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Advances in Endocrine Therapy of Breast Cancer

2004 Edition, July 2, 2004

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Active, Most Current

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ISBN: 978-0-8247-2228-9
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Product Details:

  • Revision: 2004 Edition, July 2, 2004
  • Published Date: July 2, 2004
  • Status: Active, Most Current
  • Document Language: English
  • Published By: CRC Press (CRC)
  • Page Count: 344
  • ANSI Approved: No
  • DoD Adopted: No

Description / Abstract:


Endocrine therapy is assuming an increasingly important role in the management of women with breast cancer. This is justified by new evidence from clinical research and new knowledge from the laboratory. The use of endocrine manipulations covers the spectrum from metastatic disease. adjuvant therapy, and neoad-juvant therapy to prevention, the last representing the ultimate goal. The pace of new information is accelerating. particularly from the clinical trials sector with maturation of multiple randomized clinical trials. The appearance of new agents. especially the aromatase inhibitors, has provided the basis for substantial interest and enthusiasm from investigators in the field. Laboratory investigations have also yielded important and potentially exploitable information related to the biology of breast cancer. Because of this rapidly evolving field, 36 leading authorities in clinical. basic. and translational breast cancer research assembled in Gleneagles, Scotland, to review the current state of knowledge and discuss future research directions. This book presents reviews from speakers and the discussions that ensued.Author: Ingle, James N.

The meeting consisted of five areas of focus. Part I evaluated the clinical pharmacology of the selective estrogen receptor modulators (SERMs). selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). Part II considered endocrine therapy in postmenopausal women in the metastatic, adjuvant, and neoadjuvant settings. Part III examined endocrine therapy in premenopausal women and addressed its use in the advanced disease in adjuvant settings as well as the role of chemotherapy in women with an estrogen-receptive-positive tumor. Part IV examined chemoprevention and considered the biology of premalignant lesions, estrogen-induced carcinogenesis, and the use of SERMs and AIs in clinical trials. Part V addressed new therapeutic approaches based on emerging knowledge of the biology of breast cancer. The areas examined included the interaction of the estrogen-receptor pathway with other growth factor pathways, surrogate biomarkers, new antibodies for immunohistochemical staining of aromatase, and novel therapeutics for enhancing the efficacy of endocrine therapy.

Over recent years a large number of SERMs have been developed with the primary aim of reducing the agonist activity present in the prototype drug tamoxifen on normal endometrial and malignant breast cells. The rationale for this has been enhanced by an improved understanding of the molecular pharmacology of tamoxifen. However, many of these new SERMs have been tested in comparative clinical trials, yet none have demonstrated superiority over tamoxifen. In contrast, although the pure anti-estrogen, fulvestrant, also has no greater efficacy than tamoxifen in Phase 3 studies, its ability to elicit responses in patients with acquired resistance to tamoxifen (and AIs) provides an opportunity for this drug to find a place in the hormonal treatment cascade. Comprehensive pharmacological characterization of AIs has shown that, unlike earlier inhibitors, the third-generation compounds lead to near obliteration of plasma and tumor estrogens in postmenopausal women with excellent specificity

The value of endocrine therapy is undisputed in all breast cancer patients whose tumors express the estrogen receptor and/or progesterone receptor. Considering postmenopausal women, further work is needed relating to dose-response relationships with the third-generation AIs. In particular, better means of evaluating impact of AIs on the target organ, specifically the breast, are needed. Laboratory studies have demonstrated that breast cancer cells can adapt to a changing estrogen environment and strategies for dealing with this adaptation are needed. Two classes of AIs, that is, nonsteroidal and steroidal, are available, and research is ongoing to determine if there are meaningful therapeutic differences between these two classes. Both the AIs and tamoxifen have demonstrated efficacy in the adjuvant setting, and multiple clinical trials are addressing the optimal utilization of these agents. When used as adjuvant therapy. the optimal duration of AIs therapy remains to be determined.

In premenopausal women, in the adjuvant setting, the role of chemotherapy and endocrine therapy needs resolution. A major question is whether women who receive adjuvant chemotherapy but do not become amenorrheic should also receive ovarian function suppression. Although ovarian function suppression with LHRH analogues is effective therapy, the optimal duration of such therapy needs to be determined. Evidence exists about the value of the combination of LHRH analogues plus tamoxifen but the value of AIs in place of tamoxifen needs to be resolved. Clinical trials are ongoing to address the value of ovarian function suppression and AIs in adjuvant therapy of premenopausal women, both in the presence and absence of chemotherapy.

Chemoprevention represents a major focus of breast cancer research today. The relationship of estrogens to the risk of developing breast cancer is indisputable. Tamoxifen has been studied in multiple trials and has been demonstrated to produce clear reductions in the incidence of invasive breast cancer. The large randomized trial of tamoxifen versus raloxifene (STAR) will complete accrual of 19,000 patients in 2004. Other studies involving the AIs are both underway and being planned. Cautionary notes were sounded regarding the use of potent AIs in the prevention setting, and measures to monitor patients for adverse events were emphasized. There was agreement that clinical trials of prevention strategies need to continue but that emphasis should be placed on the identification of risk profiles in order to target the most appropriate patients in prevention trials.

The session on biology and novel therapeutics addressed the extensive information forthcoming from the laboratory on signaling pathways in addition to the estrogen-receptor pathway. Multiple interactions between these pathways have been identified. It is clear that there is cross-talk between the estrogen-receptor pathway and other growth-factor-signaling pathways, and this knowledge is leading to hypotheses that can ultimately be tested in the clinic. Major opportunities exist for combining classic endocrine manipulations with growth-factor inhibitors and small molecule signal transduction inhibitors. Characterization of tissues from patients to determine the key factors responsible for de novo and acquired resistance to individual hormonal treatments will be required to deliver rational combinations of the new agents with current endocrine agents, which are likely to remain the bedrock of our therapy in hormone-receptor-positive disease for the foreseeable future. The neoadjuvant setting, whereby specimens can be obtained before, during. and after therapy, is ideal for studying surrogate biomarkers and mechanisms of de novo resistance, but tissue collections will also be required from patients at relapse to allow characterization of mechanisms of acquired resistance.

The quickening pace of discovery related to endocrine therapy was evident in the presentations and discussions from this meeting, Whereas discovery always raises questions and challenges, it is clear that the issues for future study are being articulated. The fact that breast cancer research has become a concerted, collaborative, and global effort is shown in the substance of this meeting. This second Gleneagles colloquium in the homeland of Sir George Thomas Beatson augers well for the quest to eliminate the burden of breast cancer.