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Current Status of Endocrine Therapy for Metastatic Breast Cancer

Current Status of Endocrine Therapy for Metastatic Breast Cancer

ABSTRACT: Hormonal manipulation is currently the mainstay of palliative care for metastatic breast cancer because it is well tolerated and produces significant responses in approximately one-third of unselected patients. Tamoxifen, a nonsteroidal antiestrogen, is currently considered first-line therapy. Second-line agents include progestins and aromatase inhibitors. New agents, such as the "pure" antiestrogens and the gonadotropin-releasing hormone (GnRH) agonists, are being tested. Other approaches for affecting the hormonal milieu are also under investigation, including combinations of hormonal agents, hormonal agents plus biologics, and hormonal agents plus antiproliferative agents. This review will address the basis for endocrine therapy and possible mechanisms of hormonal resistance, currently available agents and newer ones on the horizon, and areas of future interest. [ONCOLOGY 9(9):877-894, 1995]

Introduction

Breast cancer, the most common neoplasm in American women, will
result in approximately 46,000 deaths in 1995 and is second
only to lung cancer as a cause of cancer-related mortality in
women [1]. At diagnosis, approximately 5% of women have metastatic
disease, and current treatment for these women is only palliative.
Consequently, it is important to define new therapeutic modalities
and refine the therapeutic index of those already being used.

This paper reviews (1) the basis of endocrine therapy, a well-accepted
treatment for metastatic breast cancer, (2) currently available
and newer hormonal agents, (3) areas now under investigation,
and (4) mechanisms of hormonal resistance.

Endocrine therapy generally is well tolerated by women with metastatic
breast cancer and elicits a response in approximately one-third
of unselected patients and in at least 50% of patients whose tumors
are estrogen-receptor (ER) positive. Well-defined factors associated
with a greater likelihood of response to endocrine therapy include:

  • ER- and progesterone-receptor (PR) positivity
  • Late premenopausal or late post-menopausal status
  • Older age
  • Long interval from diagnosis to first recurrence (disease-free
    interval)
  • Disease limited to sites outside the viscera, such as bone
    and soft tissue
  • Previous response to endocrine therapy [2].

Because of their favorable therapeutic index, hormonal agents
are the treatment of choice for asymptomatic patients with metastatic
breast cancer, especially those who are older. Randomized trials
show no adverse effect on survival for patients initially treated
with endocrine therapy rather than chemotherapy, although initial
rates of response to chemotherapy tend to be somewhat higher [2-4].
Tamoxifen has been the drug of choice for first-line treatment
of advanced disease because of its low toxicity. Second-line therapy
now includes progestins and aromatase inhibitors, which have response
rates similar to tamoxifen but more side effects (Tables 1 and
2).

Possible Mechanisms
of Hormonal Manipulation

Breast cancer cells have steroid receptors for estrogens, progestins,
glucocorticoids, and androgens. Treatment of breast cancer in
premenopausal women traditionally has involved removal of the
ovaries, the source of estrogen, and, in postmenopausal patients,
administration of pharmacologic doses of estrogen. (In postmenopausal
women, large doses of estrogen can cause tumor regression.) The
exact mechanism of these treatment modalities and the effects
of estrogens and antiestrogens on the breast cancer cell are not
fully defined. Our current understanding is that estrogen downregulates
ERs and thereby decreases the hormone's effects [14].

Heat Shock Proteins--One speculative mechanism involves
heat-shock proteins (hsps). When an estrogen antagonist (E) interacts
with the ER, the ER-hsp complex dissociates. The DNA-binding domain
then attaches to the estrogen-binding site on the DNA, initiating
transcription of estrogen-regulated genes. Conversely, binding
of an antiestrogen (AE) to the ER stabilizes the DNA-hsp, which
prevents the ER-DNA interaction and thereby inhibits transcription
(Figure 1).

Growth Factors--Breast cancer cells also secrete other
growth factors that are autostimulatory (autocrine) and/or are
stimulated by substances secreted by surrounding cells (paracrine;
see Figure 2). Receptors for epidermal growth factor (EGFRs) and
a closely related gene product, c-erbB2 (Her-2/neu),
are found on breast cancer cells. Epidermal growth factor and
transforming growth factor-alpha (TGF-alpha) interact with the
EGFR and activate tyrosine kinase, a signal transduction pathway
shown to induce proliferation of breast cancer cell lines in nude
mice [15].

Transforming growth factor-alpha can act as an autocrine or paracrine
growth factor. Receptors for TGF-beta also are present on breast
cancer cells (primarily those that are ER-negative), and some
breast cancer cells produce TGF-alpha in response to estrogens.
Using antibodies against TGF-alpha or EGFR to block the effects
of TGF-alpha can inhibit some breast cancer cells.

Insulin-like growth factor (IGF) also is produced by breast cancer
cells in vitro and may result in both autocrine and paracrine
mitogenic effects [16]. Factors that increase IGF production include
estrogen, TGF-alpha, EGF, and insulin. Antiestrogens, TGF-beta,
and glucocorticoids inhibit its secretion [15].

Currently Available Hormonal Therapies

Currently available additive therapies include androgens, progestins,
gonadotropin-releasing hormone (GnRH) agonists, corticosteroids,
and, paradoxically, estrogens. Androgens, which were discovered
to be effective in the 1940s, cause breast cancers to regress
in approximately 20% of patients but are poorly tolerated because
of virilization and other major toxicities.

Physiologic doses of estrogen (hormone replacement therapy) are
generally avoided in women with breast cancer because of theoretical
concerns that they might stimulate breast cancer cell growth.
Higher doses yield response rates in postmenopausal women similar
to those produced by other available agents, but estrogen therapy
is frequently associated with nausea, vomiting, and other toxic
effects [17,18]. During the 1950s, progestins were found to yield
response rates of 30% in unselected patients with breast cancer
[19].

Response rates of 20% to 25% also were reported for corticosteroid
therapy alone [20]. For example, in elderly patients in whom endocrine
therapy has failed, 15 mg of prednisolone administered daily caused
tumor regression in 14% of patients and tumor stabilization lasting
6 months or longer in 21% [21]. Corticosteroids also can improve
sense of well being, appetite, and functional status in seriously
ill cancer patients [22]. However, because of their long-term
undesirable toxicities, corticosteroids typically are reserved
for reducing inflammation and swelling in patients with intracranial
metastases or the superior vena cava syndrome.

Gonadotropin-releasing hormone agonists have proven effective
in pre-menopausal patients with metastatic breast cancer, but
their role in standard practice has not yet been defined.

Tamoxifen, the prototypic hormonal agent used in breast cancer,
is one of several antiestrogens now available and falls into the
broad category of hormone antagonists. Other groups of hormone
antagonists only recently introduced into the breast cancer treatment
armamentarium include antiprogestins, antiandrogens, and aromatase
inhibitors.

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