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Objectives: This study sought to investigate long-term cardiovascular mortality and its relationship to the use of radiotherapy for breast cancer., Background: Cardiovascular diseases are among the main long-term complications of radiotherapy, but knowledge is limited regarding long-term risks because published studies have, on average, <20 years of follow-up., Methods: A total of 4,456 women who survived at least 5 years after treatment of a breast cancer at the Institut Gustave Roussy between 1954 and 1984 were followed up for mortality until the end of 2003, for over 28 years on average., Results: A total of 421 deaths due to cardiovascular diseases were observed, of which 236 were due to cardiac disease. Women who had received radiotherapy had a 1.76-fold (95% confidence interval [CI]: 1.34 to 2.31) higher risk of dying of cardiac disease and a 1.33-fold (95% CI: 0.99 to 1.80) higher risk of dying of vascular disease than those who had not received radiotherapy. Among women who had received radiotherapy, those who had been treated for a left-sided breast cancer had a 1.56-fold (95% CI: 1.27 to 1.90) higher risk of dying of cardiac disease than those treated for a right-sided breast cancer. This relative risk increased with time since the breast cancer diagnosis (p = 0.05)., Conclusions: This study confirmed that radiotherapy, as delivered until the mid-1980s, increased the long-term risk of dying of cardiovascular diseases. The long-term risk of dying of cardiac disease is a particular concern for women treated for a left-sided breast cancer with contemporary tangential breast or chest wall radiotherapy. This risk may increase with a longer follow-up, even after 20 years following radiotherapy., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: There is no consensus on how to separate contralateral breast cancer (CBC) occurring as distant spread of the primary breast cancer (BC) from an independent CBC., Methods: We used standardised incidence ratios (SIRs) to analyse the variations in the risk of CBC over time among 6629 women with BC diagnosed between 1954 and 1983. To explore the most appropriate cutoff to separate the two types of CBC, we analysed the deviance between models including different cutoff points as compared with the basal model with no cutoff date. We also performed a prognostic study through a Cox model., Results: The SIR was much higher during the first 2 years of follow-up than afterwards. The best cutoff appeared to be 2 years. The risk of early CBC was linked to tumour spread and the risk of late CBC was linked to age and to the size of the tumour. Radiotherapy was not selected by the model either for early or late CBC risk., Conclusion: A clearer pattern of CBC risk might appear if studies used a similar cutoff time after the initial BC.

Purpose: To investigate the impact of initial tumour characteristics and loco-regional radiotherapy on long-term survival following breast cancer diagnosis., Methods and Materials: This study was conducted among 6,800 French women from a cohort of 7 711 subjects diagnosed at the IGR with breast cancer between 1954 and 1983 and followed-up until January 2004. Overall mortality in the cohort was compared with that in the French general population using Standardized Mortality Ratios (SMR) and the Absolute Excess Risk (AER) estimated by Poisson regression., Results: During the 1954-2004 follow-up period, 5,436 women died. Mortality was 3.15-fold higher in the cohort than in the general female population in France. It decreased from 6.86 to 1.26 during the first 30 years of follow-up then rose again to 1.60. Both SMRs and AERs were more than 2-fold higher in women who had received radiotherapy during initial treatment than in those who had not, this difference being higher for women treated before 1976 than afterwards (p < 0.0001). They (SMRs and AERs) were also higher for subjects who had stage II, III or IV lesions than for those with less advanced tumours., Conclusion: The results of this study suggest that the excess deaths observed during the first two decades are closely linked to the initial clinical characteristics of the tumour and to radiotherapy. The late increase in mortality may be partially due to deleterious late effects of radiotherapy.

Purpose: The aim of the study was to compare reproductive factors in patients with inflammatory breast cancer (IBC), and with non-inflammatory breast cancer (non-IBC). The study was performed in two centers: one French including 49 IBC patients and 140 non-IBC and another Tunisian including 97 IBC and 139 non-IBC. Unconditional logistic regression was used for the analyses., Patients and Methods: The French IBC patients had a lower educational level, a higher body mass index and a longer cumulative duration of breast-feeding, and they included a greater proportion of non-European women, than the non-IBC patients. In the multivariate analysis, only breast-feeding duration remained associated with the IBC status (P=10(-3)). These results could not be verified in the Tunisian series, because the duration of breast-feeding was unavailable in this center., Results: This study suggests that the etiology of IBC might be different of that of non-IBC.

Cyclical mastalgia is a common complaint, with a potentially important relationship to breast cancer risk. In the last decade, case-control studies have reported that cyclical mastalgia could be considered as an independent risk factor for breast cancer. The subjectivity of a retrospectively collected symptom questioned the validity of this finding. We have examined the association between cyclical mastalgia and breast cancer risk in the French cohort study of women with benign breast disease diagnosed in two breast clinics between 1976 and 1979 and followed-up until 1997. The present study was restricted to the women free of any hormonal treatment (n = 247). The mean follow-up was 16 +/- 5 years, and a total of 22 breast cancers occurred during the follow-up. Using a Cox model with duration of cyclical mastalgia as a time-varying variable, the adjusted relative risk of breast cancer increased with the duration of cyclical mastalgia (P = 0.006). The corresponding relative risk for 37 months of cyclical mastalgia was 5.31 (95% confidence interval, 1.92-14.72). We show here that the conclusion still holds when the symptom cyclical mastalgia was collected prospectively in a cohort study, bringing additional evidence that cyclical mastalgia may represent an independent and useful clinical marker of increased breast cancer risk. It might be a confounding factor when assessing the effects of hormonal treatments on breast cancer risk such as hormonal replacement therapy or oral contraceptives.

Background: We studied whether dermal lymphatic emboli (DLE) add independent prognostic information to the clinical definition of inflammatory breast cancer (IBC)., Patients and Methods: The study was performed in 2 centers, one each in France and Tunisia. For every patient with IBC, 1-3 patients with noninflammatory breast cancer (non-IBC) were included. All patients were to have a surgical tumor biopsy, including a sample of the skin surrounding the tumor. The endpoint was the risk of a relapse at 2 years, which was estimated using univariate and multivariate Cox models., Results: Three hundred thirty-seven patients were included (150 in France and 187 in Tunisia). The IBC status was divided into 2 clinical categories according to the extent of inflammation in the breast (localized IBC, which was defined as clinical inflammation in the tumor area, vs. diffuse IBC, which was defined as inflammation of at least two thirds of the breast). In total, 57 patients presented with localized IBC, 71 with diffuse IBC, and 209 with non-IBC. Dermal lymphatic emboli were found in 7% of non-IBC cases, in 25% of localized IBC cases, and in 45% of diffuse IBC cases. We found a significant interaction between the presence of DLE and diffuse IBC (P = 0.01). In patients with diffuse IBC, the presence of DLE increased the risk of relapse 3-fold. Conversely, DLE were not associated with the risk of relapse in patients with non-IBC, nor in patients with localized IBC. In patients with diffuse IBC and no DLE, the risk of relapse was similar to that of patients with localized IBC., Conclusion: A DLE status might be a useful prognostic indicator exclusively in patients with diffuse IBC. However, because all patients with localized and diffuse IBC generally receive similar types of treatment, additional information on the presence or absence of DLE will not have an impact on treatment practice.

Purpose: The aim of this multicenter trial was to evaluate the role of ovarian suppression in patients with early breast cancer previously treated with local surgery and adjuvant chemotherapy., Patients and Methods: Nine hundred and twenty-six premenopausal patients with completely resected breast cancer and either axillary node involvement or histological grade 2 or 3 tumors were randomized after surgery to adjuvant chemotherapy alone (control arm) or adjuvant chemotherapy plus ovarian suppression (ovarian suppression arm). Ovarian suppression was obtained by either radiation-induced ovarian ablation or triptorelin for 3 years. The analyses were performed with Cox models stratified by center., Results: Median follow-up was 9.5 years. Mean age was 43 years. Ninety per cent of patients had histologically proven positive axillary nodes, 63% positive hormonal receptors and 77% had received an anthracycline-based chemotherapy regimen. Ovarian suppression was by radiation-induced ovarian ablation (45% of patients) or with triptorelin (48%). At the time of randomization, all patients had regular menses or their follicle-stimulating hormone and estradiol levels indicated a premenopausal status. The 10-year disease-free survival rates were 49% [95% confidence interval (CI) 44% to 54%] in both arms (P = 0.51). The 10-year overall survival rates were 66% (95% CI 61% to 70%) for the ovarian suppression arm and 68% (95% CI 63% to 73%) for the control arm (P = 0.19). There were no variations in the treatment effect according to age, hormonal receptor status or ovarian suppression modality. However, in patients <40 years of age and with estrogen receptor-positive tumors, ovarian suppression significantly decreased the risk of recurrence (P = 0.01)., Conclusions: The results of this trial, after at least 10 years of follow-up, do not favor the use of ovarian suppression after adjuvant chemotherapy. The potential beneficial effect in younger women with hormono-dependent tumors should be further assessed.

Background: To quantify the risk of soft tissue and bone sarcomas after breast cancer according to the doses and technical modalities of irradiation., Methods: We followed a cohort of 6597 breast-cancer patients for 8.3 years on average. The number of soft tissue and bone sarcomas was compared to the expected number based on the incidence rates in the general French population. We also estimated the risk of sarcoma according to the radiation dose received at site of the sarcoma in a nested case control study of 14 breast-cancer patients who subsequently developed a sarcoma and 98 controls matched for age at diagnosis of breast cancer, period of initial treatment and length of follow-up., Results: In the cohort-study, 12 women who had initially received radiotherapy treatment developed a bone or soft tissue sarcoma during the follow-up period. The expected number of cases during this period was 1.7 (SIR = 7.0, 95% CI: 3.7-11.7) and the mean annual excess incidence during the same period was 21 per 100,000 person-years. The 15-year cumulative incidence of sarcoma was 0.28% (95% CI: 0.10-0.45%). In the case-control study, all the 14 cases had received at least 11.8 Gray at the site of the sarcoma, which was always located in the irradiated field or in the upper ipsilateral extremity of the arm. A dose-effect relationship was observed (p < 0.001). The best fit was obtained for a quadratic dose-response relationship, without a negative exponential term for cell killing at high doses. The risk of sarcoma was 30.6 higher for doses of more than 44 Gray than for doses of less than 15 Gray., Conclusions: High doses of radiation strongly increase the risk of bone and soft tissue sarcoma.

Background: The relationship between the use of anti-hypertensive drugs and cancer risk remains controversial. The main objective of this study was to assess the potential effect of beta-blocker use on cancer risk., Methods: In a cohort of 839 patients with cardiovascular disease, followed up prospectively for an average period of 10 years, cancer occurrence was recorded according to the exposure to beta-blockers. The relative risk of cancer associated with beta-blocker use was estimated using a Cox model adjusted on gender and age. Ever- vs never-use of beta-blockers and duration of exposure to the drug were analyzed as time-dependent variables. In addition, the standardized incidence ratios (SIR) were calculated using the corresponding age- and gender-adjusted cancer incidences in the French general population., Results: A total of 326 beta-blocker users and 513 users of other treatments were included in the cohort. During the follow-up period, representing 8,466 person-years, incident cancer cases were 15 and 59 in beta-blocker ever-users versus never-users, respectively. Using the Cox model, the overall relative risk of cancer was 0.51 (95% confidence interval [95% CI]: 0.29-0.90) in the beta-blocker ever-users versus never-users (p=0.02), with a 6% decrease per year of use (95% CI: 1%-12%; p=0.03). The corresponding SIR ratio between these two groups was 0.44 (95% CI: 0.24-0.76)., Conclusion: In this cohort, the beta-blocker treatments appeared to decrease the cancer risk significantly. However, this result should be considered with caution; further work is needed, as some sources of bias associated with this type of epidemiological study cannot be totally excluded.

Background: A randomised trial was conducted comparing wide lumpectomy and breast irradiation with modified radical mastectomy. As the follow-up was long (mean duration 22 years), we analysed the variation in the effect of treatment over time., Patients and Methods: The trial included 179 patients with a breast cancer measuring

Background: The current study was performed to analyze the effects of radiotherapy and chemotherapy on visual improvement in patients with choroid metastases (CM), and to determine the clinical factors potentially related to the risk of death., Methods: One hundred twenty-three consecutive patients were diagnosed with CM at the Institut Gustave-Roussy between 1966 and 1992. Treatment failure was defined as the absence of tumor regression or choroid tumor progression documented at the time of last ophthalmologic examination. The Cox proportional hazards model was used to estimate the risk of treatment failure associated with analyzed covariates., Results: Approximately 81% of the patients were women. The most frequent primary tumors were breast carcinoma (71%) and lung carcinoma (9%). Bilateral CM were found in 25% of patients. Sequential vinca alkaloid-based chemoradiotherapy was reported to be significantly associated with a decreased rate of treatment failure compared with radiotherapy alone (relative risk [RR] = 0.3; 95% confidence interval [95% CI], 0.03-2.2). However, when considered separately, each type of treatment also decreased the risk of treatment failure (RR = 0.5 [95% CI, 0.3-0.8] for radiotherapy and RR = 0.4 [95% CI, 0.3-0.7] for chemotherapy). The total dose of radiotherapy (< 30 grays [Gy] vs. > or = 30 Gy) was not found to modify treatment results. The 2-year overall survival rate was 25% (95% CI, 17-34%). The risk of death was found to be correlated with the presence of metastases in the liver (P = 0.02) or lung pleura (P = 0.04) at the time of the diagnosis of CM., Conclusions: Sequential combination radiotherapy and vinca alkaloid-based chemotherapy appear to be the most beneficial treatment modality. However, because treatments were not prescribed randomly, the results of the current study should be interpreted with caution., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11622)

Background: Some studies have suggested that there is an association between breast carcinoma and thyroid carcinoma. Because ionizing radiation is a well known risk factor for breast and thyroid carcinomas, the authors studied the effect of the radiation dose delivered for the treatment of each of these two malignancies on the risk of subsequently developing the other malignancy., Methods: The risk of developing thyroid carcinoma subsequent to treatment for breast carcinoma was analyzed in 8 patients (cases) and 192 matched control patients (controls) nested in a cohort of 7711 women who were treated at Institut Gustave Roussy between 1954 and 1983. The risk of developing breast carcinoma after treatment for thyroid carcinoma was studied in a cohort of 2365 women who were treated in 3 French cancer centers between 1934 and 1995., Results: Six of 8 patients with breast carcinoma (75%) who developed thyroid carcinoma and 71% of patients in the control group received radiation therapy during their treatment. The median dose to the thyroid was 6.6 grays (Gy) in the case group and 9.4 Gy in the control group. The overall relative risk of thyroid carcinoma associated with radiation therapy was 1.2 (95% confidence interval, 0.2-6.2). No relation was observed between the radiation dose and the risk of thyroid carcinoma (P = 0.8). Among 2365 women who were treated for thyroid carcinoma, 48 women developed a subsequent breast carcinoma. A significant excess of breast carcinoma was observed among women younger than 59 years at the time of diagnosis of breast carcinoma compared with women in the same age group in the general population. The mean absorbed dose delivered to the breasts by (131)I and external radiation therapy was 0.7 Gy. No relation was found between the radiation dose and the risk of breast carcinoma (P = 0.8)., Conclusions: The previously reported excess incidence of breast carcinoma after thyroid carcinoma was not related to radiation treatment with (131)I and/or external radiation therapy. Radiation therapy for breast carcinoma did not increase the risk of subsequent thyroid carcinoma., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11626)

In total, 281 of the 7711 women who were initially treated for breast cancer between 1954 and 1983 at the Gustave Roussy Institute developed a second malignant neoplasm (SMN) other than second primary breast cancer and nonmelanoma skin cancer at least 1 year after breast cancer treatment. We carried out a nested case-control study to determine the overall relationship between the dose of radiotherapy received at a given anatomical site and the risk of SMN at the same site. In total, 75% of the cases of SMN were previously treated by radiotherapy, as compared to 73% of the controls. In the irradiated patients, the median local dose was higher among cases (3.1 Gy) than among controls (1.3 Gy). More than 40% of the irradiated patients received a local dose of less than 1 Gy. A purely quadratic relationship was observed between the dose of radiation received at an anatomical site and the risk of SMN at this site. According to the quadratic model, the excess risk of SMN was 0.2% (95% CI 0.05-0.5%) when the target organ received 1 Gy. This risk did not differ significantly according to age at the time of radiotherapy (<40 vs >or=40 years). The risk of SMN was 6.7-fold higher for doses of 25 Gy or more than in the absence of radiotherapy. No carcinogenic effect of chemotherapy was observed and a dose-effect relationship between the length of tamoxifen treatment and SMN occurrence was found. This relationship was limited to endometrial cancers and did not modify the relationship with radiation dose. Our results suggest that high radiation doses slightly increase the risk of second malignancies after breast cancer.

Objectives: To study how often women put on weight when on the pill and to analyse the relationship between that gain in weight and the characteristics of the last 2 types of pill that had been used., Patients and Methods: Three thousand six hundred and nine women representative of the French female population, aged 15 to 45, were recruited thanks to a survey that took place in 2001. Our study mainly concerned the 1665 women who were actually taking the pill at the time of the survey. The data were collected from self-questionnaires., Results: Thirty per cent of women declared to have gained weight since using their latest pill - only one more kg for 4% of them, 2 kg for 10% but 3 kg or more for the remaining 16%. Gain in weight was more frequent with women less than 25 years of age (35%) than with older ones (29%). This gain in weight did not vary according to either the type of pill, which was then used, or the length of time spent in using it, or the age of first using. It was more frequent when found with other side effects such as breast pain, skin disorders or metrorrhaegias; it was less frequent among women who had already been on the pill in the past than among women using an oral contraceptive for the first time (28% vs 34%; P = 0.008). The shorter the taking the latest pill had been, the greater the frequency of gain in weight was (P = 0.005), women who had presented the most side-effects in the past having changed their pill more rapidly than other women. Finally, a gain in weight was found far more often in women who "did" put on weight with their latest pill than in those who "did not" (53% vs 14%; P = 0.0001). All in all, 8% of women who had been previously been taking the pill had given up this method over a weight problem., Discussion and Conclusion: Putting on weight when on the pill being in the long term independent of the type of patent medicine used, it would seem necessary to orientate new research centred both on a chemical and a biological as well as a nutritional approach, so as to answer one of the major preoccupations of oral contraceptive users to the fullest.

Objectives: The aim of this study concerning the taking of the pill in France in 2001 was threefold, i.e. to assess its rate as well as its characteristics of use, and to appraise the most frequent side effects as reported by women., Material and Method: Three thousand six hundred and nine women representative of the French female population between 15 and 45 years of age were recruited thanks to a survey, which took place in 2001. The data were collected from self-questionnaires., Results: Women on the whole have quite a good opinion of oral contraception and most of them are convinced of its efficiency. As far as pill tolerance is concerned, opinions do vary, more than half of the women judging that being on the pill is not without side-effects. Though, the rate of use of oral contraceptives has increased by 12% since 1994. Most women (48%) use first and second generation pills and this in all age brackets. Thirty per cent of women aged 30 to 45 keep loyal to the same patent medicine, which they keep using for more than 10 years. Among the side-effects that can be found, two of them--putting on weight (31%) and hydrosodium retention (26%)--are the most frequently quoted, in all age brackets. This accounts for the relatively low ratio of women who find their pill quite satisfactory (58% of the cases)., Discussion and Conclusion: Despite the diversity of all the different patented pills that are available, efforts are still to be made in order to reduce what side-effects are encountered when using them.

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.

Background: Analyses of predictive factors for local recurrences are important, as an increasing number of patients with early breast cancer opt for a breast-conserving procedure. This study investigates whether factors predictive of local recurrence differ between patients treated with conservative or radical surgery., Patients and Methods: Two thousands and six patients with invasive breast carcinoma (< or =25 mm) were included. Of these patients, 717 were treated conservatively (lumpectomy and breast irradiation) and 1289 were treated with total mastectomy. All patients had axillary dissection and received lymph node irradiation if axillary nodes were positive. Most patients did not receive adjuvant chemotherapy or additive hormonal treatments. The mean duration of follow-up was 20 years. The main end point was the total local recurrence rate. The risk factors of local recurrence were estimated by multivariate analyses and interaction tests were used for intergroup comparisons., Results: Statistically significant predictive factors for mastectomized patients were histological grade, extensive axillary node involvement (10 nodes or more), and inner quadrant tumors, which were of borderline significance. Young age, however, was not a prognostic indicator for local recurrence. The main statistically significant factor for patients treated with a conservative approach was young age (< or =40 years). These younger patients had a five-fold increased risk of developing a breast recurrence compared with patients older than 60 years., Conclusions: Younger patients with early breast cancer treated with breast-conserving surgery should in particular be followed up at regular intervals so that any sign of local failure can be diagnosed early.

Background: The authors analyzed the outcome of patients with early-stage breast carcinoma after an isolated local recurrence, taking into account initial tumor characteristics and the type of initial treatment and local salvage treatment., Methods: One hundred five patients were studied who presented with a breast tumor measuring

Our aim was to compare the prognostic value of c-erbB-2 gene amplification analyzed by Southern blot with that of protein (p185) over-expression measured by immunohistochemistry in 172 patients with operable breast cancer (BC). Amplification and p185 over-expression were found in 31 (18%) and 51 (30%) BCs, respectively. All but 1 of the tumors showed both amplification and over-expression, while 21 (12%) tumors displayed over-expression without amplification. The risk of death associated with c-erbB-2 gene amplification and p185 over-expression was evaluated by multivariate analysis, taking into account tumor size, histoprognostic grade, hormone receptors and axillary node status. During a mean follow-up of 9.5 (+/-2) years, node involvement (p < 0.001), c-erbB-2 gene amplification (p = 0.02) and negative hormone receptors (p = 0.02) were found to be independent prognostic indicators of the risk of death. Over-expression of p185 with no amplification was not correlated with this risk. When the risk of death associated with c-erbB-2 amplification was studied according to chemo- and hormone therapy, no significant difference was observed between subgroups of subjects. Amplification was also associated (p = 0.02) with the risk of multifocal distant metastases (i.e., metastases detected concomitantly in at least 2 sites) and, thus, with BC aggressiveness. These data show the importance of c-erbB-2 gene amplification in predicting the long-term outcome of patients and in selecting eligible patients for c-erbB-2-targeted therapies., (Copyright 2001 Wiley-Liss, Inc.)

Objectives and Methods: The risk of second primary malignancies (SMN) was studied in a cohort of 4,416 one-year survivors of a breast cancer. The role of the menopausal status and of the initial treatment modalities (surgery, radiotherapy, and chemotherapy) was investigated., Results: Excluding second primary breast cancer and non-melanoma skin cancer, a total of 193 (4.4%) patients developed a SMN between 1973 and 1992, compared with 136 expected (Standardised Incidence Ratio, SIR = 1.4, 95% CI (1.2-1.6)). No trend towards either an increase or a decrease was noted in the SIR with time after treatment (p = 0.2). The greatest increase in the relative risk concerned soft tissue cancers (SIR = 13.0, 95% CI: 6.8-22.3), followed by leukaemia (SIR = 3.1, 95% CI: 1.7-5.0), melanoma (SIR = 2.7, 95% CI: 1.4-4.8), kidney (SIR = 2.5, 95% CI: 1.2-4.5), ovary (SIR = 2.0, 95% CI: 1.2-3.1) and uterine tumours (SIR = 1.9, 95% CI: 1.4-2.5). The SIR was 3.0 (95% CI 1.8-4.7) in women under 40 at the time of the breast cancer, 1.9 (95% CI: 1.4-2.4) in those aged 40-49 and 1.2 (95% CI 1.0-1.4) in those aged 50 or more. In the 2,514 women who had received radiotherapy as initial treatment without chemotherapy, the SIR for all SMN was 1.6 (95% CI: 1.1-2.3) fold higher than in those who had not received radiotherapy as initial treatment., Conclusion: In conclusion, this study confirms the increased risk of second malignancies in women treated for a breast cancer, and particularly in those who were younger at the time of treatment for breast cancer. Our results also suggest that radiotherapy may play a role in the onset of these second lesions.

Adjuvant radiotherapy decreases the risk of locoregional recurrences threefold, according to the results of many randomized trials and overviews. In patients treated with total mastectomy, the risk of local recurrence is mainly related to the number of involved axillary nodes, i.e. about 25%, 35% and 55% at 10 years when 1-3, 4-9 and 10 or more nodes are involved, respectively. In contrast, at 10 years, less than 15% of patients with negative axillary nodes relapse locally. The effect of adjuvant radiotherapy on distant metastases and overall survival is a controversial issue. On the one hand, recent results are compatible with the existence of a mechanism of secondary dissemination generated from locoregional tumor nests. The beneficial effect of radiotherapy can be observed whether with or without adjuvant systemic treatment. On the other hand, a deleterious late toxic effect, mainly cardiac, has also been shown. The importance of improvements in radiation techniques and quality assurance to obtain a positive balance in terms of overall survival is emphasized.

Apoptosis is an important physiological process controlled by multiple genes, including c-myc, p53 and bcl-2, and its inhibition may lead to the development of human cancers. In this study, we analyzed expression of the c-myc gene using Northern blot and of the p53 and bcl-2 proteins by immuno-histochemistry in 175 breast tumor specimens obtained from patients with operable breast cancer. We evaluated the relation between expression of these 3 genes and (i) the main usual prognostic factors (tumor size, histo-prognostic grade, hormone receptors and number of positive nodes); (ii) the risk of death and relapse, taking into account these 4 factors, after a mean period of follow-up of 9.5 years (SD 2 years). Over-expression of c-myc, p53 and bcl-2 was observed in 35%, 23% and 63% of tumors, respectively. Over-expression of c-myc was strongly linked to the number of positive nodes (p = 0.0005). p53 protein expression was associated with both high-grade (p = 0.0001) and hormone receptor-negative (p = 0.0001) tumors. In contrast, bcl-2 protein over-expression was associated with the main favorable prognostic factors and, more particularly, with hormone receptor-positive tumors (p = 0.0001). Multivariate analysis, using the Cox model, showed that only 2 factors were independently linked to the risk of death: number of positive nodes, which increased the risk (p = 0.0001), and bcl-2 protein over-expression, which decreased the risk (p = 0.008). When bcl-2 over-expression was studied in relation to nodal status, hormone receptor status and chemo- and hormone therapy, no significant difference was observed between different subgroups of patients. bcl-2 expression was also associated with a significantly lower risk of distant metastasis (p = 0.04). In conclusion, bcl-2 expression characterizes a particular phenotype of breast cancer with a favorable prognosis, and it may therefore be used as a marker of long-term survival. Int. J. Cancer (Pred. Oncol.) 84:562-567, 1999., (Copyright 1999 Wiley-Liss, Inc.)

Postmastectomy radiotherapy decreases threefold the risk of locoregional recurrences according to the results of many randomized trials and overviews. This risk is mainly related to the number of involved axillary nodes (ie, about 25%, 35%, and 55% at 10 years when 1 to 3, 4 to 9, and 10 or more nodes are involved). In contrast, at 10 years, fewer than 15% of patients with negative axillary nodes relapse locally. The effect of postmastectomy radiotherapy on distant metastases and overall survival is a controversial issue. On the one hand, results are compatible with the existence of a mechanism of secondary dissemination generated from locoregional tumor nests. The beneficial effect of radiotherapy may be observed in the absence or presence of adjuvant systemic treatment. On the other hand, a deleterious late toxic, mainly cardiac, effect of radiation has also been shown. This point emphasizes the importance of radiation technique and quality to obtain a positive balance in terms of overall survival.

Percutaneous progesterone topically applied on the breast has been proposed and widely used in the relief of mastalgia and benign breast disease by numerous gynecologists and general practitioners. However, its chronic use has never been evaluated in relation to breast cancer risk. The association between percutaneous progesterone use and the risk of breast cancer was evaluated in a cohort study of 1150 premenopausal French women with benign breast disease diagnosed in two breast clinics between 1976 and 1979. The follow-up accumulated 12,462 person-years. Percutaneous progesterone had been prescribed to 58% of the women. There was no association between breast cancer risk and the use of percutaneous progesterone (RR = 0.8; 95% confidence interval 0.4-1.6). Although the combined treatment of oral progestogens with percutaneous progesterone significantly decreased the risk of breast cancer (RR = 0.5; 95% confidence interval 0.2-0.9) as compared with nonusers, there was no significant difference in the risk of breast cancer in percutaneous progesterone users versus nonusers among oral progestogen users. Taken together, these results suggest at least an absence of deleterious effects caused by percutaneous progesterone use in women with benign breast disease.

The evaluation of carcinologic risks associated with various types of oral contraceptives remains unclear, because the constant evolution of composition and dosages in oestrogen and progestagen of pill. Since the oral contraceptives introduction 30 years ago, numerous epidemiological studies have analysed the association between OC and breast cancer risk. The recent meta-analysis of the Collaborative Group on Hormonal Factors in Breast Cancer provides large results. Original data from 54 studies representing about 90% of the published epidemiological studies were reanalyzed. The main findings are that is a small increase in the risk of having breast cancer diagnosed in current users of combined oral contraceptives and in women who had stopped use in past 10 years but that there is no evidence of an increase in the risk more than 10 years after stopping use. However, the cancers diagnosed in women who had used oral contraceptives are less advanced clinically than the cancers diagnosed in women who had not used them, suggesting a bias of screening in oral contraceptives users. However, the benefice-risk balance of OC is largely positive. The evaluation of third generation of pill is not yet available. Studies of third generation pill use and breast cancer risk are necessary.

Background: The randomized trials comparing breast-conserving therapy (BCT), i.e., surgery and radiation to the breast, with mastectomy in early-stage breast cancer use a variety of protocols. Meta-analysis may assist in understanding the impact of these differences on survival., Purpose: To evaluate the possible variations of the relative efficacy of BCT and mastectomy in terms of overall survival according to tumor size, nodal status, and use of adjuvant radiation therapy., Methods: The most recent published results and, where available, updated patient-level data from randomized controlled trials of BCT and mastectomy for early-stage breast cancer were combined in a meta-analysis using a random effects model. Pooled survival rates and odds ratios were generated according to subgroups of nodal status and tumor size. Five- and 10-year odds ratios were also determined according to adjuvant radiation protocol., Results: The pooled odds ratio comparing 10-year survival for BCT and mastectomy was 0.91. The odds ratios comparing the two treatment regimens were not significant after grouping according to tumor size and nodal status. When more than 50% of node-positive patients in both the mastectomy and BCT arms received adjuvant radiation, both arms had similar survival rates. When less than 50% of node-positive patients in both arms received adjuvant nodal radiation, the odds ratio was 0.69, and patients receiving BCT had a survival advantage., Conclusions: Patients allocated to BCT have survival rates at least as high as patients allocated to mastectomy. When all protocols were combined, nodal status and tumor size did not significantly alter the relative survival rates. However, under some conditions, particularly for node-positive patients, BCT may confer a relative survival advantage over mastectomy. In particular, mastectomy without adjuvant radiation appears to be inferior to BCT for node-positive patients.

Four studies recently showed an increased risk of venous thromboembolic events (VTE) in current users of oral contraceptives (OCs). This risk was higher in users of Ocs containing third generation progestagens than in users of Ocs containing levonorgestrel. The excess of VTE attributable to the third generation pills should be about 10 per 100 000 woman-years. Conversely, the risk of death due to cardiovascular disease was not significantly increased in users of third generation pills. In addition, the risk of myocardial infarction associated with these latter types of pill was two-fold lower than the risk associated with the pills containing levonorgestrel, and this decrease was of borderline significance (p = 0.10). The results of these different studies are described and discussed in this paper.

Purposes: A randomized trial was conducted to compare tumorectomy and breast irradiation with modified radical mastectomy. We have analyzed the patterns of failure in each arm of the trial and the prognostic factors that have an independent effect on treatment failures and overall survival., Patients and Methods: The trial included 179 patients with breast cancer of up to 20 mm in diameter at macroscopic examination. Eighty-eight patients had conservative management and 91 a mastectomy. All patients had axillary dissection with frozen-section examination. For patients with positive axillary nodes (N+), a second randomization was performed: lymph node irradiation versus no further regional treatment. Patterns of failure were determined by a competing-risk approach and multivariate analysis. A prognostic-score was determined by multivariate analysis., Results: Overall survival, distant metastasis, contralateral breast cancer, new primary malignancy, and locoregional recurrence rates were not significantly different between the two surgical groups, or between lymph node irradiation groups. Most recurrences appeared during the first 10 years. Three distinct prognostic groups were determined taking into account age, tumor size, histologic grading, and number of positive axillary nodes., Conclusion: Long-term results support conservative treatment with limited surgery and systematic breast irradiation as a safe procedure for the management of small breast cancers. Four easily obtainable clinical and histologic factors may be combined in a prognostic score that is highly predictive of overall and event-free survival.

Therapeutic trials comparing hormonal replacement therapy (HRT) with a placebo are rare and bring up non conclusive results. The last meta-analysis reported included 31 non randomized studies. It did not show an increased risk of breast cancer in women treated with HRT, compared with untreated women. However, on and after the 10th year of use, the risk increased significantly, although only slightly. This increase of the risk was restricted to the current users of HRT. The three studies published after the meta-analysis showed controversial results, and did not allow any conclusion. These wide disparities between the studies have highlighted the difficulty in interpreting the results of epidemiological studies.

Each year, more than 10,000 women die of breast cancer in France. Whatever the prevention measures adopted, they must be considered with undivided attention. Three factors are associated with an elevated risk of breast cancer: to be 50 or over, a family history of breast cancer affecting the mother and at least one sister (particularly in the event of early-onset breast cancer), or a personal history of benign proliferative breast disease with cellular atypia. High risk subjects can be defined as those who regroup these three factors, but this definition only applies to a population of 800 women in the entire French population. By broadening the definition of high risk subjects to include those aged 50 or over, who have a benign proliferative breast disease with cellular atypia, and a family history defined as "at least two cases if it concerns their mother or sister; or at least three cases, if it concerns aunts, grandmothers or daughters", the number of women would rise to 40,000 in France. In this high risk population, one in every two women will develop a breast cancer during the next 30 years. We consider therefore it ethically feasible to propose a prevention trial to this group of women in France.

In a recent meta-analysis of three American case-control studies, Whittermore et al found an increased risk of ovarian cancer in women treated for infertility. We have studied the mortality due to ovarian cancer in France between 1968 and 1991 in order to verify whether the use of these treatments could have modified mortality rates during the 24 years period studied. First, we have noted that among the 3175 deaths from ovarian cancer registered in France in 1991, only 136 occurred in women under 45 years of age, and 943 occurred in women between 45 and 59 years of age. We then observed an important geographical diversity with a higher frequency of ovarian cancer in the North of France as compared to the South. Finally, we observed a 72% increase in mortality during the study period. This increase can be entirely explained by the increase in the mortality rates among women over 60 years of age. Among women under 45, the ovarian cancer rate decreased by 24% between 1968 and 1991. Among women between 45 and 59 years of age, these rates increased by only 8% (or about 0.3% per year). These results imply that a possible effect--in terms of public health--of treatment for infertility does not necessarily translate into a significant increase in mortality from ovarian cancer among women under 60 years of age. This result in no way nullifies the role that epidemiological studies have in verifying the accuracy of risks associated with treatments for infertility.

It is now accepted that c-erbB2-gene amplification is correlated with poor clinical outcome for patients, mainly when axillary nodes are invaded. We have confirmed this result by multivariate analysis in 178 patients with non-inflammatory breast cancer followed up for a mean period of 6.8 years (SD, 1.6 years). In addition, we have shown that c-erbB2 amplification, found in 30 (17%) specimens, was associated with a high risk of multiple metastases developing simultaneously. In contrast, for the 67 patients with inflammatory breast carcinoma, the most aggressive type of breast carcinoma, the c-erbB2 amplification detected in 24 (36%) specimens was not found to be associated with a higher risk of death, suggesting that the c-erbB2 gene plays a different role in the progression of these 2 types of breast cancer. Furthermore, our data stress the importance of the methodological approach used to determine gene amplification. Although Southern blot hybridization is a tumour- and time-consuming method not easy to adopt in routine clinical practice, this method remains a reference quantitative method.

An increased risk of cancer and autoimmune disease associated with gel-filled silicone implants has been suggested recently, but these possible detrimental effects have not been adequately studied in patients with breast cancer. In order to evaluate these effects, we have studied 146 patients with breast cancer treated by mastectomy at the Gustave Roussy Cancer Institute between 1965 and 1983 and who received a gel-filled silicone implant for immediate or delayed breast reconstruction between 1976 and 1984. These patients were compared with 146 matched controls with breast cancer who were treated in the same center by mastectomy without breast reconstruction and were matched for age at diagnosis (within 10 years), year of diagnosis (within 3 years), stage, histologic type of the tumor, histopathologic grade, and nodal status. The relative risks of death, relapse, and second primary cancer were estimated by means of the Cox proportional hazards model stratified on age at diagnosis. The risks of distant metastasis and death due to breast cancer were significantly lower in the breast reconstruction group than in the control group. The risks of local recurrence, second breast cancer, and second primary cancer in another site than the breast were not significantly different between the two groups of patients. Our results do not support the hypothesis of a detrimental effect of gel-filled silicone implants either in the course of breast cancer or in the risk of death due to other diseases.

In a case-control study of 495 breast cancer patients and 785 controls between 20 and 56 years of age, the risk of breast cancer associated with a family history of breast cancer was studied according to age and reproductive factors. The familial risk of breast cancer was not significantly modified by age at onset, age at menarche, number of children, age at first full-term pregnancy, menstrual cycle length or age at menopause. However, the familial risk significantly increased with the number of abortions (p < 0.05) and seemed to decrease after a natural menopause (p = 0.08). These results suggest that a familial predisposition to breast cancer exerts the same influence during the first six decades of life, except maybe when there are isolated or repeated events such as abortions or artificially imposed menopause, in which case the risk is apparently greater.

Background: Immediate breast reconstruction (IBR) after mastectomy represents a clear improvement in the quality of life of patients with breast cancer, but prosthesis removal is relatively frequent. Therefore, it is important to identify risk factors related to this removal., Methods: A series of 142 patients treated with mastectomy and IBR at the Institut Gustave-Roussy between January 1976 and December 1988 were studied. Forty-seven had an in situ carcinoma, 93 an infiltrating carcinoma, and 2 a fibrosarcoma. IBR failures were defined as removal of the prosthesis, and early failures as removal during the first 7 weeks after IBR., Results: The early failure rate was significantly higher in patients with invasive carcinomas or fibrosarcomas than patients with in situ carcinomas (12% versus 0%, P = 0.04). The risk of late IBR failure was significantly higher in patients who had received postoperative radiation therapy than patients who did not (P = 0.0002). However, this increased risk applied only to women in whom the chest wall was exposed to radiation because of a high risk of recurrence., Conclusion: It might be preferable to postpone breast reconstruction for patients with infiltrating breast carcinoma because early complications are not infrequent and could delay adjuvant chemotherapy. Late complications associated with chest wall irradiation could be avoided with the use of alternative techniques such as the transverse rectus abdominis myocutaneous (TRAM) flap procedure.