Italian randomized trial among womenwith histerectomy: tamoxifen and hormone-dependent breast cancer in hight-risk women

Abstract Tamoxifen improves outcome in women with breast cancer and reduces the incidence of estrogen receptor-positive (ER+) breast tumors in prevention trials. Tamoxifen use is associated with an increased risk of potentially serious adverse events, principally endometrial cancer and venous thromboembolic events and, therefore, detailed knowledge of the effects of tamoxifen is important. With more cases of breast cancer being found as the follow-up time increases, it is now possible to perform more detailed analysis of the Italian Randomized Trial of Tamoxifen. Women with hysterectomy (N = 5408) were randomly assigned to receive 20 mg tamoxifen per day (N = 2700) or placebo (N = 2708). After a median of 81.2 months of follow-up, 79 case subjects (34 in the tamoxifen arm and 45 in the placebo arm) were diagnosed with breast cancer. We were able to identify a group of women at increased risk of ER+ breast cancers (high-risk group) on the basis of baseline as well as reproductive and hormonal characteristics (height, age at menarche, parity, age at first birth, and oophorectomy). Tamoxifen administered to women in the high-risk group showed statistically significantly reduced incidence of breast cancer (tamoxifen, 3 and placebo, 15; P =.003), but no such effect was seen in the low-risk group (tamoxifen, 31 and placebo, 30; P =.89). The positive effect of tamoxifen on breast cancer among high-risk women is most marked for ER+ tumors (tamoxifen, 1 and placebo, 11; P =.002). Chemoprevention of breast cancer with tamoxifen appears to be effective in women at high risk of ER+ tumors but not among women at low risk, who may well be protected naturally by late age at menarche or early first pregnancy, or artificially by removal of the ovaries. Tamoxifen could be offered as a preventive agent to women identified at high-risk of breast cancer because of hormone-related risk factors. Such a strategy would greatly reduce the numbers of women who would need to take tamoxifen to obtain the same absolute reduction in breast cancer. These findings are exploratory and need to be confirmed in other randomized trials

Tamoxifen for Breast cancer among Hysterectomised women.

Abstract Tamoxifen is a candidate drug for prevention of breast cancer, although findings from trials have not been consistent. In our extended follow-up (median 81.2 months, IQR 66.0-87.2) of the Italian Tamoxifen Trial, this drug did not significantly protect against breast cancer in women at usual or slightly reduced risk of the disease (p=0.215). Use of hormone replacement therapy increased risk of breast cancer, and users of such treatment who were randomly allocated to tamoxifen had a rate of breast cancer that was close to that of never-users. So far, no woman has died from breast cancer in this study. Decisions about introduction of tamoxifen to reduce risk of breast cancer remain important and open questions

Effect of tamoxifen venous thromboembolic events in a breast cancer prevention trial.

Abstract BACKGROUND: Tamoxifen, a selective estrogen-receptor modulator, increases venous thromboembolic events (VTE), but the factors explaining this risk are unclear. Atherosclerosis may induce VTE, or the 2 conditions may share common risk factors. We assessed the effect of tamoxifen on VTE in a breast cancer prevention trial and studied its association with risk factors for VTE. METHODS AND RESULTS: The incidence of VTE was studied in 5408 hysterectomized women randomly assigned to tamoxifen 20 mg/d or placebo for 5 years. There were 28 VTEs on placebo and 44 on tamoxifen therapy (hazard ratio [HR]=1.63; 95% confidence interval [CI], 1.02 to 2.63), 80% of which were superficial phlebitis, accounting for all of the excess due to tamoxifen within 18 months from randomization. Compared with placebo, the risk of VTE on tamoxifen was higher in women aged 55 years or older, women with a body mass index > or =25 kg/m2, elevated blood pressure, total cholesterol > or =250 mg/dL, current smoking, and a family history of coronary heart disease (CHD). Of the 685 women with a CHD risk score > or =5 who entered the trial, 1 in the placebo arm and 13 in the tamoxifen arm developed VTE (log-rank P=0.0013). In multivariate regression analysis, age > or =60 years, height > or =165 cm, and diastolic blood pressure > or =90 mm Hg had independent detrimental effects on VTE risk during tamoxifen therapy, whereas transdermal estrogen therapy concomitant with tamoxifen was not associated with any excess of VTE (HR=0.64; 95% CI, 0.23 to 1.82). CONCLUSIONS: Women with conventional risk factors for atherosclerosis have a higher risk of VTE during tamoxifen therapy. This information should be incorporated into counseling women on its risk-benefit ratio, particularly in the prevention setting

Impact of smoking on patients with idiopathic chronic pancreatitis.

OBJECTIVES: Chronic pancreatitis is usually caused by heavy alcohol intake and, in many studies, also smoking. Because heavy drinkers usually smoke, making it difficult to separate the effects of these 2 factors, we thought to study the impact of smoking on the progression of nonalcoholic idiopathic chronic pancreatitis (ICP) METHODS: We used data from 83 patients with ICP in Switzerland and from 83 patients in Italy. We studied the impact of smoking on progression of disease as measured by the appearance of calcification and diabetes using Cox regression models. RESULTS: In both centers, the prevalence of smoking was significantly higher in patients with ICP than in the background population. In Italian patients, smoking increased the risk of pancreatic calcifications (hazard ratio = 2.09; 95% confidence interval, 1.07-4.10). Smoking also shortened the time to appearance of calcification. Heavy smoking (>20 cigarettes per day) was associated with the appearance of diabetes (hazard ratio = 3.94; 95% confidence interval, 1.14-13.6). For those patients who never reported consuming alcohol, smoking remains a significant risk factor. CONCLUSIONS: In nonalcoholic ICP, smoking is associated with disease progression as measured by the appearance of pancreatic calcification and, to a lower extent, of diabetes. These findings were chiefly observed in patients who were older than 35 years at the time of onset of disease

Effect of tamoxifenand transdermal hormone replacement therapy on cardiovascular risk factors in a prevention trial.

Effect of tamoxifen and transdermal hormone replacement therapy on cardiovascular risk factors in a prevention trial. Italian Chemoprevention Group. Decensi A, Robertson C, Rotmensz N, Severi G, Maisonneuve P, Sacchini V, Boyle P, Costa A, Veronesi U. SourceFIRC Chemoprovention Unit, European Institute of Oncology, Milan, Italy. Abstract The combination of tamoxifen and transdermal hormone replacement therapy (HRT) may potentially reduce risks and side-effects of either agent, but an adverse interaction could attenuate their beneficial effects. We assessed the effects of their combination on cardiovascular risk factors within a prevention trial of tamoxifen. Baseline and 12-month measurements of total, low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol, platelets and white blood cells were obtained in the following four groups: tamoxifen (n = 1117), placebo (n = 1112), tamoxifen and HRT (n = 68), placebo and HRT (n = 87). The analysis was further extended to women who were on HRT at randomization but discontinued it during the 12-month intervention period (n = 33 on tamoxifen and n = 35 on placebo) and to women who were not on HRT but started it during intervention (n = 36 in both arms of the study). Compared with small changes in the placebo group, tamoxifen was associated with changes in total, LDL- and HDL-cholesterol of approximately -9%, -19% and +0.2% in continuous HRT users compared with -9%, -14% and -0.8% in never HRT users. Similarly, there was no interaction on platelet count. In contrast, the decrease in total and LDL-cholesterol levels induced by tamoxifen was blunted by two-thirds in women who started HRT while on tamoxifen (P = 0.051 for the interaction term). We conclude that the beneficial effects of tamoxifen on cardiovascular risk factors are unchanged in current HRT users, whereas they may be attenuated in women who start transdermal HRT while on tamoxifen. Whereas a trial of tamoxifen in women already on transdermal HRT is warranted, prescription of HRT during tamoxifen may attenuate its activity

Clinico-pathological characteristics of invasive lobular carcinoma of the breast: results of an analysis of 530 cases from a single Institution

BACKGROUND. Although invasive lobular carcinoma (ILC) is the second most common histotype of breast cancer, the prognostic implications of its clinicopathologic characteristics remain controversial. METHODS. The authors undertook a retrospective analysis of a large series of cases treated and followed at a single institution, with the objective of assessing the prognostic/predictive value of distinct clinicopathologic features of the tumors, after revision of the original histopathologic preparations and statistical analyses. RESULTS. Overall, 530 patients with pure ILC (57% with the classic type; 19% with the alveolar type; 11% with the solid type; and the remaining 13% characterized by pleomorphic, signet ring cell, histiocytoid, or apocrine features) were included in the study. Tumor size, lymph node metastatic involvement, and hormonal status were confirmed to be significant prognostic factors. In addition, statistically significant correlations were demonstrated between the ‘classic’ histotype of ILC and a lower risk of axillary lymph node metastases (P 5 .0005), a reduced number of metastatic lymph nodes (P 5 .04), and lower tumor grade (P <.0001). Patients with ILC of the ‘nonclassic’ subtype demonstrated significantly increased breast-related events (hazards ratio of 1.80; 95% confidence interval, 1.04-3.10) and a trend toward reduced disease-free survival and overall survival. CONCLUSIONS. The results of the current study confirm the clinical usefulness of several traditional clinicopathologic features of ILC as prognostic parameters but also emphasize the prognostic role of the histopathologic subtyping of these tumors, documenting the more favorable outcome of the classic subtype of ILC