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Purpose: To investigate the impact of initial tumour characteristics and loco-regional radiotherapy on long-term survival following breast cancer diagnosis., Methods and Materials: This study was conducted among 6,800 French women from a cohort of 7 711 subjects diagnosed at the IGR with breast cancer between 1954 and 1983 and followed-up until January 2004. Overall mortality in the cohort was compared with that in the French general population using Standardized Mortality Ratios (SMR) and the Absolute Excess Risk (AER) estimated by Poisson regression., Results: During the 1954-2004 follow-up period, 5,436 women died. Mortality was 3.15-fold higher in the cohort than in the general female population in France. It decreased from 6.86 to 1.26 during the first 30 years of follow-up then rose again to 1.60. Both SMRs and AERs were more than 2-fold higher in women who had received radiotherapy during initial treatment than in those who had not, this difference being higher for women treated before 1976 than afterwards (p < 0.0001). They (SMRs and AERs) were also higher for subjects who had stage II, III or IV lesions than for those with less advanced tumours., Conclusion: The results of this study suggest that the excess deaths observed during the first two decades are closely linked to the initial clinical characteristics of the tumour and to radiotherapy. The late increase in mortality may be partially due to deleterious late effects of radiotherapy.

For the last four decades, the treatment of cancer has relied on four treatment modalities, namely surgery, radiotherapy, cytotoxic chemotherapy, and hormonotherapy. Most of these therapies are believed to directly attack and eradicate tumor cells. The emerging concept that cancer is not just a disease of a tissue or an organ but also a host disease relies on evidence of tumor-induced immunosuppression and polymorphisms in genes involved in host protection against tumors. This theory is now gaining new impetus, based on our recent data showing that optimal therapeutic effects require the immunoadjuvant effect of tumor cell death induced by cytotoxic anticancer agents. Here, we show that the release of the high mobility group box 1 protein (HMGB1) by dying tumor cells is mandatory to license host dendritic cells (DCs) to process and present tumor antigens. HMGB1 interacts with Toll-like receptor 4 (TLR4) on DCs, which are selectively involved in the cross-priming of anti-tumor T lymphocytes in vivo. A TLR4 polymorphism that affects the binding of HMGB1 to TLR4 predicts early relapse after anthracycline-based chemotherapy in breast cancer patients. This knowledge may be clinically exploited to predict the immunogenicity and hence the efficacy of chemotherapeutic regimens.

Background: Prion protein (PrPc) has been previously reported to be associated with resistance to proapoptotic stimuli. We evaluated whether the expression of PrPc was associated with the resistance to adjuvant chemotherapy in patients with estrogen receptor (ER) -negative breast cancer., Patients and Methods: The expression of PrPc by primary tumors was assessed by immunohistochemistry in a series of 756 patients included in two randomized trials that compared anthracycline-based chemotherapy to no chemotherapy. The PrPc expression was correlated with ER expression and the benefit of adjuvant chemotherapy was assessed according to PrPc expression in patients with ER-negative tumors., Results: Immunostaining analysis showed that PrPc was mainly expressed by myoepithelial cells in normal breast tissue. Tissue microarray analysis from 756 breast tumors showed that PrPc was associated with ER-negative breast cancer subsets (P < 0.001). Adjuvant chemotherapy was not associated with a significant risk reduction for death in patients with ER-negative/PrPc-positive disease [adjusted hazard ratio (HR) for death = 0.98, 95% confidence interval (CI) 0.45-2.1, P = 0.95], while it decreased the risk for death (HR = 0.39, 95% CI 0.2-0.74, P = 0.004) in patients with ER-negative/PrPc-negative tumors., Conclusion: These data indicate that ER-negative/PrPc-negative phenotype is associated with a high sensitivity to adjuvant chemotherapy.

We report a case of a 43-yr-old woman with a granular cell tumor of the breast. She presented with a palpable mass of the left breast of 2-yr duration. On physical examination, a firm, painless, well-defined mass located at the union of the upper quadrants was observed and a palpable homolateral axillary lymph node. The tumor was dense with ill-defined borders at mammography and hypoechoic, hypovascular, and poorly limited at ultrasonography. Fine needle aspiration cytology of the lesion was performed. Cytologic examination revealed the presence of highly cellular material, composed of both large cohesive groups and single cells often admixed with connective tissue. These cells had ill-defined abundant granular cytoplasm and bland regular small nuclei. Nucleoli were inconspicuous. Neither mitoses nor necrosis were noted. The cytological diagnosis of granular cell tumor of the breast was confirmed by histological examination of the surgical specimen following a breast lumpectomy., ((c) 2007 Wiley-Liss, Inc.)

When a former breast cancer patient asks for pregnancy, several questions have to be considered. The physician has to answer and counsel clearly and honestly his/her patient regarding the possibilities, risks and specificities associated with a pregnancy in this case. The individual risk of relapse should be considered, together with individual predictive factors and theoretical benefits of specific prolonged treatments such as hormone therapy. Both risks associated with the pregnancy itself and with the modification of treatment schemes have to be evaluated. Risks related to Assisted reproductive techniques when indicated, should also be considered and explained. Potential foetal risks should be explained too. The aim of this review is to summarize the current knowledge and then available tools that the physician can use to help the couple making decision regarding subsequent pregnancy.

Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen-specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death.

Background: The purpose of this study was to determine the predictive value of breast cancer molecular subclassification regarding the benefit of adjuvant anthracycline-based chemotherapy., Patients and Methods: Tumor samples from 823 patients included in two randomized trials that compared an anthracycline-based chemotherapy with no treatment were used to construct a tissue array. Estrogen receptor (ER), Her2, epidermal growth factor receptor, cytokeratine 5/6 expressions were determined by immunohistochemistry (IHC). The potential predictive factors of treatment effect on disease-free survival (DFS) were assessed by interaction tests and multivariate analysis., Results: Sixty-four (8%), 98 (12%), 109 (14%) and 527 (66%) patients presented a Her2+/ER-, basal-like, Her2-/ER-/nonbasal and luminal-like breast cancer. ER expression, when assessed by IHC, was an independent predictive factor for the benefit of chemotherapy on DFS (test for interaction, P = 0.0015). The molecular subclassification significantly predicted the efficacy of chemotherapy (test for interaction, P = 0.01), but had no significant added value (P = 0.32) as compared to the ER by treatment interaction. Adjuvant chemotherapy was associated with an adjusted hazard ratio for relapse or death of 0.42 [95% confidence interval (CI): 0.17-1.05], 0.54 (95% CI: 0.27-1.08), 0.35 (95% CI: 0.18-0.68), 1.07 (95% CI: 0.81-1.41) for patients with Her2+/ER-, basal-like, Her2-/ER-/nonbasal and luminal-like tumors, respectively., Conclusion: The breast cancer molecular subclassification was predictive for chemotherapy efficacy in adjuvant setting, but did not provide significant additional information to ER.

Purpose: To determine the risk factors for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after breast cancer., Patients and Methods: We conducted a case-control study among women treated for breast cancer between 1985 and 2001 in French general hospitals, cancer centers, or clinics. We included 182 AML and MDS patients and 534 matched controls. Breast cancer characteristics, type of treatment, and family history of cancer were compared in both groups., Results: The risk of AML/MDS was increased after topoisomerase-II inhibitor-based chemotherapy (P < 10-16) and was higher for mitoxantrone-based chemotherapy than for anthracycline-based chemotherapy (relative risk [RR] = 15.6; 95% CI, 7.1 to 34.2; and RR = 2.7; 95% CI, 1.7 to 4.5, respectively). After adjustment for other treatment components, the risk of AML/MDS in patients who received radiotherapy was multiplied by 3.9 (95% CI, 1.4 to 10.8) but was not increased by alkylating agents. Patients receiving granulocyte colony-stimulating factor (G-CSF) support had an increased risk of AML/MDS (RR = 6.3; 95% CI, 1.9 to 21), even when controlling for chemotherapy doses. Similar results were obtained when AML and MDS were considered separately., Conclusion: This large case-control study demonstrates that the risk of AML/MDS is much higher with mitoxantrone-based chemotherapy than with anthracyclines-based chemotherapy in a population of women recently treated for breast cancer. The risk of AML/MDS associated with mitoxantrone must be kept in mind when using this drug to treat diseases other than breast cancer (eg, prostate cancer or multiple sclerosis). In addition, our study suggests the need to monitor the long-term effects of G-CSF therapy.

Background: Pure or metaplastic squamous cell carcinoma (SCC) of the breast is a rare entity with an unclear pathogeny and aggressive clinical behaviour. An attempt was made to characterize its differential immunohistochemical and biological profile., Patients and Methods: Twenty-seven cases of SCC (pure or not) of the breast were matched with 27 ductal invasive carcinomas (IDC) for age, tumour size, nodal involvement and year of diagnosis. The expression levels of oestrogen receptor (ER), progesterone receptor (PR), Ki-67, epidermal growth factor receptor (EGFR), HER2, Cyclin Bl, hTERT, cytokeratins (CK) 5/6 and p63 were determined immunohistochemically in both cohorts. The presence of the human papilloma virus (HPV) genome was investigated by polymerase chain reaction (PCR)., Results: Pure and metaplastic SCC displayed common profiles typifying a basal origin: they never expressed ER or PR, were HER2-negative in 93% of cases, exhibited positivity for CK5/6 or EGF-R in 75% and 85%, and for p63 in 70% of cases and were highly proliferative. These profiles were markedly different from those of matched controls (p<0.001 for five markers) except for HER2 and hTERT. The HPVgenome was detected in 2 out of 14 cases (14%) of SCC., Conclusion: The expression profile of SCC of the breast was markedly different from that of IDC. A typical "basal-like" phenotype was displayed that may explain part of their behaviour and justify specific therapeutic approaches. HPV infection was not a leading oncogenic event in SCC of the breast.

Background: Neoadjuvant chemotherapy (NACT) increases the likelihood that breast conservation therapy for breast cancer patients will be successful. There is no available nomogram to predict breast conservation after NACT. The aim of the current study was to develop and validate nomograms for predicting residual tumor size and probability of a patient becoming eligible for breast conservation surgery after NACT., Methods: A total of 1147 patients treated at M. D. Anderson Cancer Center (Houston, TX) and the Institut Gustave Roussy (Villejuif, France) who received anthracycline with or without paclitaxel NACT were included in the analysis. Clinicopathologic data from 1 series were used to construct logistic regression models for breast conservation and residual tumor size < 3 cm after NACT and were validated on an independent series., Results: The discrimination and the calibration of the nomogram for predicting the probability of residual tumor size < 3 cm after anthracycline-based NACT were good when applied to the validation set (concordance index = 0.79; U-index = 10(-3)). The discrimination of the nomogram for predicting eligibility for breast conservation therapy was also good (concordance index = 0.67). However, the calibration had to be adjusted to take into account global rates of breast conservation surgery. A second nomogram adapted to preoperative chemotherapy regimens containing paclitaxel was established. The concordance index of the nomogram for predicting breast conservation was 0.71 (P < 10(-6)) for the independent dataset and the calibration was also good. The confrontation of both nomograms showed that predictions were highly correlated (r = 0.97), suggesting that eligibility for breast conservation therapy was independent of the preoperative chemotherapy regimen used., Conclusions: Nomograms were developed for breast cancer patients who received NACT to predict residual tumor size and whether the patient would thus become eligible for breast conservation therapy. These tools may be useful when counseling patients about treatment options, and a web-based interface is now available to help guide patients and physicians in these decisions., ((c) 2006 American Cancer Society.)

Aim: This study aimed to evaluate the role of specimen radiography in predicting margin status for non-palpable breast malignancies., Methods: We retrospectively reviewed the clinical and pathological data together with specimen radiographs of 164 women with ductal carcinoma in situ, who were referred to our centre between January 1997 and December 2000. In all cases microcalcifications were discovered on mammography. Lesions were localized preoperatively using a guide-wire. Specimen radiography findings and clinicopathological data were correlated with pathological findings., Results: Findings comprised 122 pure ductal carcinomas in situ (74%) and 42 mixed carcinomas, both infiltrating and in situ (26%). On the specimen radiographs, the lesions were close (<1mm) to one edge of the lumpectomy in 34 (21%) cases. Histologically, there were 103 positive resection margins (<1mm, 63%) and only 61 negative margins (> or =1mm, 37%). On univariate analysis, factors associated with positive resection margins were found to be distance from microcalcifications to edge of lesion on specimen radiographs, and radiological multifocality. On multivariate analysis (logistic regression), a radiological margin <5mm and multifocality were the only risk factors for close histological margins. Radiological margins were not associated with surgical findings., Conclusion: Our results demonstrate that there is a correlation between specimen radiographs and histological results. The clinical relevance of this should be evaluated in a prospective study.

Background: Recent studies have suggested that chemokine receptors are involved in development of organ-specific pattern of metastases. In the present study, we evaluated the association between the chemokine receptors expressed in primary tumor cells and the site of metastatic relapse in patients with breast cancer., Methods: Primary tumors were obtained from 142 patients with axillary node-positive breast cancer and stained for CX3CR1, CXCR4, CCR6, and CCR7 expression. All statistical analyses were adjusted for systemic post-operative treatment., Results: After a median follow-up of 13 years, none of the chemokine receptors was associated with overall survival or disease free survival. However, expression of chemokine receptors was found to be associated with increased risk of relapse in certain organs. By estimating the Mantel-Haenszel odds ratios (OR), CXCR4 was associated with increased risk of metastasis to the liver (OR = 3.71, P = 0.005), CX3CR1 was associated with metastasis to the brain (OR = 13.18, P = 0.01). Patients with CCR6 positivity were more likely to develop a first metastasis in the pleura (OR = 2.82, P = 0.06). In addition, CCR7 expression was associated with the occurrence of skin metastases (11% versus 0%, P = 0.017)., Interpretation: Expression of chemokine receptors in the primary tumor predicts the site of metastatic relapse in patients with axillary node positive breast cancer. This study, in concordance with the data obtained in animal models, suggests that the chemokine receptors family could be the biological support of the 'seed and soil' theory.

Purpose: To combine clinical variables associated with pathologic complete response (pCR) and distant metastasis-free survival (DMFS) after preoperative chemotherapy (PC) into a prediction nomogram., Patients and Methods: Data from 496 patients treated with anthracycline PC at the Institut Gustave Roussy were used to develop and calibrate a nomogram for pCR based on multivariate logistic regression. This nomogram was tested on two independent cohorts of patients treated at the M.D. Anderson Cancer Center. The first cohort (n = 337) received anthracycline; the second cohort (n = 237) received a combination of paclitaxel and anthracycline PC. A separate nomogram to predict DMFS was developed using Cox proportional hazards regression model., Results: The pCR nomogram based on clinical stage, estrogen receptor status, histologic grade, and number of preoperative chemotherapy cycles had good discrimination and calibration in the training and the anthracycline-treated validation sets (concordance indices, 0.77, 0.79). In the paclitaxel plus anthracycline group, when the predicted pCR rate was less than 14%, the observed rate was 7.5%; for a predicted rate of > or = 38%, the actual rate was 85%. For a predicted rate between 14% to 38%, the observed rates were 50% with weekly and 27% with 3-weekly paclitaxel. This indicates that patients with intermediate chemotherapy sensitivity benefit the most from the optimized schedule of paclitaxel. Patients unlikely to achieve pCR to anthracylines remain at low probability for pCR, even after inclusion of paclitaxel. The nomogram for DMFS had a concordance index of 0.72 in the validation set and outperformed other prediction tools (P = .02)., Conclusion: Our nomograms predict pCR accurately and can serve as a basis to integrate future molecular markers into a clinical prediction model.

Background: The majority of patients with breast carcinoma with > or = 10 metastatic axillary lymph nodes (ALNs) develop recurrent disease within 5 years from diagnosis. The purpose of the current study, performed retrospectively, was to characterize the natural history of this subset of patients, both before and after the advent of adjuvant anthracycline-based chemotherapy and tamoxifen., Methods: Retrospectively, patients with primary breast carcinoma (N = 882) with > or = 10 metastatic ALNs, treated between 1954 and 1998, were selected from 3 institutions: The University of Texas M. D. Anderson Cancer Center (Houston, TX); the Institut Gustave Roussy (Villejuif, France); and Hospital Clinico Universitario (Valencia, Spain). All patient data had been registered prospectively in clinical databases. One group consisted of 314 patients treated with locoregional therapy alone (no adjuvant therapy) from 1954 to 1983. The second group included 568 patients who received adjuvant anthracycline-based chemotherapy between 1974 and 1998 with or without adjuvant tamoxifen., Results: The median follow-up time was 140 months. Disease-free survival rates at 15 and 20 years for the no adjuvant therapy and adjuvant therapy groups were 17% and 16% versus 26% and 24%, respectively. The overall survival rates at 20 years for the no adjuvant therapy and the adjuvant therapy groups were 9% and 21%, respectively. By multivariate analysis, the independent factors associated with survival in the adjuvant therapy group were tumor size and the number of metastatic lymph nodes., Conclusions: The retrospective analysis suggested that adjuvant anthracycline-based chemotherapy and hormonal therapy have altered the natural history in this high-risk group of patients. However, despite such improvements, survival rates remained low, and innovative therapeutic approaches are, therefore, needed to improve clinical outcomes.

Purpose: We have evaluated whether the mitotic index could predict the benefit of adjuvant anthracycline-based chemotherapy in patients with early breast cancer who are eligible for adjuvant chemotherapy according to Saint Gallen guidelines., Patients and Methods: A total of 937 patients from a single institution were included in two randomized trials that compared adjuvant anthracycline-based chemotherapy with no chemotherapy. These patients account for 83% of the overall population included in these trials. The first trial included premenopausal patients with node-negative disease, and the second one included postmenopausal patients, regardless of lymph node status. The treatment benefit was assessed according to the number of mitoses per field (x400)., Results: The mitotic index was assessable in 888 patients (94%). All the patients presented as either node-positive or an average-risk breast cancer according to 2003 Saint Gallen consensus conference guidelines. The 5-year overall survival rates were 91% and 87% for patients treated or not with adjuvant chemotherapy (P = .09). In patients with low/medium mitotic index (< three mitoses/field; n = 450), the 5-year overall survival rate was 95% for patients treated or not with adjuvant chemotherapy (P = .56). In patients with high mitotic index (>/= three mitoses/field; n = 438), the 5-year overall survival rates were 86% and 79% for patients treated or not treated with adjuvant chemotherapy, respectively (P = .02)., Conclusion: A high mitotic index is associated with the efficacy of adjuvant anthracycline-based chemotherapy in patients eligible for adjuvant chemotherapy in daily practice.

The purpose of our study was to explore and evaluate an innovative imaging approach, which consists on imaging the breast parenchyma by means of photoluminescence detectors (LED) and analysis of dynamic data. Breast magnetic resonance imaging (MRI) was chosen as the reference imaging method, as this is considered to be nowadays the gold standard for breast vascularisation evaluation. Preliminary results reveal a good correlation between breast MRI findings and light images.

Local-regional radiation therapy is one of the major therapeutic means in the management of breast cancer. Three questions however arise from the important advances achieved in this domain in the past years. The first question concerns the possibilities to identify and overcome the radioresistance of a subset of tumours. The second question is how to recognize women likely to benefit from adjuvant radiation therapy, and therefore to diminish treatment indications in other groups. Finally, the third question is how to identify subjects at high risk for long term injury following breast irradiation, in order to adapt techniques and indications in such populations. The major advances of breast cancer molecular genetics in the past years should provide clinicians with tools to answer these important questions. In this paper, we review the molecular germline (BRCA1, BRCA2, ATM, ...) and somatic (p53, tyrosine kinase receptors, as well as actors of cell cycle, signal transduction, apoptosis, DNA repair ...) main bases of breast cancer radiosensitivity. Recent methods of exploration of the genetic background of both the host and the tumours (gene and protein expression profiles) are also reviewed as major tools of breast cancer management in the next few years.

Chemokine receptors are involved in the trafficking of leucocytes. It has been shown recently that chemokine receptors (CXCR4, CCR7...) are expressed by breast cancer cells and could be involved in the metastasis phenomenon. Since this discovery, new data have been generated in this topic. These data confirm that chemokine receptors are involved in the occurrence of metastases, suggest that their expression is regulated by genes involved in the carcinogenesis and/or angiogenesis (VHL...) and that inhibitors could be of interest in the treatment of breast cancer. In this paper, we will review all these data and will discuss the perspectives that opens this new concept.

Background: The occurrence of brain metastases is an emerging problem in patients with metastatic breast cancer. In the present study, we looked at risk factors for brain metastasis among patients with metastatic breast cancer., Patients and Methods: The risk factors for brain metastasis were first determined in a series of 215 patients with metastatic breast cancer. Risk factors identified in the multivariate analysis were re-evaluated in a confirmatory series of 199 patients with metastatic breast cancer. All the patients had been included in prospective randomized trials that evaluated chemotherapy or endocrine therapy in an adjuvant setting., Results: In the first series, the presence of lung metastases (hazard ratio = 4.3, 95% CI: 1.9-9.3, P=0.0003) and negative hormone receptor status (hazard ratio = 4.2, 95% CI: 1.7-11, P=0.002) were the only predictive factors associated with the occurrence of brain metastases in the multivariate analysis. The second series confirmed that the presence of lung metastases and negative hormone receptor status were associated with the occurrence of brain metastases., Conclusion: The presence of lung metastases as the first site of relapse and a negative hormone receptor status are predictive for the occurrence of brain metastases in patients with metastatic breast cancer. A prophylactic treatment should be evaluated in these subsets of patients.

Aim: This study assessed the effects of multiple therapeutic factors on quality of life (QOL) in the treatment of breast cancer., Methods: We surveyed 179 recurrence-free women with early breast cancer who had undergone a sentinel lymph node procedure, between January 1999 and June 2001. Age, tumour size, breast and axillary procedure, nodal status, chemotherapy, supra-clavicular fossa radiotherapy, and hormone therapy were tested as possible factors associated with poor QOL., Results: Information on QOL was obtained for 148 out of 179 patients. Age less than 55 years and chemotherapy were factors associated with impairment of physical well-being. Tumour size was associated with poor socio-familial well-being. Factors associated with altered arm subscale scores were age <55, axillary procedure, nodal status, chemotherapy and supra-clavicular fossa radiotherapy. Unexpectedly, sentinel lymph node (SLN) procedure delayed the onset of chemotherapy if the metastatic status of SLN was not diagnosed intra-operatively., Conclusion: Efforts are needed to improve the QOL of young patients. Axillary procedure affects only QOL related to arm morbidity.

Background: Randomized trials comparing neoadjuvant versus adjuvant chemotherapy show that primary chemotherapy allows more frequent breast-preserving surgery even though no survival advantage has been demonstrated. The aim of the current study was to determine the predicting factors and the survival impact of breast conservation in patients with large breast tumors treated with neoadjuvant chemotherapy., Methods: Between January 1987 and December 2001, 594 patients with invasive T2-3 breast carcinoma who were ineligible for breast-conserving surgery (the mean initial tumor diameter was 49 mm) were treated with 3 or 4 courses of an anthracycline-based primary chemotherapy, surgery, and radiotherapy. Various clinicopathologic factors were tested as possible predicting factors of breast-preserving surgery. Survival analyses were performed to determine the implications of breast-conserving surgery on outcome., Results: After primary chemotherapy, 287 (48%) patients were eligible for breast-conserving surgery and 307 patients underwent a mastectomy. Initial tumor diameter > 5 cm, low histologic grade, lobular histology, and multicentricity were independent predicting factors of breast conservation ineligibility in the multivariate analysis (logistic regression). In the univariate survival analysis, a failure of breast-preserving surgery was associated with a poor outcome. Local disease recurrence-free survival rates were similar in patients treated with lumpectomy and mastectomy., Conclusions: The results reported in the current study suggested that initial diameter, histologic type and grade, and multicentricity are potential prechemotherapy predicting factors of breast conservation. When carefully selected, patients treated with breast conservation had a risk of local disease recurrence similar to the risk of chest wall disease recurrence after mastectomy., (Copyright 2004 American Cancer Society.)

Purpose: Although new drugs were approved during the 1990s for the treatment of metastatic breast cancer, it is not clear whether their use has changed the outcome of patients in daily practice. This study sought to determine whether survival has improved over time for breast cancer patients who had metastases at diagnosis., Patients and Methods: A total of 724 patients have been treated in three French cancer centers for an initially metastatic breast cancer between 1987 and 2000; 343 were diagnosed between 1987 and 1993, and 381 were diagnosed between 1994 and 2000. Tumor characteristics, treatments, and outcomes of these patients were compared by chi(2) test, log-rank test, and Cox regression analysis., Results: Characteristics were not different between the patients diagnosed from 1987 to 1993 and those diagnosed from 1994 to 2000. Ten percent of patients treated from 1987 to 1994 and 58% of patients treated from 1994 to 2000 have received either a taxane or a new aromatase inhibitor. The 3-year overall survival rates were 27% for patients treated from 1987 to 1993 and 44% for patients treated from 1994 to 2000 (P <.001). The treatment period (1994 to 2000 v 1987 to 1993) was a prognostic factor in multivariate analysis (relative risk, 0.6; P <.001)., Conclusion: The survival of breast cancer patients presenting with metastases at diagnosis has improved over time. This study strongly suggests that this improvement is related to treatment.

Background: This phase I and pharmacokinetic study of pemetrexed in combination with oxaliplatin was performed to determine the maximum tolerated dose (MTD), and to evaluate safety and pharmacokinetics in patients with metastatic solid tumors., Patients and Methods: Pemetrexed was administered as a 10- min i.v. infusion followed 30 min later by oxaliplatin as a 2- h infusion, once every 21 days. Up to two previous chemotherapy regimens were allowed. Vitamin B(12) supplementation and folic acid were not included in this study., Results: Thirty-six patients were treated in six escalating dose levels. Dose-limiting toxicities at dose level 6 (pemetrexed 500 mg/m(2) plus oxaliplatin 130 mg/m(2)) were febrile neutropenia, grade 3-4 diarrhea and grade 3 paresthesia. The MTD was not reached. The most common toxicity was neutropenia, with grade 3-4 occurring in 61% of patients. The pharmacokinetics of this pemetrexed-oxaliplatin combination are consistent with those following single-agent administration. Five responses (all partial) were observed over a broad range of solid tumors., Conclusions: This pemetrexed-oxaliplatin combination (without vitamin supplementation) every 21 days can be administered using full therapeutic doses of each agent with acceptable tolerability and no overlapping toxicity. The recommended regimen for phase II studies is pemetrexed 500 mg/m(2) plus oxaliplatin 120 mg/m(2).

The purpose of this phase I study was to determine the pharmacokinetics and toxicity of gemcitabine in patients with advanced, recurrent, and/or metastatic cancer and renal impairment. Patients were entered in 4 groups estimated by EDTA-Cr plasma clearance (CLp, mL/min): > or =80; > or =60 and <80; > or =30 and <60; and > or =30 and <80 plus renal insufficiency induced by previous chemotherapy, respectively. Gemcitabine 500 to 1000 mg/m was administered intravenously on days 1, 8, and 15 every 4 weeks. Plasma concentration data were pooled and analyzed using a population pharmacokinetic program (NONMEM). Eighteen white patients (14 females, 4 males) entered the study with a median age of 55 years. Linear regression analyses revealed no significant relationship between gemcitabine CLp and indices of renal impairment (EDTA-Cr CL; p = 0.797 or beta2-microglobulin; p = 0.153). Hematologic and nonhematologic toxicities were mild. Thus, there seems to be no significant impact of mild to moderate renal insufficiency on gemcitabine pharmacokinetics in patients with advanced cancer.

The aim of this study was to discuss the surgical management for ovarian or tubal cancers diagnosed at the time of prophylactic oophorectomy. Two patients with BRCA1 & BRCA2 mutations carriers had ovarian cancer diagnosed during laparoscopic oophorectomy. Conversion to laparotomy was performed in order to complete surgery (hysterectomy, multiple peritoneal biopsies, omentectomy, pelvic and para-aortic lymphadenectomy). These two patients were upstaged on the basis of para-aortic lymphadenectomy and had massive nodal spread into para-aortic area. One of them had no intra-peritoneal disease and the other one had minor peritoneal disease (only one positive pelvic biopsy in the Douglas pouch). These two patients are alive, one of them with 3.5 years of follow-up after the end of adjuvant treatment. In order to ensure the exact spread of the disease. Lymphadenectomy should be performed in patients with ovarian cancer diagnosed at the time of prophylactic surgery.

The aim of this study was to determine the chemosensitivity of infiltrating lobular breast carcinoma (ILC) in comparison with infiltrating ductal carcinoma (IDC). Between 1987 and 1995, 457 patients with invasive T2>3 cm-T4 breast carcinomas were treated with primary chemotherapy (CT), surgery, radiation therapy. Clinical response, the possibility of breast preservation, pathological response and survival were evaluated according to the histological type. In order to evaluate the biological differences between ILC and IDC patients and their implication with regard to tumour chemosensitivity, additional immunohistochemical stainings (oestrogen receptor (ER), Bcl2, p53, c-erbB-2 and Ki67) were performed on 129 pretherapeutical specimens. 38 (8.3%) ILC were diagnosed by core needle biopsy before CT. ILC was an independent predictor of a poor clinical response (P=0.02) and ineligibility for breast-conserving surgery after neoadjuvant chemotherapy (P=0.03). Histological and biological factors predicting a poor response to CT (histological grade, ER, Ki67 and p53 status) were more frequent in ILC than in IDC patients. After a median follow-up of 98 months (range: 3-166), the low chemosensitivity of ILC did not result in a survival disadvantage. Our results demonstrate that ILC achieved a lower response to CT than IDC because of their immunohistochemical profile. Preoperative CT did not allow a high rate of conservative treatment for ILC and therefore the use of neoadjuvant CT for ILC patients should be questioned.

Tamoxifen estrogenic action in the uterus induces several uterine diseases, benign and/or malignant ones. The risk of endometrial adenocarcinoma is multiplied by two to three in post-menopausal women. It is mainly linked with the doses and the length of the treatment. However, the global benefit of that drug is not questioned anymore. What matters now though is to find the best way to follow patients on tamoxifen. As a matter of fact, there is no such thing as a consensus that would include specific tests, nor a surveillance protocol in women on tamoxifen. Most teams do not propose any special follow-up. Some patients already show uterine anomalies prior to the beginning of tamoxifen treatment. A yearly gynecologic examination, together with a cervico-vaginal smear, is enough when there are no specific endometrial adenocarcinoma risk factors, nor anomalies detected during the pre-therapeutical evaluation, nor clinical symptomatology. In case of risk factors, or cervical stenosis, or again initial abnormalities though, a yearly transvaginal sonography may be proposed. There is no need for other exploratory examinations if the results are satisfying. In case of symptoms, anomalies in the cervico-vaginal smears, intra-uterine liquid retention with a stenosed cervix, or suspicious endometrial thickness, then an endometrial sampling must be carried out. MRI could be of interest in asymptomatic patients with unclear ultrasonography images. Follow-up must be continued after interruption of tamoxifen. It is important to inform patients about the additional risks of developing an endometrial cancer because of tamoxifen, while still being reassuring. Besides, it is absolutely necessary to recommend them to take quickly medical advice in case of gynecologic symptoms.

Sentinel lymph node (SLN) biopsy is effective to assess axillary nodal status and avoiding axillary lymph node dissection (ALND) in patients with clinically node-negative early stage breast cancer. No standardization of the technique has yet been established. This review discusses the feasibility, the accuracy and the different techniques for this procedure. Although the SLN can be successfully identified by either the dye or gamma probe-guided method, its identification is facilitated when the two techniques are combined. To increase the sensitivity of the pathological examination of the SLN, it is necessary to make multiple step sections with hematoxylin and eosin staining immunohistochemistry on permanent sections. The intraoperative frozen sections and imprint cytology examinations of the SLN may be useful in determining its status, but further studies are needed to establish their performance. In clinical practice, routine ALND can be avoided for small tumours when the multidisciplinary team has an extensive experience of this technique. However, long-term regional control and survival have to be studied in prospective randomised trials, before SLN biopsy can replace routine ALND as the preferred staging method for women with localized breast cancer.

Background: Liver metastases (LM) from breast cancer are generally considered as disseminated disease with a poor prognosis. However in selected patients hepatectomy may be an important adjunct to systemic treatment., Methods: Fifty-four breast cancer patients (mean age 49.2 +/- 5.2 years) with LM as the sole site of metastatic disease (except for bone metastases in 3 patients) underwent hepatectomy between 1986 and 2000. The mean number of LM was 4.0 +/- 8. All patients presented either a stable disease or an objective response to chemotherapy. The last 25 patients also underwent hepatic artery catheter installation in order to receive postoperative hepatic artery infusion chemotherapy (HAIC)., Results: The postoperative morbidity was 12.9%. There was no postoperative mortality. R0 and R1-R2 resections were obtained in, respectively, 81.5% and 18.5% of patients. After a median follow-up of 32 months the median survival was 34 +/- 9 months, with 3- and 5-year overall survival rates of 50% and 34%, and 3- and 5-year disease-free survival rates of 42% and 22%, respectively. The number of LM, the presence of hilar lymph nodes (33%), and the completeness of resection had no significant prognostic impact. The only factor influencing survival in both the univariate and multivariate analysis was the hormone receptor status (P = 0.03): the relative risk of death was increased by 3.5-fold when negative. In the HAIC group, the liver recurrence rate decreased from 60.5% to 31.2% without any impact on global survival., Conclusions: Hepatectomy is beneficial for selected patients with isolated LM. Indications should be based more on technical (low operative risk, probable R0 resection) than on oncologic criteria. The decision is simple for young patients but more difficult for older patients in whom a negative hormone receptor status appears to be a contraindication.

The risk of tamoxifen-related endometrial adenocarcinoma is well established with daily dose and treatment duration of adjuvant tamoxifen as risk factors. There have also been in the past years, a few descriptions of uterine nonepithelial malignancies occurring after tamoxifen. We describe five recent cases of uterine carcinosarcomas occurring under/after tamoxifen administered in an adjuvant setting. None of these patients had received prior pelvic radiation therapy. Their median age at the diagnosis of breast cancer was 58 years (41-68), and 69 years (50-84) at the diagnosis of uterine carcinosarcoma. The median length of exposure to tamoxifen was 9 years (5-20), and the median time from the initiation of tamoxifen to the diagnosis of the uterine malignancy (latency period) 9 years (7-20). All patients presented with an advanced stage (IIA-IVA). Our data, together with those of the literature, plead for a causal role of a prolonged exposure to tamoxifen on the subsequent development of uterine carcinosarcoma. The long latency period observed even in patients receiving only 5 years of treatment leads us also to consider a prolonged gynecologic follow-up of the patients.

Purpose: To report the activity of the chemotherapeutic agent ecteinascidin-743 (ET-743) in advanced pretreated sarcoma patients observed during a phase I study and a named-patient basis, compassionate use program., Patients and Methods: Twenty-nine pretreated, advanced soft tissue sarcoma (STS) and bone sarcoma patients consecutively seen in our centers were included, 12 from a phase I trial and 17 from a compassionate use program cohort. Patients were treated every 3 weeks at either 1,200 microg/m(2) (six patients), 1,500 microg/m(2) (the recommended dose, 22 patients), or 1,800 microg/m(2) (the maximum-tolerated dose, one patient), given as a 24-hour infusion every 3 to 4 weeks., Results: Fifteen men and 14 women were treated. The median patient age was 46 years (range, 16 to 71 years), with a median World Health Organization performance status of 1 (range, 0 to 2). Twenty-five patients had STS, three had osteosarcoma, and one had Ewing's sarcoma, and all had progressive disease at accrual. Fifteen patients had bulky disease, and 14 had clinical resistance to anthracyclines. A total of 136 treatment cycles were administered (median per patient, five cycles; range, one to 12 cycles). Transient grade 3 and 4 transaminitis was reported in 24% and 5% of cycles, respectively, grade 3 to 4 neutropenia occurred in 32% of cycles, with concomitant sporadic grade 3 to 4 thrombocytopenia in 5.1% of cycles. Grade 2 to 3 asthenia occurred in 21% of cycles. There were two partial responses (PRs) in STS patients and two PRs in osteosarcoma patients. Two minor responses and 10 disease stabilizations were seen. Median duration of response was 10.5 months (range, 2.8 to 15 months), and mean duration of stabilization was 5.2 months., Conclusion: ET-743 has activity in advanced, highly pretreated STS and osteosarcoma patients and warrants further trials to establish the extent of its activity in this setting.

To determine the feasibility of the paclitaxel, oxaliplatin, cisplatin combination in advanced ovarian cancer (AOC), 15 patients with AOC (8 chemonaive, and 7 second-line, disease-free interval > or = 12 months) received paclitaxel 135 mg/m2 at day 1, with oxaliplatin 100 mg/m2 and cisplatin 75 mg/m2 at day 2, every 3 weeks for 6 cycles. Pretreated patients received prophylactic granulocyte colony-stimulating factor (5 microg/kg/d, days 6-13). Seventy cycles were administered; median 5 (range: 2-6 cycles) in chemonaive, and 4 (range: 2-6) in pretreated patients. There were grades III to IV neutropenia in 77%, febrile neutropenia in 24%, and grades III to IV thrombocytopenia in 4% of the cycles. Besides neutropenia, cumulative neurosensory toxicity was also limiting although reversible, with National Cancer Institute Common Toxicity Criteria grades II to III observed in 13 patients. Three of the pretreated patients had complete responses (43%), three had partial responses, and one had disease stabilization. Six of the 8 chemonaive patients had complete responses (75%), 1 had disease stabilization, and 1 had disease progression. The median follow-up is 17 months (range: 9-20 months) in chemonaive and 41 months (range: 13-58 months) in pretreated patients, and time to progression has been consistently more than 12 months, with 6 patients (5 chemonaive) still progression free (range: 15+ to 22+ months). This active combination shows acceptable hematologic toxicity, and reversible cumulative neurosensory toxicity. Further clinical exploration of the present combination appears warranted.

Neuroendocrine small cell carcinoma of the uterine cervix (NESCCC) is an entity with very aggressive behaviour. The optimal initial therapeutic approach to this rare disease has not yet been clearly defined. We reviewed our experience of this disease over the past 10 years with regard to chemosensitivity. Since 1988, ten patients (mean age 33 years; range 24-47) have been diagnosed with NESCCC and treated in our institutions. Disease stage at presentation was IA (one), IB (five, two with lymph node involvement), IIB (one), IIIB (one), and IV (two). One patient had metastatic disease at presentation; three developed metastases during initial treatment. Eight patients underwent surgery and eight received radiation therapy. Six patients received pre- or postoperative cisplatinumvepeside (PE) combination chemotherapy, either alone or concurrently with radiation therapy. PE alone as primary chemotherapy led to disease stabilization in the two patients so treated; concurrent PE and radiation therapy resulted in a pathological complete response in one patient. Eight patients relapsed within 16 months and died of their disease within 29 months from the initial diagnosis. Two patients are alive with no evidence of disease at 13 and 53 months. Our series confirms the previously described very poor prognosis of NESCCC, despite initial aggressive multidisciplinary treatment. It may be that the introduction of chemotherapy, especially combined primary chemoradiotherapy, might allow patients to do a little better, although at the moment there is no good evidence one way or the other.

Purpose: This retrospective study was performed to evaluate two postoperative radiotherapy schedules in terms of dose, fractionation, and overall treatment time in soft tissue sarcoma (STS) of the extremities., Methods and Materials: Between January 1984 and December 1993, 62 patients with newly diagnosed localized STS of the extremities were treated with maximal conservative surgery and postoperative radiotherapy (RT). Forty-five patients received 50 Gy with conventional fractionation plus a boost dose (5 to 20 Gy). Seventeen patients had hyperfractionated accelerated radiotherapy (HFART) up to a dose of 45 Gy in 3 weeks., Results: With a median follow-up of 72 months, the 5-year local failure rate was 25%, the 5-year disease-free and overall survival rates were respectively 42% and 62%. The 3-year local relapse, disease-free, and overall survival rates were respectively 16%, 44%, and 70% in the conventional radiotherapy group, and 36%, 47%, and 82% in the HFART group (NS). No factor significantly influenced local control with a trend, however, in favor of conventional RT (p = 0.10)., Conclusion: HFART at the dose of 45 Gy does not seem to be superior to the standard RT schedule, neither in terms of local control, survival, nor in terms of long-term side effects. However this dose could be considered too low as well as the power of comparison between the two groups to draw definitive conclusions.

The hormonal status of 95% of the women treated for epithelial ovarian carcinoma is menopausal, either naturally or after treatment. This raises the important question of the hormonal replacement therapy (HRT) among these patients. Several retrospective studies have explored the potential positive or negative influence of HRT on the genesis of ovarian adenocarcinoma. Although somehow contradictory, these studies taken all together fail to show any favouring nor protective role of HRT. In vitro, estrogens have been shown to induce the proliferation of ovarian cancer cell lines. On the opposite, progesterone and antiestrogens have antiproliferative effects. Both types of effects are mediated by intracellular steroid hormone receptors (ER, PgR). Although high dose progesterone derivatives and antiestrogens have been shown to obtain therapeutic responses in patients carrying advanced ovarian carcinoma, response rates were usually less than 20%, and no clinico-biological correlation (with ER, PgR status) could be demonstrated. There is therefore no evidence for a clinical significance of the presence of hormonal receptors in these tumors. A single retrospective study explored the possible influence of HRT on the prognosis of patients treated for ovarian carcinoma, and did not demonstrate any deleterious effect. This review of recent epidemiological, biological and clinical data fails to find any argument against the prescription of HRT in patients treated for ovarian adenocarcinoma, in the absence of other contra-indications.