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PubMed2005

Endocrine therapy--current benefits and limitations.

Endocrine therapy is a valuable option for the treatment of postmenopausal women with estrogen receptor (ER)-positive breast cancer due to its demonstrated efficacy and favorable safety profile. Although tamoxifen has been the established treatment for more than 20 years its long-term use is associated with several tolerability concerns and may lead to increased risk of endometrial cancer and thromboembolic complications. In addition, many patients who initially respond to treatment with endocrine agents such as tamoxifen eventually relapse with resistant disease. Sequential use of endocrine therapies is often used in patients as resistance to individual agents develops. Several endocrine approaches have been developed that deprive the tumor of estrogen stimulation, either by directly modulating the ER-signaling pathway or by lowering serum or tumor concentrations of estrogen. In the classic pathway of estrogen signal transduction, the steroid hormone binds to its intracellular ER, triggering a cascade of events that ultimately leads to altered gene transcription. More recently, it has become apparent that ER activation can also occur via estrogen-independent receptor activation or by non-nuclear action through cell surface receptors. Consequently, molecular cross-talk exists between the ER and growth factor signaling cascades, which is a key factor in de novo and acquired resistance to endocrine therapy. Inappropriate activation of growth factor signaling can readily promote endocrine therapy failure in breast cancer cells, either by overriding the growth-inhibitory properties of antiestrogenic drugs or by establishment of a new self-propagating autocrine loop that efficiently drives resistant cell growth. Fulvestrant is a new type of ER antagonist with no agonist effects that binds, blocks and causes degradation of the ER. As multiple signaling pathways are involved in the activation of ER, the use of agents such as fulvestrant that directly target the ER and lead to both degradation of the receptor and abrogation of ER signaling may prevent or delay the development of absolute endocrine resistance. In addition, combining antiestrogenic drugs with inhibitors of cell signaling molecules to target both the ER and growth factor signaling pathways is likely to provide a means of delaying endocrine therapy resistance, leading the way to more effective breast cancer treatment.

Antineoplastic Agents, Hormonal↗
PubMed2004

Endocrine approaches for the treatment of early and advanced breast cancer in postmenopausal women.

Preventing clinical progression is the major treatment goal for both early and advanced breast cancer. For hormone-responsive cases (about 70% of the total), this can necessitate the use of sequential hormone therapies at various points during the patient's life. Newer hormonal therapies, such as the third-generation aromatase inhibitor anastrozole, are now competing with tamoxifen as first choice endocrine therapy in breast cancer. In addition, a further non-steroidal aromatase inhibitor letrozole has been shown to be beneficial when given at completion of 5 years adjuvant tamoxifen. In light of these new data, current treatment paradigms need to be reviewed. Already well established as second-line treatments for advanced breast cancer, the improved risk:benefit profiles of anastrozole and letrozole compared with tamoxifen mean that these agents are now also recognised alternative treatments in the first-line relapse setting. More recent studies demonstrate that anastrozole may also have an improved risk:benefit profile compared with tamoxifen when used as initial adjuvant therapy in early breast cancer. Anastrozole is also being evaluated as a preventative treatment in women at high risk of developing breast cancer. A new addition to the endocrine treatment armamentarium is the oestrogen receptor antagonist fulvestrant, which, unlike tamoxifen, has no agonist effects. Fulvestrant is at least as effective as anastrozole in the second-line treatment of advanced breast cancer, and provides similar benefits to tamoxifen when used as first-line therapy in patients with advanced, hormone receptor-positive tumours.

Anastrozole↗
PubMed2005

Intrinsic mechanism of estradiol-induced apoptosis in breast cancer cells resistant to estrogen deprivation.

BACKGROUND: We previously developed an estrogen receptor (ER)-positive breast cancer cell line (MCF-7:5C) that is resistant to long-term estrogen deprivation and undergoes rapid and complete apoptosis in the presence of physiologic concentrations of 17beta-estradiol. Here, we investigated the role of the mitochondrial apoptotic pathway in this process. METHODS: Apoptosis in MCF-7:5C cells treated with estradiol, fulvestrant, or vehicle (control) was investigated by annexin V-propidium iodide double staining and 4',6-diamidino-2-phenylindole (DAPI) staining. Apoptosis was also analyzed in MCF-7:5C cells transiently transfected with small interfering RNAs (siRNAs) to apoptotic pathway components. Expression of apoptotic pathway intermediates was measured by western blot analysis. Mitochondrial transmembrane potential (psim) was determined by rhodamine-123 retention assay. Mitochondrial pathway activity was determined by cytochrome c release and cleavage of poly(ADP-ribose) polymerase (PARP) protein. Tumorigenesis was studied in ovariectomized athymic mice that were injected with MCF-7:5C cells. Differences between the treatment groups and control group were determined by two-sample t test or one-factor analysis of variance. All statistical tests were two-sided. RESULTS: MCF-7:5C cells treated with estradiol underwent apoptosis and showed increased expression of proapoptotic proteins, decreased psim, enhanced cytochrome c release, and PARP cleavage compared with cells treated with fulvestrant or vehicle. Blockade of Bax, Bim, and p53 mRNA expression by siRNA reduced estradiol-induced apoptosis relative to control by 76% [95% confidence interval (CI) = 73% to 79%, P < .001], 85% [95% CI = 90% to 80%, P < .001], and 40% [95% CI = 45% to 35%, P < .001], respectively, whereas blockade of FasL by siRNA had no effect. Estradiol caused complete regression of MCF-7:5C tumors in vivo. CONCLUSION: The mitochondrial pathway of apoptosis plays a critical role in estradiol-induced apoptosis in long-term estrogen-deprived breast cancer cells. Physiologic concentrations of estradiol could potentially be used to induce apoptosis and tumor regression in tumors that have developed resistance to aromatase inhibitors.

Annexin A5↗
PubMed2006

Development and therapeutic options for the treatment of raloxifene-stimulated breast cancer in athymic mice.

PURPOSE: Selective estrogen receptor modulators (SERM) are used for the treatment and prevention of breast cancer (tamoxifen) and osteoporosis (raloxifene). Mechanisms of tamoxifen-resistance in breast cancer are incompletely understood but current research is focused on crosstalk between growth factor receptors and the estrogen receptor alpha (ERalpha) pathway. There is increasing clinical use of raloxifene for the treatment of osteoporosis, but the widespread use of this SERM will have consequences for the treatment of breast cancer in raloxifene-exposed women. EXPERIMENTAL DESIGN: We took the strategic step of developing a raloxifene-resistant tumor (MCF-7RALT) model in vivo and investigating the mechanisms responsible for resistance. RESULTS: MCF-7RALT tumors exhibited phase I SERM resistance, growing in response to SERMs and 17beta-estradiol. Epidermal growth factor receptor/HER1 and HER2/neu mRNAs were increased in MCF-7RALT tumors. The HER2/neu blocker, trastuzumab, but not the epidermal growth factor receptor blocker, gefitinib, decreased the growth of MCF-7RALT tumors in vivo. Consequently, trastuzumab decreased prosurvival/proliferative proteins: phospho-HER2/neu, total HER2/neu, phospho-Akt (protein kinase B), glycogen synthetase kinase-3, cyclin D1, and the antiapoptotic protein X chromosome-linked inhibitor of apoptosis, whereas increasing the proapoptotic protein, caspase-7, in raloxifene-treated MCF-7RALT tumors. Interestingly, ERalpha protein was overexpressed in untreated MCF-7RALT tumors and hyperactivated in cells derived from these tumors. Only fulvestrant completely inhibited the growth and ERalpha activity of MCF-7RALT tumors. The coactivator of ERalpha, amplified in breast cancer-1 protein was modestly increased in the raloxifene-treated MCF-7RALT tumors and increased both basal and estradiol-induced activity of ERalpha in cells derived from the MCF-7RALT tumors. CONCLUSIONS: These results suggest that overexpression and increased activity of HER2/neu might be responsible for the development of raloxifene-resistant breast cancer. The results also suggest that increased expression of basal activity of ERalpha could contribute to the hypersensitivity of MCF-7RALT tumors in response to estradiol because only fulvestrant blocked growth and ERalpha activity.

Animals↗
PubMed2004

Tamoxifen--what next?

Most patients with advanced breast cancer (ABC) ultimately die due to disease progression. Consequently, treatments for ABC are predominantly palliative in nature and, therefore, the tolerability profile of a given treatment is particularly relevant in these patients. While cytotoxic chemotherapy and endocrine therapy exhibit efficacy in hormone-sensitive, advanced disease, it is endocrine therapy that combines efficacy with minimal acute toxicity. Tamoxifen has been the chosen endocrine therapy for postmenopausal, hormone-sensitive, ABC for over 20 years. More recently, new endocrine agents with different mechanisms of action from tamoxifen have been introduced. Evidence indicates that the aromatase inhibitors anastrozole (Arimidex; AstraZeneca; Wilmington, DE), letrozole (Femara; Novartis Pharmaceuticals Corp.; East Hanover, NJ) and exemestane (Aromasin; Pharmacia Corp.; Peapack, NJ) offer superior efficacy and tolerability to tamoxifen in the first-line treatment of postmenopausal, hormone-sensitive ABC. Similarly, after tamoxifen failure, fulvestrant (Faslodex; AstraZeneca), a new estrogen receptor (ER) antagonist that downregulates the ER, is at least as effective as anastrozole, is well tolerated, and is not cross-resistant with tamoxifen. Unlike tamoxifen, fulvestrant has no known agonist effects. The sequential use of such agents may prolong the time during which endocrine therapies can be used, thereby avoiding the more acute toxicities associated with cytotoxic chemotherapy. Indeed, a series of studies has shown that this sequential use is a relevant, active, and well-tolerated option. Establishing the comparative efficacies and optimal sequences that incorporate the newer endocrine agents will be central in determining the future role of hormonal therapy in ABC; the results of this work will determine the relative place of tamoxifen in what is a rapidly changing therapeutic environment.

Antineoplastic Agents, Hormonal↗
PubMed2006

Endocrine therapy resistance can be associated with high estrogen receptor alpha (ERalpha) expression and reduced ERalpha phosphorylation in breast cancer models.

Hormone-dependent estrogen receptor (ER)-positive breast cancer cells may adapt to low estrogen environments such as produced by aromatase inhibitors. In many instances, cells become insensitive to the effects of estrogen but may still retain dependence on ER. We have investigated the expression, function, and activation of ERalpha in two endocrine-resistant MCF-7 models to identify mechanisms that could contribute to resistance. While MCF-7/LCC1 cells are partially estrogen dependent, MCF-7/LCC9 cells are fully estrogen insensitive and fulvestrant and tamoxifen resistant. In both MCF-7/LCC1 and MCF-7/LCC9 cell lines, high expression of ERalpha was associated with enhanced binding to the trefoil factor 1 (TFF1) promoter in the absence of estrogen and increased transcription of TFF1 and progesterone receptor. In contrast to the observations derived from hypersensitive and supersensitive models, these cells were truly estrogen independent; nevertheless, removal of ERalpha by siRNA, or fulvestrant, a specific ER downregulator, inhibited growth indicating dependence on ERalpha. In the absence of estrogen, neither ERalpha Ser118 nor Ser167 were phosphorylated as frequently found in other ligand-independent cell line models. Addition of estrogen activated ERalpha Ser118 in MCF-7 and LCC1 cells but not in LCC9 cells. We suggest that the estrogen-independent growth within these cell lines is accounted for by high levels of ERalpha expression driving transcription and full estrogen independence explained by lack of ERalpha activation through Ser118.

Antineoplastic Agents, Hormonal↗
PubMed2005

The apoptotic action of estrogen following exhaustive antihormonal therapy: a new clinical treatment strategy.

Long-term antihormonal therapy is effective at controlling the recurrence of estrogen receptor (ER)-positive breast cancer, but there may be unanticipated consequences for the development of new forms of drug resistance. Laboratory studies of exhaustive antihormonal therapy demonstrate there are at least two phases of resistance to selective ER modulators (SERMs; tamoxifen and raloxifene) and to estrogen withdrawal (aromatase inhibitors). In Phase I drug resistance, estrogen or a SERM promote tumor growth, but in Phase II drug resistance estrogen induces apoptosis. Understanding of the new biology of estrogen action has clinical relevance. There are paradoxical interactions between fulvestrant and postmenopausal levels of estrogen that cause robust growth of Phase II tamoxifen resistance or autonomous aromatase-resistant tumors. These new data suggest a rational approach for the treatment of patients with ER-positive breast cancer that have failed exhaustive antihormonal treatment. Low-dose estrogen could be used to debulk patients followed by fulvestrant in a low estrogen environment (aromatase treatment) to maintain tumor control.

Apoptosis↗
PubMed2005

New approaches to reverse resistance to hormonal therapy in human breast cancer.

Breast cancer is now the most common malignancy diagnosed in women. Growth factor and estrogen receptors elicit tight regulation of breast tumor progression. Estrogen receptors occur in about two-thirds of breast tumors, and endocrine therapy targeted to these receptors is effective in a large proportion of tumors that express both estrogen and progesterone receptors. However, after an initial period of response to hormonal therapy, such as tamoxifen, most tumors develop resistance leading to disease relapse. Emerging data suggest that previously unsuspected interactions between growth factor and estrogen signaling pathways contribute to growth promotion in breast cancer. Targeting different components of this signaling axis may allow development of more effective and less toxic anti-hormone treatments for breast cancer. In recent clinical studies, anastrozole, letrozole and exemestane, inhibitors of the estrogen synthase, aromatase, have shown advantages over tamoxifen as treatment for advanced disease. Fulvestrant is a new type of estrogen receptor antagonist that down-regulates cellular levels of estrogen receptor and has no agonist activity. Due to its unique mode of action, fulvestrant may be an ideal candidate for combination treatment with inhibitors targeted to growth factor receptor signaling pathways. New understanding of estrogen receptor genes, gene transcripts and variants, post-translational modifications of receptor protein products and interactions with other signaling networks in tumor cells are leading us to unique targeted approaches in the hormonal therapy of breast cancer.

Antineoplastic Agents, Hormonal↗
PubMed2002

Sequencing of endocrine therapies in breast cancer--integration of recent data.

A wide range of endocrine therapies has demonstrated activity in the treatment of hormone receptor-positive metastatic breast cancer and sequential tumor responses to sequential hormonal therapies are common. However, the optimal sequence of the hormonal therapies has not yet been determined. The selection of endocrine therapies in women with hormone receptor-positive breast cancer is strongly influenced by the menopausal status of the patient. For premenopausal women, tamoxifen alone or combined with ovarian suppression using a luteinizing hormone-releasing hormone (LHRH) agonist - such as goserelin or leuprolide - is an appropriate first-line hormonal therapy. Ovarian ablation or megestrol acetate is an appropriate second-line hormonal therapy for premenopausal women treated with tamoxifen as first-line therapy, or ovarian ablation plus an aromatase inhibitor (AI) or megestrol acetate for women treated with first-line tamoxifen plus an LHRH agonist. For postmenopausal women, the non-steroidal AIs anastrozole and letrozole now represent the preferred first-line hormonal treatment for metastatic breast cancer, based upon both efficacy and toxicity considerations. For second-line therapy in postmenopausal women, a number of options now exist, including tamoxifen, the steroidal AI exemestane, and the new agent fulvestrant. Fulvestrant, a novel estrogen receptor (ER) antagonist that downregulates the ER and has no known agonist effects, has been demonstrated to be at least as effective as anastrozole in postmenopausal women whose tumors progress on tamoxifen. The establishment of the optimal sequence of the endocrine therapies should offer significant benefits to women with hormone-sensitive metastatic breast cancer.

Antineoplastic Agents, Hormonal↗
PubMed2004

The Bik BH3-only protein is induced in estrogen-starved and antiestrogen-exposed breast cancer cells and provokes apoptosis.

Evidence has been accumulating that some estrogen-dependent human breast cancers require estrogen for not only proliferation but also survival. To obtain insights into the molecular mechanisms of apoptosis of breast cancer cells subjected to estrogen starvation or exposed to antiestrogens, we characterized changes in the gene expression profile of MCF-7/BUS human breast cancer cells and revealed a strong induction of Bik, a member of the BH3-only proapoptotic proteins. The Bik mRNA transcript and protein were strongly induced by estrogen starvation or exposure to fulvestrant, a pure antiestrogen that competes with the natural estrogens for binding to the estrogen receptors. This Bik induction preceded apoptotic cell death, which was blocked by zVAD-fmk, a pancaspase inhibitor. Amounts of the Bcl-2-related proteins, such as Bcl-2, Bcl-XL, or Bax, showed only marginal changes in the presence or absence of estrogens or antiestrogens. Suppression of Bik expression by using the small interfering RNA effectively blocked the fulvestrant-induced breast cancer cell apoptosis. These results indicate that Bik is induced in MCF-7/BUS cells in the absence of estrogen signaling and plays a critical role in the antiestrogen-provoked breast cancer cell apoptosis.

Apoptosis↗
PubMed2004

Therapeutic strategies using the aromatase inhibitor letrozole and tamoxifen in a breast cancer model.

BACKGROUND: The antiestrogen tamoxifen has potent activity against estrogen receptor-positive breast cancer, but two nonsteroidal aromatase inhibitors, letrozole and anastrozole, show considerable advantages over tamoxifen with respect to patient survival and tolerability. To determine the optimal way to use letrozole and tamoxifen, we studied their effects on a breast tumor xenograft model, MCF-7Ca, that is responsive to both antiestrogens and aromatase inhibitors. METHODS: Female ovariectomized BALB/c athymic nude mice carrying xenograft tumors were treated daily subcutaneously with one of the following first-line therapies for varying durations: no drug (control), tamoxifen (100 microg/day) alone, letrozole (10 microg/day) alone, both drugs at the same time, or alternating 4-week courses of each drug (beginning with a course of tamoxifen or beginning with a course of letrozole). Tumor volumes and weights were estimated using linear mixed-effects models. The time to tumor doubling was calculated, and tumor weights in the treatment groups were compared, with adjustments for multiple comparisons being made with either Tukey's or Dunnett's procedure. Second-line therapies (with tamoxifen, letrozole, or fulvestrant) were initiated when tumors doubled in size under first-line therapies. All statistical tests were two-sided. RESULTS: The times for doubling of tumor volume were as follows: control, 3-4 weeks; tamoxifen alone, 16 weeks; tamoxifen alternating with letrozole, 17-18 weeks; tamoxifen plus letrozole, 18 weeks; letrozole alternating with tamoxifen, 22 weeks; letrozole alone, 34 weeks. First-line treatment with letrozole was superior to treatment with tamoxifen alone or with the two drugs combined (at week 16, both P<.001). Alternating tamoxifen and letrozole and alternating letrozole and tamoxifen were also not as effective as letrozole alone (at week 16, P =.002 and P<.001, respectively). Tumors progressing on tamoxifen remained sensitive to second-line therapy with letrozole compared with those remaining on tamoxifen at the end of treatment (week 28, P<.001), whereas tumors progressing on letrozole were unaffected by second-line treatment with the antiestrogens tamoxifen or fulvestrant. CONCLUSIONS: First-line letrozole therapy extends time for tumor progression in this model relative to the other treatment regimens tested. However, further studies are needed to determine the most effective second-line therapy for tumors that progress on letrozole.

Animals↗
PubMed2005

Identification of a novel, orally bioavailable estrogen receptor downregulator.

Tamoxifen has been widely used for the treatment of estrogen receptor (ER)-positive breast cancer, but its partial agonist activity is considered to limit the efficacy, and cause tumor flare and endometrial cancer. Fulvestrant, on the other hand, binds and degrades ER, thereby acting as a pure anti-estrogen without partial agonist activity. However, due to its low oral bioavailability, fulvestrant has to be intramuscularly administered to patients, which limits the convenience of the drug, and causes pain and inflammation at the site of injection. In search of a patient- friendly pure anti-estrogen, we screened and identified an ER antagonist, CH4893237, which bound to ER with an IC50 value of 1.4 muM and, by oral administration, inhibited estrogen-stimulated uterine growth in ovariectomized mice. CH4893237 reduced the amount of ER at the protein level and impaired the nuclear accumulation of ER, indicating an orally active pure anti-estrogen. Furthermore, CH4893237 inhibited the estrogen-stimulated proliferation of MCF-7, ZR-75-1 and BT-474 cells, and caused a marked growth inhibition of the MCF-7 xenograft in vivo. Thus, CH4893237 will provide an additional option for second-line hormone treatment of breast cancer.

Administration, Oral↗
PubMed2006

Optimal sequence of hormonotherapy in advanced breast cancer.

PURPOSE OF REVIEW: Several active, well tolerated hormonal agents have become available in recent years for the treatment of patients with advanced, hormone receptor-positive breast cancer. When used in an appropriate sequential strategy, hormonal therapies offer the opportunity of prolonging disease control and maintaining quality of life. The widening use of aromatase inhibitors in the adjuvant setting, however, means that traditional sequential cascades must be revised. The review describes the most relevant evidence that can contribute to the optimal positioning of each agent in the sequence. RECENT FINDINGS: Most recent phase II and III trials of hormonal therapy in advanced breast cancer have examined the role of exemestane, letrozole, anastrozole, and fulvestrant in postmenopausal women. SUMMARY: Partial non-cross resistance between nonsteroidal (letrozole and anastrozole) and steroidal (exemestane) aromatase inhibitors may allow treatment with exemestane after a nonsteroidal aromatase inhibitor and vice versa. The estrogen receptor downregulator fulvestrant is also an option after treatment with aromatase inhibitors. The role of the progestin megestrol acetate and, paradoxically, of tamoxifen in the sequential strategy for advanced breast cancer is less well studied.

Antineoplastic Agents↗
PubMed2004

Sequencing of endocrine therapy in postmenopausal women with advanced breast cancer.

The introduction of the nonsteroidal aromatase inhibitor (NS-AI) anastrozole as an alternative to tamoxifen for adjuvant therapy of women with resected hormone receptor-positive breast cancer has added a management category into which patients presenting with metastatic disease can be placed. There are now essentially three such categories: (a) tamoxifen sensitive (no prior AI); (b) tamoxifen resistant (no prior AI); and (c) NS-AI resistant (no prior tamoxifen). Well-conducted Phase III trials provide evidence for choosing first-line therapy for advanced disease in categories a and b. In tamoxifen-sensitive patients, one can choose either NS-AI, anastrozole, or letrozole. In tamoxifen-resistant patients, one can choose either of the NS-AIs, the steroidal AI exemestane, or the estrogen receptor down-regulator fulvestrant. The situation is quite different for patients in category c. There are no Phase III trials of agents in patients who have experienced disease progression on a NS-AI. Phase II data are available for exemestane and high-dose estrogens, and retrospective data are available for tamoxifen and fulvestrant. Additional clinical trials are needed to determine an optimal sequencing strategy.

Androstadienes↗
PubMed2003

Advances in endocrine treatments for postmenopausal women with metastatic and early breast cancer.

For the past 25 years, the estrogen antagonist tamoxifen has been the hormonal treatment of choice for postmenopausal patients with hormone-sensitive metastatic and early breast cancer (EBC). However, tamoxifen is associated with certain tolerability and safety concerns. In addition, the hormonal options after progression are limited, and thus, alternative endocrine treatments have been developed. This review provides a synopsis of the newer alternatives in endocrine therapy of breast cancer: the aromatase inhibitors (AIs) and fulvestrant Faslodex), the estrogen receptor antagonist that downregulates estrogen and progesterone receptors and has no known agonist activity. The third-generation AIs, anastrozole and letrozole, have been shown to be as effective or more effective than megestrol acetate and tamoxifen as second- and first-line therapies for the treatment of postmenopausal patients with metastatic breast cancer, and exemestane has been approved for second-line use. Fulvestrant has been shown to be as effective as anastrozole as second-line therapy for metastatic breast cancer and has been approved in the U.S. for the treatment of postmenopausal women with hormone-receptor-positive metastatic breast cancer following progression on antiestrogen therapy. Anastrozole is the only AI with published clinical trial data and U.S. Food and Drug Administration approval for adjuvant therapy of postmenopausal women with EBC. The 'Arimidex,' Tamoxifen, Alone or in Combination (ATAC) trial, a double-blind, multicenter trial with 9,366 patients, compared tamoxifen with anastrozole, alone and in combination, as adjuvant endocrine treatment for postmenopausal patients with operable, invasive, EBC. The first analysis (at a median follow-up of 33.3 months) showed longer disease-free survival and, in general, better tolerability with anastrozole than with tamoxifen. This pattern was maintained at later analyses with a median follow-up of 47 months for efficacy and 37 months for safety and tolerability. Although longer follow-up is warranted, anastrozole appears to be a well-documented choice of endocrine adjuvant therapy for postmenopausal women with hormone-responsive breast cancer.

Aged↗
PubMed2005

Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer.

Tamoxifen has been the mainstay of hormonal therapy in both early and advanced breast cancer patients for approximately three decades. The availability of novel compounds such as aromatase inhibitors (AIs) and fulvestrant, with different mechanism of action, is changing the scenario of endocrine treatment of postmenopausal breast cancer patients. In this review article, we have summarized the current knowledge of the mechanisms of resistance to endocrine therapy, in order to derive information that might be useful for therapeutic intervention. We propose that resistance to endocrine therapy is a progressive, step-wise phenomenon induced by the selective pressure of hormonal agents, which leads breast cancer cells from an estrogen-dependent, responsive to endocrine manipulation phenotype to a non-responsive phenotype, and eventually to an estrogen-independent phenotype. In particular, evidence suggests for each 'action' introduced to block estrogen stimulation of breast cancer cells (i.e. treatment with anti-estrogen), there are one or more corresponding 'reactions' that tumor cells can use to escape our attempts to block their growth: estrogen hypersensitivity associated with increased transcriptional activity of estrogen receptor alpha (ERalpha) and/or increased non-genomic activity of ERalpha, estrogen supersensitivity, increased growth factor signaling, suppression of ERalpha expression and finally estrogen independence. Activation of growth factor signaling is involved in each step of this phenomenon, and might ultimately substitute estrogen in sustaining the growth and the survival of breast cancer cells. In this respect, results of pre-clinical and clinical studies with AIs, fulvestrant and signaling inhibitors sustain this hypothesis. More importantly, the knowledge of the mechanisms involved in the resistance of breast cancer cells to endocrine therapy offers potential for novel therapeutic strategies.

Antineoplastic Agents, Hormonal↗
PubMed2005

Growth factor signalling and resistance to selective oestrogen receptor modulators and pure anti-oestrogens: the use of anti-growth factor therapies to treat or delay endocrine resistance in breast cancer.

De novo insensitivity and acquired resistance to the selective oestrogen receptor modulator tamoxifen and the pure anti-oestrogen fulvestrant (faslodex) severely limit their effectiveness in breast cancer patients. This is a major clinical problem, since each year upward of 1 million women are dispensed anti-oestrogenic drugs. In order to investigate the phenomenon of anti-oestrogen resistance and to rapidly screen drugs that target the resistance mechanism(s), we have previously established several in vitro breast cancer models that have acquired resistance to anti-hormones. Such cells commonly develop an ability to proliferate after approximately 3 months of exposure to 4-hydroxytamoxifen or fulvestrant, despite an initial endocrine-responsive (i.e. growth-suppressive) phase. The current paper explores the role that growth factor signalling plays in the transition of oestrogen receptor-positive endocrine-responsive breast cancer cells to anti-oestrogen resistance or insensitivity and how we might, in the future, most effectively use anti-growth factor therapies to treat or delay endocrine-resistant states.

Breast Neoplasms↗
PubMed2003

Cancer vaccine THERATOPE- Biomira.

Biomira is developing a therapeutic cancer vaccine [THERATOPE] for treatment of breast and other cancers. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. THERATOPE consists of the mucin antigen, sialyl-Tn (STn), a carbohydrate located on the surface of breast, colorectal and ovarian cancer cells, conjugated to keyhole limpet haemocyanin (KLH). Merck KGaA has acquired a worldwide licence to THERATOPE for treatment of breast cancer. Under the terms of the licence, Biomira and Merck KGaA, via its US affiliate, EMD Pharmaceuticals, will jointly market the vaccine in the US. Merck KGaA holds exclusive marketing rights for the rest of the world, except in Canada (where Biomira retains rights), Israel and the Palestine Autonomy Area. Merck KGaA is now collaborating on phase III development for breast cancer. Biomira stands to receive $US150 million in licence, milestone payments and equity investments. The development costs will be shared between the two companies in North America but Merck KGaA will be solely responsible for these costs in countries outside the US. Previously, Chiron Corporation had purchased a licence to THERATOPE in 1997; however, Chiron terminated this agreement in June 2000. Under the terms of the termination, Biomira paid Chiron $US2.25 million to compensate the company for its investment in the development of THERATOPE. In addition, Biomira will make another payment of $US3.25 million to Chiron upon FDA approval of the vaccine. No further payments or royalties will be made. In the third quarter of 2002, an independent review of interim data from the trial was conducted. This was the fifth scheduled review of the data by the Independent Data Safety Monitoring Board (DSMB), all of which produced a positive response. Following the completion of the review, the DSMB stated that the trial should continue and that it had no safety concerns regarding this trial. Although the data, to which Biomira and Merck KgaA are blinded, did not meet the predetermined statistical significance for either endpoint at the time of the review, both companies have chosen to continue with the trial. Biomira has since announced that the p-value for the interim survival analysis was set at 0.01, while it is set at 0.03 for final survival analysis. The tighter criteria was set for the interim analysis to potentially give the companies the opportunity of applying for marketing approval earlier than expected. Final analysis of the trial will take place in mid-2003. If these analyses indicate therapeutic efficacy, Biomira will meet the FDA and Canadian regulatory officials to obtain marketing approval for the vaccine for breast cancer under the accelerated review guidelines. Assuming a best-case scenario, the vaccine could be filed for approval in 2004. The phase III trial was initiated following positive preliminary results achieved in a bridging study in patients with metastatic breast cancer in the US and UK. Biomira announced final results of the bridging study in May 1999. The results confirmed that antibody titres against the STn antigen were significantly higher in patients treated with the improved formulation of THERATOPE, compared with the corresponding titres of patients in the phase II trials of the old formulation of THERATOPE. In September 2002, the first patient was enrolled in a phase II THERATOPE trial, which is enrolling patients with metastatic breast cancer who are taking either an aromatase inhibitor or fulvestrant. Approximately 95 patients will be enrolled in the trial at up to 12 US sites. The study is primarily designed to evaluate THERATOPE's ability to induce an immune response in these patients. However, the safety and tolerability of the aromatase inhibitor plus THERATOPE, and the fulvestrant plus THERATOPE combinations will also be evaluated. The trial has not been designed to evaluate the efficacy of the two combinations. The US FDA has granted fast-track status tranted fast-track status to THERATOPE for development as an adjunct to first-line combination chemotherapy in responding patients with metastatic breast cancer. A phase II trial in patients with metastatic colorectal cancer has been completed in the US; positive preliminary results from this trial were released in May 2001. On 24 November 1999, Biomira announced that it had licensed two patents covering methods of preventing growth of cancer cells expressing a mucin-type glycoprotein. The patents have been issued in the US and are pending in Japan and Canada. When issued in Japan, the patents will provide additional protection for THERATOPE in that country. The patents were licensed from Dr Sen-itiroh Hakomori of the Biomembrane Institute in Seattle, with whom Biomira has also entered into a research collaboration. Biomira announced in April 2003 that following examination of its re-issue application by the US Patent and Trademark Office, its patent 5798090 was re-issued (RE 38046) with additional claims. These additional claims represent broader patent coverage. The additional coverage will last until 2015. Earlier, in February 2000, Biomira announced an expansion of equity line for up to $US100 million; a 3-fold rise that was done without any additional shares of Biomira stock being issued. In June 2002, Biomira stated that it believes the market size for THERATOPE in the US, Europe and Japan to be approximately 184000 patients for the indication of metastatic breast cancer, of which the US would be 100000, Europe 75000 and Japan 9000. For the indication of colorectal cancer, the total market population for THERATOPE is expected to be 183000 patients, of which the US has been estimated at 100000, Europe 75000 and Japan 9000.

Adjuvants, Immunologic↗