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Keywords:

  • breast carcinoma;
  • endocrine adjuvant therapy;
  • tamoxifen;
  • aromatase inhibitors;
  • clinical trials

Abstract

  1. Top of page
  2. Abstract
  3. Landmark Trials with Tamoxifen in Breast Carcinoma Therapy
  4. Adjuvant Aromatase Inhibitor Therapy
  5. Comparison of Trials
  6. Unresolved Issues
  7. Revised Guidelines Include Outcomes From Aromatase Inhibitor Trials
  8. Conclusions
  9. REFERENCES

The review summarizes the outcomes of several landmark trials involving aromatase inhibitors that helped formulate current therapeutic approaches recommended by the American Society of Clinical Oncology for breast carcinoma treatment. Cancer 2006. © 2006 American Cancer Society.

Tamoxifen was the mainstay of adjuvant endocrine therapy for women with hormone-sensitive breast carcinoma for nearly three decades, but its limited efficacy span and side-effect profile prompted the development of other therapeutic agents. Aromatase inhibitors such as anastrozole, letrozole, and exemestane block estrogen conversion and have demonstrated greater benefit for disease-free survival (DFS) than tamoxifen. Several landmark trials have supported the use of aromatase inhibitors for the treatment of breast carcinoma in postmenopausal women, leading the American Society of Clinical Oncology to recommend their standard use.

Some two-thirds of breast carcinoma tumors are hormone-receptor–positive,1, 2 and approximately 60–70% respond to antiestrogen therapy with tamoxifen, the gold standard of endocrine adjuvant therapy worldwide for over 20 years. The third-generation aromatase inhibitors anastrozole, letrozole, and exemestane suppress estrogen production by blocking the aromatase enzyme and thereby impeding androgen conversion to estrogen.2 In the US, most postmenopausal women with newly diagnosed hormone-sensitive breast carcinoma are treated with aromatase inhibitors because of their superior efficacy compared with that of tamoxifen, which has been demonstrated by several trials. This review summarizes the outcomes of several landmark trials that helped formulate current therapeutic approaches for breast carcinoma treatment.

Landmark Trials with Tamoxifen in Breast Carcinoma Therapy

  1. Top of page
  2. Abstract
  3. Landmark Trials with Tamoxifen in Breast Carcinoma Therapy
  4. Adjuvant Aromatase Inhibitor Therapy
  5. Comparison of Trials
  6. Unresolved Issues
  7. Revised Guidelines Include Outcomes From Aromatase Inhibitor Trials
  8. Conclusions
  9. REFERENCES

Approved in 1986, the use of tamoxifen expanded from treatment of metastatic disease to first-line therapy for early-stage breast carcinoma to preventative use in some patients.3 The 1983 Nolvadex Adjuvant Trial Organization (NATO) results supported the benefits of using tamoxifen as monotherapy for node-negative breast carcinoma in over 1100 postmenopausal women.3, 4 When patients were randomized to either tamoxifen 10 mg twice a day or no additional therapy after definitive surgery for up to 5 years, significantly fewer breast carcinoma recurrences occurred in subjects receiving tamoxifen. The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) study of 20,000 women with early breast carcinoma who received tamoxifen found that 5 years of adjuvant tamoxifen therapy provided proportional DFS reductions of 47%.5, 6 However, tamoxifen is associated with infrequent but potentially severe side effects; the incidence of endometrial cancer quadrupled in women taking tamoxifen for 5 years.

A recent study found that more than 50% of recurrences occur after 5 years of tamoxifen treatment,5, 6 and when the 5-year and 10-year relapse-free survival rates were calculated for patients who had received standard adjuvant therapy, it was evident that a large number of these patients still had a substantial risk of breast carcinoma recurrence and would benefit from additional risk reduction.7 The B-14 National Surgical Adjuvant Breast and Bowel Project (B-14 NSABP), a randomized, placebo-controlled clinical assessment of 4127 women, showed that individuals with estrogen-receptor–positive breast carcinoma and negative axillary lymph nodes had a statistically significant increase in DFS after 5 years of tamoxifen therapy.8 When these subjects underwent rerandomization to placebo or to a longer period of tamoxifen treatment, they showed no further benefit from the drug. After 7 years of followup, patients in the placebo group demonstrated a slight advantage in DFS (82%) compared with those who continued to receive tamoxifen (78%) (P = 0.03), leading researchers to conclude that additional tamoxifen use is not warranted.9 Extending tamoxifen use beyond 5 years resulted in poor tolerability and exacerbation of the drug's side effects.

Currently, the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial10 and the Adjuvant Tamoxifen Treatment, Offer More? (ATTOM) trial11 are following women who had tamoxifen treatment for up to a decade after their initial tamoxifen therapy. In the ATLAS trial, women are randomized to receive 5 or 10 years of adjuvant tamoxifen therapy,11 whereas in the ATTOM trial women who discontinue tamoxifen therapy after at least 2 years of treatment (but as many as 5 or more years) are randomized to receive either an additional 5 years of treatment with tamoxifen or no additional therapy.11 Until the results of these two long-term trials are available, research suggests stopping tamoxifen after 5 years of treatment, but considering the current use of aromatase inhibitors, the results of these trials may prove to be irrelevant.

Adjuvant Aromatase Inhibitor Therapy

  1. Top of page
  2. Abstract
  3. Landmark Trials with Tamoxifen in Breast Carcinoma Therapy
  4. Adjuvant Aromatase Inhibitor Therapy
  5. Comparison of Trials
  6. Unresolved Issues
  7. Revised Guidelines Include Outcomes From Aromatase Inhibitor Trials
  8. Conclusions
  9. REFERENCES

Several large trials of third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane) have demonstrated efficacy that is as good as or better than that of tamoxifen and provide a different, somewhat more manageable side-effect profile. Adverse effects observed with the aromatase inhibitors generally include fewer incidences of endometrial cancer, cerebrovascular events, hot flushes, and vaginal problems, but more musculoskeletal disorders and fractures.

Results from the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial demonstrated that anastrozole is effective and well tolerated in the treatment of postmenopausal women with hormone-responsive early breast carcinoma after a median followup of 33 months.12 The ATAC trial was the first adjuvant breast carcinoma trial evaluating an aromatase inhibitor to complete recruitment and to have results published at a median followup of greater than 5 years. However, the study population included women with unknown estrogen-receptor/progesterone-receptor status and one-third of the ATAC patients participated in a trial arm (anastrozole + tamoxifen) that was stopped after 47 months of treatment. After a median followup of 68 months, patients treated with anastrozole had a significantly better outcome for DFS than patients treated with tamoxifen (hazards ratio [HR], 0.87; 95% confidence interval [CI], 0.78–0.97) (P = 0.01).13 A significant reduction in distant metastasis in the intent-to-treat population (14%) occurred, but no significant outcome advantage was seen for distant metastasis in the hormone-receptor–positive population. Furthermore, there was a trend showing that the benefits of anastrozole therapy are maintained regardless of the type of chemotherapy given,14 but patients receiving chemotherapy and node-positive patients did not experience any significant benefit in DFS when taking anastrozole and no survival advantage for anastrozole over tamoxifen has been demonstrated thus far.13 Hot flushes and arthralgias were the most common adverse events. Ischemic cardiovascular disease, angina pectoris, and hypercholesterolemia were observed more often in patients taking anastrozole (4.1% vs. 3.4%), but the outcomes of these events were not specifically reported.13, 15 All groups had similar overall quality-of-life impacts, showing gradual improvement over time.16

BIG 1-98 is a large (N = 8010) Phase III multinational, double-blind, randomized clinical trial of letrozole, conducted independently by the International Breast Cancer Study Group.17 Women recruited early to the trial (n = 1835) were randomized to receive letrozole (2.5 mg/day) or tamoxifen (20 mg/day). A further 6193 women were randomized to the four-arm section that includes 5 years of letrozole, 5 years of tamoxifen, 2 years of letrozole followed by 3 years of tamoxifen, or 2 years of tamoxifen followed by 3 years of letrozole. Letrozole reduced the overall risk of disease recurrence by 19% (P = 0.003); the risk was reduced by 30% in patients receiving chemotherapy and by 29% in those with node-positive disease. The risk of distant metastases was reduced by 27%, whereas the risk of death was reduced by 14% (P = 0.16). Results of the BIG 1-98 trial suggest that letrozole may provide higher efficacy for breast carcinoma patients, particularly for patients at increased risk of recurrence. Tamoxifen therapy was associated with higher incidences of thromboembolic events and vaginal bleeding, whereas a greater number of bone fractures, NCI CTC Grade 3–5 cardiovascular events, and mild elevations in cholesterol were reported with letrozole. With respect to lipids, the BIG 1-98 trial is the only trial to do such an analysis; because many other trials did not investigate lipid profiles in a systematic manner, the long-term relevance of these mild elevations is unknown at this point. Data from the sequential arms are expected in 2008.

The Intergroup Exemestane Study (IES) evaluated the sequencing of tamoxifen with exemestane during the first 5 years after surgery.18, 19 The IES study compared 5 years of tamoxifen treatment with 2–3 years of tamoxifen therapy followed by 2–3 years of treatment with exemestane.18, 19 Randomization to continued treatment with tamoxifen or to exemestane occurred after 2–3 years of tamoxifen only. The investigators found that sequential therapy with tamoxifen followed by exemestane demonstrated a 32% significant improvement in DFS compared with 5 years of treatment with tamoxifen alone and produced a significant 50% reduction in contralateral breast carcinoma.18, 19 This trial may also show a survival advantage because it is trending in that direction. Adverse events experienced by patients receiving exemestane included diarrhea and arthralgia, whereas patients receiving tamoxifen experienced more gynecologic symptoms, vaginal bleeding, and muscle cramps. Cardiovascular disease was reported at a higher frequency for patients taking exemestane (42.6% vs. 39.2%; P = 0.11) as was the incidence of myocardial infarction (0.9% vs. 0.4%; P = 0.23, NS).18, 19

Data from the Arimidex-Nolvadex (ARNO 95) and the Austrian Breast Cancer Study Group (ABCSG 8) trials were combined to assess if switching from tamoxifen to anastrozole after 2 years is more effective than tamoxifen alone for a full 5 years after surgery.20 These trials were similar in design but did have differences in tamoxifen dosage, patient age, and tumor grades. One hundred percent of patients had hormone-receptor–positive breast carcinoma, received primary surgery, and exposure to tamoxifen for 2 years; none of the patients had received chemotherapy. Preliminary analysis of 2176 patients in ABCSG 8 and 947 in ARNO 95 at 26-month followup found the hazard ratio for recurrence-free survival with anastrozole versus tamoxifen to be 0.59 (P < 0.0018).20 The authors conclude that changing from anastrozole after 2 years of tamoxifen treatment resulted in significantly better distant recurrence-free survival. More fractures occurred in women who switched to anastrozole. Complete results and data analysis from these two trials have not been published.

The MA-17 trial investigated extended adjuvant therapy with letrozole after 5 years of tamoxifen treatment after surgery.21, 22 The MA-17 trial, an international study independently coordinated by the National Cancer Institute of Canada clinical trial groups, investigated whether late-intervention treatment could reduce the potential risk of late cancer recurrence. Breast carcinoma patients who previously received 5 years of tamoxifen treatment were randomized to letrozole treatment or to placebo for a median followup period of 2.4 years.21 Results indicate that letrozole treatment after standard tamoxifen therapy significantly improved DFS, with an estimated 4-year DFS that was significantly higher in the letrozole arm (93% vs. 87%, respectively; P =0.001). Letrozole produced a significant reduction in contralateral breast carcinoma (39%) and a reduced risk of distant metastases (40%). An updated analysis confirmed the DFS benefit and demonstrated a significant improvement in distant DFS as well as a significant survival gain in (39%) in the node-positive subgroup.22, 23 Patients receiving letrozole had more frequent hot flushes, arthritis, arthralgias, and myalgias.

Comparison of Trials

  1. Top of page
  2. Abstract
  3. Landmark Trials with Tamoxifen in Breast Carcinoma Therapy
  4. Adjuvant Aromatase Inhibitor Therapy
  5. Comparison of Trials
  6. Unresolved Issues
  7. Revised Guidelines Include Outcomes From Aromatase Inhibitor Trials
  8. Conclusions
  9. REFERENCES

In the absence of head-to-head trials, some insights about the various therapeutic options for breast carcinoma treatment today may be gained from a comparative review of these trials (Table 1). Time of randomization or preselection of patients is similar in the BIG 1-98 and ATAC trials, in that patients are enrolled in the study at the beginning of their endocrine therapy. Patients in IES and MA-17 in the meanwhile had received tamoxifen for several years and were free of disease before randomization to an aromatase inhibitor or placebo in these trials. Patients in the BIG 1-98 trial underwent randomization after surgery to 5 years of tamoxifen treatment or 5 years of letrozole treatment. For trials assessing therapy sequencing, the IES study did not randomize patients after surgery but randomized only patients who were disease-free at 2–3 years after tamoxifen treatment, whereas the MA-17 trial protocol randomized patients after 5 years of tamoxifen to an additional 5 years of treatment with letrozole or placebo. Thus, the inconsistent application of measurement variables prevents direct comparisons of these trial designs and results.

Table 1. Comparison of Landmark Trials of Endocrine Adjuvant Therapy for Breast Carcinoma
 ATACBIG 1-98IESARNO/ABCSGMA-17
  • ATAC: Arimidex, Tamoxifen Alone or in Combination; IES: Intergroup Exemestane Study; ARNO: Arimidex-Nolvadex; ABCSG: Austrian Breast Cancer Study Group; EBC: early breast cancer; ER+: estrogen-receptor positive; PgR+: progesterone-receptor positive; hormone-receptor positive; TAM: tamoxifen; BC: breast cancer; ANA: anastrozole; LET: letrozole; EXE: exemestane; DFS: disease-free survival; EFS: event-free survival; CLBC: contralateral breast carcinoma; OS: overall survival; BMD: bone mineral density; DDFS: distant disease-free survival; ITT: intent to treat.

  • a

    Data reported on 6000+ patients at 68 months.

  • b

    This arm was dropped after 47 months of followup.

  • c

    Secondary cancer, death without recurrence, and diagnosis of CLBD not included as events in this analysis.

  • d

    Excluding basal cell carcinoma and squamous cell carcinoma of skin.

  • e

    Data reported on at 37.4 months.

  • f

    Data reported on at 30.6 months.

  • g

    Data presented by R. Jakesz at the 2004 SABCS meeting.

PopulationPostmenopausal women; after primary surgery/chemotherapy (where given); candidates for adjuvant hormonal therapyPostmenopausal women with EBC, ER+ and/or PgR+Postmenopausal women with EBC, ER+ and/or PgR+100% HR+ patientsPostmenopausal women with primary BC; ER+ and/or PgR+; completed 4.5-6 yrs adjuvant TAM therapy postsurgery
Size (N)9366a801047243224 (ABCSG, 2262; ARNO, 962)5187
RandomizationRandomized to receive ANA, TAM, or ANA + TAMbFirst 1835 randomized to LET (2.5 mg/d) or TAM (20 mg/d); another 6193 women randomized to 5 yrs LET; 5 yrs TAM; 2 yrs LET/3 yrs TAM; or 3 yrs TAM/2 yrs LETDisease-free with 2 to 3 yrs TAM therapy; randomized to TAM or EXE to complete 5 yrs of adjuvant therapyPost primary surgery + 2 yrs TAM randomized to 3 yrs TAM or ANARandomized to receive LET or placebo for 5 yrs; re-randomized after 5 yrs extended therapy to 5 yrs LET or placebo
Primary endpoint (DFS or EFS)DFS: time to earliest occurrence of local or distant recurrence, new primary BC, or death from any causeDFS: time from randomization to the first recurrence of the invasive breast carcinoma; development of a new invasive breast carcinoma in the contralateral breast; development of any second malignancy; or death from any cause.DFS: time from randomization to BC recurrence, CLBC (second primary), or intercurrent deaths (from any cause, prior to BC recurrence)EFS: loco-regional recurrences, distant metastases, CLBC, with deaths not includedDFS: time from randomization to recurrence of primary disease (in the breast, chest wall, or nodal or metastatic sites) or development of new primary CLBCc
Secondary end pointsTime to recurrence (including new contralateral tumors, but not patients who died from non-BC causes before recurrence), incidence of new primary CLBC, distant recurrence, OSOS, systemic DFS (time from randomization to systemic recurrence, metastases, second primary tumord or death from any cause). SafetyOS, incidence of CLBC, long-term safety/tolerability, and substudies investigating uterine thickening, BMD, and bone metabolism, and patient-assessed quality of lifeDistant recurrence-free survival and tolerabilityOS, quality of life, long-term safety, incidence of CLBC, and pharmacogenomics
Followup68 months25.8 mos30.6 and 37.4 mos28 mos30 mos
DFS (%)13%, P = 0.0119%, P = 0.00332%, P >0.001e40%, P = 0.001842%, P = 0.00004
ATACBIG 1-98IESARNO/ABCSGMA-17
DDFS (%)14%, P = 0.04 ITT 16%, P = 0.06 HR+27%, P = 0.0012HR:0.66,fP = 0.000439%, P = 0.0067g40%, P = 0.002
Mortality reduction3%, P = 0.714%, P = 0.1612%, P = 0.37fNot reported24%, P = 0.25; 39% (Node-positive patients), P = 0.04

The trials also varied in their definitions of DFS. The MA-17 trial did not include secondary cancer and death without a recurrence or a diagnosis of contralateral breast carcinoma as events in their analysis. The ATAC trial defines DFS as the time-to-the-earliest-occurrence of local or distant recurrence, new primary breast carcinoma, or death from any cause, whereas the BIG 1-98 trial describes DFS as the time from randomization to the first recurrence of the invasive breast carcinoma, development of a new invasive breast carcinoma in the contralateral breast, development of any second malignancy, or death from any cause. Thus, DFS in the ATAC trial does not include secondary cancers, but DFS in the BIG 1-98 trial does, and is, therefore, more inclusive of events.

The benefit derived from aromatase inhibitors in patients previously treated with chemotherapy or in particular subsets of patients (i.e., node-positive) remains controversial. The IES and BIG 1-98 studies evaluated these subsets of patients and data will be forthcoming. The ATAC trial did not show any significant improvement for the node-positive population, and whereas anastrozole did provide benefits over tamoxifen for patients who were pretreated with chemotherapy, it did not demonstrate a significant improvement in DFS in these patients, although this may be demonstrated with longer followup.13, 14 For distant DFS in the ATAC trial, anastrozole reduced the risk of distant metastases by 14% (HR = 0.86, P = 0.04), whereas the BIG 1-98 trial demonstrated almost twice the reduction in distant metastases.

The quality, robustness, and consistency of data in these trials appear to vary as well. Subgroup analyses reveal inconsistencies in efficacy between the aromatase inhibitors. The BIG 1-98 trial demonstrated significant benefit in the node-positive population, but at 33-month followup the ATAC trial showed that only the node-negative patients significantly benefited from treatment, which is difficult to explain because node-negative disease should recur later than node-positive cancer. Furthermore, the ATAC trial showed a beneficial effect of anastrozole mainly in patients with estrogen-receptor–positive and progesterone-receptor–negative tumors, whereas in the BIG 1-98 study, all estrogen-receptor–positive patients had a similar risk reduction associated with letrozole, irrespective of progesterone-receptor status.24 In ATAC, anastrozole showed significant time-to-recurrence benefit only in the node-negative patients, who have a better prognosis and who tend to have breast carcinoma recurrence later in the disease course.

When evaluating results of these large trials, safety assessments and reporting of adverse events must be closely scrutinized. In the BIG 1-98 trial, the overall incidence of cardiovascular adverse events was similar in the two groups. Fewer patients receiving letrozole experienced Grade 3–5 venous thromboembolic events but slightly more experienced Grade 3–5 cardiac events. In the MA-17 trial, however, letrozole demonstrated no increase in cardiovascular events compared with placebo. The IES trial also found an increased risk of cardiovascular and coronary heart disease, whereas the cardiac data from the ATAC trial is not readily available. Thus, reporting of adverse events also varies in these trials and may not be directly comparable.

Unresolved Issues

  1. Top of page
  2. Abstract
  3. Landmark Trials with Tamoxifen in Breast Carcinoma Therapy
  4. Adjuvant Aromatase Inhibitor Therapy
  5. Comparison of Trials
  6. Unresolved Issues
  7. Revised Guidelines Include Outcomes From Aromatase Inhibitor Trials
  8. Conclusions
  9. REFERENCES

All trials of aromatase inhibitors show a reduction in the relative risk of recurrence of breast carcinoma that ranges from 13–43%, and studies comparing aromatase inhibitors to tamoxifen therapy demonstrate a reduction in the relative risk of contralateral breast carcinoma ranging from 39–56%, as well as an absolute gain in DFS of 2.4–6% (Table 1). Whereas these aromatase inhibitors are superior to tamoxifen, there are some distinctions between them. Data from a directly comparative trial has suggested that some subgroups of women experience an increased benefit from letrozole but not from anastrozole in the second-line treatment of advanced breast carcinoma. However, this was an open-label trial, and half of the patients in this study had unknown estrogen-receptor status; in those who had known estrogen-receptor–status disease, the efficacy endpoints were similar.25 However, considering the size of the estrogen-receptor/progesterone-receptor status-unknown subgroup (n = 340), the well-distributed demographics between the trial arms and the high probability that a tumor of undetermined hormone-receptor status would be positive, it is unlikely that the increase in response rate achieved with letrozole was due to a statistical imbalance of estrogen-receptor/progesterone-receptor status in favor of letrozole.26 Moreover, studies of letrozole compared with tamoxifen in the first-line setting also demonstrate the high efficacy of letrozole in the estrogen-receptor/progesterone-receptor status-unknown tumors.26

Letrozole produces the highest level of aromatase inhibition,27 and this may in fact offer enhanced benefit to certain patients.28 More trials directly comparing aromatase inhibitors and more mature data from the IES, ARNO/ABCSG, and BIG 1-98 trials are needed to provide more complete comparisons among these agents. Questions about the optimal duration of treatment and the ideal therapeutic sequence for aromatase inhibitor therapy in breast carcinoma are being addressed by the rerandomization of MA-17 patients and by the sequential arms of BIG 1-98, respectively. The Tamoxifen, Exemestane Adjuvant Multinational trial (TEAM) that randomizes patients to tamoxifen or exemestane was also amended to evaluate sequential therapy as well.

Revised Guidelines Include Outcomes From Aromatase Inhibitor Trials

  1. Top of page
  2. Abstract
  3. Landmark Trials with Tamoxifen in Breast Carcinoma Therapy
  4. Adjuvant Aromatase Inhibitor Therapy
  5. Comparison of Trials
  6. Unresolved Issues
  7. Revised Guidelines Include Outcomes From Aromatase Inhibitor Trials
  8. Conclusions
  9. REFERENCES

With several large clinical trials now demonstrating that aromatase inhibitors produce better long-term clinical results for women with breast carcinoma, physicians have new therapeutic options. The American Society of Clinical Oncology (ASCO) Technology Assessment Panel recommends that optimal adjuvant hormonal therapy for postmenopausal women with receptor-positive breast carcinoma should include an aromatase inhibitor as initial therapy or after tamoxifen treatment.23 Specifically, the panel supports at least 2.5 years of extended adjuvant letrozole therapy for patients who have completed tamoxifen therapy. However, they do caution that the long-term side effects of aromatase inhibitors such as osteoporosis remain unclear.23 Whereas the 2005 St. Gallen International Conference on Primary Therapy of Early Breast Cancer guidelines have not been published yet, this committee panel also recommends an aromatase inhibitor as adjuvant therapy for most postmenopausal women with endocrine-responsive breast carcinoma.29

Conclusions

  1. Top of page
  2. Abstract
  3. Landmark Trials with Tamoxifen in Breast Carcinoma Therapy
  4. Adjuvant Aromatase Inhibitor Therapy
  5. Comparison of Trials
  6. Unresolved Issues
  7. Revised Guidelines Include Outcomes From Aromatase Inhibitor Trials
  8. Conclusions
  9. REFERENCES

Tamoxifen was the gold standard in breast carcinoma therapy, but several landmark studies have found aromatase inhibitors to be superior. The ASCO guidelines consensus now recommends that every postmenopausal woman with estrogen-receptor/progesterone-receptor–positive disease receive an aromatase inhibitor as part of her adjuvant therapy regimen.

Although there are some limitations to making indirect comparisons between the trials, they may help with the decision-making process. Results from BIG 1-98 and ATAC demonstrate the benefit of receiving anastrozole or letrozole as initial adjuvant treatment. The outcomes of the IES and ARNO/ABCSG trials support the safety and efficacy of anastrozole and exemestane as sequential therapy in this patient population. The BIG 1-98 trial will define optimal adjuvant therapy by determining if letrozole is more effective when given as initial adjuvant therapy or as sequential therapy. The MA-17 trial is the first to demonstrate that late intervention can reduce the recurrence of breast carcinoma and save lives, particularly for women with node-positive cancer or distant metastases. Results from MA-17 have altered the current treatment paradigms for the management of breast carcinoma by offering an extension of adjuvant therapy beyond the previous 5-year protocol. Overall, results from all of the landmark trials of aromatase inhibitors recommend that physicians consider aromatase inhibitors as options for the sustained health of women treated for breast carcinoma.

REFERENCES

  1. Top of page
  2. Abstract
  3. Landmark Trials with Tamoxifen in Breast Carcinoma Therapy
  4. Adjuvant Aromatase Inhibitor Therapy
  5. Comparison of Trials
  6. Unresolved Issues
  7. Revised Guidelines Include Outcomes From Aromatase Inhibitor Trials
  8. Conclusions
  9. REFERENCES
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  • 23
    Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol. 2005; 23: 619629.
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    Geisler J, Haynes B, Anker G, Dowsett M, Lonning PE. Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, crossover study. J Clin Oncol. 2002; 20: 751757.
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    Bhatnagar AS. Aromatase inhibitors in advanced breast cancer: there are efficacy differences. Br J Cancer. 2005; 92: 11731174; author reply 1175–1176.
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    Bhatnagar AS, Batzl C, Hausler A, Schieweck K, Lang M, Trunet PF. Pharmacology of nonsteroidal aromatase inhibitors. In: PasqualiniJR, KatzenellenbogenBS, editors. Hormone dependent cancer. New York: Marcel Dekker, 1996: 155168.
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    Janicke F. Are all aromatase inhibitors the same? A review of the current evidence. Breast. 2004; 13: S10S18.
  • 29
    St. Gallen Conference Authors. Primary therapy of early breast cancer, 9th International Conference. Breast. 2005; 14: S1S56.