Endocrine therapy has been shown to be effective therapy for women with all stages of breast cancer, and the nonsteroidal antiestrogen tamoxifen is being evaluated as a potential preventive agent for this disease. Kimmick and Muss review the use of endocrine therapy for the treatment of patients with metastatic breast cancer. They discuss the basis for endocrine therapy and potential mechanisms of endocrine resistance, currently available and new agents, as well as new areas of investigation. I would like to highlight a few practical points regarding the use of endocrine therapy in the treatment of patients with metastatic breast cancer and some key areas of research.
In 1995, there remains no proven cure for metastatic breast cancer and treatment remains largely palliative with any form of therapy. Given the significant response rates and favorable toxicity profiles, hormonal agents represent an excellent therapeutic option for many patients.
As discussed by the authors, 30% of unselected patients respond to hormonal therapies. However, 70% to 80% of patients with tumors positive for both the estrogen receptor (ER) and progesterone receptor (PR) can be expected to respond, as can 50% of patients with ER-positive/PR-negative tumors. A small proportion of patients with hormone-receptor-negative tumors (5% to 10%) may respond to endocrine manipulations. Furthermore, both the level of ER protein detected and a prior response to endocrine therapy are predictors of response to endocrine therapies. Hormonal agents are indicated for the treatment of patients with hormone-receptor-positive disease, particularly in patients with disease in the soft tissues or skeleton.
An important clinical point to remember when treating metastatic breast cancer patients with endocrine therapy is the poorly understood phenomenon of tumor "flare," wherein patients exhibit signs or symptoms usually associated with tumor progression shortly after initiation of a new therapy. These parameters include clinical signs (pain, tumor swelling), laboratory changes (hypercalcemia or increasing tumor markers), or scintigraphic findings (worsening bone scan).
Vogel et al recently published a retrospective review of patients participating in a large-scale trial of first-line hormonal therapy . These authors evaluated patients for a possible scintigraphic flare by week 8 or 16 of the trial. Of 376 assessable patients, 108 (29%) with bone disease had a possible scintigraphic flare. Of these patients, 69 (64%) remained on therapy and 50 (72%) derived clinical benefit. Thus, in the remaining 39 patients (36%), who were removed from the study, a potential-ly beneficial treatment may have been discontinued prematurely in some cases.
Areas of Research
Several areas of clinical research involving hormonal agents should provide us with some very useful clinical information. Kimmick and Muss provide a list of current trials in Table 6. These trials involve the use of new agents (mifepristone, fadrazole), as well as standard agents in combinations (tamoxifen combined with tretinoin, fenretinide [4-HPR], buserelin, or octreotide [Sandostatin]).
Several other studies are designed to define the optimal method of utilizing currently available therapies, for example, continuous vs intermittent tamoxifen vs alternating tamoxifen and medroxyprogesterone acetate; medical vs surgical castration with goserelin (Zoladex) in premenopausal women; and various doses of aminoglutethi-mide (Cytadren) alone or in combination with hydrocortisone.
Still other clinical trials involve the use of chemotherapy in addition to endocrine therapy for the treatment of metastatic breast cancer. Results from one such trial recently reported by Falkson et al indicated that a subset of patients with metastatic breast cancer may experience long-term survival following chemoendocrine therapy . In this Eastern Oncology Group study of premenopausal women with metastatic breast cancer, 80 women with ER-positive tumors or tumors of unknown receptor status were randomized to CAF (cyclophosphamide, Adriamycin, and fluorouracil) chemotherapy alone or CAF chemotherapy plus oophorectomy. The median survival of ER-positive women who received CAF plus oophorectomy was an impressive 59 months.
Mechanisms of Resistance
Endocrine manipulation remains a mainstay of therapy for many women with metastatic breast cancer, and the sequencing of endocrine agents can provide effective therapy for patients with minimal toxicity. Response durations can last from weeks to years. However, most patients with metastatic breast cancer ultimately experience disease progression while on hormonal therapy. Wolf and Jordan have reviewed many of the model systems that have provided laboratory support for the potential mechanisms of tamoxifen resistance . These mechanisms include metabolic alterations of tamoxifen (systemic or intracellular) into metabolites with either more estrogen-like or less antiestrogenic activity; changes in ligands for tamoxifen; modifications in cellular tamoxifen uptake or excretion; changes in the transcription complex; and alterations in the ER. In some instances, tamoxifen may actually stimulate growth of breast cancer cell lines, and a mechanism involving a mutation in the ER has been postulated.
Clearly, no single mechanism is adequate to explain clinically observed tumor resistance. Both clinical and basic science research in this area are necessary to provide information leading to the optimal use of endocrine therapy.
1. Vogel CL, Schoenfelder J, Shemano I, et al: Worsening bone scan in the evaluation of antitumor response during hormonal therapy of breast cancer. J Clin Oncol 13:1123-1128, 1995.
2. Falkson G, Gelman RS, Tormey DC, et al: Median survival of 59 months for premenopausal women with ER-positive metastatic breast cancer: An ECOG study. Proc Am Soc Clin Oncol 13:57, 1994.
3. Wolf DM, Jordan VC: Drug resistance to tamoxifen during breast cancer therapy. Breast Cancer Res Treat 27:27-40, 1993.