Introduction to the Conference, Aromatase New Perspectives for

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					[CANCER RESEARCH (SUPPL.) 42, 3268s, August 1982]

Introduction to the Conference, Aromatase: New Perspectives for
Breast Cancer^

Richard J. Santen
Division of Endocrinology,   The Milton S. Hershey Medical Center. The Pennsylvania    State University, Hershey, Pennsylvania     1 7033

    Basic and clinical data suggest that human breast cancers                         drugs with desired mechanistic effects can then be rationally
 can be divided into hormone-dependent      and hormone-inde                          developed. These must be tested in biological systems and
 pendent subtypes. The biological behavior and responsiveness                         compared with alternative therapy approaches.
to treatment of these two subgroups are different. Measure                               The development of aromatase inhibitors for treatment of
ment of estrogen and progesterone receptors serves to char                            hormone-dependent breast cancer has generally followed the
acterize mammary tumors as hormone dependent or hormone                               deductive approach. Because of this, the conference on aro
independent with an overall accuracy of approximately 80%.                            matase was structured upon an outline of the deductive strat
Clinical and biochemical data suggest that one-third of human                         egy. Several years ago, Dr. Peniti Siiteri first raised the hy
tumors fall into the hormone-dependent       category and two-                        pothesis that aromatase, the rate-limiting step for estrogen
thirds are the independent subtype. Thus, of the 110,000 new                          biosynthesis, is important for the growth of breast and endo-
cases of breast carcinoma diagnosed in the United States                              metrial cancers (1). The speakers in the first two sessions,
                                                                                      entitled "Physiology,    Biochemistry   and Biological Signifi
yearly, approximately 35,000 will be hormone dependent. A
                                                                                      cance" and "Epidemiological        Considerations:   Aromatase,
variety of data suggest that estrogen is the major hormonal
stimulus for growth of the hormone-dependent type of breast                           Obesity, and Breast Carcinoma," discussed the concepts re
carcinoma. The enzyme aromatase is the rate-limiting step in                           lated to this unifying hypothesis. The next several sessions
estrogen production. Consequently, it is logical to consider                           covered experimental data regarding biochemical, biological,
that this enzyme could play a key role both in the pathogenesis                        and structure-function  studies of aromatase. The design of a
of hormone-dependent breast cancer and in its treatment.                               number of competitive and suicide aromatase inhibitors was
    The conference, Aromatase: New Perspectives for Breast                            then reviewed in the sessions entitled "Pharmacological  Inhib
                                                                                      itors of Aromatase: Biochemical Studies," and "Pharmacolog
 Cancer, was organized to bring together a group of investiga
 tors with breadth and depth of expertise regarding aromatase.                        ical Inhibitors of Aromatase: In Vivo Studies."
 The speakers represented the disciplines of anatomy, biochem                            Several speakers outlined the efficacy of available aromatase
 istry, physiology, endocrinology, obstetrics-gynecology,    on                       inhibitors for treatment of breast carcinoma in animal models
 cology, pharmacology, medicinal chemistry, and surgery. The                          and in patients in the sessions entitled "Aromatase Inhibitors
 multidisciplinary interchange which ensued stimulated new in                         as Treatment       of Animal    Breast Carcinoma        Models,"
sights into the significance of aromatase and the potential of                        "Aromatase in Human Breast Carcinoma—Biochemistry:            In
 reversible and irreversible inhibitors of this enzyme.                               Vitro Inhibitors," and "Aromatase Inhibitors as Treatment of
                                                                                      Human Breast Carcinoma." The use of aromatase inhibitors
    During the conference, development of pharmacological
 methods to block estrogen synthesis as potential treatment of                        was compared with other ways of antagonizing the biological
 breast cancer was discussed. For the design of any new                               effects of estrogens in breast carcinoma in additional sessions:
anticancer agent, two alternative investigative strategies, the                       "Antiestrogens    as Alternative Means of Inhibiting Estrogen
                                                                                      Action," "Randomized Trials of Aromatase Inhibitors versus
inductive and deductive approaches, can be used. The first, or
inductive, approach has been most commonly used in the last                           Antiestrogens,"    "Aminoglutethimide   in Tamoxifen-resistant
                                                                                      Patients," "Aromatase Inhibition versus Surgical Ablation,"
 15 years to develop new anticancer drugs. With this method,
                                                                                      and "A Combination of Agents to Inhibit Estrogenic Actions as
the need to develop cytotoxic antitumor drugs was first identi
fied as a targeted goal. Multiple compounds were then                                 Treatment of Breast Carcinoma."
screened in animals using the destruction of experimental                                 The data presented at this workshop conference provided a
tumors as the end point of therapeutic efficacy. Promising                            framework for further study of the significance of aromatase
agents were then introduced into Phase I clinical trials in                           and the importance of developing ideal inhibitors. Important
patients. After the antitumor activity of certain compounds was                       target areas for further studies were identified. These included
established, hypotheses were then developed to explain the                            establishment of the significance of estrogen production di
exact mechanism of action of these agents. This strategy has                          rectly in breast cancer tissue, further epidemiological studies
led to the development of a wide variety of useful therapeutic                        of aromatase and its relevance for development of breast
agents.                                                                               cancer, the development of better treatment regimens with
    The second strategy, the deductive approach, best describes                       available aromatase inhibitors to reduce side effects and tox-
the history of development of aromatase inhibitors. This strat                        icity, and the development of more potent or selective aroma
egy requires as the first step the development of a hypothesis.                       tase inhibitors to allow inhibition of ovarian as well as extra-
Experimental data are then collected to substantiate the hy                           glandular estrogen production.
pothesis and to develop a broad understanding of the biological
and biochemical mechanisms involved. Specific inhibitors or                           References
  1 Presented at the Conference "Aromatase: New Perspectives         for Breast        1. Siiteri, P. K . et al. Steroid abnormalities in endometrial or breast carcinoma:
Cancer.' December 6 to 9, 1981, Key Biscayne. Fla.                                        a unifying hypothesis. J. Steroid Biochem.. 7: 897-903,        1976.

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