surgical decisions made prospectively on the basis of standard (clinical, mammographic, and sonographic) assessments of response with decisions that would have been made had MRI findings also been considered. MRI investigators were blinded to the ultimate surgical results. Successful breast-conserving surgery was judged on pathologic confirmation of excision margins that were negative for cancer. RESULTS: The standard evaluation led to 16 successful breast-conserving and 14 mastectomy procedures. Using MRI results would have led to major beneficial therapeutic changes in six (20%) of the 30 patients: five patients undergoing primary mastectomy (chemotherapy avoided) and one patient undergoing postchemotherapy mastectomy (unsuccessful breast-conserving surgery avoided). MRI would have added valuable information in 14 (46.7%) of the 30 patients. In seven (23.3%) of the 30 patients, the decision to perform postchemotherapy mastectomy would have been unchanged. In one patient (3.3%), MRI results would not have prevented unsuccessful breast-conserving surgery. In two patients (6.6%), MRI results would have prevented successful breast-conserving surgery from being performed. CONCLUSION: Although the ultimate incidence of breast conservation was potentially similar for the patients (16/30, 53%) in whom the standard evaluation was used and for the patients (14/30, 47%) in whom the MRI-added evaluation was used, MRI was useful in establishing the final treatment earlier in the process, avoiding unnecessary preoperative chemotherapy, or selecting high-risk breast-conserving procedures.
Adult↗
[Tamoxifen and aromatase inhibitors in the treatment of breast cancer in menopausal women: pharmacological and clinical aspects].
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.
Anastrozole↗
[Management of ductal carcinoma in situ by the pathologist: current questions].
As a consequence of increased screening mammography, ductal carcinoma in situ represents a growing percentage of breast cancer diagnoses. The management of per-cutaneous biopsies as well as wire-localized surgical biopsies is a difficult task for pathologists. In this Article, we describe the diagnostic criteria of these lesions as well as the histopathological characteristics of their two principal differential diagnoses: atypical ductal hyperplasia and micro-infiltrating carcinoma. We also detail the utility of immunohistochemistry in the diagnosis of these lesions. This paper reviews the accepted prognostic factors for ductal carcinoma in situ and describes the important techniques needed to characterize them (grade and extent, status of margins and exclusion of microinvasion). Correct handling of pathological specimens, as detailed here, is one of the main keys for therapeutic success with ductal carcinomas in situ. Indeed, if dealt with adequately, such lesions should almost never affect the patient's long-term survival.
Adult↗
[Lobular neoplasia].
The concept of lobular lesions has greatly evolved during the last 30 Years. This disease is still not fully understood and patient management is probably not always optimal. Changes in the histopathological categorization of the lobular changes should help us to better categorize high-risk lesions. The concept of lobular neoplasia conceived as simply a risk factor and not a precursor for subsequent development of invasive carcinoma is a subject of current debate. Molecular biology data and immunoprofiles isolate lobular phenotypes and link them to invasive cancer. Mass screening is challenging the current opinion that lobular disease cannot be detected by mammography. This raises the problem of the optimal management of patients with lobular neoplasia on needle core biopsies.
Biomarkers↗