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Background: About 15 to 20% of breast cancer cases overexpress human epidermal growth factor receptor-2 (HER-2). This overexpression is associated with poor clinical prognosis but therapeutic success of trastuzumab or lapatinib. HER-2 extracellular domain (ECD) undergoes a proteolytic cleavage and is shed into biologic fluid as a circulating antigen called ECD/HER-2, which can be detected by immunochemical assays., Objective: The aim of our review was to determine the clinical usefulness of ECD/HER-2 measurement in the management of breast cancer patients., Material and Methods: A Pubmed search for publications in English or French was carried out until March 31, 2010 (69 original articles and 8 reviews)., Results: The measurement of ECD/HER-2 concentration does not exempt from the pathological determination of HER-2 expression in tumors; some HER-2 negative tumors are associated with high levels of ECD/HER-2, on the other hand, some HER-2 positive tumors present low levels of ECD/HER-2. The concentration of ECD/HER-2 is correlated to disease progression, since 10% of loco-regional breast cancers and more than a third of metastatic breast cancers have high levels of ECD/HER-2. The elevation of ECD/HER-2 levels generally occurs several months before the diagnosis of symptomatic metastases. The relevance of ECD/HER-2 measurements during chemotherapy, hormone therapy and trastuzumab treatment remains uncertain. Similarly, it is not commonly agreed that high levels of ECD/HER-2 before any treatment in the case of an early breast cancer, is an independent prognostic factor., Discussion: A close analysis of a variety of pathological, biochemical, clinical and methodological data may explain these discrepancies., Conclusion: New prospective studies using immunochemical measurements of ECD/HER-2 (with a consensual threshold) and based on both detailed pathological analyses and a comprehensive collection of clinical data are still required to establish the clinical usefulness of circulating ECD/HER-2 measurement for breast cancer patients' management., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Purpose: The aim of this prospective study was to analyze the safety of methylene blue dye (MBD) and compare its efficacy with that of isotopic mapping for sentinel lymph node (SLN) identification in breast cancer., Patients and Methods: The SLN procedure, involving isotopic mapping and MBD (subareolar intraparenchymal injections of 2 mL, 10 mg/mL), was performed on 100 patients with early breast cancer., Results: The procedure was safe with a success rate of 99%; SLNs were, respectively, found in 65% by MBD, in 73% by lymphoscintigraphy and in 94% by gamma-probe. Out of 40 metastatic SLNs, 37 were "hot" and 32 stained. Digital examination allowed the detection of 2 additional metastatic LNs., Conclusion: MBD is safe and combination mapping associated with digital examination is the superior method. Modification of the procedure, favouring injections of dilute MBD (4 mL, 1.25 mg/mL) increases MBD efficiency (90%) and maintains low rates of complications.

Mammographic density is a risk factor for breast cancer and it reflects variations in the tissue composition of the breast. It is notably influenced by body mass index and by endogenous hormones as well as hormone replacement therapy (HRT). The pathways that are responsible for the increase in mammographic density following exposure to hormones and those that increase risk of breast cancer are probably not the same. Careful clinical and mammographic follow-up is appropriate in women undergoing HRT because an increase in density is not only a risk factor for breast cancer but it also reduces screening sensitivity. We present a case in which mammographic density decreased after menopause, then dramatically increased after HRT and finally, surgical biopsy allowed the diagnosis of an infiltrative breast carcinoma. We discuss appropriate HRT changes in case of increasing mammographic density.

Objectives: Identification of women who survived infiltrative breast cancer and subsequently conceived and determination of the rate of pregnancy, the time from diagnosis to pregnancy, the outcome of breast cancer and of subsequent pregnancies., Patients and Methods: Women treated for breast cancer at the Gynaecology and Obstetrics Unit of the University Hospital of Strasbourg between 1993 and 2007 who subsequently conceived were prospectively registered and followed yearly., Results: Twenty pregnancies subsequent to surgery for breast carcinoma were observed in 598 patients. This association accounted for 3.3% of the cases of infiltrative breast carcinoma in potentially fertile women under 45. Six pregnancies were observed less than two years after breast cancer diagnosis (four abortions and two live births) and 17 pregnancies occurred after two years (three abortions, three miscarriages, one extra-uterine pregnancy and 10 live births). Two patients who developed distant metastases after pregnancy (less than one year and more than five years after diagnosis respectively) died. One patient, whose pregnancy occurred three years after the diagnosis, is still alive with a lung cancer and brain metastases. One patient was treated for local breast cancer recurrence. The overall prognosis was good, 18 patients (90%) being alive with a mean follow-up of 105 (S.D. 43) months., Discussion and Conclusion: Pregnancy is more likely to occur in patients with a prolonged survival and no evidence of disease. Maternal prognosis is mainly related to initial stadification of breast cancer and not to its hormonodependence.

Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58,515 women with invasive breast cancer and 95,067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, women's age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19-1.45, P<0.00001) for an intake of 35-44 g per day alcohol, and 1.46 (1.33-1.61, P<0.00001) for >/=45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5-8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1% per 10 g per day, P<0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers=1.03, 95% CI 0.98-1.07, and for current smokers=0.99, 0.92-1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver.

Purpose: To assess difficulties in reading screening mammographies related to hormone replacement therapy (HRT) in the setting of a breast cancer screening program. Disagreement between two readers is used as the assessment criterion., Population and Methods: The study population consisted of all women participating in the ADEMAS breast cancer screening program in Bas-Rhin (France). Agreement between the two radiologists was considered when the same global conclusion (call-back or not of the women for further examination) or the same conclusion for each of the nine possible lesions was observed., Results: HRT is associated with a higher risk of disagreement between the two radiologists on global conclusion and on opacities. Conversely, disagreement risk is lowered for microcalcifications (whether benign or malignant) for HRT users., Conclusion: HRT is associated with a higher risk of disagreement on global conclusion. This has an impact on whether the women should be called-back or not according to reading of breast cancer screening program mammographies.

Since 1989, in the French department of Bas-Rhin, a breast cancer screening program in going on and its results are presented here. This program, concerning women of 50 to 65 years-old, is decentralized, based on private or public radiologists and the motivation of women because there is no invitation. The interval between screening test is 2 years. After 8 years, the results are rather satisfactory: participation rate of the initial cohort is 77% in December 31st 1997, participation at incident screenings is above than 85%, early indicators (recall rate, detection rate, PPV of screening, PPV of biopsy) are improving with time to attain numbers like international studies. The ADEMAS program shows that a decentralized screening program, based on existing medical structures is possible in France. Anyway, it must be organized, evaluated at any time, with a quality assurance system to guarantee the women the best taking charge.

Purpose: This paper presents the cost of two decentralised breast cancer screening programmes in France, in the Bas-Rhin and the Bouches du Rhône districts. Materials and methods. The costs directly related to running the two screening programmes were collected for the time period 1990-1997. Only direct costs of each programme, excluding assessment and treatment costs, are included in the cost analysis. Costs are presented per screening period, per programme attender and per cancer detected by screening., Results: The screening programme costs an average of 397 francs per woman screened and 90,828 francs per cancer detected in the Bas-Rhin, and 379 francs and 76,159 francs, respectively, in the Bouches du Rhône., Conclusions: These costs are high compared to those of existing centralised programmes. Further research is needed to investigate means of ensuring the optimal efficiency of these programmes. The results of this study may help guide future decisions on the further development of breast cancer screening in France.

Large block macrosectioning of segmental excision specimens for breast cancer, and especially ductal carcinoma in situ, provides detailed information regarding size of the lesions, extent of spread and margin status which are essential for local recurrence risk assessment. However, the expansion of this technique has been curbed due to its reputation of being technically difficult, time-consuming, costly and providing slides of poor quality. We assessed the feasibility of the large section technique and adapted it to the everyday practice of a routine pathology laboratory. The time spent cutting a large block on a motorized microtome is half the time spent cutting the great number of conventional blocks needed to assess the same amount of tissue. Finally, 4 mm-thick stained large preparations of high quality are produced within 3 days after receiving the specimen. Analysis and report are both more precise and easier since the pathologist is saved the trouble of having to mentally re-assemble a great quantity of numbered small blocks. 805 primary monobloc segmental excision specimens have been examined in this way over the last 50 months period and we advocate its use as a standard procedure for breast-conserving surgery specimen management.

The objective were to study the relevance of the subareolar injection for sentinel node [SN] detection in multiple foci breast cancer. Seventy-nine patients with infiltrative breast carcinoma (diagnosed pre-operatively by core biopsy) and a mean age of 55 (31-78) years were enrolled. All patients were free of previous homolateral surgery, chemotherapy, locoregional radiotherapy or prevalent axillary lymph node. Using four 0.1 ml injections of 1.8 MBq, the technetium-99m 100 nm filtered sulfur colloid was injected by subareolar way (group I) in 16 cases of radiologically cancer with multiple invasive foci and 31 cases of radiologically unifocal cancer, and by peritumoral way (group II) in 32 cases of radiologically unifocal cancer. Scintigrams were obtained 2 to 4 hours after the injections and radioactive nodes were detected peroperatively 18 hours after the injection by intraoperative detection probe. Individual removal of all radioactive nodes was followed by axillary dissection at levels I and II of Berg including Rotter area control. All sentinel nodes were submitted to standard histopathological analysis on serial sections at 500 mu intervals completed by immunohistochemistry for cytokeratin on negative SN. SN were detected by scintigrams in 85% and 88% of the cases of group I and group II respectively, but in 98% and 97% of the cases of respectively both groups by intraoperative probe. Group I was composed of 69% ductal, 22% lobular and 9% tubular carcinomas, and group II of 87% ductal, 10% lobular and 3% tubular carcinomas. Seven and 5 radiologically unifocal tumors were in fact with multiple invasive foci at histology in groups I and II respectively. The complete scintigraphic procedure permitted the detection of a mean number of 2.7 (1-7) SN in group I and 2.3 (1-4) in group II (NS). In group I, the SN were metastatic in 22 patients (48%), 15 of them with the metastases being restricted to the SN, whereas in group II, the SN were metastatic in 9 patients (28%), 5 of them with the positivity restricted to the SN. No false negative result (SN negative and other axillary nodes positive) was observed in group I and only one false negative result in group II which was related to a cancer with histological multiple invasive foci. Sensitivities were 100% and 90%, and negative predictive values were 100% and 95%, for groups I and II respectively. Subareolar injection of radiocolloid allows identification of SN in cases of unifocal and multiple cancer. The mean number of SN detected by the subareolar method is not significantly different, although higher, to that detected by peritumoral injection.

Breast cancer is the most frequent cancer in women: more than 8 to 9% of women will develop a breast cancer during their life and the incidence rate is regularly increasing. Despite therapeutic improvements, breast cancer mortality still remains important and varying according to regions (five years survival: 62 to 80% for the last years). The risks factors analysis shows that a primary prevention of the major risks factors is not yet possible (genetic or endogenous hormonal risk). The chemoprevention is still is discussion and under investigation. For the moment, secondary prevention using screening is the only way to improve survival. The lead-time induced by the screening allows an earlier detection of breast cancers. The randomized trials have demonstrated a significant benefit on mortality and morbidity from breast cancer in women aged 50 to 69. So many countries started regional, pilot or national breast cancer screening programmes using mammography with a 2-year interval and specialized centers.

New isoforms of CD44 with alternatively spliced exons have recently been described. Expression of exon v6 seems to be of particular interest. It has indeed been associated with poorer outcome of breast cancer patients with node invasion at diagnosis. However, no data were available for patients N0M0 (with neither metastasis nor node invasion at diagnosis). Moreover, previous statistical analyses were realized using immunohistochemical methods to detect CD44v6 expression although several variants with exon v6 have been described. We investigated expression of isoforms containing CD44v6 using an RT-PCR approach and a panel of 25 normal breast specimens, 10 mammary fibroadenomas, 8 cystic samples and 52 primary breast tumors (38 invasive N0M0). Normal breasts, fibroadenomas, and cysts all express the same variant, A (with exon v6 only), while several transcripts are amplified in tumors. Expression of variants other than A correlates with acquisition of a malignant phenotype. Invasive cancers also express additional variants in comparison with in situ carcinomas. Metastasis capacities seem to be associated with transcription of variants other than A but also with no transcription of some of them, variants D (with exons v6 and v10) and L (with exons v6 to v10). Expression of variants D and L correlates with higher percentages of disease-free survival and better outcome. Expression of CD44 splice variants with exon v6, as detected by RT-PCR, might be a useful prognostic factor for breast cancer. However, since the series size is small, our results need to be confirmed by later studies on a larger number of patients.

Cancer registries are necessary to evaluate the efficacy of cancer screening programmes. They provide early indicators of screening efficacy, needed to correct certain campaign failings without waiting for the mortality data, available only 7 to 10 years after the beginning of the screening. They allow to mesure the screening effect not only on the screened women, but also on the entire target population. They also allow to mesure the negative and deleterious effects of the screening. Finally, they are essential to all cost/efficacy study. The evaluation of the breast cancer screening programme in the French department of Bas-Rhin by the cancer Registry showed very quickly the interest of the mesures concerning the quality assurance programme and to estimate on the first screen results basis, that it will be difficult to reduce the mortality by breast cancer to 25%.

E-cadherin (Epithelial-cadherin) is a subclass of the cadherin family that plays a major role in the maintenance of intercellular junctions in epithelial tissues. E-cadherin is also involved in the interactions between epithelial cells and T lymphocytes. In order to explore the relationship between E-cadherin expression, cancer invasion and metastases in vivo, we estimated its expression in normal breast specimens, fibroadenomas, cystic samples and primary breast carcinomas using a semiquantitative reverse transcription-polymerase chain reaction. The relationship between E-cadherin expression, survival and disease-free survival was also investigated. In comparison with normal breasts, 70% of the primary tumors showed reduced expression of E-cadherin suggesting that downregulation of this cell adhesion molecule is a common event in breast carcinoma. Significant correlation was found between E-cadherin expression and the histological classification. Most of the advanced tumors grades (10/13 tumors with grade III) presented decreased E-cadherin expression. No correlation was found between E-cadherin expression, estrogen and progesteron receptors, age and menopausal status at diagnosis. However, disease-free and overall survival was associated with E-cadherin expression. Patients showing poorly expressed E-cadherin in tumor tissue had a worse prognosis. The same results were observed for women without lymph node invasion or metastasis at diagnosis even when they were grouped according to their histological grade for statistical analysis. Therefore, E-cadherin mRNA expression in invasive breast carcinomas might be an early prognostic factor of metastasis.

The relationship between a family history of cancer and the risk of breast cancer was investigated in a study of 495 breast cancer cases and 785 controls aged 20 to 56 years. A positive association was found between the occurrence of breast cancer and a history of breast cancer in families. This relationship increased linearly with both the number of the affected relatives and with the degree of kinship between the affected relative and the case. The highest risk was observed when a sister was affected by breast cancer. This could be explained by longer common environmental exposures between sisters than between mother and daughter. This could also be explained by a genetic factor segregating under a recessive model. The risk of breast cancer associated with colon, uterus, ovary, and prostate cancer in the family was not significantly different from one. However, the estimated odds ratios associated with a family history of colon cancer increased with the degree of kinship between the affected relative and the case in a similar manner to those of breast cancer. A relationship between the risk of breast cancer and a family history of colon cancer would support the existence of a common familial factor (be it genetic or not) for these cancers. Further genetic epidemiological studies might help to define the mode of inheritance of the same susceptibility to cancer at different sites.

We found that the risk of breast cancer associated with a family history of breast cancer increased with the number of abortions (induced as well as spontaneous) in a study of 495 breast cancer cases and 785 controls aged 20 to 56 years. For the women who had undergone at least two abortions, the risk associated with a family history did not seem to depend on the type of abortion. This finding suggests that the effect of a family history on the risk of breast cancer is modified by event(s) resulting from abortions. Further epidemiological studies should be conducted to verify the existence of this interaction.

A questionnaire survey of 200 doctors who were a sample of the general practitioners of the Bas-Rhin department was carried out. This was in order to ascertain what they knew about cancer of the breast and how they practised medically in this area, what were their doubts and what motivated them to screen for this kind of cancer? The questionnaire was found on the whole to acceptable. The enquiry showed that undoubtedly doctors were in favour of screening for cancer of the breast but were less enthusiastic carrying it out routinely. They also were unaware of ways in which such screening could be carried out (mammography being considered and examination which shows where the cancer was and not as a screening method). Furthermore, there was some confusion between screening and means of diagnosis. Results of this study show that it should be possible to outline the content and means of informing general practitioners about how to screen in order to enable them to participate in the Alsatian pilot campaign for screening for breast cancer.

In a case-control study, the relationship between a family history of cancer of the breast, ovary, colon, uterus or prostate and the risk of breast cancer was investigated. The data consisted of family histories from 495 breast cancer cases and 785 controls aged 20-56 years. A positive association was found between the occurrence of breast cancer and a history of breast cancer in the families of the subjects affected. This relationship increased linearly with both the degree of kinship of the affected relatives and with their number. The risk of breast cancer associated with other types of cancer in the family was not significantly different from unity.

A mammographic breast cancer screening began in May 1989 in the Bas-Rhin. It has been selected by "Europe against Cancer" for France. Its aim is not to prove the efficiency of mammography screening by one view every two years, as many studies has proven it. Its purpose is to find the best methodological model for a national campaign. Its principles are to change attitudes and to obtain the active participation of the physicians without creating new structures. This campaign is offered to women aged 50 to 65, living in Bas-Rhin (74,200 women) without individual convocations. Their participation is obtained by a continuous information and motivation. The mammographic examinations are taken in charge by the Health Insurance and performed by the radiologists who have signed a convention. The homogeneity of the results is assured by a double and triple reading under the responsibility of the ADEMAS. In May 1990, after one year, 17,228 women had presented to the screening test. The positive test rate is 7.6% and 7.6% of the women had a diagnostic procedure which indicated a biopsy for 188 women. Among the first 176 histological results, 76 cancers have been diagnosed, 100 women had a benign lesion. The ratio cancer/benign lesion is 0.76.

The results of different programmes for screening carried out at present in foreign countries give sufficient proof of the value of screening for cancer of the breast in asymptomatic women of over 50 years of age. There is a significant reduction in mortality between 30 and 70%, according to different studies. Women who were screened had their cancers diagnosed at an earlier stage of the illness than those who were not screened whatever the ages of the women were. These results give a basis for planning screening in France. However, controlled pilot studies should still be carried out to widen screening in a country. These studies should in particular look at technical methods, evaluate the quality of the information that is obtained and the acceptability by women, as well as the training of radiologists and the qualities of the methods used. Finally, each programme should be controlled by the Public Authorities who will be paying for it.

The degree of hormone-dependence of endometrial cancers may be evaluated by the presence and the rate of estradiol and mostly progesterone receptors in an endometrial fragment. The most differentiated tumors have a high receptor content, while anaplastic cancers are most of the time without them. They must be systematically determined regardless of other prognostic factors enabling to evaluate the prognosis and guide the treatment. It is presently facilitated by the method of immunochemical titration on histological section, available for estrogen receptors, disclosing the spatial and functional distribution of hormono-dependent cells.

This attempt at comparison between the absorption and thermogenesis of breast tumour tissue is currently being continued using a larger group of patients and complemented by measurement of tumour thermogenesis in situ and of the acoustic properties of operative specimens. Such studies define the contributions of thermographic and ultrasonic findings in diagnosis, prognosis and indications for biopsy and treatment, by their integration and combination alongside the data obtained by palpation/inspection and radiological, cytological and histological findings.

The follow-up of women treated for breast cancer rather varies according to school of thought. This follow-up is often too irregular, insufficient or unnecessarily exhaustive and costly. It depends on numerous factors such as the doctor-patient relationship, stage of disease, frequency and usual site of metastases, time lapsed since first treatment, and validity and reliability of tests. In early stages, attention must be paid to discovery of recurrence and metastasis, either in the opposite breast or in other organs. In advanced stages, the examination involves an evaluation of the degree of extension and ongoing disease activity with search for evidence of stability.

It is correct to add hormone or chemotherapy in advanced metastatic disease of endometrial carcinoma and in recurrences. Large doses of hormone treatment have to be given. These are progestagens and the success rate with them, no matter which product is used, is approximately 30%. The use is limited by high blood pressure and the risks of vascular complications and metabolic upsets. Tamoxifen seems to the better tolerated and gives similar results. The response to hormone treatment depends on how sensitive the tumor is to the hormones. It is better when it has large numbers of progesterone receptors and it is of low grade. When the tumour is resistant to hormones, chemotherapy with cytotoxic drugs should be used. These drugs are adriamycine and mono or combined chemotherapy, but there is no protocol as yet that is better than any other. The debate about whether to use adjuvant treatment in stage I or II cases is open. It must be considered when the prognosis seems to be bad or there seem to be large risks of recurrences.

The hormone-dependence of some human breast cancers is well recognized. However, the molecular mechanisms responsible for the growth stimulation of these cancers by oestrogens are still poorly understood. With the hope of elucidating these mechanisms, we have recently cloned and studied the structure-function relationship of the human oestrogen and progestin receptors, and also undertaken a study aimed at characterizing genes whose expression is controlled by oestrogens in hormone-dependent breast cancers. We review here our findings concerning one of these genes and its expression products, the pS2 gene. We discuss also whether a systematic determination of pS2 gene expression in breast cancer biopsies could be useful to establish a new biochemical classification of these cancers which may be useful to improve the diagnosis of hormone-dependent cancers.