Hormonal Treatment: A Look to the Future
Paul Goss, MD, Division of Hematology/Oncology, Princess Margaret Hospital, Toronto, Canada
Tamoxifen has become a household word because of its premier role in the treatment of early stage and advanced breast cancer over the past 2 to 3 decades. It may be the most important single anti-cancer drug ever discovered in terms of number of years of life saved. However, tamoxifen has several drawbacks. Tamoxifen is incompletely effective reducing mortality by only one-third in early stage breast cancer. Additionally, it has rare but serious toxicities (e.g., endometrial cancer and venous thromboembolism) and frequent and troublesome vasomotor symptoms (hot flashes) and urogenital side effects.
The aromatase inhibitors are a new class of agents that have challenged tamoxifen as a means of antagonizing estrogen's effects on the growth and development of breast cancer. While at first glance they seem to act the same as tamoxifen, they lack the partial estrogen agonist effect of tamoxifen and thus, inhibit the synthesis not only of the parent compound, but also naturally occurring and potentially carcinogenic estrogen metabolites. Aromatase inhibitors have been tested in postmenopausal women with receptor positive breast cancer in the advanced disease setting and more recently in adjuvant treatment. Data presented at the 2001 San Antonio Breast Cancer Symposium confirmed the displacement of tamoxifen as the drug of first choice in metastatic breast cancer. Letrozole has been shown to be superior to tamoxifen in response rates and in all time-dependent variables.
In the adjuvant setting, exciting and important results were presented suggesting superiority of anastrozole over tamoxifen. While further follow up data is needed to confirm survival advantage, many physicians will now use an aromatase inhibitor as initial therapy in the adjuvant setting. With virtual ablation of postmenopausal estrogen, the obvious risk of an adverse effect on bone and lipid metabolism comes to mind, as well as aggravation of menopausal symptomatology. Quantitative and qualitative data in humans is still lacking regarding the aromatase inhibitors on these endpoints although early data outlined in this report suggests an increase in bone turnover with the non-steroidal aromatase inhibitors. There has been a belief, and some preliminary human data, to suggest that the steroidal aromatase inhibitor exemestane may protect against these effects because of the potential androgenic nature of the parent compound and its metabolites. For this reason, we have conducted an animal experiment in rats and have demonstrated the powerful bone-preserving and lipid-lowering effects of exemestane. We are conducting follow up experiments comparing these results to those seen with the nonsteroidal aromatase inhibitors. If there is a difference in these critical endpoints, then exemestane could become the anti-aromatase agent of choice; particularly in healthy women such as at-risk women and early stage breast cancer patients in whom all organ, health and quality of life considerations are critical.
A Review of the Latest Evidence-Based Medicine
Exemestane (Aromasin, Pharmacia Corp) is a third-generation, irreversible steroidal aromatase (estrogen synthetase) inactivator showing potent bone preserving and lipid-lowering effects in experimental animals that may distinguish it from other aromatase inhibitors, according to research presented at the 24th Annual San Antonio Breast Cancer Symposium. Other investigators reported that combining exemestane with celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, resulted in enhanced tumor response. Although conducted in animal models, these studies prompted tremendous interest at the Symposium's poster sessions, and the clinical implications are being further explored in continuing investigational studies.
"We have very profound bone data. In this model, our findings rival the best bone [protective] drugs," according to Paul Goss, MD, Division of Hematology/Oncology, Princess Margaret Hospital, Toronto, Canada, and a leading investigator of aromatase inhibitors, who presented a study in ovariectomized rats.
Large clinical trials have firmly established that aromatase inhibitors now compete with tamoxifen as effective first-line therapy for breast cancer in the metastatic1,2 and adjuvant settings.3,4 Moreover, emerging evidence in preclinical models suggests that aromatase inhibitors may be very useful as chemopreventive therapy.5,6,7,8 The target populations for future studies of aromatase inhibitors as chemopreventive therapy include women at risk of breast cancer by virtue of clinical markers such as elevated plasma estradiol levels, premalignant breast lesions, or breast density.9,10 In this prolonged therapeutic role, there is a clinical necessity for agents that will not exert detrimental systemic effects, such as bone loss and lipid abnormalities.
For example, the ATAC trial11 showed a significant increase in disease free survival and reduced risk of contralateral cancers in advanced breast cancer patients treated with anastrozole as compared to tamoxifen. However, there was a difference of 2.1% in the risk of clinical fractures that could have been attributable to a protective effect on bone by tamoxifen or accelerated bone loss by anastrozole. Corroborative evidence that the aromatase inhibitors may increase bone loss however, has been presented. According to several opinion leaders at the Symposium, this raised a precautionary red flag that bone loss, associated with a corresponding increase in the risk of fracture, may prove troublesome for this class of agents.
"This is very real and compelling clinical data, not just a measurement of bone mineral density. A 2% increase in fractures could indicate serious toxicity and should be followed up carefully," according to Dr. Goss.
In a study presented by Dr. Goss, exemestane is one aromatase inactivator that may protect against bone loss, as well as reduce serum cholesterol levels. Goss et al.12 randomized 79 ten-month old Sprague-Dawley female rats into five groups: controls, intact controls (sham-operated plus vehicle), sham plus exemestane 100 mg/kg/week, ovariectomized controls, and ovariectomized plus exemestane. Blood samples were collected for lipid and bone biochemical assays and bone mineral density (BMD) was measured on lumbar vertebra and femora.
After 16 weeks of treatment, exemestane markedly prevented bone loss and lowered serum cholesterol and LDL levels in the ovariectomized animals. Dr. Goss remarked, "When you castrate the animals, you see all the obvious changes that occur with castration in humans. You get substantial increase in bone turnover, as in menopause, and you see lipid metabolism change dramatically.
"When we gave exemestane replacement, these animals looked as if they had not been castrated," he noted. "Essentially, a castrated animal on exemestane looks identical to a cycling animal."
Specifically, the BMD of the lumbar spine was 11% lower in ovariectomized control animals than in intact controls (p = 0.0001). Interestingly, the ovariectomized animals given exemestane still had 99% of the BMD value observed in intact animals (p = 0.0001), the BMD value being significantly higher that those of the ovariectomized control animals. Similar effects were observed on femoral BMD.
Pyridinoline, a biomarker of bone resorption,13 and osteocalcin, a marker of bone formation,14 were significantly increased in ovariectomized controls over intact controls, but this increase was almost completely prevented by administering exemestane (p = 0.0001), suggesting a prevention of bone resorption.
Ovariectomized animals had a 49% increase in total serum cholesterol, but ovariectomized animals treated with exemestane experienced a 28% decrease in serum cholesterol (p = 0.0001 vs. ovariectomized controls). LDL cholesterol was reduced by 64% (p = 0.0001 vs. ovariectomized controls) Dr. Goss reported.
A presentation by Memorial Sloan-Kettering investigators also found no bone loss, no cholesterol increases, and a reduction in breast density among four patients receiving exemestane.15 "The data suggest it may at least be bone sparing, potentially because of an androgenic metabolite," said Maura Dickler, MD principal investigator. Her study also found no evidence of antagonistic drug interaction between exemestane and raloxifene, indicating the combination did not diminish each drug's individual effects.
In contrast, another presentation discussing aromatase inhibitors revealed that 3 months of letrozole administration in healthy, postmenopausal women was found to produce significant rises in products of bone metabolism (p = 0.02) while showing no significant changes on lipids.16 The possible negative impact [increase in bone resorption] on bone leads to concerns for aromatase inhibitors in the low-risk setting, said Catherine Harper-Wynne, MD, of The Royal Marsden Hospital, London, United Kingdom.
Therefore, not all anti-aromatase agents may behave similarly in this regard, Dr. Goss noted. "We would be foolish to think the three available agents are identical. If the data in bone is substantiated, these agents could start to separate."
The investigational evidence for bone sparing and cholesterol lowering with exemestane is derived from emerging clinical evidence in humans that exemestane precludes adverse effects on bone and lipid metabolism in postmenopausal women normally seen with other breast cancer treatments. If these data are confirmed in women with breast cancer or at risk for it, exemestane should be very suitable therapy in the adjuvant [breast cancer therapy] or chemopreventive setting, Dr. Goss predicted.
"I think if these findings pan out in humans, exemestane will distinguish itself dramatically from the other aromatase inhibitors," he said. "If I were to bet the field, I'd say Aromasin [exemestane] could emerge the victorious anti-aromatase agent of all three compounds because of its steroidal structure."
Dr. Goss will be conducting a Canadian/US study17 through the National Cancer Institute of Canada that randomizes postmenopausal women with high breast density to exemestane or placebo, to evaluate reduction in breast density and effects on bone and lipid metabolism.
A large multicenter Italian study18 is also underway to evaluate exemestane's chemopreventive effects in postmenopausal, unaffected carriers of BRACA1/2 mutations. Six hundred and sixty-six eligible women will be blindly randomized to exemestane 25 mg daily or placebo for 3 years. Exemestane was selected for study because it nearly eliminates peripheral estrogen production, said Paulo Marchetti, MD, on behalf of the Aromasin Prevention Study Group, University of L'Aquila, Italy.
"Among the different anti-aromatase agents, exemestane's particular mechanism of action is to completely abrogate the aromatase activity," he said. "Compared to the other agents, there is a progressive reduction in activity inside the cells of the breast. In addition, its tolerability is excellent."
Exemestane Plus Celecoxib: Marked Inhibition of Tumor Growth
In an animal breast tumor model, the combination of exemestane and celecoxib, a COX-2 inhibitor, produced marked inhibition of tumor growth in breast cancer cell lines.19 Pesenti et al. reported that 48% of rats administered exemestane (50 mg/kg/week) and celecoxib (500 mg/kg of diet) had a complete/partial tumor response, while only 5% of tumors responded (complete/partial) to single-agent exemestane and 0% responded to single-agent celecoxib.
Percent tumor growth was only 50% with the exemestane and celecoxib combination compared to 100% and 200% with the respective single agents, and over 200% with placebo. Furthermore, the combination of exemestane and celecoxib greatly reduced the development of new tumors, essentially cutting the rate by up to two-thirds over single agents.
The rationale for the combination is two-fold: the antitumor activity shown by celecoxib on a variety of tumor types,20 and celecoxib's inhibition of prostaglandin E2,21 a major stimulator of local aromatase expression in the breast. "By inhibiting this prostaglandin, you shut down another pathway of aromatase activity," he explained.
The high degree of tumor inhibition with this combination leads Dr. Pesenti to believe the two agents are synergistic, which could have exciting implications for the therapy for human breast cancer, he said.
One of the side effects of metastatic breast cancer therapy with aromatase inhibitors appears to be detrimental effects on bone and lipid metabolism. However, according to reports at this meeting, exemestane, a steroidal irreversible aromatase inactivator, may show the opposite property, exerting positive benefits on these two clinically important parameters in both animal models and human subjects. Furthermore, preclinical data suggested the combination of exemestane and celecoxib may have a synergistic inhibitory effect on reducing tumor growth and new tumor incidence.
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