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Introduction The use of third-generation aromatase inhibitors for treating postmenopausal women with oestrogen-dependent advanced breast cancer is increasing ( Hamilton & Piccart 1999 ). Among the available aromatase inhibitors
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ABSTRACT
Insulin-like growth factor-I (IGF-I) is a potent mitogen for breast cancer cells. Oestrogens, as well as androgens, modify plasma IGF-I levels. More recent investigations have revealed that antihormone treatment with tamoxifen suppresses plasma IGF-I. Treatment with luteinizing hormone-releasing hormone (LHRH) agonists also suppresses plasma IGF-I, but treatment with the aromatase inhibitor aminoglutethimide or the progestin megestrol acetate have both been found to elevate plasma IGF-I levels. Apart from influencing plasma levels of total IGF-I, endocrine therapy may act on IGF-I disposition by modifying the concentration of IGF-binding proteins. IGF-binding proteins play an important role in modulating the biological activity of IGF-I. Tamoxifen significantly elevates the concentration of IGF-binding protein-1 (IGFBP-1), whereas megestrol acetate has been found to inhibit a plasma protease modifying IGF-binding protein-3 (IGFBP-3), leaving more of this binding protein in a 'high affinity' state for IGF-I. Thus not only alterations in IGF-I but also changes in IGF-binding proteins may interact with antiendocrine treatment in a complex manner. Such effects may add to treatment effectiveness but could also be detrimental to the antitumour effects of the drugs. Studies of alterations in the IGF-I system not only in relation to drug effects but also in relation to the emergence of resistance to endocrine therapy in breast cancer patients are warranted.
Endocrine-Related Cancer (1995) 2 127-130
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The development of aromatase inhibitors for breast cancer therapy is a result of successful translational research exploring the biochemical effects of different compounds in vivo. Studies assessing plasma oestrogen levels as well as in vivo aromatase inhibition have revealed a consistent difference with respect to biochemical efficacy between the third generation compounds (anastrozole, letrozole and exemestane) and the previous, first and second generation drugs, corresponding to the improved clinical effects of these compounds as outlined in large phase III studies. Thus, endocrine evaluation has been found to be a valid surrogate parameter for clinical efficacy. Moreover, the results from these studies have added important biological information to our understanding of endocrine regulation of breast cancer. Based on the clinical results so far, aromatase inhibitors are believed to play a key role in future adjuvant therapy of postmenopausal breast cancer patients and potentially also for breast cancer prevention. Interesting findings such as the lack of cross-resistance between steroidal and non-steroidal compounds should be further explored, as this may add additional information to our understanding of breast cancer biology.
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The preoperative use of systemic therapy for primary breast cancer has the potential to downstage tumours. This would render suitable for breast conservation some tumours that were unsuitable at initial presentation, or would convert some inoperable locally advanced breast cancers into tumours that are operable. No survival benefit has been demonstrated for neoadjuvant chemotherapy compared with the same therapy given in an adjuvant setting. Preoperative endocrine therapy, in contrast to neoadjuvant chemotherapy, has fewer side effects and has the potential additional advantage that it can be continued throughout the perioperative period. Current data have shown that, in patients with an oestrogen receptor (ER)-positive tumour, a response approaching 70% could be reached in approximately 3 months using traditional endocrine manipulation such as tamoxifen. Randomised clinical trials are warranted to demonstrate the superiority of preoperative endocrine therapy over conventional adjuvant endocrine therapy, to define the optimum duration of therapy, and to identify the best endocrine agents. Both clinical and laboratory studies are also required to identify factors (in addition to ER) that would precisely predict the response and hence to select appropriate patients and to improve existing methods of monitoring response.
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Abstract
Beatson identified the fact that some breast cancers responded to oophorectomy. Equally, some did not but the surgical procedures carried considerable morbidity. In the more recent years of additive endocrine therapy, there is still a very good case for only giving first-line endocrine therapy to those patients who will definitely benefit from it. There is now convincing evidence from many fields that breast cancers are only steroid hormone sensitive if the majority of cells contain functional oestrogen receptors. Further evidence shows that the extent of response is proportional to the amount of receptor present in the tumour. Thus, there is a case for measuring receptor content by both a biochemical (quantitative) assay and an immunohistochemical assay (semi-quantitative but also a measure of extent of heterogenicity). Steroid receptor content is very useful as a predictive tool for response to endocrine therapy but has limited use as a prognostic index. Overall, biological markers of tumour growth and invasive potential should only be used as combinations which may be useful in specific clinical subgroups. Nevertheless, tumour receptor content is an important/essential piece of information that should be established in the primary tumour of every breast cancer patient. Receptor status is remarkably constant from initial detection to death and so therapies should be geared to keeping receptor-mediated therapies useful, rather than basing treatment on the concept that steroid-sensitive tumours become totally insensitive as they progress.
Endocrine-Related Cancer (1997) 4 289-296
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Abstract
A common phenotypic consequence of the genetic changes that occur in breast cancer is a loss of steroid hormone growth sensitivity, a feature manifested clinically by primary or acquired resistance to antihormones. Although it appears that the absence of steroid receptor machinery determines the failure of oestrogen receptor (ER) negative tumours to respond to endocrine therapies, the erbB signalling pathway seems far from redundant in these tumours and in vivo evidence suggests that elevated epidermal growth factor receptor (EGFR) and c-erbB-2 proteins are fundamental elements in ER negative disease growth control. In contrast, neither diminished ER nor elevated EGFR expression appears to be essential in determining any primary endocrine insensitivity demonstrated by ER positive tumours, although elevated expression of additional erbB pathway components (e.g. transforming growth factor-α, Fos, Myc and c-erbB-2 protein) may be important. However, none of these factors appears to direct endocrine unresponsive, ER positive cell proliferation. Furthermore, it is unlikely that selective outgrowth of endocrine unresponsive, EGFR membrane positive/ER negative cells constitutes a major event in ER positive tumours during their progression towards endocrine resistance.
Endocrine-Related Cancer (1997) 4 297-305
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The ability of oestrogens and androgens to stimulate the growth of a number of endocrine cancers is well established and several endocrine therapies are widely used to reduce the availability of the hormones or to block their action. These include non-steroidal hormone antagonists such as tamoxifen and flutamide, steroidal compounds which include ICI 182780 and cyproterone acetate, and both steroidal and non-steroidal aromatase inhibitors. Although we have learned a great deal about the molecular mechanism of steroid hormone action, it is still unclear as to how hormones stimulate the proliferation of tumour cells and how hormone antagonists function. In part this is a result of the ability of oestradiol and testosterone to regulate the expression of many proteins implicated in the control of cell proliferation making it difficult to identify the crucial targets. Some of these targets are growth factors and/or their receptors which suggests that the mitogenic effects of steroids may be mediated by indirect autocrine or paracrine mechanisms (Clarke et al. 1991, Roberts and Sporn 1992). Alternatively since steroids regulate the expression of certain cyclins or kinase inhibitors (Musgrove and Sutherland 1994, Altucci et al. 1996) they may control cell cycle progression directly. Recent work suggests that as well as the cyclin D1 gene, cyclin D1 itself may be a crucial target (Zwijsen et al. 1997) but additional proteins could also be important in different subsets of tumours.
The identification of target genes for steroid hormones is further complicated by the observation that receptor signalling is cross-coupled with that of other signalling pathways. It used to be thought that signalling by receptors was relatively straightforward compared with most other signalling pathways, since the receptor itself is a transcription factor. It is now clear however, that growth factors, neurotransmitters and other hormones are able to modulate the activity of steroid hormone receptors (Power et al. 1991, Aronica and Katzenellenbogen 1993, Ignar-Trowbridge et al. 1993 ). This means that alterations in the activity of receptors and the expression of individual target genes involved in cell proliferation is determined not only by hormonal signals but also by changes in other signalling pathways, which undoubtedly take place during breast and prostate cancer progression. Receptors are also capable of regulating the activity of a number of other transcription factors, either directly or indirectly, and thereby modulate the ability of other signalling pathways to control gene transcription (Shemshedini et al. 1991, Philips et al. 1993, Stein and Yang 1995, Webb et al. 1995).
Although the precise role of steroid hormones in cell proliferation is still ill-defined, tremendous progress has been made in elucidating the role of hormones in receptor activation and the mechanism by which hormone antagonists block this activity. In particular two recent advances have been made which provide new insights into steroid hormone action and the function of nuclear receptors in general. Firstly, models for the three-dimensional structure of the ligand binding domain of several receptors have been determined (Bourguet et al. 1995, Renaud et al. 1995, Wagner et al. 1995) and secondly, novel proteins have been identified (Halachmi et al. 1994, Cavaillés et al. 1994) which interact with receptors in a ligand dependent manner and may play a role in gene transcription. These developments are helping to provide a better understanding of the mechanism of action of both hormones agonists and antagonists and the links between nuclear receptors and other signalling pathways. In this review we will outline these advances, with reference to the oestrogen receptor, and discuss their relevance to antioestrogen therapy and tamoxifen resistance.
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Postmenopausal patients with oestrogen receptor-positive locally advanced T4b, N0-1, M0 and large operable breast cancers T2>3 cm, T3, T4, N0-1 and M0 have been treated with 2.5 mg letrozole (12 patients), 10 mg letrozole (12 patients), 1 or 10 mg anastrozole (24 patients) and 20 mg tamoxifen (65 patients). There was no apparent difference in response rate between 2.5 and 10 mg letrozole. Only 17 patients with anastrozole have so far completed the 3-month treatment period. Median clinical, mammographic and ultrasound reductions in tumour volumes for patients treated with letrozole were 81% (95% confidence interval (CI) 66-88), 77% (95% CI 64-82) and 81% (95% CI 69-86) respectively and for anastrozole, values were 87% (95% CI 59-97), 73% (95% CI 58-82) and 64% (95% CI 52-76) respectively. This compares with a median reduction in tumour volume for tamoxifen-treated patients as assessed by ultrasound of 48% (95% CI 27-48). There were seven complete clinical responses (CR), sixteen patients who achieved 50% or greater reduction in tumour volume (PR) and one no change (NC) for letrozole and four CRs, twelve PRs and one progressive disease for anastrozole. Best radiological responses were one CR, twenty PRs and three NCs for letrozole and one CR, fifteen PRs and one NC for anastrozole. This study has shown that the new aromatase inhibitors, letrozole and anastrozole, are highly effective agents in the neoadjuvant setting and they should now be compared with tamoxifen as first-line treatment in a randomised study.