Chirurgie du cancer du sein [Breast cancer surgery].

Breast conserving surgery followed by radiation therapy is the treatment of choice for early breast cancer. For patients who choice or need a mastectomy, breast reconstruction provides an acceptable alternative. Breast cancer surgery has been evolving through minimally invasive approaches. Sentinel node biopsy has already remplaced axillary lymph node dissection in the evaluation of the axilla. Local ablation of the tumor may be a valuable alternative to surgery in the future.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Bone mineral density in breast cancer patients treated with adjuvant letrozole, tamoxifen, or sequences of letrozole and tamoxifen in the BIG 1-98 study (SAKK 21/07).

BACKGROUND: The risk of osteoporosis and fracture influences the selection of adjuvant endocrine therapy. We analyzed bone mineral density (BMD) in Swiss patients of the Breast International Group (BIG) 1-98 trial [treatment arms: A, tamoxifen (T) for 5 years; B, letrozole (L) for 5 years; C, 2 years of T followed by 3 years of L; D, 2 years of L followed by 3 years of T]. PATIENTS AND METHODS: Dual-energy X-ray absorptiometry (DXA) results were retrospectively collected. Patients without DXA served as control group. Repeated measures models using covariance structures allowing for different times between DXA were used to estimate changes in BMD. Prospectively defined covariates were considered as fixed effects in the multivariable models. RESULTS: Two hundred and sixty-one of 546 patients had one or more DXA with 577 lumbar and 550 hip measurements. Weight, height, prior hormone replacement therapy, and hysterectomy were positively correlated with BMD; the correlation was negative for letrozole arms (B/C/D versus A), known osteoporosis, time on trial, age, chemotherapy, and smoking. Treatment did not influence the occurrence of osteoporosis (T score < -2.5 standard deviation). CONCLUSIONS: All aromatase inhibitor regimens reduced BMD. The sequential schedules were as detrimental for bone density as L monotherapy.

Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1-98 comparing adjuvant tamoxifen with letrozole.

PURPOSE: To evaluate the prognostic and predictive value of Ki-67 labeling index (LI) in a trial comparing letrozole (Let) with tamoxifen (Tam) as adjuvant therapy in postmenopausal women with early breast cancer. PATIENTS AND METHODS: Breast International Group (BIG) trial 1-98 randomly assigned 8,010 patients to four treatment arms comparing Let and Tam with sequences of each agent. Of 4,922 patients randomly assigned to receive 5 years of monotherapy with either agent, 2,685 had primary tumor material available for central pathology assessment of Ki-67 LI by immunohistochemistry and had tumors confirmed to express estrogen receptors after central review. The prognostic and predictive value of centrally measured Ki-67 LI on disease-free survival (DFS) were assessed among these patients using proportional hazards modeling, with Ki-67 LI values dichotomized at the median value of 11%. RESULTS: Higher values of Ki-67 LI were associated with adverse prognostic factors and with worse DFS (hazard ratio [HR; high:low] = 1.8; 95% CI, 1.4 to 2.3). The magnitude of the treatment benefit for Let versus Tam was greater among patients with high tumor Ki-67 LI (HR [Let:Tam] = 0.53; 95% CI, 0.39 to 0.72) than among patients with low tumor Ki-67 LI (HR [Let:Tam] = 0.81; 95% CI, 0.57 to 1.15; interaction P = .09). CONCLUSION: Ki-67 LI is confirmed as a prognostic factor in this study. High Ki-67 LI levels may identify a patient group that particularly benefits from initial Let adjuvant therapy.

A critical evaluation of secondary cancer risk models applied to Monte Carlo dose distributions of 2-dimensional, 3-dimensional conformal and hybrid intensity-modulated radiation therapy for breast cancer.

The comparison of radiotherapy techniques regarding secondary cancer risk has yielded contradictory results possibly stemming from the many different approaches used to estimate risk. The purpose of this study was to make a comprehensive evaluation of different available risk models applied to detailed whole-body dose distributions computed by Monte Carlo for various breast radiotherapy techniques including conventional open tangents, 3D conformal wedged tangents and hybrid intensity modulated radiation therapy (IMRT). First, organ-specific linear risk models developed by the International Commission on Radiological Protection (ICRP) and the Biological Effects of Ionizing Radiation (BEIR) VII committee were applied to mean doses for remote organs only and all solid organs. Then, different general non-linear risk models were applied to the whole body dose distribution. Finally, organ-specific non-linear risk models for the lung and breast were used to assess the secondary cancer risk for these two specific organs. A total of 32 different calculated absolute risks resulted in a broad range of values (between 0.1% and 48.5%) underlying the large uncertainties in absolute risk calculation. The ratio of risk between two techniques has often been proposed as a more robust assessment of risk than the absolute risk. We found that the ratio of risk between two techniques could also vary substantially considering the different approaches to risk estimation. Sometimes the ratio of risk between two techniques would range between values smaller and larger than one, which then translates into inconsistent results on the potential higher risk of one technique compared to another. We found however that the hybrid IMRT technique resulted in a systematic reduction of risk compared to the other techniques investigated even though the magnitude of this reduction varied substantially with the different approaches investigated. Based on the epidemiological data available, a reasonable approach to risk estimation would be to use organ-specific non-linear risk models applied to the dose distributions of organs within or near the treatment fields (lungs and contralateral breast in the case of breast radiotherapy) as the majority of radiation-induced secondary cancers are found in the beam-bordering regions.

Comparing interval breast cancer rates in Norway and North Carolina: results and challenges.

OBJECTIVE: To compare interval breast cancer rates (ICR) between a biennial organized screening programme in Norway and annual opportunistic screening in North Carolina (NC) for different conceptualizations of interval cancer. SETTING: Two regions with different screening practices and performance. METHODS: 620,145 subsequent screens (1996-2002) performed in women aged 50-69 and 1280 interval cancers were analysed. Various definitions and quantification methods for interval cancers were compared. RESULTS: ICR for one year follow-up were lower in Norway compared with NC both when the rate was based on all screens (0.54 versus 1.29 per 1000 screens), negative final assessments (0.54 versus 1.29 per 1000 screens), and negative screening assessments (0.53 versus 1.28 per 1000 screens). The rate of ductal carcinoma in situ was significantly lower in Norway than in NC for cases diagnosed in both the first and second year after screening. The distributions of histopathological tumour size and lymph node involvement in invasive cases did not differ between the two regions for interval cancers diagnosed during the first year after screening. In contrast, in the second year after screening, tumour characteristics remained stable in Norway but became prognostically more favorable in NC. CONCLUSION: Even when applying a common set of definitions of interval cancer, the ICR was lower in Norway than in NC. Different definitions of interval cancer did not influence the ICR within Norway or NC. Organization of screening and screening performance might be major contributors to the differences in ICR between Norway and NC.

Place du pathologiste dans la prise en charge néoadjuvante des cancers du sein [Neoadjuvant treatment of breast cancer: implications for the pathologist].

These past few years, neoadjuvant strategy has taken an increasing place in the management of breast cancer patients. This strategy is mainly indicated to obtain a tumour bulk regression allowing a breast conserving surgery in patients that otherwise would have undergone mastectomy. Of note, development of new chemotherapy agents and targeted therapies has critically helped in the progress of neoadjuvant strategy as it is currently associated with better pathological response rates. In this context, the pathologist is at the crossroad of this multidisciplinary process. First, he provides on the initial core needle biopsy the tumour pathological characteristics that are critical for the choice of treatment strategy, i.e. histological type, histological grade, proliferative activity (mitotic count and Ki67/MIB1 index labeling), hormone receptor status (oestrogen receptor and progesterone receptor) and HER2 status. Secondly, the pathologist evaluates the pathological response and the status of surgical margins with regards to the residual tumour on the surgical specimen after neoadjuvant treatment. These parameters are important for the management of the patient, since it has been shown that complete pathological response is associated with improved disease free survival. Several grading systems are used to assess the pathological response in breast and axillary lymph nodes. The most frequently used in France are currently the systems described by Sataloff et al. and Chevallier et al. In this review, we detail the different steps involving the pathologist in neoadjuvant setting, with special regards to the quality process and future perspectives such as emerging predictive biomarkers.

Cancer du sein: radiothérapie et signalisation oestrogénique [Breast cancer: radiotherapy and estrogen signaling].

Hormone receptors are expressed in more than 75% of breast cancer. Therefore, two prescription modalities of endocrine therapy could be proposed: either sequential or concomitant to breast cancer irradiation. If combined to radiotherapy, is endocrine therapy a radiosensitizer? Does endocrine therapy enhance the risk factor of radio-induced toxicity? Here, we will distinguish the interaction of ionizing radiation combined with therapies targeting oestrogen receptor (REα) from the interaction of ionizing radiation with oestrogen. This review aims at making clear all these items.

Carcinoembryonic antigen expression, antibody localisation and immunophotodetection of human colon cancer liver metastases in nude mice: a model for radioimmunotherapy.

Colorectal cancer frequently disseminates through the portal vein into the liver. In this study, outbred Swiss nude mice were adapted to facilitate the induction of liver metastases by a pre-grafting treatment with 6 Gy total body irradiation and i.v. injection of anti-asialo GM1 antibody. One day later, cultured LS 174T human colon cancer cells were injected into the surgically exposed spleen, which was resected 3 min later. In 48 of 65 mice, a few to several hundred liver metastases were macroscopically observed at dissection 3 to 4 weeks after transplantation. Ten of 10 mice, followed-up for survival, died with multiple large confluent liver metastases. By reducing the radiation dose to 4 or 0 Gy, or omitting the anti-asialo GM1 antibody injection, only 60%, 37% or 50% of mice, respectively, had visible metastases 3 weeks after transplantation. Carcinoembryonic antigen (CEA) measured in tumour extracts was in the mean 25.6 micrograms/g in liver metastases compared with 9.2 micrograms/g in s.c. tumours. Uptake of radiolabelled anti-CEA monoclonal antibody (MAb) in the metastases 12, 24 and 48 hr after injection gave a mean value of 39% of the injected dose per gram of tissue (ID/g). In comparison, MAb uptake in s.c. and intrasplenic tumours or lung metastases gave a mean percentage ID/g of 20, 18 and 15, respectively. Laser-induced fluorescence after injection of indocyanin-MAb conjugate allowed direct visual detection of small liver metastases, including some that were not visible under normal light. Preliminary results showed that mice, pre-treated with 4 Gy irradiation and the anti-asialo GM1 injection, were tolerant to radioimmunotherapy with a total dose of 500 muCi 131I labeled anti-CEA intact MAbs given in 3 injections.

New insights into the mechanisms of organ-specific breast cancer metastasis.

Despite the substantial advances obtained in the treatment of localized malignancies, metastatic disease still lacks effective treatment and remains the primary cause of cancer mortality, including in breast cancer. Thus, in order to improve the survival of cancer patients it is necessary to effectively improve prevention or treatment of metastasis. To achieve this goal, complementary strategies can be envisaged: the first one is the eradication of established metastases by adding novel modalities to current treatments, such as immunotherapy or targeted therapies. A second one is to prevent tumor cell dissemination to secondary organs by targeting specific steps governing the metastatic cascade and organ-specific tropism. A third one is to block the colonization of secondary organs and subsequent cancer cell growth by impinging on the ability of disseminated cancer cells to adapt to the novel microenvironment. To obtain optimal results it might be necessary to combine these strategies. The development of therapeutic approaches aimed at preventing dissemination and organ colonization requires a deeper understanding of the specific genetic events occurring in cancer cells and of the host responses that co-operate to promote metastasis formation. Recent developments in the field disclosed novel mechanisms of metastasis. In particular the crosstalk between disseminated cancer cells and the host microenvironment is emerging as a critical determinant of metastasis. The identification of tissue-specific signals involved in metastatic progression will open the way to new therapeutic strategies. Here, we will review recent progress in the field, with particular emphasis on the mechanisms of organ specific dissemination and colonization of breast cancer.

Improving breast cancer education: the case of an evolving multidisciplinary module for undergraduate medical students (lausanne medical school, 1993-2008).

Breast cancer is a public health issue in numerous countries. Multidisciplinary collaboration is required for patient care, research, and also education of future physicians. This paper uses Kern's framework for curriculum design to demonstrate how a breast diseases module for undergraduate medical students created in 1993 evolved over 15 years. The main outcomes of program refinements were better integrated course content, the development of electronic course documents, and implementation of computer-aided small group learning. A main future challenge is to further develop efficient instructional strategies in line with well-defined learning needs for undergraduate students.

Role of MT1-MMP in cancer dissemination : insights from the real time imaging of tumors

Abstract : Matrix metalloproteinases (MMPs) are thought to play a major role in the tumor dissemination process as they degrade all components of the extracellular matrix. However, failure of clinical trials testing broad MMP inhibitors in cancer led to the consensus that a better understanding of the MMP biology was required. Using intravital multiphoton laser scanning microscopy, we developed an in vivo model to observe tumor dissemination and extracellular matrix remodeling in real time. We show that the matrix-modifying hormone relaxin increases tumor associated fibroblast interaction with collagen fibers by inducing integrin beta-1 expression. This causes changes in the collagen network that are mediated by MMP-8 and MT1-MMP. Also, we show that MMP-mediated collagen remodeling in vivo requires a direct contact between stationary tumor associated fibroblasts (TAFs) and collagen fibers. As MMPs are expressed in the tumor and stromal compartment of breast cancers we determined the importance of Membrane-type 1 MMP (MT1-MMP) from each compartment for cancer progression. We find that tumor-MT1-MMP promotes the invasion of the blood vasculature and blood-borne metastasis in vivo by enhancing tumor cell migration and endothelial basement membrane degradation. Interestingly, stromal-MT1-MMP cannot compensate for the lack of tumor-MT1-MMP but promotes peritumor collagen I remodeling. Thus, the function of MT1-MMP is context dependent and we identify the different but complementary roles of tumor and stromal MT1-MMP for tumor dissemination. Finally, we translate our preclinical findings in to human breast cancer samples. We show that tumor-MT1-MMP expression correlates with tumor invasion of the blood vasculature in ER-PR-HER2- breast cancers and that MT1-MMP expression increases with cancer progression. MT1-MMP could thus represent an interesting therapeutic target for the prevention of blood vasculature invasion in these tumors. Resumé : Les matrix metalloproteinases (MMPs) semblent jouer un rôle majeur pour la dissémination tumorale en raison de leur capacité à dégrader l'ensemble des composants de la matrice extracellulaire (MEC). Néanmoins, les résultats décevants des études cliniques testant les inhibiteurs des MMP ont conduit à la notion qu'une compréhension plus précise de la biologie des MMP était requise. Dans ce travail de thèse, nous avons développé un modèle murin qui permet d'observer simultanément la dissémination tumorale ainsi que les modifications de la MEC en temps réel. Nous démontrons que le traitement de tumeurs par l'hormone relaxin augmente l'interaction des fibroblastes tumoraux avec les fibres de collagène via l'intégrine beta-1. Nous montrons que cette interaction favorise et est nécessaire à la dégradation des fibres de collagène par MMP-8 et MT1-MMP. Ensuite, étant donné que les MMPs sont exprimées dans les cellules tumorales et stromales des cancers du sein, nous nous sommes intéressés au rôle de la MMP membranaire type 1 (MT1-MMP) exprimée dans chacun de ces compartiments. Nous démontrons que MT1-MMP dérivant des cellules tumorales favorise leur invasion dans les vaisseaux sanguins par la dégradation de la membrane basale vasculaire. De manière inattendue, nous montrons que l'expression de MT1-MMP par le compartiment stromal ne peut compenser le manque de MT1-MMP dans le compartiment tumoral. Néanmoins, nos résultats prouvent que MT1-MMP dérivant du compartiment stromal est impliqué dans la dégradation de collagène peritumorale. La fonction de la protéine MT1-MMP varie donc selon le compartiment tumoral d'origine. Finalement, nous avons testé nos résultats pré cliniques chez l'humain. Dans des biopsies de cancer du sein nous montrons une corrélation entre l'expression de MT1-MMP dans les cellules tumorales et l'invasion de vaisseaux sanguins par des tumeurs ER-PR-HER2-. MT1-MMP pourrait donc être une cible intéressante pour la prévention de dissémination vasculaire de ces tumeurs

The Oncogene Metadherin Modulates the Apoptotic Pathway Based on the Tumor Necrosis Factor Superfamily Member TRAIL (Tumor Necrosis Factor-related Apoptosis-inducing Ligand) in Breast Cancer.

Metadherin (MTDH), the newly discovered gene, is overexpressed in more than 40% of breast cancers. Recent studies have revealed that MTDH favors an oncogenic course and chemoresistance. With a number of breast cancer cell lines and breast tumor samples, we found that the relative expression of MTDH correlated with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity in breast cancer. In this study, we found that knockdown of endogenous MTDH cells sensitized the MDA-MB-231 cells to TRAIL-induced apoptosis both in vitro and in vivo. Conversely, stable overexpression of MTDH in MCF-7 cells enhanced cell survival with TRAIL treatment. Mechanically, MTDH down-regulated caspase-8, decreased caspase-8 recruitment into the TRAIL death-inducing signaling complex, decreased caspase-3 and poly(ADP-ribose) polymerase-2 processing, increased Bcl-2 expression, and stimulated TRAIL-induced Akt phosphorylation, without altering death receptor status. In MDA-MB-231 breast cancer cells, sensitization to TRAIL upon MTDH down-regulation was inhibited by the caspase inhibitor Z-VAD-fmk (benzyloxycarbonyl-VAD-fluoromethyl ketone), suggesting that MTDH depletion stimulates activation of caspases. In MCF-7 breast cancer cells, resistance to TRAIL upon MTDH overexpression was abrogated by depletion of Bcl-2, suggesting that MTDH-induced Bcl-2 expression contributes to TRAIL resistance. We further confirmed that MTDH may control Bcl-2 expression partly by suppressing miR-16. Collectively, our results point to a protective function of MTDH against TRAIL-induced death, whereby it inhibits the intrinsic apoptosis pathway through miR-16-mediated Bcl-2 up-regulation and the extrinsic apoptosis pathway through caspase-8 down-regulation.