Switching trial of adjuvant tamoxifen with an aromatase inhibitor in postmenopausal patients with breast cancer

Tamoxifen is currently a standard of care for postmenopausal patients with breast cancer with hormone receptor-positive tumors who are candidates for adjuvant endocrine therapy. This treatment is highly effective and relatively safe. However, a significant proportion of women are constitutively resistant or become resistant to tamoxifen, despite having hormone receptor-positive tumors. Moreover, the prolonged exposure to tamoxifen can produce severe and life-threatening side effects like endometrial carcinoma or thromboembolic disease. Aromatase inhibitors (AI) have been shown to be quite effective in advanced disease, and also have promising efficacy in early-stage breast cancer as alternatives to tamoxifen. This article reviews the results achieved by AI following 2-3 years or 5 years of tamoxifen. At least 3 trials indicate that switching to an AI following 2-3 years of tamoxifen can produce a substantial benefit. A fourth trial indicates that additional benefit can be achieved by a few years of treatment with an AI after 5 years of tamoxifen. The updated results of previous trials and ongoing trials will soon establish criteria for selecting patients who might be better candidates for sequencing, and to fine tune strategies that are more appropriate.     

Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer.

This study examined whether the addition of tamoxifen to the treatment regimen of patients with advanced breast cancer being treated with the aromatase inhibitor letrozole led to any pharmacokinetic or pharmacodynamic interaction. Twelve of 17 patients completed the core period of the trial in which 2.5 mg/day letrozole was administered alone for 6 weeks and in combination with 20 mg/day tamoxifen for the subsequent 6 weeks. Patients responding to treatment continued on the combination until progression of disease or any other reason for discontinuation. Plasma levels of letrozole were measured at the end of the 6-week periods of treatment with letrozole alone and the combination and once more between 4 and 8 months on combination therapy. No further measurements were done thereafter. Hormone levels were measured at 2-week intervals throughout the core period. Marked suppression of estradiol, estrone, and estrone sulfate occurred with letrozole treatment, and this was not significantly affected by the addition of tamoxifen. However, plasma levels of letrozole were reduced by a mean 37.6% during combination therapy (P<0.0001), and this reduction persisted after 4-8 months of combination therapy. Letrozole is the first drug to be described in which this pharmacokinetic interaction occurs with tamoxifen. The mechanism is likely to be a consequence of an induction of letrozole-metabolizing enzymes by tamoxifen but was not further addressed in this study. It is possible that the antitumor efficacy of letrozole may be affected. Thus, sequential therapy may be preferable with these two drugs. It is not known whether tamoxifen interacts with other members of this class of drugs or with other drugs in combination.     

Meta-analysis of pre-operative aromatase inhibitor versus tamoxifen in postmenopausal woman with hormone receptor-positive breast cancer

Purpose  Clinical trials have reported conflicting results as to whether pre-operative aromatase inhibitors (AIs) improve outcome over pre-operative tamoxifen in postmenopausal women with hormone receptor-positive breast cancer. Methods  We performed a meta-analysis comparing primary and secondary end points of pre-operative AI and pre-operative tamoxifen. The event-based risk ratio (RR) with 95% confidence intervals (95% Cis) were derived, and a test of heterogeneity was applied. Results  Four studies (1,160 patients) met the inclusion criteria for the analysis. Meta-analysis showed that pre-operative AI was more effective than pre-operative tamoxifen. Pooled results of clinical efficacy were as follows: clinical objective response rate (RR, 1.29; 95% CI, 1.14–1.47; P < 0.001), ultrasound objective response rate (RR, 1.29; 95% CI, 1.10–1.51; P = 0.002), and breast conserving surgery (BCS) rate (RR, 1.36; 95% CI, 1.16–1.59; P < 0.001). Hot flashes, nausea, and fatigue were not different between the pre-operative AI and pre-operative tamoxifen groups. Although headache was more frequent in the pre-operative AI group (P = 0.011), it was a manageable toxicity and was not clinically relevant. Conclusion  Pre-operative AI has better BCS rate than tamoxifen and in terms of toxicities, is not inferior to tamoxifen; therefore, we could suggest pre-operative AI instead of tamoxifen for those postmenopausal patients with hormone receptor positive breast cancer, not eligible for chemotherapy.     

Randomized phase III trial comparing the new potent and selective third-generation aromatase inhibitor vorozole with megestrol acetate in postmenopausal advanced breast cancer patients. North American Vorozole Study Group.

PURPOSE: To compare the efficacy and safety of vorozole (VOR) 2.5 mg once daily with that of megestrol acetate (MA) 40 mg four times per day as second-line therapy in postmenopausal women with advanced breast cancer whose disease progressed after tamoxifen treatment. PATIENTS AND METHODS: A total of 452 patients were enrolled onto an open, multicenter, randomized phase III trial comparing VOR to MA for tumor response, safety, and quality of life (as indicated by the Functional Living Index-Cancer score). RESULTS: Vorozole produced a response rate of 9.7%, compared with 6.8% for MA (P = .24). Clinical benefit (complete response + partial response + no change in > 6 months) was demonstrated in 23.5% and 27.2% of patients treated with VOR and MA, respectively (P = .42). Median duration of response was 18.2 months for VOR versus 12.5 months for MA (P = .074). There was no significant difference in time to progression or survival between the treatment groups. Discontinuation of treatment because of adverse events occurred less frequently in the VOR-treated group (3.1% v 6.2%; P = .18). Patients on the VOR arm reported significantly more nausea, hot flushes, arthralgia, upper respiratory tract infection, anorexia, and paresthesia, whereas those treated with MA had significantly more dyspnea, increased appetite, and weight increase. There was no difference between the two treatment groups in Functional Living Index-Cancer scores (total or subscales). However, when analyzed by objective response, patients with complete or partial responses (P = .032) or no change (P = .033) who were receiving VOR had significant improvement in the psychologic well-being subscale, compared with patients given MA. CONCLUSION: Vorozole is well tolerated and as effective as MA in the treatment of postmenopausal advanced breast cancer patients with disease progression after tamoxifen treatment.     

Modeling for cost-effective-adjuvant aromatase inhibitor strategies for postmenopausal women with breast cancer.

BACKGROUND: To determine cost-effective (CE) strategies comparing adjuvant upfront aromatase inhibitor (AI) with sequential tamoxifen (TAM) AI in postmenopausal (PM) women with breast cancer (BC). Design: A Markov model was constructed to calculate cumulative costs and quality-adjusted life year (QALY) gains for upfront AI and TAM-AI in a hypothetical cohort of 60-year-old PM women with BC. Costs, utilities and probabilities were derived from the literature. The hazard ratios (HRs) of AI strategies were applied to a baseline cancer recurrence risk (RR) to determine CE strategies at the $50,000/QALY gain threshold. A direct payer perspective is utilized, and costs and benefits were discounted at 3%. RESULTS: Two-way sensitivity analyses are presented to determine CE strategies across a wide range of HRs and in different clinical scenarios including varying RRs (low, average, high and very high). TAM-AI is the preferred CE strategy at low and average RR, while upfront AI is CE at very high RR. The CE strategy in patients with high RR was dependent on the scenario examined. CONCLUSIONS: This model may help health care providers select CE-adjuvant AI strategies in PM women with BC, until further direct evidence is available from randomized clinical trials.     

The effect of second-line antiestrogen therapy on breast tumor growth after first-line treatment with the aromatase inhibitor letrozole: long-term studies using the intratumoral aromatase postmenopausal breast cancer model.

PURPOSE: The aromatase inhibitors letrozole and anastrozole have been approvedrecently as first-line treatment options for hormone-dependent advanced breast cancer. Although it is established that a proportion of patients who relapse on first-line tamoxifen therapy show additional responses to aromatase inhibitors, it has not been determined whether tumors that acquire resistance to aromatase inhibitors in the first line remain sensitive to second-line therapy with antiestrogens. The aim of this study was to determine whether aromatase-transfected and hormone-dependent MCF-7Ca human breast cancer cells remain sensitive to antiestrogens after: (a) long-term growth in steroid-depleted medium in vitro; and (b) long-term treatment with the aromatase inhibitor letrozole in vivo. METHODS: In the first approach, a variant of the MCF-7Ca human breast cancer cell line was selected that had acquired the ability to grow in estrogen-depleted medium after 6-8 months of culture. Steroid-deprived UMB-1Ca cells were analyzed for aromatase activity levels, hormone receptor levels, and sensitivity to estrogens and antiestrogens in vitro and in vivo. In the second approach, established MCF-7Ca breast tumor xenografts were treated with letrozole 10 microg/day for 12 weeks followed by 100 microg/day for 25 weeks until tumors acquired the ability to proliferate in the presence of the drug. Long-term letrozole-treated tumors were then transplanted into new mice, and the effects of antiestrogens and aromatase inhibitors on tumor growth were determined. RESULTS: Steroid-deprived UMB-1Ca breast cancer cells continued to express aromatase activity at levels comparable with the parental cell line. However, compared with MCF-7Ca cells, UMB-1Ca cells expressed elevated levels of functionally active estrogen receptor. The growth of UMB-1Ca cells in vitro was inhibited by the antiestrogens tamoxifen and faslodex and tumor growth in vivo was inhibited by tamoxifen. In the second approach, the time for MCF-7Ca tumor xenografts to approximately double in volume after being treated sequentially with the increasing doses of letrozole was thirty-seven weeks. Long-term letrozole-treated tumors continued to express functionally active aromatase. When transplanted into new mice, growth of the long-term letrozole-treated tumors was slowed by tamoxifen and inhibited more effectively by faslodex. Tumor growth was refractory to the aromatase inhibitors anastrozole and formestane but, surprisingly, showed sensitivity to letrozole. CONCLUSIONS: Steroid-deprived UMB-1Ca human breast cancer cells selected in vitro and long-term letrozole-treated MCF-7Ca breast tumor xenografts remain sensitive to second-line therapy with antiestrogens and, in particular, to faslodex. This finding is associated with increased expression of functionally active estrogen receptor after steroid-deprivation of MCF-7Ca human breast cancer cells in vitro.     

Cellular effects of tamoxifen in primary breast cancer.

We have investigated the effect of tamoxifen on the biological characteristics of the primary tumour in 33 patients with breast cancer. All patients had pre-treatment biopsy of the primary breast cancer and subsequent trucut biopsy of the primary tumour after 1-4 months on tamoxifen therapy. The staining patterns in the primary tumour of each of the tumour antigens 115D8, DF3, NCRC-11, and carcinoembryonic antigen (CEA) were unaffected by tamoxifen therapy: there was 16%-31% change before vs. during tamoxifen therapy, but this did not reach significance for any of the four antigens. Comparison of the pattern of staining between the four antigens showed 115D8, DF3, and NCRC-11 to be similar to each other both before and during tamoxifen therapy. All three antigens were significantly different from the staining pattern shown by CEA before and during therapy. Tumour antigen expression pre-treatment did not correlate with therapeutic response for any of the four antigens. However, NCRC-11 staining during tamoxifen therapy did correlate with response (p = 0.004). There was no significant difference in oestrogen receptor status before and during tamoxifen therapy, both of which correlated with response. DNA ploidy of the tumour before tamoxifen did not correlate with response to therapy, but there was a weak correlation between response and DNA ploidy measured during tamoxifen therapy. In only a minority of tumours (up to 30%) did tamoxifen exert an effect on the biological characteristics studied. Changes in these biological markers were mainly in tumours which responded to tamoxifen, and the changes seen were a tendency to greater expression of differentiation antigens.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Chemopreventive effects of the aromatase inhibitor vorozole (R 83842) in the methylnitrosourea-induced mammary cancer model

The chemopreventive activity of the highly specific nonsteroidal aromatase inhibitor, vorozole, was examined in the methylnitrosourea (MNU)-induced rat model of mammary carcinogenesis. Various doses of vorozole (0.08-1.25 mg/kg body wt/day) were administered daily (by gavage) to female Sprague-Dawley rats starting at 43 days of age. Seven days later, the rats were given a single i.v. dose of MNU (50 mg/kg body wt). Rats were continually treated with vorozole until the end of the experiment (120 days post-MNU). Vorozole caused a dose dependent inhibition of mammary cancer multiplicity. The highest dose of vorozole (1.25 mg/kg body wt/day) decreased cancer multiplicity by approximately 90%, and simultaneously decreased cancer incidence from 100 to 44%. The next two highest doses of vorozole (0.63 and 0.31 mg/kg body wt/day) inhibited MNU-induced mammary cancer multiplicity by 70-80%. Even the two lowest doses of vorozole (0.16 and 0.08 mg/kg body wt/ day) decreased cancer multiplicity -50%. Serum level determinations were performed on a variety of endpoints at either 4 or 24 h following the last dose of vorozole. Insulin-like growth factor (IGF)-1 levels were slightly, but significantly, increased by vorozole treatment. Vorozole induced striking increases in serum testosterone levels at 4 h at all the dose levels employed. Testosterone levels were significantly elevated over controls at 24 h in rats given the lower doses of vorozole (0.08-0.31 mg/kg body wt/day), but were significantly lower than in rats administered the higher doses of vorozole (0.63 or 1.25 mg/kg body wt/ day). This result presumably reflects the limited half- life of vorozole in rats. In a second series of experiments, the effects of limited duration of dosing with vorozole (2.5 mg/kg body wt/day) or intermittent dosing with vorozole were determined. Treatment of rats with vorozole for limited time periods, from 3 days post-MNU administration until 30 or 60 days post-MNU treatment, resulted in significant delays in the time to appearance of palpable cancers. However, these limited treatments did not greatly affect the overall incidence or multiplicity of mammary cancers when compared with the MNU controls at the end of the study (150 days post-MNU). Finally, the effects of intermittent dosing with vorozole (2.5 mg/kg body wt/day) were examined. Rats were administered cycles of vorozole daily for a period of 3 weeks followed by treatment with the vorozole vehicle for the next 3 weeks (total of four cycles). Although this intermittent treatment did inhibit the appearance of new tumors during each of the periods that vorozole was administered, it did not cause regression of palpable cancers.      

Cellular effects of tamoxifen in primary breast cancer

We have investigated the effect of tamoxifen on the biological characteristics of the primary tumour in 33 patients with breast cancer. All patients had pre-treatment biopsy of the primary breast cancer and subsequent trucut biopsy of the primary tumour after 1–4 months on tamoxifen therapy.The staining patterns in the primary tumour of each of the tumour antigens 115D8, DF3, NCRC-11, and carcinoembryonic antigen (CEA) were unaffected by tamoxifen therapy: there was 16%–31% change before vs. during tamoxifen therapy, but this did not reach significance for any of the four antigens. Comparison of the pattern of staining between the four antigens showed 115D8, DF3, and NCRC-11 to be similar to each other both before and during tamoxifen therapy. All three antigens were significantly different from the staining pattern shown by CEA before and during therapy.Tumour antigen expression pre-treatment did not correlate with therapeutic response for any of the four antigens. However, NCRC-11 staining during tamoxifen therapy did correlate with response (p=0.004).There was no significant difference in oestrogen receptor status before and during tamoxifen therapy, both of which correlated with response. DNA ploidy of the tumour before tamoxifen did not correlate with response to therapy, but there was a weak correlation between response and DNA ploidy measured during tamoxifen therapy.In only a minority of tumours (up to 30%) did tamoxifen exert an effect on the biological characteristics studied. Changes in these biological markers were mainly in tumours which responded to tamoxifen, and the changes seen were a tendency to greater expression of differentiation antigens. It is uncertain whether these changes are a primary or a secondary effect of tamoxifen with respect to inducing tumour response.     

Femoral fractures in postmenopausal breast cancer patients treated with adjuvant tamoxifen

Summary The anti-estrogen tamoxifen is the prevalent endocrine treatment in postmenopausal breast cancer patients. However, nothing is known about the long-term effects of the drug on the skeleton as assessed by the occurrence of fractures.We investigated the occurrence of fractures of the femur in patients from a Danish Breast Cancer Cooperative Group (DBCG) trial initiated in 1977 by a linkage of data from the Danish National Registry of Patients with data from the DBCG registry. 1716 postmenopausal women with high-risk breast cancer were randomized to local radiotherapy with or without tamoxifen, 30 mg daily for 1 year.Fifty-one patients in the control group had one femoral fracture and 64 tamoxifen treated patients had one femoral fracture. Eleven patients in the control group had one trochanteric fracture compared to 27 patients in the tamoxifen group (logrank = 5.28, P = 0.022; hazard ratio = 2.12, 95% CL 1.12, 4.01).The results could not be explained by a longer survival in the tamoxifen group nor by bone metastases with pathological fractures.In conclusion, our study suggests that tamoxifen does not seem to offer protection against fractures in old age and may even increase the risk of fractures at particular sites. This hypothesis needs to be disproved or confirmed in other trials.     

Therapeutic effects of the aromatase inhibitor fadrozole hydrochloride in advanced breast cancer.

The endocrine and therapeutic effects of the aromatase inhibitor fadrozole hydrochloride have been assessed in 80 post-menopausal patients with recurrent breast cancer after tamoxifen failure. Treatment allocation was randomly 0.5, 1.0 or 2.0 mg orally b.d. Eight patients were not assessable for response. All patients were evaluated for toxicity (intent-to-treat analysis). In general, the patients'' characteristics were well balanced between the three randomised groups. The endocrine data from this study previously reported suggest a dose-related suppression of oestrone, but not oestradiol or oestrone sulphate. The objective response rate was 17% (95% CI 8.9-27.3%) with no complete responders. Fifteen patients (21%) had stable disease (NC) and 45 patients (63%) had progressive disease (PD). The median duration of objective response was 36 weeks. The median time to treatment failure was 12.7 weeks. The log-rank test showed no statistical difference between the dosage groups. The main adverse events reported were mild to moderate severity: nausea in 11 patients (15%), hot flashes in four (5%) and somnolence in three (4%). No serious adverse events were reported. In conclusion, fadrozole is a clinically active aromatase inhibitor with a low incidence of side-effects and phase III clinical trials in post-menopausal women are currently under way.     

Cognitive dysfunction in postmenopausal breast cancer patients on aromatase inhibitors

As mortality in breast cancer patients has improved, morbidity of treatment has become increasingly important. Cognitive dysfunction has been considered as a morbid condition that may possibly result from aromatase inhibitor therapy, the standard treatment in postmenopausal, estrogen/progesterone receptor-positive breast cancer patients. Chemotherapy has been associated with cognitive dysfunction through neuropsychological testing and neurological functional imaging, but the relationship between estrogen and cognition remains largely unexplained. In focusing on aromatase inhibitor therapy, most of the studies yielding mixed results have been limited by confounders and small numbers of populations studied. This article briefly summarizes the major studies evaluating aromatase inhibitor therapy and cognitive dysfunction while considering new directions in future study design.