Adjuvant tamoxifen in postmenopausal breast cancer: Preliminary results of a randomized trial

Summary Between May 1978 and March 1982, 179 postmenopausal women with operable breast cancer were randomized to receive either adjuvant tamoxifen, 40 mg daily for three years (TAM group), or no further treatment (controls).The difference in five-year survival rates (61% in the control group, 72% in the TAM group) was not statistically significant. However, there was a significant improvement in disease-free survival in the TAM group (61%) relative to the controls (44%) (p = 0.008). In estrogen receptor positive patients, tamoxifen improved both the disease-free rate (47% controls, 80% with tamoxifen) and the survival rate (63% to 83%). Similar results were observed in progesterone receptor positive patients. In patients that were estrogen receptor negative, tamoxifen modified neither the survival rate nor the disease-free interval.     

Adjuvant antiestrogen treatment with tamoxifen in postmenopausal women with breast cancer: A longitudinal study of blood coagulation and fibrinolysis

Potential effects of tamoxifen therapy on blood coagulation and fibrinolysis were investigated in women with breast cancer. We studied 14 parameters of hemostasis in 19 postmenopausal women receiving 20 mg tamoxifen/day as an adjuvant treatment. Blood sampling was done before and after the 1st, 3rd, and 6th month of treatment. Pretreatment values of procoagulation, anticoagulation, plasminogen, and plasminogen activator inhibitor were found within the reference range, whereas tissue-plasminogen activator, fibrin degradation products, and prothrombin-fragment 1+2 were elevated. On therapy an initial decrease of all measured parameters was observed. The effect was pronounced in coagulation inhibitors (antithrombin III, protein C and S). No pathological values (below 60%) were observed. No further effects were found during the 3rd and 6th month of treatment. Our data indicate that the decrease of hemostatic parameters during the initial phase of tamoxifen treatment is due to the timing of blood collection, which took place no more than 14 days after surgery. The reduction of coagulation inhibitors was not associated with pathological values. No cumulative effects were seen during tamoxifen therapy. The decrease was not associated with a concomittant increase of in vivo coagulation markers (prothrombin-fragment 1+2, thrombin-antithrombin-complex, fibrin degradation products). Therefore our results are likely to reflect only the resolution of postoperative activation and do not translate into a drug related thrombogenic effect.     

Haemostatic changes and thromboembolic risk during tamoxifen therapy in normal women.

Tamoxifen has been implicated as a risk factor for venous thrombosis in advanced breast cancer although the evidence for increased arterial or venous thrombosis with tamoxifen in early breast cancer is less clear. The effect of tamoxifen on haemostasis, and thereby possible thromboembolic risk, was investigated in normal women enrolled in a placebo controlled trial of tamoxifen as a chemopreventative agent for breast cancer. There was an initial reduction in fibrinogen levels in all women on tamoxifen over the first year of follow-up and a marginal reduction in antithrombin III and Protein S in postmenopausal women at 6 months. There were no changes in cross linked fibrinogen degradation products or Protein C for pre or post-menopausal women. There was no increase in the incidence of thromboembolic events on tamoxifen. This study demonstrates that tamoxifen has only marginal effects on factors involved in haemostasis reported to affect the incidence of arterial or venous thromboembolic disease. The follow-up time is relatively short (maximum 36 months) and careful long term follow-up is necessary to detect clinically significant morbidity.     

Adjuvant tamoxifen for pre- and postmenopausal women with estrogen receptor positive,node positive breast cancer: A randomized study

Summary 370 patients with operable, axillary node positive breast cancer, were randomized to receive tamoxifen (TAM) 20 mg/day for 2 years or no adjuvant hormone therapy. All patients had estrogen receptor (ER) positive (ER > 10 pmol/g) primary tumours. 350 patients, 93 younger than 50 years of age and 257 patients 50 years or older, were evaluable for the study. After a median follow up of 76 months, significantly (p = 0.0001) fewer loco-regional, but not distant (systemic), relapses have been recorded in the TAM group. Overall survival was also improved, but even though the study was designed to give maximum benefit from TAM statistically significant effect of TAM seemed to be limited to patients 50 years of age and older.     

Neoadjuvant tamoxifen for hormone-sensitive non-metastatic breast carcinomas in early postmenopausal women.

BACKGROUND: From 1984 to 1996, 1581 postmenopausal women aged 50-70 years old were treated at Institut Bergonié for an infiltrative non-metastatic breast carcinoma with a positive estrogen and/or progesterone receptor determination. PATIENTS AND METHODS: Among them, 199 were treated with first line tamoxifen. Ninety-seven had operable disease (T2 >30 mm, T3, N0/1) and 102 had T4 tumours. RESULTS: After a mean treatment duration of 5.3 months, 89 T2 and T3 (92%) and 93 T4 (91%) were treated by surgery (conservative or not) with or without irradiation, or by irradiation alone. Conserving treatment levels were 53.6% and 44%, respectively. The other women were treated with either second-line chemotherapy or another hormonotherapy; the remaining patients continued regularly with tamoxifen. Overall survival is analysed with a 83 month median follow-up. CONCLUSIONS: A comparison between neoadjuvant endocrine therapy and surgery seems feasible to assess the concept of neoadjuvant hormonotherapy.     

Endocrine effects of tamoxifen plus exemestane in postmenopausal women with breast cancer.

PURPOSE: In some specific circumstances, combined hormonal therapies for breast cancer seem to be more effective than single maneuvers. In two laboratory mammary cancer models, the combination of the aromatase inactivator exemestane plus tamoxifen gives a higher response rate than is found with either agent alone.To evaluate the endocrine effects of the combination of exemestane and tamoxifen, we studied 33 postmenopausal women disease-free following primary treatments for breast cancer who were taking tamoxifen for at least 3 months. DESIGN: After observation for symptoms on tamoxifen for 4 weeks, blood samples were taken and patients were begun additionally on exemestane 25 mg p.o. qd. Eight weeks later, blood samples were again taken, and exemestane was discontinued. RESULTS: A decrease in alkaline phosphatase was found with exemestane treatment (P = 0.06), whereas no change in osteocalcin level was observed. A decrease in high-density lipoprotein cholesterol level was found (P = 0.0025), whereas total cholesterol, low-density lipoprotein cholesterol and triglyceride levels showed no changes with exemestane treatment. Estradiol, estrone, and estrone sulfate levels decreased to immeasurable or very low levels with exemestane treatment (all P < 0.001). No significant changes in frequencies of common drug-associated side effects, such as vasomotor symptoms or weight change, were found. CONCLUSIONS: Based on the absence of adverse endocrine effects with the addition of exemestane to tamoxifen therapy observed in this study, further clinical evaluation of the efficacy of this combination is warranted.     

Evidence that tamoxifen preserves bone density in late postmenopausal women with breast cancer

Tamoxifen, which is used for treating breast cancer, exhibits estrogenic and antiestrogenic characteristics, depending on the tissue. In the human breast it acts as an antiestrogen, whereas estrogenic effects have been reported on endometrium and bone. The purpose of this study was to determine whether tamoxifen (TAM) prevents bone loss in elderly, postmenopausal women. Bone mineral density of the lumbar spine (SBD) was measured in elderly women (at least 10 years after menopause) 5 years after stage I or II breast cancer (n = 111). The results showed that SBD in untreated patients (n = 74) was significantly lower (p < 0.05) than SBD in patients (n = 37) treated with TAM over 5 years. In a subgroup of patients (n = 24) with positive estrogen receptor status, changes in SBD 12 months after discontinuation of 5-year TAM therapy were measured and compared with the changes of extended TAM treatment over a sixth year. Twelve months after withdrawal of 5-year TAM medication (n = 11) bone density decreased significantly (- 4.8+/-2.5%; p > 0.05), whereas in the group of women (n = 13) receiving extended TAM medication (20 mg) for an additional 12 months, SBD ( + 1.9+/-3.5 %) was maintained during the observation period, and was significantly higher when compared with the group of untreated patients (p <0.05). We conclude that tamoxifen has a preventive effect on trabecular bone loss at the lumbar spine, when compared to age-matched data and to untreated women with breast cancer in the late menopause. Our data give evidence of benefits to bone density provided by prolonged administration in patients after breast cancer and at risk of osteoporosis.     

Randomized clinical trial of tamoxifen plus sequential CMF chemotherapy versus tamoxifen alone in postmenopausal women with advanced breast cancer

Summary Eighty-eight postmenopausal women with metastatic breast cancer, in whom estrogen receptors (ER) were positive or unknown, were treated on a controlled trial to determine the effectiveness of tamoxifen and to assess the therapeutic advantage of sequentially adding low-dose cyclophosphamide-methotrexate-5-fluorouracil (CMF) chemotherapy in tamoxifen responders. Patients with known ER negative status were not studied. After the initial 12-week treatment with tamoxifen alone, 60% of ER positive patients achieved complete or partial response as did 35% in whom ER were unknown. Response status further improved in 18% randomized to continue tamoxifen alone vs 31% in whom CMF was added to tamoxifen. There were no statistically significant differences in time to the development of progressive disease or survival between the ER positive and ER unknown patients or between the tamoxifen and tamoxifen plus CMF groups. We conclude that inability to determine ER status should not prejudice against the use of tamoxifen in postmenopausal patients with advanced breast cancer. No benefit has been demonstrated from the addition of CMF chemotherapy in tamoxifen responders. Address for reprints: J.H. Glick, M.D., Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104.