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PubMed2005

Resistance to endocrine therapy in breast cancer.

Endocrine therapy is the treatment of choice for patients with breast cancer expressing estrogen receptor (ER) and/or progesterone receptor. The efficacy of endocrine therapy is well established in the prevention, adjuvant and metastatic settings. However, either de novo or acquired resistance is frequently observed. Much effort has been made to elucidate the mechanisms of action underlying resistance to endocrine therapy in breast cancer, and several possible explanations have been suggested. Our previous studies have indicated that combined treatment with an antiestrogen, fulvestrant, and an inhibitor of the HER2 signaling pathway, trastuzumab, or an inhibitor of the HER1 signaling pathway, gefitinib, leads to an additive antitumor effect in breast cancer cells expressing ER and HER2 or HER1, respectively. It has also been suggested that the HER1 or HER2 signaling pathway is upregulated during the development of antiestrogen-resistant growth in breast cancer cells. These findings suggest that signal transduction inhibitors are effective for the treatment of antiestrogen-resistant breast cancer. A hypoxic microenvironment has been shown to promote malignant progression in cancer cells. Our previous study and others have suggested that hypoxia posttranscriptionally reduces ER expression and decreases sensitivity to hormonal agents in breast cancer cells. Our preliminary study has also shown that a hypoxic cytotoxin, tirapazamine, increases ER expression in breast cancer xenografts. Differential antitumor activity of tirapazamine on tumor cells under normoxic or hypoxic conditions may cause this phenomenon. These findings suggest that hypoxic cytotoxins may retard the development of endocrine resistance induced by hypoxia. Molecular mechanisms responsible for endocrine resistance in breast cancer are reviewed and possible therapeutic strategies against this resistance are discussed.

Antineoplastic Agents, Hormonal↗
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↗
PubMed1984

[Internal endocrine therapy of breast cancer].

Additive endocrine therapy of breast cancer was first initiated by androgen treatment through intramuscular administration which proved to be effective in about 25% of trial cases. It was followed by another trial of massive administration of estrogens mainly to patients of more than 60 years of age, and this showed a similar efficacy. Under these circumstances, additive endocrine therapy's position was established as a special therapy for advanced breast cancer. Breast cancer patients have a considerably longer period of progress after disease recurrence than in other types of cancer, so oral androgens were developed for treating recurrent breast cancer patients at home. However, the side effects of androgens (e.g., virilization, hepatic disorders) presented problems with Long-term administration. Since then more androgens with less side effects have been developed which have contributed to the remarkable progress of androgen therapy. On the other hand, recently an anti-estrogen was found which specifically antagonizes estrogen and has few side effects. Additive endocrine therapy's reputation has improved with the emergence of this anti-estrogen agent. Another study has also been started on a progesterone agent which is completely different from conventional sex hormone agents. Anti-estrogen agent is widely accepted for post-operative adjuvant endocrine therapy of breast cancer taking over as the conventional post-operative adjuvant chemotherapy, and also as a partner of chemo-endocrine therapy.

Androstanols↗
PubMed1990

How to improve endocrine therapy of breast cancer.

The characteristics of endocrine therapy have made it a standard therapy in metastatic breast cancer. Principles for endocrine therapy in the advanced situation are discussed. Recent overviews have shown a definite, although limited effect also in the adjuvant situation. Three possible ways for further improvement of endocrine therapy are discussed. Firstly, the relevance of results with endocrine therapy in advanced disease for the adjuvant situation is challenged. It is suggested that the most meaningful parameter to look for in the metastatic situation might still be the response rate. Secondly, the question is raised of more reliable predictors of effect of endocrine therapy. A possible model for testing in a neoadjuvant setting in operable cancers is suggested. Thirdly, selection criteria for drugs used in endocrine treatment are discussed, in relation to proven efficacy and short-term and long-term toxicity. As endocrine therapy in the future will probably be more frequently used in patients with better prognosis, the aspect of long-term toxicity will be of major concern.

Breast Neoplasms↗
PubMed1998

Endocrine therapy in metastatic breast cancer.

Endocrine therapy represents a mainstay of effective, minimally toxic, palliative treatment for metastatic breast cancer. Research focusing on the mechanism of action of endocrine agents will provide new insights leading to new hormonal approaches in breast cancer treatment. Development of new agents, especially the 'pure' antiestrogens, is of great interest. Combining endocrine therapy with biologic agents, especially antiproliferative compounds, may lead to more effective treatment in the adjuvant as well as the advanced setting. Tables 4 and 5 summarize response rates to the different groups of endocrine agents used in metastatic breast cancer and doses of commonly used agents, respectively. At present, tamoxifen is the drug of choice as first-line endocrine therapy for metastatic breast cancer with no or minimal symptoms in premenopausal or postmenopausal women. Second-line therapy usually consists of megace. Aromatase inhibitors may be used as second- or third-line therapy in postmenopausal women. In premenopausal women, LHRH analogues are a reasonable choice. The other hormonal agents may be beneficial as salvage therapy. More effective endocrine approaches are under development.

Adult↗
PubMed2005

[Chemo-endocrine therapy for newly diagnosed stage D2 prostate cancer].

We evaluated 175 patients with newly diagnosed stage D2 prostate cancer who had been treated in our hospital between 1992 and 2003 to compare chemo-endocrine therapy with endocrine therapy alone. One hundred and thirty seven patients were treated with endocrine therapy alone. The other 38 patients received chemo-endocrine therapy, which included medical or surgical castration with/without antiandrogen plus VIP (Vincristine, Ifosfamide, Peplomycin) regimen or other cytotoxic agents. The patients treated with chemo-endocrine therapy had a significantly better prognosis than the patients treated with endocrine therapy alone (p<0.05), although treatment was not randomized. The cause-specific survival rates at 5 years for the chemo-endocrine therapy group and the endocrine therapy group were 61.6% and 34.8%, respectively. These data suggest that chemo-endocrine therapy is a potentially effective treatment for newly diagnosed stage D2 prostate cancer.

Aged↗
PubMed1999

Current Status and Controversial Issues concerning Endocrine Therapy for Patients with Recurrent Breast Cancer in Japan.

BACKGROUND: Four different endocrine therapeutic agents have been used in Japan since 1996. However, a consensus regarding proper use of these agents has notyet been established. Therefore, a questionaire survey of Japanese breast cancer authorities on endocrine therapy and a multi-institute survey to investigate the efficacy of a single first-line endocrine therapy for recurrent breast cancerwere conducted. MATERIALS AND PATIENTS: A total of 279 questionaires were sent to the Councilors of the Japanese Breast Cancer Society. The clinico-pathological data of 77 breast cancer patients who underwent a single first-line endocrine therapy were collected from five institutes. RESULTS: The response rate to this questionaire survey was 67.4%. The resultsshow that many authorities consider that: 1) both ER and PgR in primary tumors should be measured, 2) patient age, the disease-free interval and postoperative adjuvant therapy do not provide enough information for the selection of endocrine therapies, 3) antiestrogen and LH-RH agonists should be used as first-line endocrine therapies, 4) combined endocrine therapies, such as an antiestrogen plus an LH-RH agonist, should be used, 5) the optimal sequence of use of endocrine therapeutic agents is most controversial. The objective response rate to first-line endocrine therapies was 40.3% and the duration of response was over 15 months.The objective response rate to second-line endocrine therapies was 42.1%. A multiple regression analysis of predictive factors for the efficacy of first-line endocrine therapies indicated two factors, the disease-free interval and dominantsite of metastasis, to be significant. Conclusions: This questionaire survey suggests that clinical trials to investigate the optimal sequence of use of endocrine therapies and to clarify the usefulness of combined endocrine therapies should be conducted. Single first- or second-line endocrine therapies for recurrent breast cancer are effective and should be carried out by general clinicians.

Journal Article↗
PubMed2005

Endocrine therapy for prostate cancer.

Endocrine therapy of prostate cancer has mostly been reserved to patients with advanced stages of the disease. The principle for endocrine treatment of prostate cancer is elimination of stimulatory effects of testicular androgens on the prostate tumour cells. This can be achieved by surgical removal of the testes, by inhibition of pituitary gonadotrohin secretion by GnRH-angonsists or antagonists, by oestrogens or by non-steroidal antiandrogens. Since non-steroidal antiandrogens have fewer side-effects than castrational therapies, there is an increased interest for using endocrine treatment as adjuvant therapy after localized treatment. At least in certain stages of the disease, early hormonal treatment may have survival benefits. The timing of endocrine therapy, the usage of combined androgen blockade and intermittent endocrine therapy will be discussed in this overview.

Androgen Antagonists↗
PubMed1998

Adjunctive value of cell proliferation but not of apoptosis to interpret pathologic effects on prostatic cancer after neoadjuvant endocrine therapy.

BACKGROUND: The current histological evaluation of the effects of endocrine therapy has difficulty in distinguishing pathologic degeneration caused by androgen ablation from residual poorly differentiated tumor. Therefore, we examined the changes in cell proliferation and apoptosis before and after endocrine therapy and analyzed whether they correlated with pathologic effects and histological differentiation. METHODS: Between January 1986 and December 1995, 52 patients with clinical stage B2 and C prostate cancer underwent radical prostatectomy after neoadjuvant endocrine therapy (median duration 3.8 months). Proliferative and apoptotic activities of pretreatment biopsy specimens and radical prostatectomy specimens were analyzed with MIB-1 monoclonal antibody and in situ end-labeling of fragmented DNA. RESULTS: The mean proliferative index (PI) of radical prostatectomy specimens was significantly lower than that of biopsy specimens (P = 0.000003) and the decrease in PI after endocrine therapy was significantly related to histological differentiation (P = 0.014). There was a weak relationship between the decrease in PI after endocrine therapy and pathologic effects (P = 0.054), while in pathologically effective cases (Grades 2 and 3), three out of 16 (19%) showed a < 50% decrease in PI after endocrine therapy, and may be regarded as having poorly differentiated tumors. The mean apoptotic index (AI) of prostatectomy specimens tended to be higher than that of biopsy specimens (P = 0.054). The increase in AI after endocrine therapy was not related to histological differentiation and pathologic effects. CONCLUSION: Pathologic effects caused by endocrine therapy may be in part misled by routine histopathologic staining and the change in PI may help in recognizing the pathologic effects of endocrine therapy and have adjunctive value for the interpretation of the effects of endocrine therapy.

Aged↗
PubMed1999

Aromatase inhibitors in relation to other forms of endocrine therapy for breast cancer.

Most endocrine therapies for breast cancer inhibit tumor growth by depriving the cell of estrogen or by blocking its receptor. However, some drugs, such as tamoxifen, can bind to the estrogen receptor (ER) and have both estrogenic and antiestrogenic effects, depending on the tissue, cell, or promoter context. These mixed properties may be explained by new information on ER function at the molecular level. Whether a synthetic drug acts as an estrogen or antiestrogen on a specific gene may be dictated by the particular ensemble of ER subtype, receptor interacting proteins, other transcription factors, or specific elements within the promoter of estrogen-regulated genes. Alterations in these other factors may also play a role in resistance to hormonal therapies. Aromatase inhibitors, like ovarian ablation, inhibit growth by lowering the estrogen concentration in blood or in the tumor tissue itself. Aromatase inhibitors are effective even in postmenopausal women with low estrogen concentrations - probably because of the ability of the tumor to become hypersensitive to estrogen after prolonged estrogen deprivation. Given that the ER itself is the prime target for endocrine manipulation, the ideal endocrine therapy may be one that reduces or eliminates ER from the tumor cell. Pure steroidal antiestrogens are then of great interest because, not only do they inhibit ER-induced transactivation of estrogen regulated genes, they also induce ER degradation. Additional clinical trials are necessary to identify the optimal endocrine therapy and optimal sequence of available therapies.

Antineoplastic Agents↗
PubMed1993

[Determination of tumor marker doubling time in the patients with prostate cancer relapsed from endocrine therapy].

Twenty seven patients with endocrine therapy relapsed prostate cancer were studied by measuring their prostatic acid phosphatase (PAP), prostate specific antigen (PSA), gamma-semino-protein (gamma-Sm) and alkaline phosphatase (ALP) serially before change of the treatment, and tumor marker doubling time was calculated. The exponential increase in PAP, PSA and gamma-Sm was observed in all patients and ALP showed a similar pattern in some. The values of PAP doubling time were the same as those of PSA, but gamma-Sm doubling time was slightly longer than the former ones. Tumor marker doubling time correlated with survival after the increase in markers, and also with time between the start of endocrine therapy and the increase in markers. Patients who showed either NC or PR to chemotherapy had a longer tumor marker doubling time than those with PD. In cases showing progression of bone metastasis, patients with exponential increase in ALP showed worse prognosis when compared with those showing other patterns. From these results, it was demonstrated that determination of tumor marker doubling time in patients with endocrine therapy relapsed prostate cancer was a valuable method to measure rate of regrowth, and to assess the prognosis after relapse.

Acid Phosphatase↗
PubMed1998

Economic evaluation of endocrine therapy in the treatment of breast cancer.

Endocrine therapy has become an integral part of the management of breast cancer and its different clinical applications raise different economic issues. The low toxicity, good response and relatively low cost of agents makes endocrine therapy an attractive treatment option for breast cancer patients at different stages of their disease. The method, hypotheses and expectations from economic analysis of endocrine therapy depend on the objectives of treatment (preventive, curative or palliative), the therapies being compared, the population being treated and the clinical benefits expected. The economic and quality of life literature has focused mainly on the analysis of endocrine therapy in the adjuvant setting. As budgets continue to shrink and treatment guidelines become challenged by new therapeutic and preventive approaches, decision analysis in breast cancer management is likely to become more explicit. Economic analysis can be a useful tool to guide clinical decisions in the management of this complex and chronic disease. Ultimately, the positioning of endocrine therapy with respect to other complementary or alternative treatment modalities will depend on the level of expected effectiveness, and on finding the best therapeutic solution to meet the breast cancer patient's clinical situation, expectations and needs.

Antineoplastic Agents, Hormonal↗
PubMed1995

Chemo-endocrine therapy in patients with stage D2 prostate cancer.

There have only been a few studies of chemo-endocrine therapy compared with endocrine therapy alone in newly diagnosed prostate cancer patients. We assessed the effects of these two therapies by comparing long-term survival rates. One hundred and twenty-nine patients were entered in this study between November 1977 and March 1992. Seventy-seven patients were treated with endocrine therapy alone. Other 52 patients received chemo-endocrine therapy, which included orchiectomy and/or diethylstilbestrol diphosphate (DES-DP) plus Cisplatin, with or without other cytotoxic agents. All patients had bone metastasis at the beginning of the study. There was a significant difference in survival between patients who received endocrine therapy and chemo-endocrine therapy (P = 0.0078). That is, survival rate was superior for the chemoendocrine therapy patients throughout the entire follow-up period. These data suggest that early chemo-endocrine therapy containing Cisplatin, with or without maintenance chemotherapy, is a potentially effective treatment for newly diagnosed metastatic prostate cancer and is worth further investigation via a randomized trial.

Aged↗
PubMed2005

Patients' preferences for adjuvant endocrine therapy in early breast cancer: what makes it worthwhile?

Adjuvant endocrine therapy improves recurrence and survival rates, but has side effects and is inconvenient. The aim of this study was to determine the preferences of premenopausal women who had adjuvant endocrine therapy in a randomised trial. In all, 85 (or eighty-five) women completed semistructured interviews 6-30 months after finishing adjuvant endocrine therapy. Hypothetical scenarios based on known potential survival times (5 or 15 years) and rates (60% or 80% at 5 years) without adjuvant endocrine therapy were used to determine the smallest gains women judged necessary to make their adjuvant endocrine therapy worthwhile. Although a third of the women considered gains of 1% in survival rates or 6 months in survival times sufficient to make their adjuvant endocrine therapy worthwhile, more than half the women required gains of at least 5% in survival rates or 3 years in survival time as necessary to make adjuvant endocrine therapy worthwhile. Larger benefits were required by women who had longer treatment, worse side effects, and by those who were treated with goserelin alone. The route of administration (tablet vs injection) did not affect preferences and some women judged small benefits sufficient to make their adjuvant endocrine therapy worthwhile, but many women required larger benefits than their counterparts in similar studies of preferences for adjuvant chemotherapy.

Adult↗
PubMed1994

A prospective randomized trial for treating stages B2 and C prostate cancer: radical surgery or irradiation with neoadjuvant endocrine therapy.

A randomized clinical trial of neoadjuvant endocrine therapy followed by either surgery or irradiation and a resumption of endocrine therapy for stages B2 and C prostate cancer has been in progress since 1989. A hundred patients entered the trial between 1989 and 1993, and 95 cases were evaluated. Forty-six patients received surgery and 49 were treated with irradiation. Neoadjuvant endocrine therapy for two months resulted in prostate shrinkage and prostate specific antigen lowering. Except for two patients, one dying of a progression of disease and the other of another concurrent cancer, all are alive with an average follow-up term of 25 (range 3-53) months. The good prognostic results obtained from both treatment groups at present seem to be due in part to the neoadjuvant endocrine therapy; but in order to reach a final conclusion further comparisons need to be made.

Aged↗
PubMed1987

Fundamental research leading to improved endocrine therapy for breast cancer.

Whilst endocrine therapy has a long-established role in the management of patients with advanced breast cancer, current therapies produce remission in, at best, only between 30 and 40% of cases. The most efficient use of hormonal measures therefore requires the accurate identification of individuals with hormone-responsive tumours. Oestrogen receptor measurements are useful but not fully discriminatory and additional predictive factors are required. Markers, such as specific hormonally induced proteins and mRNA, and antagonistic systems, such as epidermal growth factor receptors and cyclic AMP binding proteins are currently being evaluated. In terms of therapy, surgical manoeuvres such as adrenalectomy and hypophysectomy have already been replaced by the medical administration of anti-oestrogens, progestogens and drug regimes such as aminoglutethimide-hydrocortisone. Although castration by surgery or radiation remains the first-line treatment in premenopausal women with advanced disease, the advent of depot preparations of LHRH agonists offers the opportunity of performing medical ovariectomies which have the added advantage of being reversible. As a result of laboratory studies, more potent anti-oestrogens and more specific "suicide" aromatase inhibitors are entering into clinical practice. These can be expected to increase efficacy of treatment whilst reducing its side-effects. Research using cell-lines of human breast cancer also suggests that anti-progestins and agents capable of antagonizing steroid-induced growth factors will inhibit tumour growth. Such novel therapies potentially could make a major impact in the endocrine management of breast cancer. Lastly, although the primary management of early breast cancer predominantly involves non-hormonal modalities, clinical trials are now providing evidence of survival benefit from adjuvant endocrine therapy. The knowledge accrued from the use of newer endocrine agents in advanced cancer could therefore ultimately be relevant to the treatment of earlier stages of the disease.

Adrenal Cortex Hormones↗
PubMed2001

[Endocrine therapy for advanced or recurrent breast cancer].

Endocrine therapy of advanced or recurrent breast cancer was described. The presence of ER or PgR in primary breast tumors is the best-established marker for response to endocrine therapy. However, ER-positive breast tumors overexpressing EGF-R and/or HER-2 (Erb B2) are resistant to endocrine therapy. Recently it was suggested that an elevated level of the circulating extracellular domain of HER-2 could be a predictor for poor response to endocrine therapy. LH-RH agonist is used as a first-line therapy for premenopausal patients. And LH-RH agonist plus tamoxifen (TAM) has shown a higher response rate and more prolonged survival than LH-RH agonist or TAM alone. As two new aromatase inhibitors, anastrozole (ANA) and letrozole, have shown an equal or higher response rate and a prolonged time to progression than TAM as a first-line therapy, these could be used as a first-line therapy instead of TAM. In a cross-over trial of ANA and TAM, the response rate of ANA after TAM failure was equal to that of TAM after ANA failure. As these drugs showed an equal or higher response rate and longer survival than progestin in TAM resistant cases, these drugs could also used as a second-line therapy. In addition, the trend of recent studies regarding the mechanisms of hormone resistance is also described.

Antineoplastic Agents, Hormonal↗