[Breast density: a major parameter to follow during hormone replacement therapy]. / Densité mammaire: un paramètre à surveiller lors de la prise d'un traitement hormonal de la ménopause.

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.

[Pregnancy after infiltrative breast cancer treatment: experience of the CHRU of Strasbourg with literature review]. / Grossesse après cancer infiltrant du sein: expérience du CHRU de Strasbourg et revue de littérature.

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.

Comparison of early performance indicators for screening projects within the European Breast Cancer Network: 1989-2000.

In 1989 the European Breast Cancer Network (EBCN) was established by the first pilot projects for breast cancer screening, co-funded by the Europe Against Cancer programme. We report early performance indicators for these EBCN projects while taking into account their organizational setting. Out of 17 projects in the network, 10 projects from six European countries contributed aggregated data on number of invitations, screening examinations, and breast cancers detected over the period 1989-2000. Results were summarized separately for projects in centralized versus decentralized health care environments. The European Guidelines for quality assurance in mammography screening provided reference values for the performance indicators. The most prominent finding in this study was the higher participation rate in centralized versus decentralized projects (average participation in 1998: 74 versus 33%; P<0.001), whereas the invitation system and screening policy in these projects were similar. Detection rates and characteristics of cancers detected at initial and subsequent screening examinations showed no significant differences between centralized and decentralized projects. Even though early performance indicators for centralized versus decentralized projects were similar, the impact of breast screening on mortality from this disease at the population level will differ since the decentralized projects reach only part of the target population.

[Impact of menopause hormone replacement therapy on screening mammography reading]. / Impact du traitement hormonal substitutif de la ménopause sur la lecture des mammographies de dépistage.

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.

[The cost of breast cancer screening in France]. / Le coût du dépistage du cancer du sein en France.

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.

[A decentralized breast cancer screening program in the French department of Bas-Rhin]. / Un système décentralisé de dépistage du cancer du sein: l'exemple du Bas-Rhin en France.

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.

[Large sections in routine breast pathology. A technique adapted to conservative surgery]. / Les coupes larges en pathologie mammaire de routine. Une technique adaptée à la chirurgie conservatrice.

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.

[Subareolar injection of 99m-Tc sulfur colloid for sentinel nodes identification in multifocal invasive breast cancer]. / Injection sous-aréolaire de sulfocolloïdes technétiés pour l'identification des ganglions sentinelles dans les cancers du sein invasifs à foyers multiples.

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: epidemiology, risk factors, screening]. / Cancer du sein: épidémiologie, facteurs de risque, dépistage.

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.

CD44 isoforms with exon v6 and metastasis of primary N0M0 breast carcinomas.

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.

Expression of CD44 spliced variants with both exons v9 and v10 in primary N(-)M(-) breast carcinomas correlates with metastasis.

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.

Are CD44 spliced variants involved in human breast cancer metastasis?

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.

CD44 exon 6 expression as a possible early prognostic factor in primary node negative breast carcinoma.

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 mRNA expression in breast carcinomas correlates with overall and disease-free survival.

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 role of cancer registries in the evaluation of breast cancer screening]. / Le rôle des registres de cancer dans l'évaluation des campagnes de dépistage du cancer du sein.

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%.

Reproductive factors and breast cancer risk. Effect of age at diagnosis.

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.

Quality control in mammography: an initiative in France.

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.

Familial risk of breast cancer in a French case-control study.

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.