Variation of estrogen and progesterone receptor status in breast cancer after tamoxifen therapy

In the present paper we have studied the quantitative variations in estrogen (ER) and progesterone receptor (PR) content of breast cancer induced by tamoxifen. In addition to receptors, hormonal levels of estradiol, progesterone, prolactin, FSH, LH and testosterone were also measured. The cases included in our study were consecutively selected among those breast cancers in which an aliquot of the tissue sample sent for analysis of the steroid receptors was positive for cancer and also found to have at least one of the steroid receptors positive, not only in the biopsy but also in the surgical specimen. Following this criterion, we finally collected 14 cases of breast cancer treated daily with 30 mg of tamoxifen during an interval of 3 weeks from the initial biopsy to the final surgery. From our results we can conclude that tamoxifen reduced significantly the ER concentration while no changes were observed in PR values. Concerning hormones, while in premenopausal patients tamoxifen induced a rise in plasma estradiol, in postmenopausal women the only modification observed was a decrease in plasma FSH. The variation in steroid receptor content under tamoxifen therapy may also contribute to the evaluation of the hormone dependency of gynecologic malignancies.     

Endocrine effects of adjuvant chemotherapy and long-term tamoxifen administration on node-positive patients with breast cancer

Ovarian and pituitary hormones were determined in pre- and postmenopausal breast cancer patients before and at intervals during adjuvant chemotherapy or chemotherapy plus tamoxifen (TAM). Chemotherapy did not affect gonadotrophin levels in postmenopausal patients; however, inclusion of TAM in the regimen produced a partial (approximately 50%) reduction in circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone. Gonadotrophin levels remained reduced as long as TAM therapy continued, at which time they rose to postmenopausal values. Chemotherapy (6-12 months) caused ovarian failure in premenopausal patients with decreases in estrogen (estrone plus estradiol) and rises in gonadotrophin levels to postmenopausal levels. Inclusion of TAM in the regimen caused an initial 3-fold rise in peak circulating estrogen levels before ovarian failure (6-9 months of therapy). Some younger patients (approximately 40 years of age) who had a short course (4 months) of chemotherapy plus TAM followed by continuous TAM therapy alone resumed ovulatory menstrual cycles. Estrogen, progesterone, and follicle-stimulating hormone levels were increased compared with control subjects. Those patients who experienced ovarian failure with adjuvant chemotherapy plus TAM only had a partial rise in gonadotrophins compared with patients receiving chemotherapy alone. TAM maintained the levels of gonadotrophins for as long as therapy was administered, at which time they rose to postmenopausal levels. Although TAM exhibited estrogen-like effects on gonadotrophins there was no estrogen-like increase in circulating prolactin levels in either pre- or postmenopausal patients. One patient experienced an estrogen receptor-positive recurrence during long-term tamoxifen therapy. Serum levels of tamoxifen and metabolites declined in the year prior to the recurrence and this was associated with a rise in gonadotrophins. This indicated noncompliance by the patient. Compliance can be monitored either directly with serum levels of TAM or by serial gonadotrophin determinations. We suggest that the optimal antitumor activity of TAM will be achieved in a low estrogen environment with continuous high levels of the drug in the serum. We recommend that patients undergoing long-term TAM therapy be monitored for complete ovarian failure and drug compliance.     

Molecular effects of genistein on estrogen receptor mediated pathways

Genistein, a component of soy products, may play a role in theprevention of breast and prostate cancer. However, little isknown about the molecular mechanisms involved. In the presentstudy, we examined the effects of genistein on the estrogenreceptor positive human breast cancer cell line MCF-7. We observedthat genistein stimulated estrogen-responsive pS2 mRNA expressionat concentrations as low as 10^–8 M and these effects canbe inhibited by tamoxifen. We also showed that genistein competedwith (³H)estradiol binding to the estrogen receptor with 50%inhibition at 5 x 10^–7 M. Thus, the estrogenic effectof genistein would appear to be a result of an interaction withthe estrogen receptor. The effect of genistein on growth ofMCF-7 cells was also examined. Genistein produceda concentration-dependenteffect on the growth of MCF-7 cells. At lower concentrations(10^–8-10^–6 M) genistein stimulated growth, but athigher concentrations (>10^–5M) genistein inhibitedgrowth. The effects of genistein on growth at lower concentrationsappeared to be via the estrogen receptor pathway, while theeffects at higher concentrations were independent of the estrogenreceptor. We also found that genistein, thoughestrogenic, caninterfere with the effects of estradiol. In addition, prolongedexposure to genistein resulted in a decrease in estrogen receptormRNA level as well as a decreased response to stimulation byestradiol.     

Pituitary-ovarian function in breast cancer patients on adjuvant chemoimmunotherapy.

One hundred thirty-one patients with operable breast cancer were treated with adjuvant chemoimmunotherapy consisting of 5-fluorouracil, adriamycin, cyclophosphamide, and BCG (FAC-BCG). Fifty-five of 131 patients were premenopausal of which 71% (38/55) became amenorrheic. To determine the mechanism of amenorrhea, we measured the immunoreactive serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and plasma estradiol (E2) before and after intravenous administration of luteinizing hormone-releasing hormone (LH-RH) in 11 unselected premenopausal patients who developed amenorrhea and 11 unselected patients who did not. Serum prolactin (PRL) levels were also measured before and after iv administration of thyrotropin-releasing hormone (TRH). Our results showed that patients who developed amenorrhea had abnormally high serum LH and FSH levels at basal and after LH-RH stimulation and low plasma estradiol. Serum PRL levels were normal. Patients who developed amenorrhea were older than those who did not, but their serum LH and FSH levels were also significantly higher and plasma estrogens were significantly lower than that found in 11 normal women with regular menses of the same age range. These results indicate that amenorrhea that develops in some patients with breast cancer after FAC-BCG therapy is a result of primary ovarian failure.     

Caution: Vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors.

BACKGROUND: Aromatase inhibitors (AI) are increasingly used in early breast cancer and there is a growing interest in associated long-term side-effects of profound estrogen suppression. Urogenital side-effects due to atrophic vaginitis are often managed with vaginal estrogen preparations. These are generally perceived to result in minimal systemic absorption of estrogen. We followed serum estradiol, follicle stimulating hormone (FSH) and luteinising hormone (LH) levels in seven postmenopausal women using vaginal estrogen preparations whilst on AIs for breast cancer. PATIENTS AND METHODS: Serum was analysed for estradiol, FSH and LH at baseline then 2, 4, 7-10 and 12 weeks since commencement of vaginal estradiol. Estradiol was measured on an assay specifically developed for measuring low levels in postmenopausal women. RESULTS: Serum estradiol levels rose from baseline levels < or = 5 pmol/l consistent with AI therapy to a mean 72 pmol/l at 2 weeks. By 4 weeks this had decreased to < 35 pmol/l in the majority (median 16 pmol/l) although significant further rises were seen in two women. CONCLUSIONS: The vaginal estradiol tablet Vagifem significantly raises systemic estradiol levels, at least in the short term. This reverses the estradiol suppression achieved by aromatase inhibitors in women with breast cancer and is contraindicated.     

Female sex steroid receptor status in primary and metastatic breast carcinoma and its relationship to serum steroid peptide hormone levels

In order to obtain more information on the interrelationships between cytosol estrogen (ER) and progestin (PR) receptors in breast carcinoma, and their distribution according to age, menopausal status and endocrine parameters of the patients, these receptors were measured in 605 primary and 150 metastatic lesions, and correlated with serum levels of estradiol, progesterone, FSH, LH and prolactin in some of these patients. Measurable estrogen receptor (> 3 fmol/mg cytosol protein) was found in 78.0% and progestin receptor (> 10 fmol/mg cytosol protein) in 60.5% of all the samples studied. The receptors were simultaneously present in 57.2%, estrogen receptor only in 20.8%, progestin receptor only in 3.3%, while both receptors were absent in 18.7% of the whole material. In samples from 253 premenopausal patients, measurable ER was found less frequently (71.1% of cases) and its concentration was lower (39.9 ± 5.1 fmol/mg cytosol protein, mean ± SEM) than in 502 postmenopausal patients (82%; 148.2 ± 11.6 fmol/mg). The frequencies of ER-positive samples and ER concentration were rather similar in primary and metastatic lesions, whereas PR was more often present (64 versus 47%) and its concentrations significantly higher (151.2 ± 12.5 versus 102.6 ± 21.1 fmol/mg) in primary than in metastatic tumors. When present simultaneously, there was a significant correlation between ER and PR concentrations in both primary and metastatic lesions independent of the menopausal status of the patient. ER concentration correlated significantly with age in both pre- and postmenopausal patients, while PR concentration correlated with age only in postmenopausal patients. The group with the highest ER values (above 100 fmol/mg cytosol protein) had a significantly lower serum estradiol concentration that the other patients. Serum estradiol values had a significantly positive correlation with cytosol PR content in the samples with a measurable PR. Serum progesterone, FSH, LH and prolactin did not correlate with tumor ER or PR concentrations. We conclude that concomitant assays of ER and PR from a breast carcinoma specimen provide a correct picture of the endocrine characteristics of the tumor independently of the serum concentrations of estradiol, progesterone, FSH, LH and prolactin.     

Hormonal and receptor status in postmenopausal women with endometrial carcinoma before and after treatment with tamoxifen

Twenty-four patients with endometrial carcinoma received tamoxifen (Nolvadex) for 7 days. Before and after administration, circulating hormones (estradiol, testosterone, progesterone, gonadotropins FSH and LH) were evaluated. Estrogen (ER) and progesterone receptors (PgR) in neoplastic tissue were also assayed. Our results show a net increase in PgR content and a significant decrease in gonadotropin levels after the treatment. The authors suggest that clinical trials be conducted using tamoxifen and progestins for adjuvant therapy after surgery of endometrial carcinoma and for the therapeutic approach of advanced carcinoma.     

Endocrine mechanism of action of toremifene at the level of the central nervous system in advanced breast cancer patients

Purpose: To differentiate the antagonistic and agonistic effect of toremifene at the level of the hypothalamus-hypophysis axis a leutinizing hormone-releasing hormone (LHRH) test was performed during a phase II clinical trial. Methods: In 15 postmenopausal patients with advanced breast cancer, follicle-stimulating hormone (FSH) and LH release – induced by an LHRH agonist (Suprefact injection, 0.5 mg s.c.) – was monitored during a 16-week period of toremifene treatment (60 mg/day p.o.). Prolactin, estradiol, and sex hormone-binding globulin (SHBG) levels were also measured. The functional test was carried out prior to toremifene therapy and then 4, 8, 12, and 16 weeks afterward. Results: The drug sensitized the pituitary to the action of the gonadotrophins; the LHRH-induced FSH and LH release showed a considerably increasing tendency during the toremifene therapy. Estradiol levels decreased statistically significantly and SHBG levels showed a statistically significant increase. A decreased level of prolactin is the sign of an antiestrogenic effect of toremifene on the hypophysis and, as a result, provides evidence for a direct influence of toremifene upon the pituitary. An increase in LH and prolactin release in response to the LHRH test was characteristic in the responders. Conclusion: According to the LHRH test, the antagonistic effect of toremifene seems to be more dominant than the concomitantly existing agonistic property. Neither clinical nor endocrinological side effects could be observed at the level of the CNS during a prolonged period of toremifene administration. Received: 13 July 1997 / Accepted: 17 February 1998     

绝经后乳腺癌雌、孕激素受体状态与血清性激素水平的关系

目的探讨绝经后乳腺癌雌激素受体(ER)、孕激素受体(PR)状态与患者血清性激素水平的关系及意义。方法使用全自动免疫分析仪化学发光分析法检测41例乳腺癌患者血清性激素六项(LH、FSH、PRL、E2、P、T)水平,免疫组化EnVision二步法检测乳腺癌ER、PR表达状态。结果绝经后乳腺癌PR阴性组与PR阳性组比较,患者血清LH、FSH水平显著增高(P值分别为0.005和0.031),PRL、E2、P、T水平在二组间差异无统计学意义;在ER阴性组与ER阳性组之间所测性激素水平差异无统计学意义。结论绝经后乳腺癌PR表达状态可能与垂体激素LH、FSH水平有关。     

Current status of endocrine therapy for breast cancer

Endocrine therapy is usually indicated prior to chemotherapy as the first line therapy for metastatic breast cancer patients because of its milder toxicity. Patients who respond to a first-line endocrine therapy have a high chance of responding to a second-line endocrine therapy, and thus the responders to a first-line endocrine therapy would better be treated with second or third-line endocrine therapy. In the adjuvant setting, tamoxifen (antiestrogen) has been proven to improve the prognosis of both pre- and postmenopausal estrogen receptor positive breast cancer patients, and goserelin (LH-RH agonist) has been proven to improve prognosis in premenopausal women comparable to chemotherapy (CMF). Very recently, preliminary results have indicated that anastrozole (aromatase inhibitor) is superior to tamoxifen as adjuvant treatment for estrogen receptor positive postmenopausal breast cancer patients. In addition, the recent success of tamoxifen in a chemoprevention trial seems to have ushered in a new era wherein prevention of breast cancer is much more emphasized than treatment of established breast cancer.     

Effects of Hypophysectomy on Patients With Advanced Breast Cancer in Relation to Pituitary Hormone Reserve Before and After the Operation

In four patients with advanced breast cancer, the TSH, prolactin,LH and FSH reserve was measured, before and after hypophysectomy,by stimulation with TRH and LH-RH. Two out of the four patientswere objectively improved following the operation. It was foundthat the clinical effects of hypophysectomy did not correlatewith changes in secretion of any of these pituitary hormones.In addition, the complete absence of pituitary hormones afteroperation did not necessarily mean that treatment had been effective. ^*This study was supported by Grants for Cancer Research andfor Specific Diseases from the Ministry of Health and Welfareand by a Grant-in-Aid for Cancer Research from the Ministryof Education, Science and Culture, Japan     

Luteinizing hormone-releasing hormone agonists in premenopausal hormone receptor-positive breast cancer

Ovarian function suppression for the treatment of premenopausal breast cancer was first used in the late 19th century. Traditionally, ovarian function suppression had been accomplished irreversibly via irradiation or surgery, but analogues of the luteinizing hormone-releasing hormone (LH-RH) have emerged as reliable and reversible agents for this purpose, especially the LH-RH agonists. Luteinizing hormone-releasing hormone antagonists are in earlier stages of development in breast cancer and are not currently in clinical use. Luteinizing hormonereleasing hormone agonists act by pituitary desensitization and receptor downregulation, thereby suppressing gonadotrophin release. Limited information is available comparing the efficacies of the depot preparations of various agonists, but pharmacodynamic studies have shown comparable suppressive capabilities on estradiol and luteinizing hormone. At present, only monthly goserelin is Food and Drug Administration-approved for the treatment of estrogen receptor-positive, premenopausal metastatic breast cancer in the United States. Luteinizing hormone-releasing hormone agonists have proven to be as effective as surgical oophorectomy in premenopausal advanced breast cancer. They offer similar outcomes compared with tamoxifen, but the endocrine combination appears to be more effective than LH-RH agonists alone. In the adjuvant setting, LH-RH agonists versus no therapy reduce the annual odds of recurrence and death in women aged>50 years with estrogen receptor-positive tumors. Luteinizing hormone-releasing hormone agonists alone or in combination with tamoxifen have shown disease-free survival rates similar to chemotherapy with CMF (cyclophosphamide/methotrexate/5-fluorouracil). Outcomes of chemotherapy with or without LH-RH agonists are comparable, though a few trials favor the combination in young premenopausal women (aged<40 years). Adjuvant LH-RH agonists with or without tamoxifen might be as efficacious as tamoxifen alone, and the additional benefit from chemotherapy is unclear. Adequately powered studies are now studying the relative merits of combining adjuvant tamoxifen or aromatase inhibitors with ovarian function suppression, the additional benefits of adding ovarian function suppression to chemotherapy, and the need for adjuvant chemotherapy for women treated with combined ovarian function suppression and anti-estrogen therapy.     

Irinotecan HCl, an anticancer topoisomerase I inhibitor, frequently induces ovarian failure in premenopausal and perimenopausal women

The effects of irinotecan HCl (CPT-11) combination chemotherapies on the hypothalamus-pituitary-ovary endocrine system were examined clinically. The incidences of typical menopausal malaises and/or endocrinological findings were investigated in 32 gynecological cancer patients treated by CPT-11 combination chemotherapies. Patients who complained of menopausal malaises or had been treated by hormone replacement therapy before chemotherapy were excluded from the study. Menopausal malaise-like symptoms (MMLS) appeared in 6 of 32 patients (18.8%) during CPT-11 combination chemotherapy, and these symptoms were completely cured within a few days by administration of conjugated estrogen tablets (0.625 mg/day). All the MMLS cases were perimenopausal patients (47-57 years of age), and MMLS were not found in any of the postmenopausal patients who had exceeded 3 years since endocrinological menopause or patients who had recurrent cancer after pelvic radiotherapy. After exclusion of these 3-year-postmenopausal patients and postirradiation patients, 6 of 7 patients aged 45-59 years complained of MMLS during CPT-11 combination chemotherapy. The incidence of CPT-11-induced MMLS showed no relationships with the anticancer drugs combined with CPT-11, mean total CPT-11 dose, mean number of CPT-11 injections, mean individual CPT-11 dose, grade of CPT-11-specific diarrhea or anticancer effects of each CPT-11 combination chemotherapy. The perimenopausal cancer patients with CPT-11-induced MMLS showed decreased serum estradiol and increased serum FSH and LH levels accompanying the CPT-11 injections. A young patient with CPT-11-induced secondary amenorrhea showed decreased serum estradiol and increased serum FSH and LH levels accompanying the CPT-11 injections. None of the postmenopausal patients with high FSH and LH levels showed any significant differences in their serum FSH, LH, PRL and TSH levels during CPT-11 combination chemotherapy. No differences in the results of LHRH and TRH tests during chemotherapy were found for postmenopausal patients. Histopathological examinations of normal ovarian tissues surgically removed from 4 young cervical cancer patients treated with preoperative CPT-11 combination chemotherapies revealed no growing ovarian follicles in the ovarian tissues. CPT-11 injections can induce estrogen-rescued MMLS in cancer patients aged approximately 50 years at a very high rate and may induce secondary amenorrhea in young women. The endocrinological and histopathological studies revealed that CPT-11 causes ovarian follicular loss and ovarian failure within a short time without affecting hypothalamic and pituitary hormone secretion. These clinical results indicate that CPT-11 has strong ovarian toxicity and that repeated CPT-11 administrations may frequently induce ovarian follicular loss and premature ovarian failure, even in young women.     

Hormonal status of patients with uterine cancer during surgical treatment

A radioimmunoassay was conducted in the pituitary-ovary and pituitary-adrenals systems in 37 cases of endometrial carcinoma before treatment and 1, 3, 5 and 14 days after extirpation of the uterus and adnexa. The levels of follicle-stimulating (FSH) and luteinizing (LH) hormones of the pituitary, prolactin, ACTH, estradiol, progesterone, testosterone, cortisol and aldosterone were studied. Such disturbances as decreased production of FSH, LH, progesterone and testosterone were observed before operation. Surgery was followed by a considerable rise in prolactin production and basal levels of FSH and LH, a decrease in estradiol, progesterone and testosterone concentrations and was accompanied by a sizeable release of cortisol and aldosterone.     

Comparative effects of tamoxifen and bromocriptine on prolactin and pituitary weight in estradiol-treated male rats

Male ACI rats were treated with estradiol to induce hyperprolactinemia and pituitary hypertrophy and hyperplasia. Animals received estradiol alone or with tamoxifen or bromocriptine for 4, 8, or 12 weeks. Estradiol treatment resulted in time-dependent increases in pituitary wet weight and serum prolactin concentrations. Tamoxifen completely blocked the increase in both variables; bromocriptine decreased but did not prevent time-dependent increases. Animals were also treated for 8 weeks with estradiol alone, followed by 4 weeks with estradiol and tamoxifen or bromocriptine. Neither compound reversed the hyperprolactinemia, although the pituitary wet weight of animals treated with bromocriptine was slightly but significantly reduced. These findings suggest that in this model if treatment is initiated simultaneously with estrogen stimulation, tamoxifen is more effective than bromocriptine at the doses studied; and, if therapy is initiated subsequent to the establishment of estrogen-induced hyperprolactinemia and pituitary hyperplasia, bromocriptine is more effective than tamoxifen at the doses studied.     

Growth inhibitory effect of LH-RH analogs on human breast cancer cells

The antiproliferative effect of two LH-RH agonists (Pro 9-LH-RH ethylamide and D Ser(t BU)6 Aza Gly 10-LH-RH, ICI 118630) on the human breast cancer cell line CG5 is reported. Although ineffective when used alone, both analogs inhibited in a dose-dependent fashion the growth stimulatory effect of estradiol. LH-RH analogs did not influence the growth inhibitory effect of tamoxifen and medroxyprogesterone acetate. Likewise, these compounds neither modified basal estrogen and progesterone receptor levels nor prevented estrogen-induced increase of progesterone receptor. A marked antiproliferative effect of the analogs was also seen in cells stimulated with other mitogens, such as insulin and epidermal growth factor.     

Estrogenic Effects of Toremifene and Tamoxifen in Postmenopausal Breast Cancer Patients

Intrinsic estrogenicities of the selective estrogen receptor modulators (SERMs) toremifene 60 mg daily or 200 mg daily and tamoxifen 20 mg daily (TOR60, TOR200 and TAM20) were compared in a randomized clinical study in postmenopausal women with advanced breast cancer. The study was open label in three parallel groups. Variables for analysis were serum follicle stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin (SHBG), estradiol (E2), antithrombin III (AT III), aspartate aminotransferase (ASAT) and vaginal cytology. Clinical efficacy and safety have been reported earlier. A total of 648 patients were randomized (221 to TOR60, 212 to TOR200 and 215 to TAM20). Sera were available for the analysis from 148, 165 and 156 and for vaginal cytology from 98, 93 and 86 patients, respectively. All treatment regimens showed tissue-specific and dose-dependent estrogen agonist effect. In the primary measure of in vivo estrogenicity, effect on hypothalamus-pituitary-axis, all three treatment regimens decreased serum FSH (p < 0.001). TOR200 was more potent than the two other treatments (p < 0.05), but surprisingly, TAM20 was more estrogenic than TOR60 (p < 0.001). As could be expected in postmenopausal women, the treatments had no effect on mean serum E2 concentrations and decrease of serum LH was similar to that of FSH. Estrogenic effect on the liver was seen as dose-dependent increase of SHBG with statistically significant differences between the treatment groups (p < 0.001). Trends of transient ASAT elevations in TOR200 group (p = 0.07) and in all treatment groups AT III decrease (p = 0.1) were seen in the beginning of the treatment. TOR60 or TAM20 did not have an effect on mean ASAT values, and AT III decreased in TAM20 group more than in the two other groups (p = 0.1 compared to TOR60 and p < 0.05 compared to TOR200). Estrogenic effects on vaginal superficial cells were higher in TOR60 and TOR200 groups when compared to TAM20 (p < 0.05). Toremifene and tamoxifen had tissue-specific and partially dose-dependent estrogenic effects in hypothalamus-pituitary-axis, in the liver and in the vaginal epithelium of postmenopausal women. In some tissues tamoxifen 20 may be more estrogenic than toremifene 60 mg/day.     

Pharmacological Characterization of 4-hydroxy-N-desmethyl Tamoxifen, a Novel Active Metabolite of Tamoxifen

The antiestrogen tamoxifen is extensively metabolized in patients to form a series of compounds with altered affinity for estrogen receptors (ERs), the primary target of this drug. Furthermore, these metabolites exhibit a range of partial agonist and antagonist activities for ER mediated effects that do not depend directly on their absolute affinity for ERs. Thus, clinical response to tamoxifen therapy is likely to depend on the aggregate effect of these different metabolites resulting from their abundance in the patient, their affinity for the receptors, and their agonist/antagonist profile. A recent study has shown that plasma concentrations of the tamoxifen metabolite 4-hydroxy- N -desmethyl tamoxifen (endoxifen), in patents undergoing tamoxifen therapy, are dependent on the cytochrome p450 (CYP) 206 ge notype of the patient and that medications commonly prescribed to patients on tamoxifen therapy can also inhibit endoxifen production. In this study we characterized the properties of this metabolite with respect to binding to ERs, ability to inhibit estrogen stimulated breast cancer cell proliferation and the regulation of estrogen responsive genes. We demonstrate that endoxifen has essentially equivalent activity to the potent metabolite 4-hydroxy tamoxifen (4-OH-tam) often described as the active metabolite of this drug. Since plasma levels of endoxifen in patients with functional CYP2D6 frequently exceed the levels of 4-OH-tam, it seems likely that endoxifen is at least as important as 4-OH-tam to the overall activity of this drug and suggests that CYP2D6 status and concomitant administration of drugs that inhibit CYP2D6 activity have the potential to affect response to tamoxifen therapy.     

Expression of Estrogen Receptor Alpha and Beta in Breast Cancers of Pre- and Post-menopausal Women

Expression of estrogen receptors (ER) is clinically relevant in designing therapeutic strategies. The relative importance of the two types of estrogen receptors (ER-alpha and ER-beta) in human breast cancers in pre- and post-menopausal women has not been properly defined. To determine the possible association between the expression of estrogen receptor and serum estradiol levels in pre- and post-menopausal women with breast cancer. 44 patients with invasive ductal carcinoma of the breast were studied and a breast tissue biopsy was taken. ER-alpha and ER-beta were detected by immunocytochemistry. Serum levels of estradiol and estrone were measured by radioimmunoassay and FSH was measured using IRMA. We studied 21 pre- and 23 post-menopausal women with breast carcinoma. Examining the number of cases with tumors positive for ER, we found no differences in the frequency of ER-alpha between pre- and post-menopausal women, but ER-beta decreased marginally after menopause (p < 0.051). In cases with tumors positive for ER, the proportion of cells positive for ER-alpha was similar post-menopausally (53.95%) and pre-menopausally (57.21%), but for ER-beta the number of positive cells decreased significantly after menopause (p < 0.051). In pre-menopausal women there was a correlation between serum estradiol levels and ER-beta; in post-menopausal women there was a correlation between serum FSH levels and ER-alpha. These results indicate that estradiol levels in women with mammary carcinoma are related to ER-beta expression in the breast tumor tissue.     

The effects of a low-fat dietary intervention and tamoxifen adjuvant therapy on the serum estrogen and sex hormone-binding globulin concentrations of postmenopausal breast cancer patients

Summary The purpose of the study was to determine the effect of a low-fat dietary intervention, with or without concomitant tamoxifen adjuvant therapy, on serum estrogen and sex hormone-binding globulin (SHBG) levels in postmenopausal patients with resected breast cancer. Ninety-three patients were randomized to either reduce their fat intake to 15–20% of total calories, or to a dietary control group. Serum estradiol, estrone, estrone sulfate, and SHBG concentrations were assayed at baseline, and at 6, 12, and 18 months thereafter. In 19% of patients, the preintervention serum estradiol levels were below the sensitivity of the assay (5 pg/ml). Tamoxifen had no significant effect on serum estrogen levels, but produced an elevation in SHBG. Patients with reliably quantifiable preintervention estradiol concentrations ( 10 pg/ml) showed a significant reduction in serum estradiol after 6 months on the low-fat diet (average, 20%; p < 0.005); this was sustained over the 18 month study period. Serum SHBG levels were increased by tamoxifen therapy, but were reduced significantly (p = 0.01) after 12 months on the low-fat diet in patients not receiving tamoxifen. No changes in serum estrone or estrone sulfate resulted from the dietary intervention. While the low-fat diet produced significant weight loss, patients treated with tamoxifen without dietary intervention showed a gain in body weight. These weight changes produced disruptions in the normal positive correlation between body weight and serum estrone sulfate, and the negative correlation with SHBG concentration.