Relation of risk of contralateral breast cancer to the interval since the first primary tumour.

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.

Randomized trial of adjuvant ovarian suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy.

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.

[Could treatments with beta-blockers be associated with a reduction in cancer risk?]. / Les traitements par beta-bloquants pourraient-ils être associés à une diminution du risque de cancer?

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.

Late local recurrences in a randomised trial comparing conservative treatment with total mastectomy in early breast cancer patients.

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

Radiation dose, chemotherapy, hormonal treatment and risk of second cancer after breast cancer treatment.

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.

[Oral contraception in France in 2001: results of an opinion poll survey conducted on 3609 women between 15 and 45]. / La contraception orale en France en 2001: résultats d'une enquête par sondage portant sur 3609 femmes âgées de 15 à 45 ans.

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.

[Factors associated with weight gain in women using oral contraceptives: results of a French 2001 opinion poll survey conducted on 1665 women]. / Facteurs associés à la prise de poids chez les femmes utilisant des contraceptifs oraux: enquête par sondage réalisée en 2001 auprès de 1665 femmes.

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.

Predictive factors for local recurrence in 2006 patients with surgically resected small breast cancer.

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.

Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women.

The largest-to-date randomized trial (Women's Health Initiative) comparing the effects of hormone replacement therapy (HRT) and a placebo concluded that the continuous use of an oral combination of conjugated equine estrogens (CEE) and medroxy-progesterone acetate (MPA) increases the risk of breast cancer. This conclusion may not apply to women taking other estrogen and progestin formulations, as suggested by discrepancies in the findings of in vitro studies, epidemiological surveys and, mostly, in vivo studies of human breast epithelial cell proliferation showing opposite effects of HRT combining CEE plus MPA or estradiol plus progesterone. To evaluate the risk of breast cancer associated with the use of the latter combination, commonly prescribed in France, a cohort including 3175 postmenopausal women was followed for a mean of 8.9 years (28 367 woman-years). In total, 1739 (55%) of these women were users of one type of estrogen replacement with systemic effect during at least 12 months, any time after the menopause, and were classified as HRT users. Among them, 83% were receiving exclusively or mostly a combination of a transdermal estradiol gel and a progestin other than MPA. Some 105 cases of breast cancer occurred during the follow-up period, corresponding to a mean of 37 new cases per 10 000 women/year. Using multivariate analysis adjusted for the calendar period of treatment, date of birth and age at menopause, we were unable to detect an increase in the relative risk (RR) of breast cancer (RR 0.98, 95% confidence interval (CI): 0.65-1.5) in the HRT users. The RR of breast cancer per year of use of HRT was 1.005 (95% CI 0.97-1.05). These results do not justify early interruption of such a type of HRT, which is beneficial for quality of life, prevention of bone loss and cardiovascular risk profile, without the activation of coagulation and inflammatory protein synthesis measured in users of oral estrogens.

c-erbB-2 (HER-2/neu) gene amplification is a better indicator of poor prognosis than protein over-expression in operable breast-cancer patients.

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.

Adjuvant radiotherapy in breast cancer--the treatment of lymph node areas.

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.

Increased risk of second cancers following breast cancer: role of the initial treatment.

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.

Variation in the interaction between familial and reproductive factors on the risk of breast cancer according to age, menopausal status, and degree of familiality.

BACKGROUND: Studies have found that reproductive factors might have a variable effect on the occurrence of breast cancer (BC) according to the existence or not of a family history of BC. The effect of a family history of BC on the risk of BC may also vary according to the age at diagnosis and the degree of kinship. This may confound the relation between familial risk and reproductive factors. A combined analysis was performed to study the interaction between familial risk and reproductive factors according to degree of familiality, age at interview and menopausal status. METHODS: The present analysis included 2948 cases and 4170 controls in seven case-control studies from four countries. The combined relative risks were estimated using a Bayesian random-effects logistic regression model. RESULTS: The main effects of reproductive life factors on the risk of BC are in agreement with previous studies. Two-way interactions between subject's age or menopausal status and a family history of BC were not significant. Although the three-way interaction between age, familial risk and parity was not significant, familial risk seemed to be increased slightly for women with high parity compared with women with low parity in the older age group, and seemed to be slightly decreased for women with high parity compared with women with low parity in younger women. The subject's age also appeared to have an effect on the interaction between familial risk and the age at first childbirth (P = 0.1). CONCLUSIONS: A possible influence of reproductive and menstrual factors on familial risk of BC has been suggested previously and was also evident in the present study. Three-way interactions between age, family history and parity or age at first childbirth might exist and they merit further investigation.

[The experience of menstruation and its disorders in 603 women using contraception in 1999]. / Le vécu des règles et de leurs troubles chez 603 femmes sous contraception en 1999.

AIM: An epidemiological survey completed during the first quarter of 1999 assesses the frequency of menstrual disorders as well as their effects on the lives of women using contraception. MATERIALS AND METHODS: The results presented involve a sample of 603 women, with 405 using the pill and 198 fitted with an IUD. The average age of onset of menstruation in the sampled population was 12.8 years. Although most women declared that they felt no anxiety at the time, over one-third of the women surveyed explained that they felt a certain hesitancy in discussing the topic. Even today, certain feelings, such as shame or pride, are still evoked in the interviews. Although over half believe that it is normal to menstruate, the process is nevertheless considered "somewhat bothersome" by certain women who also refer to "purification." Traditional cultural perspectives remain a strong influence. Menstrual disorders predating the initial use of contraception were reported in 150 women (occasional intermenstrual bleeding, 130 cases; other anomalies excluding metrorrhagia, 27 cases). Even if most of the women believe these problems to be inevitable, they also claim to be relatively troubled by these disorders, which often involve a considerable degree of discomfort. Such disorders are significantly more frequent in the "IUD" group, as well as in women who claim a very early onset of menstruation and those who consider explanations provided by the physician as "insufficient." CONCLUSION: The difference creates a certain fear with respect to any social or individual norm that may have been internalized. Thus the information presented in this study may provide ways and means to better understand women in general and our women patients in particular.

c-myc, p53 and bcl-2, apoptosis-related genes in infiltrating breast carcinomas: evidence of a link between bcl-2 protein over-expression and a lower risk of metastasis and death in operable patients.

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.

Percutaneous progesterone use and risk of breast cancer: results from a French cohort study of premenopausal women with benign breast disease.

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.

Postmastectomy radiotherapy: randomized trials.

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.

[Oral contraception and the risk of breast cancer]. / Contraception orale et risque de cancer du sein.

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.