[Breast cancer : individualized risk assessment for tailor-made screening]. / Cancer du sein : évaluation individualisée du risque en vue d'un dépistage sur mesure.

Breast cancer is the leading cause of neoplastic death in women around the world. In the era of personalized medicine, legitimately awaited by our patients, the future of breast cancer screening will depend on an individual-based risk assessment, making it possible to better adapt the age of onset, frequency and the type of examinations useful for this screening. This article reviews the three broad categories of highest risk factors available to establish a risk score appropriate for each patient.

Le cancer du sein est la première cause de mortalité par néoplasie chez la femme de par le monde. À l'ère d'une médecine personnalisée, légitimement attendue par nos patientes, l'avenir du dépistage du cancer du sein passera par une évaluation du risque sur base individuelle, permettant d'adapter, au mieux, l'âge de début ainsi que la fréquence et le type des examens utiles pour ce dépistage. Cet article passe en revue les trois grandes catégories de facteurs de plus haut risque disponibles pour établir un score de risque adapté à chaque patiente.

[Primary and secondary prevention for women at high risk for breast cancer]. / Prévention primaire et secondaire chez les femmes à haut risque de cancer mammaire.

Many factors determine a woman's risk of breast cancer; some genetic are related to family history, others are based on personal factors such reproductive and medical history. A high-risk woman must benefit of a specific screening regimen including breast examination, mammography, ultrasonography and contrast material-enhanced magnetic resonance. But she can also benefit of chemo prevention or/and risk-reducing surgery such bilateral prophylactic salpingo-oophorectomy and bilateral prophylactic mastectomy.

[Breast cancer in Belgium: why are we the first in Europe?]. / Le cancer du sein en Belgique: pourquoi sommes-nous les premiers en Europe?

Breast cancer incidence in Belgium is on the top of European countries, with 9.697 new cases in 2008 and 106/100.000 women/year. The explanation of this high incidence in our country is probably the accumulation of risk factors (many of them are linked to lifestyle), and the impact of screening and registration of cases. The relative impact of each of theses factors is less clear because we don't have powerful statistical studies. Belgium is slightly above the European mean for breast cancer mortality, with 19,4/100.000 women/year and an all stages 15-year survival of 75%. Breast cancers are responsible for around 3% of all-cause mortality in Belgian women. This article discusses the causes of this high Belgian incidence and of current decrease of incidence in western countries, and reviews known and less known risk factors of breast cancers, with a special focus on menopause hormonal treatments.

[Management of estrogen deficiency after breast cancer]. / Prise en charge des conséquences de la carence oestrogénique après cancer du sein.

The prevention and the treatment of oestrogen deficiency induced by breast cancer treatments are crucial in the management of patients. The impacts of this deficiency must not be neglected: quality of life impairments inducing eventually premature withdrawal of hormonotherapies, and excess of bone and cardio-vascular morbidities and mortalities, especially in good prognosis young women. Management strategies of short and long term effects of this deficiency are reviewed and discussed here.

[Hormone therapy for breast cancer]. / Hormonothérapie du cancer du sein.

Following Beatson's publications in 1896, various modalities of endocrine therapy applied to breast cancer have been developed. Endocrine treatment has greatly contributed to the improvement of the disease's prognosis. Tamoxifen has established itself as a first choice adjuvant therapy for patients with tumors expressing hormone receptors. Over the last decade, third generation aromatase inhibitors have demonstrated their efficacy amongst menopausal patients, alone or in combination with tamoxifen. Efficacy of these medications is dependent on patient's compliance. This article proposes a synthesis of the main knowledges available in the field of breast cancer endocrine therapy.

[Adherence to long-term medication: the particular case of the adjuvant endocrine therapy for breast cancer]. / L'observance au traitement de longue durée: le cas particulier de l'hormonothérapie adjuvante du cancer du sein.

The aim of adjuvant hormone therapy for breast cancer is to reach, in daily practice, an efficacy similar to that obtained in clinical trials. In spite of the demonstrated efficacy of hormone therapy, compliance represents a major challenge and a multidimensional problem. A better understanding of the reasons underlying non-compliance would help identify the patients at higher risk and would permit the implementation of strategies to improve compliance to adjuvant hormone therapy. With this in mind, we undertook a review of the recent literature on the topic (Pub Med 2003-2009).

Coping with menopausal symptoms: An internet survey of Belgian postmenopausal women.

OBJECTIVES: An internet survey was performed to obtain data on the current use in Belgium of hormone replacement therapy and alternative treatments for the alleviation of menopausal symptoms. A supplementary aim was to assess the use of opt-in internet opinion panels (TalkToChange, http://www.talktochange.com, and GMI, http://www.gmi-mr.com/global-panel) as a potential new way to obtain data on menopausal issues. STUDY DESIGN: Data were collected via an internet platform from 696 postmenopausal women aged 45-60 years. OUTCOME MEASURES: Respondents were asked questions about their socio-demographic profile, their experience of the menopause, the burden of the menopause, its impact on their quality of life and the treatment of menopausal symptoms (if any). RESULTS: The opt-in internet opinion panels proved a quick way (19days) to obtain reliable information with a low error margin (3.7%). The online survey collected detailed socio-demographic data. Almost all of the women (98%) had heard about the menopause before. Sixty-one percent perceived the menopause as a temporary phase (17% thought it lasted for one or two years and 44% thought it lasted for three to five years) and only 39% realized the menopause would last for the rest of their life. Twenty-three percent of the women reported any kind of impact of the menopause on their quality of life. However, for the other 77% the menopause had resulted in complaints. No differences according to the women's age, level of education or professional status were found in this respect. Sixty-nine percent of the women had 'ever' used some type of treatment for menopausal symptoms and 53% were currently using a treatment. Forty percent of those with more than three symptoms were currently untreated. Of those who were not on hormone replacement therapy (HRT), 61% would not consider taking it (54% were 'strongly opposed' and 7% simply 'opposed'), while 8% would consider asking their doctor for HRT. Among those women who were opposed to HRT, 25% indicated that they were afraid of the increased risk of breast cancer, 34% cited cardiovascular risks and 26% were worried about weight gain. In this Belgian sample, HRT was used significantly more often by French-speaking women (32%) than by Dutch-speaking women (9%) (OR 4.4, p<0.0001). The alternatives to HRT had a high satisfaction rate among users. Relaxation techniques, regular physical activity, acupuncture and avoiding stress had satisfaction rates similar to that with HRT. It was not possible to compare the alternatives in the same women. Nor was it possible to assess whether more pronounced symptoms required a specific treatment. CONCLUSION: Opt-in internet opinion panels proved a quick and efficient way to gather data on menopausal issues in Belgium. Despite the high levels of awareness and knowledge, there is some confusion concerning the duration of the menopause, and its common perception as a temporary condition is likely to mean that the menopausal burden is substantially underestimated. Many symptomatic women are untreated.

Progesterone receptor activation. an alternative to SERMs in breast cancer.

Data regarding the effects of progesterone and a progestagen on human normal breast epithelial cell proliferation and apoptosis are presented here. In postmenopausal women, adding progesterone to percutaneously administrated oestradiol significantly reduces the proliferation induced by oestradiol. In vitro and in premenopausal women, stopping the administration of nomegestrol acetate triggers a peak of apoptosis. Fibro-adenoma and cancerous cells do not show this regulation of apoptosis. Progesterone seems to be important in normal breast homeostasis.

Estradiol and progesterone regulate the proliferation of human breast epithelial cells.

OBJECTIVE: To study the effects of estradiol and progesterone on the proliferation of normal human breast epithelial cells in vivo. DESIGN: Double-blind randomized study. SETTING: Departments of gynecology and of cell biology at a university hospital. PATIENT(S): Forty postmenopausal women with untreated menopause and documented plasma FSH levels of >30 mIU/mL and estradiol levels of <20 pg/mL. INTERVENTION(S): Daily topical application to both breasts of a gel containing a placebo, estradiol, progesterone, or a combination of estradiol and progesterone during the 14 days preceding esthetic breast surgery or excision of a benign lesion. MAIN OUTCOME MEASURE(S): Plasma and breast tissue concentrations of estradiol and progesterone. Epithelial cell cycles were evaluated in normal breast tissue by counting mitoses and performing quantitative proliferating cell nuclear antigen immunolabeling analyses. RESULT(S): Increasing the estradiol concentration enhanced the number of cycling epithelial cells, whereas increasing the progesterone concentration significantly limited the number of cycling epithelial cells. CONCLUSION(S): Exposure to progesterone for 14 days reduced the estradiol-induced proliferation of normal breast epithelial cells in vivo.

Effects of a progestogen on normal human breast epithelial cell apoptosis in vitro and in vivo.

Many investigators have reported cyclic proliferation of normal human breast epithelial cells. A delicate balance between proliferation and apoptosis (programmed cell death) ensures breast homeostasis. Both the follicular and luteal phases of the menstrual cycle are characterized by proliferation, whereas apoptosis occurs only at the end of the latter phase. In this study, we observed that the withdrawal of a synthetic progestin (nomegestrol acetate or NOMAC), but not continuous treatment with it, induced apoptosis of normal human breast epithelial cells in vitro and in women who applied NOMAC gel to their breasts. Furthermore, this apoptotic response was specific to normal breast cells, since withdrawal of NOMAC did not induce apoptosis of tumoral T47D cells in vitro or of fibroadenoma cells in women. These observations open up new perspectives in the prevention of hyperplasia and breast cancer.

[Revised postmenopausal treatments? A new polemic!]. / Les traitements post-ménopause à revoir? Une polémique nouvelle!

The study by Schairer et al. aims to determine whether increases in risk of breast cancer associated with the estrogen-progestin regimen are greater than those associated with estrogen alone. This study is a cohort of follow-up data for 1980-1995 from the Breast Cancer Detection Demonstration Project, a nationwide breast cancer screening program that involved 29 screening centers throughout the United States. A total of 46,355 postmenopausal women were followed. During follow up, 2,082 cases of breast cancer were identified. Increases in risk with estrogen only and estrogen-progestin only were restricted to use within the previous 4 years. The relative risk increased by 0.01 with each year of estrogen-only use and by 0.08 with each year of estrogen-progestin-only use among recent users. Among women with a Body Mass Index of 24.4 kg/m2 or less, increases in relative risk with each year of estrogen-only use and estrogen-progestin-only use among recent users were 0.03 and 0.12, respectively. The authors conclude that the estrogen-progestin regimen increases breast cancer risk beyond that associated with estrogen alone. This study was largely commented in the lay media. Unfortunately the Belgian media introduced the confusion between the relative risk and the risk attributable to estrogen and estrogen-progestin. The aim of this manuscript is to precisely inform our colleagues, to analyze the Schairer study and to present the actual figures of risk associated with the use of estrogen and estrogen-progestin replacement therapy. Finally, we formulate some suggestions for the physician to whom the patient declares: "Did you read the negative effects of hormones?". What should we advice?

[Hormone replacement therapy after breast cancer. Yes...or no?]. / Traitement hormonal après cancer du sein. Oui ... ou non?

Clinical and experimental studies indicate that combined unique conjugated estrogens and medroxyprogesterone acetate moderately increase the risk of breast cancer in postmenopausal women. Classically, hormone replacement therapy is contra-indicated in women with a past history of breast cancer due to the fear of recurrence. However, these postmenopausal patients complain about hot flushes and adjuvant hormonal therapies (such as aromatase inhibitors, SERMs and Tamoxifen...) aggravate their symptoms. Observational studies and their meta-analyses do not show a deleterious effect but rather a beneficial impact of hormone replacement therapy among women with a past history of breast cancer. We summarise all these studies and their biological, clinical and epidemiological interpretations. We conclude that short term hormone replacement therapy is safe among those women requesting a replacement therapy after complete information. It is however advisable to conclude definitely only when prospective randomised trials with estradiol or tibolone (a promising alternative) will be available. Such ongoing studies will allow to conclude definitely the possible benefits and risks of hormone replacement therapy among patients with a past history of breast cancer.

[Transdermal replacement hormone therapy: a trend or an advantage?]. / L'hormonothérapie de substitution transdermique: une mode ou un avantage?

This review describes the clinical usefulness of transdermal hormone replacement therapy. This route of administration is particularly important in women with hypertriglyceridemia, in hypertensive postmenopausal women, in women who smoke or have an increased risk of biliary or liver disorder, for those who display a reduced glucose tolerance or in women who are at risk of thrombotic disorders. The avoidance of the "first passage effect" is ensured by the transdermal application of estrogen and probably explains the superiority of this route of steroid administration.

[Benefits and limitations of mammography]. / Intérêt et limites du dépistage de masse du cancer du sein par mammographie seule (mammotest).

The literature on screening mammography provides ample opportunity for doubt (the sceptics) and dogma (the screening zealots), and can be interpreted to prove both benefit and harm. The benefit of mammography screening, if any, is modest and the balance between beneficial (potentially, a 20% relative reduction in breast cancer mortality with no significant benefit on all-cause mortality) and harmful (physical and psychological morbidity related to the 15-40% missed cancers and the 80-90% false-positive diagnoses) effects is still delicate. The mammogram alone is a modest weapon. Concurrent clinical breast examination is mandatory. Women that are concerned about breast cancer should be fully informed of the potential benefits and risks of screening mammography. These women should benefit from mammography with concurrent clinical breast examination, and possible whole-breast ultrasound in heterogeneously dense and extremely dense breast patterns.

Should we individualize breast cancer screening?

Publicly organized population breast cancer screening is presently hotly debated. Indeed, population screening is poorly effective, induces harms in a healthy population and is costly. However, stopping all kind of screening of low- and average-risk women would be problematic as about 70% of breast cancers are diagnosed in those subgroups, and maintaining current population screening in high-risk women would be insufficient. We propose herein a review about the advantages and the inconvenience of individualized screening. The latter could be a more efficient strategy. The principles of individualized screening are (a) to start from the age at which the breast cancer risk is equal to that for an average women aged 50 years, (b) to stop when the risk of co-mortality exceeds the risk of breast cancer mortality, (c) to adapt the exams frequency and the imaging modalities to the individual risk and to the breast density, (d) to reassess regularly and individually the screening strategy, and (e) to discuss honestly with each woman in order to help her to decide if she participates or not.

Hormone therapy and breast cancer risk.

Hormone therapy (HT) is the most efficacious intervention for the relief of climacteric symptoms. Controversies surrounding HT have left many women puzzled and afraid. Gynecologists are faced with long-standing beneficial assumptions challenged by an abundance of robust detrimental new data, with little guidance on how to interpret these findings. Prescriptions for HT (and incidence of breast cancers in some areas) have fallen over the last 3 years due to anxiety provoked about breast cancer risk and recurrence. The current 'clinical climate' is against HT. Due to a lack of effective alternatives, women suffering from estrogen-deficiency symptoms are still requesting objective information about HT, particularly those at higher risk of breast cancer or those with a past history of breast cancer. In this situation, discussion of the current clinical uncertainty surrounding the use of HT must be undertaken to ensure that women are adequately informed. The objective of this presentation is to provide a framework for understanding breast cancer risk associated with HT. What are the precise molecular mechanisms of estrogen and progestin in the initiation of breast cancer? Does the risk of estrogen-only therapy on breast cancer vary by dose, constituent, route and duration of administration and cessation of use? Does HT, in addition to increasing risk for breast cancer, affect the type of breast cancer (lobular and ductal) diagnosed? Is HT associated with breast cancers that have better prognostic factors? How relevant are the changes in mammographic breast density associated with HT for the evaluation of breast cancer risk? What is the additional global health risk/benefit ratio associated with the selective use of progesterone or progestin that may confer a significant cardiovascular benefit, such as drospirenone? It is currently assumed and tested that new hormones with particular pharmacological profiles may ultimately achieve their therapeutic goal of relieving climacteric symptoms without an associated moderate increased risk of breast cancer.

Oral progestagens before menopause and breast cancer risk.

We examined the relationship between use of progestagen-only before menopause (except for mini-pills) after the age of 40 and invasive breast cancer risk in 73 664 women from the French E3N cohort study (mean age at start of follow-up, 51.8 years; mean duration of follow-up, 9.1 years). A total of 2390 cases of invasive breast cancer were diagnosed during follow-up. Risk estimates were calculated using the Cox proportional hazard model. Overall, ever use of progestagen before menopause was not significantly associated with risk (relative risk (RR): 1.01, 95% confidence interval: 0.93-1.11). However, we observed a significant increase in risk associated with the duration of use (P-value for trend: 0.012), current use of progestagens for longer than 4.5 years being significantly associated with risk (RR: 1.44, 95% confidence interval: 1.03-2.00). Prolonged use of progestagens after the age of 40 may be associated with an increased risk of breast cancer and the subject needs to be investigated further.

Highly stable lanthanide macrocyclic complexes: in search of new contrast agents for NMR imaging.

This paper presents the views of a coordination chemist on the synthesis and the properties of new contrast agents containing gadolinium. Attention is drawn to various macrocyclic complexes such as the polyaza polycarboxylic chelates, the cryptates as well as compounds obtained by template synthesis. The structural factors influencing the kinetic and thermodynamic stability of the gadolinium complexes are discussed with special emphasis on the polyaza polycarboxylic derivatives. Some of the macrocyclic complexes under investigation are more stable than Gd-DTPA.

Alteration of interendothelial adherens junctions following tumor cell-endothelial cell interaction in vitro.

The integrity of the vascular endothelium is mainly dependent upon the organization of interendothelial adherens junctions (AJ). These junctions are formed by the homotypic interaction of a transmembrane protein, vascular endothelial cadherin (VE-cadherin), which is complexed to an intracellular protein network including alpha-, beta-, and gamma-catenin. Additional proteins such as vinculin and alpha-actinin have been suggested to link the VE-cadherin/catenin complex to the actin-based cytoskeleton. During the process of hematogenous metastasis, circulating tumor cells must disrupt these intercellular junctions in order to extravasate. In the present study, we have investigated the influence of tumor cell-endothelial cell interaction upon interendothelial AJ. We show that human breast adenocarcinoma cells (MCF-7), but not normal human mammary epithelial cells, induce a rapid endothelial cell (EC) dissociation which correlates with the loss of VE-cadherin expression at the site of tumor cell-EC contact and with profound changes in vinculin distribution and organization. This process could not be inhibited by metalloproteinase nor serine protease inhibitors. Immunoprecipitations and Western blot analysis demonstrate that the overall expression of VE-cadherin and vinculin as well as the composition of the VE-cadherin/catenins complex are not affected by tumor cells while the tyrosine phosphorylation status of proteins within the complex is significantly altered. Our data suggest that tumor cells modulate AJ protein distribution and phosphorylation in EC and may, thereby, facilitate EC dissociation.

Induction of endothelial cell apoptosis by solid tumor cells.

The mechanisms by which tumor cells extravasate to form metastasis remain controversial. Previous studies performed in vivo and in vitro demonstrate that the contact between tumor cells and the vascular wall impairs endothelium integrity. Here, we investigated the effect of breast adenocarcinoma MCF-7 cells on the apoptosis of human umbilical vein endothelial cells (HUVEC). TUNEL labeling, nuclear morphology, and DNA electrophoresis indicated that MCF-7 cells induced a two- to fourfold increase in HUVEC apoptosis. Caspase-3 activity was significantly enhanced. Neither normal cells tested (mammary epithelial cells, fibroblasts, leukocytes) nor transformed hematopoietic cells tested (HL60, Jurkat) induced HUVEC apoptosis. On the contrary, cells derived from solid tumors (breast adenocarcinoma, MDA-MB-231 and T47D; fibrosarcoma, HT 1080) had an effect similar to that of MCF-7 cells. The induction of apoptosis requires cell-to-cell contact, since it could not be reproduced by media conditioned by MCF-7 cells cultured alone or cocultured with HUVEC. Our results suggest that cells derived from solid tumors may alter the endothelium integrity by inducing endothelial cell apoptosis. On the contrary, normal or malignant leukocytes appear to extravasate by distinct mechanisms and do not damage the endothelium. Our data may lead to a better understanding of the steps involved in tumor cell extravasation.