Establishing Roles for the Newer Hormonal Therapies

CHICAGO—The role of endocrine therapy in breast cancer is still evolving, with about half a dozen agents contending as players in the metastatic, adjuvant, and chemoprevention settings. At the Lynn Sage Breast Cancer Conference, William J. Gradishar, MD, summarized recent clinical trials and put the current agents into a clinical context for oncologists.

Dr. Gradishar is director of Breast Medical Oncology at the Robert H. Lurie Comprehensive Cancer Center and associate professor of medicine at Northwestern University.

Clinical trials have shown a wide range of response to various endocrine therapies, largely because of heterogeneity and variability in subjects and trial design. Generally, however, about one third of patients will respond to endocrine therapies, he said.

Candidates for Therapy

Dr. Gradishar summed up the general suitability of patients for endocrine therapies as "patients who are hormone-receptor (HR)-positive, have a long disease-free interval between their initial diagnosis of breast cancer and metastatic disease, and generally have nonvisceral disease. Although visceral disease will also respond, it is probably more suitable for chemotherapy initially."

The idea that premenopausal patients do not respond to endocrine therapy is probably a misconception, he said, "but the frequency of HR-positive disease is clearly greater in older patients."

Patients who respond to one endocrine therapy have an increased likelihood of responding to subsequent endocrine maneuvers. "While response rates generally diminish with each succeeding therapy, there are patients who can go on to second-, third-, fourth-, and even fifth-line therapy. The fundamental question we grapple with as newer agents go forward is the sequence with which to use these agents," he said.

Aromatase Inhibitors

The pathway of interest with aroma-tase inhibitors is the conversion of androstenedione to estrogen by the action of the aromatase enzyme. In postmenopausal women, the primary targets are the extra-ovarian sites of aromatase activity, including the tumor itself.

Aromatase inhibitors can be steroidal and reversible, such as exemestane (Aromasin), or nonsteroidal and irreversible such as anastrozole (Arimidex) and letrozole (Femara). While they differ in their binding sites and reversibility, both types inhibit about 98% of aromatase activity.

"Some data would suggest there are differences in these drugs, primarily in laboratory parameters, but from a clinical standpoint, I don’t think you can draw distinctions," Dr. Gradishar said.

Several important trials showed improved survival with the aromatase inhibitors over megesterol acetate (Megace), firmly establishing aromatase inhibitors in the second-line metastatic setting. More recently, other trials have proven aromatase inhibitors effective in the first-line setting, and anastrozole and letrozole have received FDA approval for this indication.

In the combined data set for the two major phase III anastrozole trials, HR-positive women getting anastrozole had a time to progression of 10.7 months vs 6.4 months for patients treated with tamoxifen (Nolvadex), and half the incidence of thromboembolic events.

Furthermore, at least one small trial has also demonstrated that neoadjuvant therapy with anastrozole decreases tumor volume by 75%, thus validating its antitumor activity, Dr. Gradishar said.

In an international trial of 916 postmenopausal patients, letrozole has also shown superiority over tamoxifen in time to progression in the first-line metastatic setting (Smith et al: Breast Cancer Res Treat 64:27, 2000, abstract 8). Time to progression was 9.6 months on letrozole vs 6.1 on tamoxifen. Response rate, clinical benefit, and thromboembolic rate were also significantly improved with the aromatase inhibitor.

This trial allowed crossover to alternate treatments, and when these data become available, they should shed light on optimal sequencing of endocrine agents, he said.

Additionally, an international trial in HR-positive postmenopausal women with T2-4, N0-2, M0 disease found that letrozole produced greater tumor responses than tamoxifen by a number of different measures and allowed for breast-conserving therapy in 45% vs 35% of patients.

"These results confirm that primary endocrine therapy is feasible in select patients who are not candidates for surgery or for whom primary chemotherapy may not be appropriate due to refusal or comorbid conditions. Additionally, the data suggest that letrozole is superior to tamoxifen in this setting," he said.

Regarding the newest aromatase inhibitor, exemestane, a European Organization for the Research and Treatment of Cancer (EORTC) phase II trial has shown improved response rates and clinical benefit vs tamoxifen (Dirix L et al: Proc Am Soc Clin Oncol 20:29a, 2001, abstract #114), and a phase III extension is evaluating progression-free survival.

Exemestane also produces "dramatic reductions" in peripheral, intratumoral, and nonmalignant breast tissue aromatase activity and tumor volumes, Dr. Gradishar said.

"The experience with exemestane as primary endocrine therapy mirrors the data available with both letrozole and anastrozole," he said.

The aromatase inhibitors can be considered for postmenopausal patients who have ER-positive and/or progesterone-positive breast cancer and are not candidates for immediate surgery or chemotherapy, Dr. Gradishar concluded. He noted that there appears to be a small fraction of patients who might benefit from using one class of these agents after progressing on another class.

Dr. Gradishar outlined a potential treatment algorithm for these agents. In the first-line metastatic setting, he said, "there are compelling data for both letrozole and anastrozole. All three drugs [anastrozole, letrozole, exemestane] work equally well in the second-line setting. And there are some data suggesting that patients who receive an irreversible aromatase inhibitor initially might benefit from exemestane."

The next step is evaluating aromatase inhibitors in the adjuvant setting, which is underway in several trials. [See "Adjuvant Anastrozole Superior to Tamoxifen in Huge ATAC Breast Cancer Trial"] Pilot trials are also assessing the aromatase inhibitors as chemopreventive agents, Dr. Gradishar said.

Selective ER Downregulator

The structure and mode of action of the investigational selective estrogen-receptor (ER) downregulator fulvestrant (Faslodex) is markedly different from the commonly used selective estrogen-receptor modulators (SERMs), tamoxifen and raloxifene (Evista).

Most important, the fulvestrant-ER complex is rapidly degraded, resulting in loss of ER protein. The net effect is that no transcription takes place, ER-dependent cell division does not occur, and the estrogen receptor is essentially destroyed, Dr. Gradishar pointed out.

The first large trials evaluating fulvestrant as second-line metastatic therapy were reported at the 2000 San Antonio Breast Cancer Symposium. Fulvestrant proved similar to anastrozole in time to progression, time to treatment failure, objective response rate, and rate and duration of clinical benefit in one trial, and superior to anastrozole by a number of measures in the second trial.

These trials established fulvestrant as a novel endocrine therapy with a unique mechanism of action that has tumor activity equivalent to anastrozole in patients who have already received tamoxifen. Data are now maturing from a trial comparing fulvestrant to tamoxifen as first-line endocrine therapy in metastatic disease.