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Adjuvant Exemestane Therapy After 5 Years of Tamoxifen: Rationale for the NSABP B-33 Trial

Adjuvant Exemestane Therapy After 5 Years of Tamoxifen: Rationale for the NSABP B-33 Trial

ABSTRACT: Tamoxifen (Nolvadex) has long been established as "standard" adjuvant therapy for receptor-positive, early-stage breast cancer. Results from clinical trials suggest that after approximately 5 years, tamoxifen may lose its effectiveness and may even become harmful if not stopped. At the time of tamoxifen discontinuation, "seemingly" disease-free patients may still have residual micrometastatic tumor cells. In a proportion of such patients, these cells may still be responsive to tamoxifen and thus could grow as a result of stopping the drug. The majority of clinical information, however, suggests that by 5 years of therapy, a greater proportion of patients will have micrometastatic tumor cells that have become resistant to tamoxifen and will be stimulated by continuation of the drug for a longer time. Because in both such cases the micrometastases are hormonally sensitive, a reasonable approach—in addition to stopping tamoxifen—is to decrease the level of estrogenic stimulation by introducing an aromatase inhibitor. The National Surgical Adjuvant Breast and Bowel Project is launching a clinical trial (NSABP B-33) to evaluate the sequential administration of 2 years of exemestane (Aromasin), a steroidal aromatase inactivator, after 5 years of tamoxifen in postmenopausal, receptor-positive patients who are disease-free at the time of tamoxifen discontinuation. [ONCOLOGY 15(Suppl 7):35-39, 2001]


Results from several clinical trials have clearly demonstrated
substantial benefit from 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,[10] the majority of researchers agree that—at least
in some patients—there 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

Optimal Duration of Adjuvant Tamoxifen Therapy

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[7]
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,[8] 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 =

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[12] and a nonrandomized trial by NSABP (the
National Surgical Adjuvant Breast and Bowl Project),[9] 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.[13] 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.[13] 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

Comparable results were obtained in a Scottish trial[14] 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

Mechanisms of Tamoxifen Resistance

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

Recently, development of estrogen hypersensitivity has been
as another mechanism of tamoxifen resistance.[25] 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

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.[22]

Sequential Administration of an Aromatase Inhibitor

Tamoxifen-Resistant Cells

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

Aminoglutethimide (Cytadren), a first-generation aromatase
inhibitor, was effective in the adjuvant breast cancer setting,[26] but was
poorly tolerated and was supplanted by the well-tolerated second-generation
aromatase inhibitor 4-OH-androstenedione (4-OHA, formestane). However, this
compound suppressed plasma 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 (Arimidex), and (b)
steroidal aromatase inhibitors, such as 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


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