Purpose of Study: To assess the effectiveness of early detec¬ tion of intrathoracic and bone métastases in reducing cancer mortality in breast cancer patients. Materials & Methods: A prospective randomized clinical trial was carried out, enrolling patients from 12 breast clinics in the vicinity of Florence, Italy, between January 1985 and Decem¬ ber 1986, with a five-year follow-up through December 1991. A total of 1243 consecutive pre- or postmenopausal patients who received surgical treatment for unilateral invasive breast carci¬ noma with no métastases in the previous six months participated in the study. Absence of métastases was ascertained at enroll¬ ment by physical examination, chest roentgenography, and bone scan, based on the knowledge that intrathoracic and bone mé¬ tastases are the most common first tumor recurrences in breast cancer. Patients were randomized to either the intensive follow- up (IF) or the clinical follow-up (CF) group. Physical exami¬ nation of patients in both groups was performed every three months in the first two years and every six months in the fol¬ lowing three years. Patients in the IF group had a two-view chest roentgenographic examination and bone scan every six months and mammography was performed annually for the duration of the study. The CF patients had a mammographie evaluation annually and underwent no other tests unless recurrences were suspected. Postoperative treatment of patients in both groups followed Italian national guidelines, whereby patients with no nodal involvement received no adjuvant therapy, whereas those with axillary involvement received hormonal therapy (tamoxi- fen citrate) and/or other chemotherapy. Treatment ofrecurrences was also recorded. Relapse-free survival was analyzed, consid¬ ering only distant métastases as relevant events. Overall survival was the principal end point of the study. Results: A total of 622 patients were randomized to the IF group, and 621 to the CF group. There were 393 recur¬ rences during the study (289 distant, the rest local). Patients with both local and distant métastases were relegated to the distant métastases count. There was an excess of isolated bone and intrathoracic métastases in the IF group. Treatment of distant métastases was similar in both groups. Recurrence- free survival was significantly different in the two groups (Figure 1) at 5 years, due to earlier diagnosis of recurrences in the IF group. This difference was reduced to insignifi¬ cance when both relapses and death were analyzed. Mortal¬ ity in the IF group was estimated to be 18.6%, compared to 19.5% in the CF group, and no difference was seen in the sur¬ vival curves of the two groups (Figure 2). Conclusion: This study, which is the first prospective ran¬ domized clinical trial of the efficacy of early detection of breast cancer métastases, found no reduction in cancer mortality as¬ sociated with intensive postoperative follow-up. Although in¬ tensive follow-up by chest roentgenography and bone scan can increase early detection of métastases, it appears to have no effect on survival. Intensive follow-up should not be the routine management for breast cancer patients postopera- tively, but should rather be reserved for patients with suspi¬ cious findings at periodic clinical examination.

Several agents have been utilised for therapy of mastalgia based on data from small trials. No meta-analysis of trials on mastalgia exists. We have conducted a meta-analysis on trials on mastalgia published in the English language. Study was restricted to randomised controlled trials comparing Bromocriptine, Danazol, Evening primrose oil (EPO) and Tamoxifen with placebo. The analysis was carried out on the REVMAN statistical package. Weighted mean difference in the pain score in favour of Bromocriptine was −16.31(95% CI −26.35 to −6.27). Danazol produced a significant benefit with a mean pain score difference −20.23(95% CI −28.12 to −12.34). EPO did not offer any advantage over placebo in pain relief, mean pain score difference being −2.78 (95% CI −7.97 to 2.40). Tamoxifen achieved a relative risk (RR) of pain relief of 1.92 (95% CI 1.42–2.58). Tamoxifen is associated with least side effects and should be the drug of first choice.

We report herein that trefoil factor 3 (TFF3) is oncogenic and mediates anti-estrogen resistance in human mammary carcinoma. Forced expression of TFF3 in mammary carcinoma cells increased cell proliferation and survival, enhanced anchorage-independent growth, and promoted migration and invasion. Moreover, forced expression of TFF3 increased tumor size in xenograft models. Conversely, depletion of endogenous TFF3 with small interfering RNA (siRNA) decreased the oncogenicity and invasiveness of mammary carcinoma cells. Neutralization of secreted TFF3 by antibody promoted apoptosis, decreased cell growth in vitro, and arrested mammary carcinoma xenograft growth. TFF3 expression was significantly correlated to decreased survival of estrogen receptor (ER)-positive breast cancer patients treated with tamoxifen. Forced expression of TFF3 in mammary carcinoma cells increased ER transcriptional activity, promoted estrogen-independent growth, and produced resistance to tamoxifen and fulvestrant in vitro and to tamoxifen in xenograft models. siRNA-mediated depletion or antibody inhibition of TFF3 significantly enhanced the efficacy of antiestrogens. Increased TFF3 expression was observed in tamoxifen-resistant (TAMR) cells and antibody inhibition of TFF3 in TAMR cells improved tamoxifen sensitivity. Functional antagonism of TFF3 therefore warrants consideration as a novel therapeutic strategy for mammary carcinoma.

There is a significant difference in the extent of treatment offered to the elderly with breast cancer; in the United States, while 98% of patients less than 65 years of age receive standard treatment, 81% of those older than 65 years were treated according to protocol. This study's goal was to evaluate disease-specific survival and local-regional recurrence in breast cancer patients more than 65 years of age at diagnosis. A total of 1500 patients with invasive breast carcinoma were treated consecutively from May 1971 to July 2002 at the University of Florence, Florence, Italy. All patients were more than 65 years of age. The median age was 70.6 years (range 65.1-87.3 years). The median follow-up was 8.7 years (range 1-30 years). The crude probability of survival (or relapse occurrence) was estimated using the Kaplan-Meier method and survival (or relapse occurrence) comparisons were carried out using Cox proportional hazard regression models. The Cox regression model by stepwise selection showed as independent prognostic factors for disease-specific survival (DSS), the occurrence of a local relapse (p < 0.0001), pN status (p < 0.0001), the type of surgery (p < 0.0001), and the use of radiotherapy (p < 0.0006) and chemotherapy (p = 0.01). For local disease-free survival (LDFS), the Cox regression model by stepwise selection showed that mastectomy (p < 0.0001), histotype (p < 0.0001), pN status (p < 0.0001), and pT status (p = 0.001) were the only independent prognostic factors. Age was not a prognostic factor for DSS nor LDFS. We suggest treating patients with appropriate treatment for their prognostic factors.

Purpose Tamoxifen, which is actually the gold standard adjuvant treatment in estrogen receptor-positive early breast cancer, is associated with an increased risk of endometrial cancer and other life-threatening events. Moreover, many women relapse during or after tamoxifen therapy because of the development of resistance. Therefore new approaches are required.Patients and Methods We conducted a prospective randomized trial to test the efficacy of switching postmenopausal patients who were already receiving tamoxifen to the aromatase inhibitor anastrozole. After 2 to 3 years of tamoxifen treatment, patients were randomly assigned either to receive anastrozole 1 mg/d or to continue receiving tamoxifen 20 mg/d, for a total duration of treatment of 5 years. Disease-free survival was the primary end point. Event-free survival, overall survival, and safety were secondary end points.Results Four hundred forty-eight patients were enrolled. All women had node-positive, estrogen receptor-positive tumors. At a median follow-up time of 36 months, 45 events had been reported in the tamoxifen group compared with 17 events in the anastrozole group (P = .0002). Disease-free and local recurrence-free survival were also significantly longer in the anastrozole group (hazard ratio [HR] = 0.35; 95% CI, 0.18 to 0.68; P = .001 and HR = 0.15; 95% CI, 0.03 to 0.65; P = .003, respectively). Overall, more adverse events were recorded in the anastrozole group compared with the tamoxifen group (203 v 150, respectively; P = .04). However, more events were life threatening or required hospitalization in the tamoxifen group than in the anastrozole group (33 of 150 events v 28 of 203 events, P = .04).Conclusion Switching to anastrozole after the first 2 to 3 years of treatment is well tolerated and significantly improves event-free and recurrence-free survival in postmenopausal patients with early breast cancer.

AIM:The aim of the current study is to identify a subgroup of patients with breast cancer who have a low risk of local recurrence after conservative surgery in order to avoid radiotherapy treatment. METHODS:A group of 472 patients underwent conservative surgery without radiotherapy, and it was compared to a second group of 755 patients with similar characteristics, but who had received radiotherapy treatment (RT) after conservative surgery. RESULTS:Breast relapse's univariate analysis demonstrated statistical significance for the following factors: radiotherapy treatment, clinical stage, pathological stage, positive axillary nodes and tumour grading. Different results were obtained studying breast relapse. In the no-RT group breast relapse was 10.6% while in the irradiated group it was 3.4%. The breast relapse incidence decreases as the age of the patients increases especially over 75 years of age. CONCLUSIONS:In conclusion, there is clinical evidence of avoiding adjuvant radiotherapy for patients over 75 years with T1-T2 cancer treated with quadrantectomy with a clear excision margin.

526 Background: We have previously shown that switching to ANA after 2–3 years of TAM is well tolerated and significantly improves event-free (EFS) and progression-free survival (PFS) of postmenopausal ebc (Breast Cancer Res Treat 82, 2003). Here we report on an additional analysis at a median follow-up time of 52 mos (1–80 mos). Methods: This was an open phase III trial comparing 5 years of TAM vs 2–3 years of TAM followed by 3–2 years of ANA (total duration of treatment: 5 years). PFS was the primary end point. EFS, OS and safety were secondary end points. Results: 448 node positive, ER positive patients were enrolled. At the time of the present analysis 87 events had occurred and 26 deaths. The first site of recurrence was the ipsilateral breast or the thoracic wall or the loco-regional nodes in 16 patients. Distant metastasis were the first site of recurrence in 47 patients; 19 patients developed second primaries (including 5 controlateral breast cancers). The Hazard Ratios of patients switched to ANA for EFS, PFS, local (l) PFS and distant (d)PFS are summarized in the table (Hazards of previous analysis are reported for comparison).17 women continued on TAM died as compared to 9 of those switched to ANA (HR: 0.52; 95% CI 0.23–1.17; p=0.1). The percentages of women developing at least one AE were 40% and 46% in the two groups respectively (p=0.2). However there were 6 endometrial cancers in the TAM group compared to 1 in the ANA group. Conclusions:Safety and clinical benefits of switching to ANA following 2 or 3 years of TAM are confirmed by this updated analysis. No significant financial relationships to disclose.

The Breast JournalVolume 11, Issue 5 p. 351-352 Renal Cell Carcinoma Metastatic to the Breast and Breast Cancer Metastatic to the Kidney: Two Rare Solitary Metastases Mauro Gacci MD, Corresponding Author Mauro Gacci MD Departments of Urology,Address correspondence and reprint requests to: Mauro Gacci, MD, Department of Urology, University of Florence, Via Masaccio No. 102, 50132, Firenze, Italy, or e-mail: [email protected]it.Search for more papers by this authorLorenzo Orzalesi MD, Lorenzo Orzalesi MD General Surgery,Search for more papers by this authorVito Distante MD, Vito Distante MD General Surgery,Search for more papers by this authorGabriella Nesi MD, Gabriella Nesi MD Pathology,Search for more papers by this authorVania Vezzosi MD, Vania Vezzosi MD Pathology,Search for more papers by this authorLorenzo Livi MD, Lorenzo Livi MD Radiotherapy, andSearch for more papers by this authorValiano Mungai MD, Valiano Mungai MD Radiotherapy, andSearch for more papers by this authorPaola Romagnani MD, Paola Romagnani MD Clinical Physiopathology, University of Florence, Florence, Italy; andSearch for more papers by this authorBrian Eisner MD, Brian Eisner MD Massachusetts General Hospital, Boston, MassachusettsSearch for more papers by this authorMarco Carini MD, Marco Carini MD Departments of Urology,Search for more papers by this author Mauro Gacci MD, Corresponding Author Mauro Gacci MD Departments of Urology,Address correspondence and reprint requests to: Mauro Gacci, MD, Department of Urology, University of Florence, Via Masaccio No. 102, 50132, Firenze, Italy, or e-mail: [email protected].Search for more papers by this authorLorenzo Orzalesi MD, Lorenzo Orzalesi MD General Surgery,Search for more papers by this authorVito Distante MD, Vito Distante MD General Surgery,Search for more papers by this authorGabriella Nesi MD, Gabriella Nesi MD Pathology,Search for more papers by this authorVania Vezzosi MD, Vania Vezzosi MD Pathology,Search for more papers by this authorLorenzo Livi MD, Lorenzo Livi MD Radiotherapy, andSearch for more papers by this authorValiano Mungai MD, Valiano Mungai MD Radiotherapy, andSearch for more papers by this authorPaola Romagnani MD, Paola Romagnani MD Clinical Physiopathology, University of Florence, Florence, Italy; andSearch for more papers by this authorBrian Eisner MD, Brian Eisner MD Massachusetts General Hospital, Boston, MassachusettsSearch for more papers by this authorMarco Carini MD, Marco Carini MD Departments of Urology,Search for more papers by this author First published: 12 September 2005 https://doi.org/10.1111/j.1075-122X.2005.00057.xCitations: 7Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume11, Issue5September 2005Pages 351-352 RelatedInformation

Somatostatin analogs are effective in inhibiting growth of human breast cancer cell lines. These antiproliferative effects are mediated by specific receptors located on cell membranes. The somatostatin receptor subtype 2 (sst2) is the principal mediator of somatostatin effects in normal and cancer cells, and its presence has already been demonstrated in breast cancer. The purpose of our study was to evaluate the clinical relevance of the expression of sst2 by quantifying its mRNA in a large group of infiltrating breast cancers and their corresponding normal tissues. The expression of sst2 mRNA was measured with quantitative real time RT-PCR in 169 breast cancers and in their corresponding unaffected tissues. We evaluated the association of sst2 expression with the commonest clinical-pathologic features of breast cancer. The correlation with a marker of cell proliferation (Ki-67) and with receptor concentration was also evaluated. In cancer tissues, we found that the absolute concentrations of sst2 mRNA were significantly higher in estrogen receptor (ER)-positive samples (P=0.002) as well as in lymph-node-negative cancers (P=0.04) (Student's t-test or one-way ANOVA). In addition, sst2 mRNA was significantly higher in breast cancers than in corresponding unaffected tissues (P=0.0002). However, when the clinical-pathologic parameters were considered, this gradient maintained its statistical significance only in tumors expressing positive prognostic markers, such as the presence of ER (P=0.0005) and progesterone receptors (PgR) (P=0005), and the lack of lymph-node involvement (P=0.0003). The same difference was also significant in postmenopausal women (P=0.001) and in T1 patients (P=0.001). In addition, sst2 mRNA expression was significantly higher (P=0.008) in low-proliferating breast cancers. Finally, we found that the quantitative expression of sst2 mRNA was directly related to the PgR concentration in breast cancer tissues (P<0.001). Our data seem to indicate that an upregulation of sst2 gene expression is a common feature of breast cancers which, on the basis of conventional predictive parameters, are expected to have a better prognosis. Featuring a possible role of somatostatin analogs in combined endocrine therapies for breast cancer, our results seem to confirm that the sst2 status of the tumor should be previously investigated.

Tankyrase promotes telomere elongation by interaction with the telomeric protein binding factor TRF1, a negative regulator of telomere extension. We measured tankyrase mRNA by real-time RT-PCR in 66 breast cancers and in paired normal tissues. Results were compared with hTERT mRNA expression. The levels of tankyrase in breast cancers were significantly higher in comparison to normal tissues (P<0.0001) and significantly related to the status of progesterone receptors. No relationship was found between tankyrase and hTERT mRNA expression in breast cancers. According to our results, tankyrase expression appeared up regulated in breast cancers.

The HER-2 gene (HER-2/neu or c-erbB-2) encodes an 185-kDa transmembrane glycoprotein that is a member of the type I family of growth factor receptors. HER-2 is constitutively activated by overexpression and contributes to cell growth, angiogenesis, survival, and metastasis (1). The assessment of HER-2 status in breast carcinomas provides valuable prognostic and predictive information. Immunohistochemistry, fluorescence in situ hybridization, chromosomal in situ hybridization, and quantitative reverse transcription-PCR (RT-PCR) may be used for this purpose. Other approaches have been proposed for the assessment of HER-2 status in peripheral blood, including evaluating either circulating HER-2 extracellular domain (ECD) or nucleated cell-associated HER-2 mRNA. Some studies have indicated that circulating ECD/HER-2 is frequently increased in metastatic disease (2)(3)(4). In addition, high concentrations of ECD/HER-2 are associated with cancer aggressiveness (5) and predict response to trastuzumab (6)(7)(8) and antiestrogen (4) therapies in advanced breast cancer. Recently, Martin et al. (9), using an array to assess circulating mRNA, pointed out that HER-2 mRNA was generally low in the blood of healthy individuals but was increased in 31% of patients with untreated invasive breast cancer. Almost all of these studies evaluated blood markers in patients with advanced or metastatic breast cancer using a single presurgical sample.Our study included 40 consecutive patients (median age, 58 years; range, 29–80 years) undergoing surgery for early breast cancer. Patients did not receive any systemic therapy before surgery and provided informed consent for the study. According to tumor size, 28 patients were classified as T1, whereas the remaining 12 were T2 or T3. Twenty-two were node negative, and 35 were positive for estrogen receptors. From each patient, we collected 12 mL of venous blood in EDTA tubes and divided the blood into two 5-mL aliquots. The first was centrifuged, and the plasma …

Recent studies report the incidence of axillary metastases in patients with ductal carcinoma in-situ (DCIS) approaches 13%. The purpose of this study was to define the incidence of axillary micrometastases in patients with pure DCIS before and after the introduction of sentinel lymph node biopsy.Patients with a final diagnosis of DCIS form the basis of this study. Data were entered prospectively into an Institutional Review Board approved Oracle database from January 1997 through July 2002.One hundred and thirty-four patients had lymph nodes evaluated. Ninety-eight percent of patients had no evidence of metastatic disease and 2% were found to have micrometastases. This was consistent in those who had level I or II lymph node sampling or both and those who had lymphatic mapping and a sentinel lymph node biopsy procedure.These data do not support axillary lymph node removal of any type in patients with pure DCIS.

The object of this study was to assess quality of care and adherence to treatment guidelines of screen-detected lesions in Italy using a new audit system. Data on screen-detected cases surgically treated in 1997 were collected using a system (QT 2.3) developed within the Italian Group for Planning and Evaluating Mammographic Screening Programmes (GISMa) and the European Breast Cancer Screening Network. Results of 18 performance parameters were considered compared with the reference standards. In 1997, 515 lesions (335 invasive, 60 in situ and 120 benign) in 496 patients were collected from 14 departments in the Central and Northern area of Italy. The 18 indicators were analysed and grouped according to six quality objectives. Some results were good and others were excellent, such as intraoperative identification, breast conservation surgery, adequate axillary procedures and completeness of pathology reports, but most of them failed: waiting times, preoperative diagnosis, employment of frozen section on small lesions and avoiding axillary procedures in ductal carcinoma-in-situ. This work is a first attempt in Italy to evaluate and uniform the criteria adopted for quality control of breast cancer treatment, using a standardised system. Some results are good or excellent, the overall level of compliance with quality indicators is not satisfactory and corrective actions should be undertaken for a number of issues. A continuous monitoring should be performed and appropriate action taken in order to verify the effectiveness of the corrective actions and to provide screen-detected patients with the best quality of care.

Careful normalization is essential when using quantitative reverse transcription polymerase chain reaction assays to compare mRNA levels between biopsies from different individuals or cells undergoing different treatment. Generally this involves the use of internal controls, such as mRNA specified by a housekeeping gene, ribosomal RNA (rRNA), or accurately quantitated total RNA. The aim of this study was to compare these methods and determine which one can provide the most accurate and biologically relevant quantitative results. Our results show significant variation in the expression levels of 10 commonly used housekeeping genes and 18S rRNA, both between individuals and between biopsies taken from the same patient. Furthermore, in 23 breast cancers samples mRNA and protein levels of a regulated gene, vascular endothelial growth factor (VEGF), correlated only when normalized to total RNA, as did microvessel density. Finally, mRNA levels of VEGF and the most popular housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), were significantly correlated in the colon. Our results suggest that the use of internal standards comprising single housekeeping genes or rRNA is inappropriate for studies involving tissue biopsies.