Results from several clinical trials have clearly demonstrated substantial benefit from tamoxifen(Drug information on tamoxifen) (Nolvadex) administration in stage I and II hormonally responsive breast cancer.[1-9] None of the newly developed antiestrogens has been shown to be superior to tamoxifen in the adjuvant setting. Thus, tamoxifen remains the "standard" adjuvant hormonal therapy for these patients.
Although the optimal duration of tamoxifen administration continues to be debated, the majority of researchers agree thatat least in some patientsthere is a time interval beyond which tamoxifen loses its effectiveness and may even become harmful if continued.
Evidence supporting this hypothesis is provided by studies evaluating various intervals of tamoxifen administration in the adjuvant setting; it is also corroborated by observations in the advanced-disease setting, where some patients progress after responding to tamoxifen therapy only to demonstrate a "withdrawal response" following tamoxifen discontinuation.
Short Duration Therapy: < 5 Years
Initial trials of adjuvant tamoxifen therapy[2-5] compared tamoxifen given for 1 to 2 years to no adjuvant therapy. Results showed reductions in recurrence rates, mostly during the period of treatment, with little or no additional benefit afterward. These data, along with preclinical information showing that tamoxifen was cytostatic rather than cytocidal, supported that the benefit of tamoxifen might be augmented by a longer duration of administration.
A Swedish multicenter trial reported in the early 1980s compared 2 years with 5 years of adjuvant tamoxifen in postmenopausal women with early-stage, node-negative or node-positive breast cancer. Of 3,887 patients entered in the trial, 91% remained alive and recurrence-free at 2 years and were included in the 2-year vs 5-year comparison. Ten years after initial randomization, disease-free and overall survival were significantly improved among patients receiving the longer tamoxifen administration (disease-free survival: 73% vs 67%, P = .009; overall survival: 80% vs 74%, P = .03).
Similar results were obtained from a British trial, in which 2,937 patients who were recurrence-free after receiving 2 years of tamoxifen were randomly assigned to no further therapy or 3 additional years of treatment. With a median follow-up of 2 years, a statistically significant benefit in time to disease relapse was seen in the patients receiving the longer treatment duration (relative risk: 0.81, 95% confidence interval [CI] = 0.69%-0.98%). Fewer deaths were also observed in the group receiving the longer treatment, but the difference was not statistically significant (relative risk: 0.89, 95% CI = 0.69%-1.15%).
Other trial results also support a longer duration (up to 5 years) of tamoxifen administration, including the Early Breast Cancer Trialists’ Collaborative Group Meta-Analysis and a nonrandomized trial by NSABP (the National Surgical Adjuvant Breast and Bowl Project), which compared 3-year vs 2-year therapy with adjuvant tamoxifen.
Long Duration Therapy: > 5 Years
The next obvious question was whether a longer duration of tamoxifen administration (ie, more than 5 years) would result in further improvement in disease-free and overall survival. To address this question, the NSABP rerandomized patients who had participated in a trial comparing adjuvant treatment with tamoxifen vs placebo and who were recurrence-free after 5 years of tamoxifen, to 5 more years of tamoxifen or 5 years of placebo. Through 4 years after rerandomization, patients receiving placebo had better disease-free survival (92% vs 86%, P = .003) and overall survival (96% vs 94%, P = .08) than those receiving tamoxifen. Thus, this trial demonstrated that node-negative patients derived no additional benefit from continuing tamoxifen therapy beyond 5 years and that continuing tamoxifen past that interval was possibly detrimental.
Comparable results were obtained in a Scottish trial of similar design in terms of continuing vs stopping tamoxifen therapy after 5 years. With 342 patients reassigned, and after a median follow-up of 6 years, a nonsignificant trend of a higher recurrence rate was noted for patients who continued tamoxifen (relative risk, 1.27; 95% CI = 0.87%-1.85%).
In contrast, a smaller Eastern Cooperative Oncology Group (ECOG) study compared tamoxifen administration for 5 years vs more than 5 years in 193 node-positive patients. Results demonstrated a nonsignificant trend towards fewer recurrences in patients receiving longer tamoxifen administration (15 vs 23).
The exact mechanism of tamoxifen resistance remains elusive. Experimental and clinical evidence suggests that more than one mechanism may be involved, including the development of partial agonistic activity of tamoxifen with stimulation of tumor regrowth,[11,13,14,16,17] alteration or mutation of the estrogen-receptor,[16,18-20,21] clonal selection of an estrogen-receptor-negative phenotype,[16,20,22] development of metabolic tolerance resulting in inadequate intra-tumoral tamoxifen concentrations,[16,20,22] and increased gene expression and growth factor production by tumor cells possibly leading to autocrine stimulation.[23,24]
Recently, development of estrogen hypersensitivity has been postulated as another mechanism of tamoxifen resistance. According to this hypothesis, deprivation of estrogen receptors from estrogen, induced by the administration of tamoxifen, can cause enhanced estrogen sensitivity. Thus, further reduction of estrogen levels by an aromatase inhibitor might be effective by further depriving hypersensitive tumor cells of estrogen levels necessary for their growth.
In patients who have disease recurrence while taking adjuvant tamoxifen therapy, several of these mechanisms may contribute to development of tamoxifen resistance. The preponderant mechanism(s) will dictate whether additional hormonal manipulations might provide further benefit. In the advanced-disease setting, patients who develop acquired resistance after an initial response have an approximate 50% chance of responding to another hormonal agent.
Based on the above information, adjuvant tamoxifen is given for approximately 5 years to most patients particularly those with negative nodes. Thus, the majority of patients are disease-free at the time of tamoxifen discontinuation. Some of these seemingly disease-free patients, however, harbor residual or micrometastatic tumor cells even after several years of tamoxifen therapy. In a proportion of these patients the residual or micrometastatic tumor cells may still be responsive to tamoxifen and may be allowed to grow and proliferate by tamoxifen discontinuation.
The clinical data, however, support the notion that in a greater proportion of patients the residual or micrometastatic tumor cells may progressively become resistant to tamoxifen and could even be stimulated by the drug if it were to be continued for a longer time. Thus, continuing tamoxifen may benefit those patients with tamoxifen-responsive tumor cells but would be detrimental to the group whose cells have become resistant to the agent. Since the residual or micrometastatic tumor cells in both of these groups are hormonally responsive, reducing the level of estrogenic stimulation at the time of tamoxifen discontinuation is a logical approach to further reduce the probability of recurrence (Figure 1).
The Role of Aromatase Inhibitors
Aromatase inhibitors act systemically to prevent estrogen biosynthesis by inhibiting the enzyme aromatase, which catalyses the conversion of adrenal and ovarian androgen to estrogen. These compounds have been shown to be effective in postmenopausal women with hormone-responsive metastatic breast cancer.
Aminoglutethimide (Cytadren), a first-generation aromatase inhibitor, was effective in the adjuvant breast cancer setting, but was poorly tolerated and was supplanted by the well-tolerated second-generation aromatase inhibitor 4-OH-androstenedione (4-OHA, formestane(Drug information on formestane)). However, this compound suppressed plasma estradiol(Drug information on estradiol) levels to only one-third of baseline levels and required parenteral administration.[27,28] Several years later, third-generation aromatase inhibitors were developed that fell into two principal categories: (a) nonsteroidal aromatase inhibitors, such as fadrozole, vorozole (Rivizor), letrozole (Femara), and anastrozole(Drug information on anastrozole) (Arimidex), and (b) steroidal aromatase inhibitors, such as exemestane(Drug information on exemestane) (Aromasin).
No information currently exists on whether additional hormonal interventions will be beneficial in breast cancer patients who are recurrence-free after discontinuation of tamoxifen therapy. Ample information, however, indicates that sequential administration of aromatase inhibitors to patients who recur during or after tamoxifen therapy results in significant antitumor activity.[27-30] The downside of waiting and treating when recurrence occurs is that by then, an additional proportion of tumors may have become hormone-resistant and another proportion would remain hormone-sensitive only for a short time. Thus, there are theoretical advantages in attempting to reduce the risk of subsequent recurrence in patients who remain disease-free after completion of adjuvant tamoxifen therapy by initiating therapy with an aromatase inhibitor.