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The relationship between the risk of breast cancer and oral contraceptive use was investigated in a case-control study conducted in France between 1983 and 1987 in five public hospitals. Some 464 cases aged 25 to 56 years and 542 matched controls were interviewed about their history of the use of oral contraceptives (OC). Results are given for the entire population and for the subgroup of 358 and 379 premenopausal cases and controls. The multivariate relative risk estimate, for ever use, was 1.5 (p<0.01) in the whole group as well as in the premenopausal subgroup (p<0.02). However, there was no evidence that the effect varied appreciably according to duration of use, age at first use, use before first full-term pregnancy (FFTP) and time since first or last use. The risk was not altered for any particular brand of OC. We conclude that, because of the widespread attention given to the relationship between OC use and breast cancer, information bias might be responsible for part of the excess in risk observed among OC ever users. [ABSTRACT FROM PUBLISHER]

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.

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.

Expression of CD44 isoforms has been investigated on normal breasts, fibroadenomas, cysts and breast cancers. Carcinomas express additional variants in comparison with normal breasts while fibroadenomas and cysts do not. Invasive cancers also express more variants than in situ carcinomas. Recent studies tend to demonstrate that overexpression of CD44 is not a survival prognostic factor whereas expression of exon 2v and/or 3v could be. Results for exons 4v to 10v are presently conflicting. Further studies will then be necessary to clarify the role of CD44 isoforms in mammary carcinogenesis and metastasis. Metastatic capacity could be linked with expression of additional variants but also with no transcription of variants associating exon 6v with either exon 10v or both exons 9 and 10v.

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.

We analyzed the representation of CD44 isoforms with both exons v9 and v10 among CD44 total amount and also examined correlation between their expression, clinical parameters and survival. We used a semi-quantitative RT-PCR reaction and a panel of 25 normal breast specimens, 10 mammary fibroadenomas, 8 cystic samples and 52 primary breast tumors. CD44 expression level was statistically higher in malignant tumors than in normal breast tissues (p = 0.038) or in fibroadenomas (p = 0.047) and correlated with histological grading, p = 0.047. Ratios CD44 variants with both exons v9 and v10/ total CD44 were similar in normal breast tissues and fibroadenomas but lower in the cystic samples. In primary N(-)M(-) breast tumors, unfavourable outcome and relapse were correlated with low ratios.

Breast cancer is the most common female malignancy affecting approximately one woman in eight. Many attempts have been made to define markers which may have potential clinical applications in diagnosis as well as therapy. New isoforms of CD44 with alternative spliced exons have recently been described. We studied the expression of CD44 exon 6 using a semi-quantitative RT-PCR reaction on a panel of 25 normal breast specimens, 10 mammary fibroadenomas, eight cystic samples and 52 primary breast tumors. Significant correlation was found between CD44 exon 6 expression and the overall survival of the N-M-population, P = 0.032, (logrank test by Mantel's method). The same result was also observed for the disease-free survival, P = 0.000002 (logrank test by Mantel's method). CD44 exon 6 expression, as detected by our RT-PCR-based method, might be a useful prognostic indicator of metastasis in breast cancer. However, these preliminary results need to be confirmed by later retrospective and prospective studies on a larger number of patients.

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.

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%.

The data from a French case-control study of 495 patients with breast cancer and 542 control subjects interviewed in five French public hospitals, were analyzed to assess the effect of reproductive factors (age at menarche, age at first full-term pregnancy, the time interval between these two ages, and parity) on the risk of breast cancer. Age at menarche, age at first full-term pregnancy, the time interval between these two ages, and parity appeared to have a limited influence on breast cancer risk. However, the relationship between these factors and the risk of breast cancer varied according to the age at breast cancer diagnosis. In the youngest group of women, the most consistent effects came from factors occurring early in life (menarche, first full-term pregnancy, and consequently the time interval between these two events). These factors had a null or weak effect on the oldest group of women. The protective effect of high parity was confined to the oldest group of women.

The ultimate effectiveness of any mass screening campaign is directly related to strict compliance with certain rules and technical protocols designed for radiological installations. Concerning radiological screening, the primary technical objective is to ensure reproducibly high quality images at low radiation dose to the patient. This paper describes the methodology followed for the implementation of a quality control (QC) programme of 48 mammography installations used within the context of the breast cancer screening campaign in the Bas-Rhin region of eastern France. In order to demonstrate the efficacy of such a programme, results of QC tests and procedures relating to each element of the radiological imaging chain are presented and compared for four control visits carried out at 6 month intervals over a period of 2 years. A reduction of 50% (from 16 mGy to 7.5 mGy) of breast entrance doses (normalized to a breast thickness of 4.5 cm) and a significant improvement of detectability of high contrast details are discussed. The importance of encouraging an extension of a similar process to the other screening experiments currently underway in France is emphasized.

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.

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 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.