Benefit With Aromatase Inhibitors in the Adjuvant Setting for Postmenopausal Women With Breast Cancer

Henning T. Mouridsen, MD, PhD; Nicholas J. Robert, MD

Disclosures
In This Article

Abstract and Introduction

Abstract

The third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, have been shown to be effective both as alternatives to tamoxifen in first-line treatment of hormone-sensitive advanced breast cancer in postmenopausal women and following failure of first-line tamoxifen for endocrine therapy. These 3 agents are now being investigated as adjuvant therapy of early breast cancer, as alternative or complementary treatments to the standard, tamoxifen. Three treatment strategies are under investigation: replacement of tamoxifen as adjuvant therapy for 5 years (early adjuvant therapy), sequencing of tamoxifen before or after an aromatase inhibitor during the first 5 years (early sequential adjuvant therapy), or following 5 years of tamoxifen (extended adjuvant therapy). In the first adjuvant trial (Arimidex, Tamoxifen Alone or in Combination [ATAC]), anastrozole was significantly superior to tamoxifen in reducing risk of disease recurrence, and recently, the Breast International Group (BIG) trial BIG 1-98 demonstrated the significant superiority of letrozole over tamoxifen in improving disease-free survival. A large trial (International Collaborative Cancer Group [ICCG] trial 96) investigated sequencing of 2 to 3 years of exemestane after 2 to 3 years of tamoxifen and found that switching to exemestane was significantly superior in disease-free survival compared with continuing on tamoxifen. The Arimidex or Nolvadex (ARNO) and the small ITA (Italian Tamoxifen Arimidex) trials similarly sequenced anastrozole after tamoxifen and also found that sequencing reduced the hazard of recurrence compared with remaining on tamoxifen. Trial MA.17 evaluated extended adjuvant therapy with letrozole vs placebo following 5 years of tamoxifen. Disease-free survival was significantly improved with letrozole vs placebo, irrespective of whether patients had lymph node-positive or node-negative tumors. All 3 aromatase inhibitors were generally well tolerated. Results of these trials indicate that aromatase inhibitors provide important benefits relative to tamoxifen in each of these adjuvant treatment settings, but the optimal approach still needs to be defined. Other trials continue to investigate some of these adjuvant treatment strategies.

Introduction

Inhibition of the activities of estrogen, the primary mitogen for breast cancer, is an important treatment strategy for patients with breast cancer.[1,2,3] Adjuvant therapy for 5 years with the antiestrogen tamoxifen has become standard therapy after primary treatment (surgery and/or chemotherapy) in women with estrogen receptor (ER)-positive tumors, reducing risk of recurrence by 47% and risk of death by 26% during the next 10 years.[4]

However, long-term experience and specific clinical trials have revealed several limitations of tamoxifen in the adjuvant setting, including limited duration of effectiveness, continuing risk of recurrence following tamoxifen, acquired resistance to tamoxifen, and serious side effects. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial revealed that treatment with tamoxifen for longer than the recommended 5 years did not further improve survival. In that trial, patients were re-randomized after 5 years of tamoxifen treatment to receive tamoxifen or placebo for an additional 5 years; those who remained on tamoxifen had significantly reduced disease-free survival (DFS) 7 years after re-randomization.[5]

A substantial proportion of all breast cancer recurrences occur following 5 years of tamoxifen treatment.[4] Preclinical studies showed that development of resistance to tamoxifen in breast cancer tumors was associated with a loss of antagonist activity, with the consequence that an otherwise weak agonist effect predominates.[6] Acquired resistance may also occur through hypersensitization of tumors to growth stimulation by extremely low levels of estrogen.[7,8] Long-term tamoxifen is also associated with a progressively increasing risk of endometrial cancer and thromboembolic events.[5]

Because of the substantial risk of relapse and other limitations of adjuvant tamoxifen therapy, a relatively new class of endocrine therapeutics, the third-generation aromatase inhibitors, has been investigated as potential therapy in the adjuvant setting. These drugs prevent estrogen-mediated breast cancer stimulation through suppression of estrogen biosynthesis rather than by blocking activation of the ER, and include 2 nonsteroidal drugs, letrozole (Femara) and anastrozole (Arimidex), and the steroid, exemestane (Aromasin).[9] These highly selective agents all effectively reduce total estrogen synthesis only after menopause.[10,11] However, letrozole was found to be the most potent aromatase inhibitor in experimental and clinical studies.[9,11]

All 3 of the new aromatase inhibitors are active as second-line therapy in metastatic breast cancer and superior to the former standard treatments, the progestin, megestrol acetate or the first-generation aromatase inhibitor, aminoglutethimide.[12,13,14,15] In first-line therapy, letrozole proved superior to the standard, tamoxifen, in time to progression, overall response rate, and clinical benefit rate ( Table 1 ).[16,17] Anastrozole was at least equivalent to tamoxifen with respect to the same end points.[18] Whereas letrozole and anastrozole were similar to tamoxifen regarding median survival times, patients taking letrozole had significantly longer early survival times (for the first 2 years) compared with patients who received tamoxifen.[17,18] Exemestane was significantly superior to tamoxifen with respect to progression-free survival (PFS).[19] The proven efficacy of the third-generation aromatase inhibitors in metastatic breast cancer and the need for new strategies in the adjuvant setting provided the rationale for evaluation of these drugs in the adjuvant setting for patients with primary or early breast cancer.[20,21,22]

In clinical investigations of aromatase inhibitors in the adjuvant setting, 3 different strategies have been evaluated[6,22,23,24]:

  • Early adjuvant therapy -- replacing tamoxifen therapy with aromatase inhibitor therapy during the first 5 years after surgery;
     

  • Early sequential adjuvant therapy -- sequencing of tamoxifen and aromatase inhibitor therapy during the first 5 years after surgery; and
     

  • Extended adjuvant therapy -- aromatase inhibitor therapy after patients have received 5 years of tamoxifen therapy after surgery.

In this article, we review current trials of aromatase inhibitors in the adjuvant setting and the clinical implications for patients with early breast cancer.

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