Alternating tamoxifen and medroxyprogesterone acetate in postmenopausal advanced breast cancer patients — short and long term endocrine effects

Summary The endocrine effects of alternating tamoxifen and medroxyprogesterone acetate have been evaluated in 26 post-menopausal patients with metastatic breast cancer. Endocrine evaluations included the RIA determination of plasma levels of sex-hormone binding globulin, follicle-stimulating hormone, luteinizing hormone, estradiol, prolactin, cortisol, and testosterone. The evaluation of the study parameters at different intervals during therapy indicates that with this schedule an alternate sequential effect on the endocrine system is achievable because each drug exerts its own endocrine activity that is completely reversed when the other drug is administered. We can hypothesize that the same alternate activity as seen on the endocrine system could be obtained also on other tissues and organs including tumors.     

Second and third line hormonotherapy in advanced post-menopausal breast cancer: a multicenter randomized trial comparing medroxyprogesterone acetate with aminoglutethimide in patients who have become resistant to tamoxifen

Summary In order to evaluate the efficacy of two different sequences of second and third line hormonotherapy in advanced post-menopausal breast cancer, 257 women aged 36–91 years (mean age: 63.6 years) who had become resistant to tamoxifen (TAM), entered into a multicenter randomized trial comparing two different regimens: 1) Aminoglutethimide (Ag) 500 mg/day with hydrocortisone supplementation from 30 to 60 mg/day; and 2) oral medroxyprogesterone acetate (MPA) 500 mg twice a day.250 patients were evaluated following second line hormone therapy and, after cross-over, 128 following third line hormonotherapy.No significant difference was observed, during either second or third line therapies, for toxicity, survival, or response rate; however, in both second and third line therapies the median time to progression was significantly longer with Ag therapy.     

Oral high-dose medroxyprogesterone acetate (MAP) in treatment of advanced breast cancer

Summary Medroxyprogesterone acetate (MAP) in the treatment of advanced breast cancer has been regarded as a minor agent according to the previous reports when used at low doses (<500 mg/day). High doses of more than 500 mg which have come into use since 1973 give a response rate of over 40%, but sometimes cause gluteal abcess or induration because of daily intramuscular injections.In order to administer easily and to avoid the side effect, we have attempted to use oral administration in a daily dose of 1200mg (400 mg × 3). Of those 20 patients treated with oral high-dose MAP, 1 showed complete response, 6 showed partial response, 7 no change, and 6 progressive disease. As for site of lesion, 4 out of 6 (67%) in skin and 4 out of 16 (25%) in bone responded. Neither severe side effects nor abnormal laboratory data were seen.Then, we examined the blood levels of MAP in vivo by RIA in 9 patients. The blood level of MAP reached 39–250 ng/ml in 3 days and was maintained at least over 50 ng/ml for 1 or 2 months of continuous administration. Subsequently, we examined the effects of MAP on binding to ER in vitro. The inhibition of binding of estradiol-17 to ER was about 60% at 10^–5 M MAP. The blood level of 50 ng/ml in vivo corresponds to about 1.3 × 10^–5 M. Address for reprints: Dr. Masaru Izuo, Department of Surgery, Gunma University School of Medicine, Maebashi, Japan     

Steroid hormone receptor levels and adjuvant tamoxifen in early breast cancer

Summary Ten year disease-free survival (DFS) results of the Naples randomized trial of adjuvant tamoxifen (TM), 30 mg per day for 2 years versus no therapy according to receptor levels, are reported. From Feb. 1, 1978, through Dec. 31, 1983, 308 pre- and postmenopausal patients with early breast cancer entered the trial. Estrogen receptor (ER) data were available on 239 (77.6%) patients, progesterone receptor (PgR) data on 194 (63.0%), and both receptor data on 181 (58.8%).ER and PgR were assayed by dextran-coated charcoal technique in a single laboratory. The effect of adjuvant TM was significantly related to ER and PgR concentration of the primary tumor. The greatest TM benefit on DFS was evident in patients with the highest levels of receptors. The interaction between the treatment effect and receptor concentration was found whether ER and PgR were considered separately or together. Address for reprints: A. Raffaele Bianco, Division of Medical Oncology, University of Naples Medical School II, via S. Pansini, 5-80131 Naples, Italy     

Adjuvant tamoxifen for pre- and postmenopausal women with estrogen receptor positive,node positive breast cancer: A randomized study

Summary 370 patients with operable, axillary node positive breast cancer, were randomized to receive tamoxifen (TAM) 20 mg/day for 2 years or no adjuvant hormone therapy. All patients had estrogen receptor (ER) positive (ER > 10 pmol/g) primary tumours. 350 patients, 93 younger than 50 years of age and 257 patients 50 years or older, were evaluable for the study. After a median follow up of 76 months, significantly (p = 0.0001) fewer loco-regional, but not distant (systemic), relapses have been recorded in the TAM group. Overall survival was also improved, but even though the study was designed to give maximum benefit from TAM statistically significant effect of TAM seemed to be limited to patients 50 years of age and older.     

Toremifene and tamoxifen in advanced breast cancer - a double-blind cross-over trial

Summary Toremifene (TOR) is a triphenylethylene derivative related to tamoxifen (TAM). TOR has antitumor activity, not dependent on estrogen receptors, and responses with TOR have been observed in patients with progressive disease during TAM-treatment. To elucidate possible cross-resistance between these two antiestrogens, we compared their anti-tumor activity in a randomized, double-blind, cross-over study.66 postmenopausal women with advanced estrogen receptor positive or unknown breast cancer and a median age of 63 years (range 38-82) were included. Patients were randomized to TAM 40mg/day or TOR 240mg/day. Treatment continued until progressive disease, when cross-over to the alternative treatment was done. The response rate with first line TOR was 29% (95% confidence limits 10–41%) and with TAM 42% (95% confidence limits 25–61%). Response rates and response durations, survival and toxicity were not significantly different between the two treatments. 44 patients progressing on first line TAM or TOR were evaluable for second line TOR or TAM treatment. As no responses were observed, the possibility of overlooking a response rate of 20% or more is less than 1%.In conclusion, this study strongly indicates that TOR and TAM are clinically cross-resistant in patients with advanced breast cancer.     

A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer

Efficacy and safety of toremifene 60 and 240mg daily (TOR60 and TOR240) are compared to40 mg tamoxifen daily (TAM40) in postmenopausal womenwith advanced estrogen receptor (ER) positive or ERunknown breast cancer. The study is randomized andopen label in three parallel groups. Primary efficacyvariables are response rate and time to progression.WHO and ECOG criteria were used for measurableand nonmeasurable disease assessment, respectively. Safety was reportedaccording to WHO criteria. Altogether 463 patients wererandomized (157 to TOR60, 157 to TOR240, and149 to TAM40). By data cut-off, after 20.5months median follow-up time, over 70% of thepatients had experienced disease progression. Response rates are20.4%, 28.7%, and 20.8% in TOR60, TOR240, andTAM40, respectively. TOR60 and TAM40 show statistically equivalentefficacy and the difference between TOR240 and TAM40is not significant (P=0.112). Median timesto progression are 4.9 (TOR60), 6.1 (TOR240), and5.0 (TAM40) months and the corresponding hazard ratios(TAM:TOR) 1.015 and 1.124. Again, TOR60 and TAM40are statistically equivalent and the difference between TOR240and TAM40 is not significant (P=0.374).All treatments were well tolerated. As a conclusion,TOR60 and TAM40 show equivalent clinical efficacy andtolerability. The higher dose of toremifene slightly butnot statistically significantly improves response rate and timeto progression. In postmenopausal women, toremifene 60 mgdaily is an effective and safe treatment ofadvanced ER-positive or ER-unknown breast cancer.     

Effects of conjugated estrogens, medroxyprogesterone acetate, and tamoxifen on the mammary glands of macaques

The purpose of this work was to examine the mammary glands of adult, ovariectomized female cynomolgus macaques (Macaca fascicularis) in a long-term study of the effects of hormone treatments on chronic disease. Treatments included conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), CEE+MPA, and tamoxifen. Doses were scaled from those given women. Treatments were given in the diet for three years, followed by necropsy and tissue collection. Endpoints evaluated included glandular histology, histomorphometry, and immunohistochemical detection of the proliferation marker Ki-67, estrogen receptor (ER), and progesterone receptor (PR) in mammary epithelial cells. Major findings were as follows: CEE induced PR expression and focal to diffuse lobuloalveolar proliferation. Proliferation was increased by the addition of MPA, but was not induced by MPA alone. Tamoxifen induced ER and PR but not Ki-67 expression or glandular hyperplasia. Neoplasms were not seen. These findings indicate that progestogens may exacerbate, not antagonize mammary gland proliferation induced by estrogen replacement therapy, and that tamoxifen has both estrogen agonist and antagonist effects on sex steroid receptor expression in the normal primate breast.     

Continuous versus intermittent tamoxifen versus intermittent/alternated tamoxifen and medroxyprogesterone acetate as first line endocrine treatment in advanced breast cancer: an EORTC phase III study (10863)

BackgroundContinuous ligand depletion of endocrine responsive tumours may enhance resistance to therapy. Intermittent treatment with tamoxifen (T) was considered to mimic (incomplete) ligand depletion and reintroduction. Furthermore it was postulated that alternating tamoxifen with a non-cross resistant endocrine modality could (further) postpone hormone resistance.Patients and methodsPostmenopausal patients with advanced breast cancer who did not progress after 4 months of first line T therapy were randomised to continue T (40 mg daily) or to 2 monthly intermittent T or intermittent/alternated T and medroxyprogesterone acetate (MPA, 300 mg daily). At progression during break or during MPA, T should be reintroduced. Endpoints of the study were progression free survival (PFS), time to resistance to tamoxifen and overall survival (OS).ResultsOf 593 registered patients, 276 were randomised. After 8 years follow-up the median PFS for continuous T, intermittent T and intermittent/alternated T and MPA was 11.0 (8.1–15.2), 8.0 (6.2–12.4) and 10.8 (7.1–16.7) months, respectively (NS). Resistance to tamoxifen was established only in 84%, 70% and 55% of patients in the three treatment arms, respectively. The median times from randomisation to resistance to tamoxifen were 12.5 (9.1–21.1), 13.2 (8.8–19.8) and 24.0 (16.9-60.9) months, respectively (p < 0.001), without translation in differences in survival times.ConclusionIntermittent T or intermittent/alternated T and MPA had no impact on PFS or OS as compared with classical continuous T in patients with advanced breast cancer.Intermittent/alternated T and MPA resulted in prolonged time to resistance to T, but this might partly be due to bias by omittance of the proof of tamoxifen resistance in a high proportion of the patients in this treatment arm.     

Oral medroxyprogesterone acetate in the treatment of metastatic breast cancer

Summary Thirty-nine evaluable, postmenopausal patients with metastatic breast carcinoma were treated with medroxyprogesterone acetate administered orally at daily doses of 800 mg/day in 29 patients and 400 mg/day in 10 patients. One patient experienced a complete remission and 16 had partial remissions for an objective remission rate of 44%. There was no apparent difference in response between the two dose levels. Median remission duration was 8 months, and median survival for the whole group is expected to exceed 18 months. Increased appetite (66%) and weight gain (97%) were the most common side effects, followed by fluid retention, muscle cramps, and increased blood pressure. Performance status improved and white blood cell and platelet counts increased in the majority of patients. Medroxyprogesterone acetate is an effective hormonal agent in the treatment of metastatic breast cancer.     

Molecular aspects of estrogen receptor variants in breast cancer

Summary Measurements of the estrogen receptor (ER) and the estrogen-induced progesterone receptor (PgR) are used by most clinicians as indicators of both overall prognosis and likelihood of response to endocrine therapy. Patients with ER+/PgR+ tumors have the highest likelihood of response; conversely, patients with ER-/PgR- tumors have the lowest likelihood of response. Unfortunately, most patients treated successfully with endocrine therapy eventually develop endocrine-resistant disease recurrence. In an effort to study potential mechanisms of endocrine resistance, we have studied discordant ER-/PgR+ tumors, in which the normally estrogen-regulated PgR gene is induced in the apparent absence of ER. Our laboratory has previously cloned, from ER-/PgR+ tumors, a variant ER mRNA precisely missing the sequence corresponding to ER exon 5, and has demonstrated that the truncated protein product translated from this variant RNA is capable of constitutively inducing the expression of an estrogen-responsive reporter gene in a yeast expression vector system (Fuqua et al, Cancer Res 51:105-109, 1991). In the present report we describe further experiments to characterize the activity and biological consequences of expression of this variant ER in human breast cancer cells. We have stably transfected MCF-7 human breast cancer cells with a mammalian expression vector for the exon 5 deletion variant ER. These transfected cells produce a truncated ER protein of the expected 40 kDa size. Cells expressing the exon 5 ER deletion variant constitutively express PgR, and manifest increased anchorage-independent colony formation in the absence of estrogen. Furthermore, the anchorage-dependent growth of these cells was not inhibited by the triphenylethylene antiestrogens tamoxifen or 4-hydroxytamoxifen, unlike MCF-7 cells transfected with a control plasmid, which were growth inhibited by both of these compounds. Interestingly, the pure antiestrogen ICI 164,384 did inhibit the growth of exon 5 ER deletion variant-expressing transfectants. The implications of these results with regard to the treatment of tamoxifen-resistant disease are discussed.     

Cyclic and sequential therapy with tamoxifen and medroxyprogesterone acetate in metastatic breast cancer

A clinical trial of sequential tamoxifen and medroxyprogesterone acetate (MPA) was carried out in 36 women with metastatic breast cancer in order to evaluate the therapeutic efficacy of this regimen and to determine if tamoxifen would increase progesterone receptor (PR) levels and thereby increase response to MPA. Fourteen patients (39%) responded to this treatment, with the duration of remission ranging from 2 to 24 + months (the mean and median were 11 months). In 22 patients, PR levels were measured both before and after 7 days of tamoxifen administration. In PR-positive patients, PR changes induced by tamoxifen did not appear to increase the response rate. In PR-negative patients, PR became positive in 3 patients following tamoxifen treatment, with 2 of 3 responding to treatment, whereas in 11 others whose PR levels remained negative, only one response was observed. Our results suggest that potentiation by tamoxifen was not observed, since in our previous study, MPA alone was equally effective. Thus, tamoxifen and MPA should be given independently for palliation of metastatic breast cancer, and MPA should be administered following therapy with tamoxifen.     

Tamoxifen metabolism is altered by simultaneous administration of medroxyprogesterone acetate in breast cancer patients

Summary We have measured the levels of tamoxifen and three of its metabolites in the blood of patients receiving tamoxifen alone or combination therapy with tamoxifen and medroxyprogesterone acetate. Our results indicate that addition of the progestogen significantly alters the metabolism of tamoxifen over a six-month period. We suggest that the interaction between these drugs may involve additional sites (probably hepatic) besides the desired target tumour.     

High dose toremifene in advanced breast cancer resistant to or relapsed during tamoxifen treatment

Summary Fifty patients with advanced breast cancer refractory to prior tamoxifen therapy were assigned to investigational treatment with high-dose toremifene administered 120 mg orally twice a day. Treatment was generally well tolerated. The majority (80%) of the patients had no side effects, and among the remaining 10 patients reported side effects were mostly mild and/or transient. Two objective tumor responses were observed: one complete response (CR), duration 6.2 months, and one partial response (PR), duration 8 months. The response rate was thus 4% (95% CI: 0.5 to 14%). In addition 3 patients experienced a mixed response, some metastatic sites responding, while at other sites disease progressed; 22 patients had disease stabilization for > 2 months. A subset analysis disclosed that a small subgroup of patients, including 7 patients in this study, who had achieved CR at some of the sites during preceding tamoxifen therapy, experienced a long progressionfree time during high dose toremifene treatment. The median time to progression in this subgroup of patients was 9.4 months (95% CI: 3.8 to 9.4) as opposed to 2.1 months (95% CI: 2.0 to 2.8) for all the remaining 43 patients, which is a significant decrease in disease progression (p < 0.03). Such results reveal that although this kind of second-line hormonal treatment with high dose toremifene cannot be recommended for all tamoxifen failures, there might be a subset of patients, i.e. those who achieve CR in some lesion during tamoxifen therapy, who benefit from this type of treatment.     

他莫昔芬治疗芳香化酶抑制剂耐药的激素受体阳性绝经后转移性乳腺癌患者的临床研究

目的:探讨他莫昔芬治疗芳香化酶抑制剂（AIs）耐药的激素受体阳性（HR+）绝经后转移性乳腺癌（MBC）患者的疗效和安全性。方法:回顾性分析他莫昔芬治疗AIs耐药的30例HR+绝经后MBC患者的临床资料,观察终点为缓解率（RR）、临床获益率（CBR）、疾病进展时间（TTP）和安全性。结果:30例患者中,CR 1例,PR 9例,SD 15例,RR为33.3%,CBR 为50%,中位TTP 6.1个月。23例骨和/或软组织转移患者中,RR为34.8%,CBR为52.2%,中位TTP 7.3个月;7例肝脏和/或肺部转移患者中,RR为28.6%,CBR为42.8%,中位TTP 4.8个月（P=0.019）。不良反应多为面部潮红、阴道干燥、白带增多、阴道出血、恶心、呕吐、腹泻等,均为I、II级。结论:他莫昔芬治疗AIs耐药的HR+绝经后MBC患者安全有效,可改善患者预后。     

Fulvestrant in the treatment of postmenopausal women with advanced breast cancer

Fulvestrant is a new type of estrogen receptor antagonist with no agonist effects, and represents a valuable addition to the range of endocrine treatments available to treat postmenopausal women with advanced breast cancer. Fulvestrant binds, blocks and degrades the estrogen receptor, thereby retarding growth and progression of hormone-sensitive tumors. Two Phase III trials have demonstrated that fulvestrant is at least as effective as the third-generation aromatase inhibitor anastrozole in the treatment of advanced breast cancer following progression on antiestrogen therapy. In addition, a Phase III trial comparing fulvestrant with tamoxifen in postmenopausal women with advanced breast cancer showed similar efficacy and tolerability. Clinical trials are ongoing to evaluate different endocrine sequence options for postmenopausal women with breast cancer, and to evaluate the efficacy of fulvestrant in combination with anticancer agents that target other signaling pathways.     

Adjuvant therapy with high-dose medroxyprogesterone acetate for operable breast cancer

Background  Medroxyprogesterone acetate (MPA) produces a comparable or higher response rate in metastatic breast cancer compared with tamoxifen which is also commonly used for adjuvant endocrine therapy. Several studies in the West have indicated the efficacy of MPA when used as an adjuvant to surgery in certain subsets of patients. The present study was undertaken as a multicenter open study in Japan to investigate the safety and efficacy of MPA in adjuvant endocrine therapy. Method and Patients  A combination of 800 mg/day MPA and a fluorouracil compound for 6 months was given postoperatively tol 19 patients with stage II or Illa breast cancer in 32 participating hospitals between June 1987 and June 1989. Results  Among the 119 patients, 59 patients (49.6%) experienced some kind of adverse reaction. The major adverse reaction was abnormal menstruation, seen in 13 (25.0%) of the 52 premenopausal patients. Vaginal bleeding was a major adverse reaction in the 67 postmenopausal patients (8/67 or 11.9%). An increase in body weight and moon face were observed in 23 (19.3%) and 9 (7.6%) of the 1 19 patients, respectively. Administration of drugs was discontinued because of adverse reaction in 17 patients (14.3%), and dose reduction or temporary suspension was necessary in 7 patients (5.9%). Increase in body weight was the main reason for discontinuation of the treatment. No severe adverse reactions were observed. After a median follow-up of 74.5 months (range, 2.2–90.0 months), 84 of the 119 patients are alive with no evidence of disease. The 3-year and 5-year disease-free survival rates were 88.2% and 82.6% in stage II patients, and 64.7% and 52.9% in stage Illa patients, respectively. The 3-year and 5-year disease-free survival rates according to age were 87.8% and 79.3% in patients aged 50 years or more, and 78.6% and 71.4% in patients aged under 50 years. Conclusion  These results show that 800 mg/day MPA plus a fluorouracil compound can be administered with acceptable morbidity as an adjuvant treatment to selected breast cancer patients.     

The Stockholm trial on adjuvant tamoxifen in early breast cancer

Summary The paper presents interim results of an on-going randomized trial of adjuvant tamoxifen (40 mg daily for 2 years) versus no endocrine adjuvant therapy in postmenopausal women with early breast cancer. A total of 1407 patients were included in the study between November 1976 through June 1984. Estrogen receptor (ER) data were available on 1184 patients (84%). The median follow-up was 53 months. Adjuvant tamoxifen increased the recurrence-free interval (P<0.01) but had no significant effect on overall survival. Treatment failures were reduced by 25% (P<0.01) and deaths by 7% (P>0.05). Tamoxifen mainly decreased the frequency of loco-regional recurrence whereas distant metastases were less affected. The treatment effect was independent of tumor stage but was significantly related to the estrogen receptor (ER) content of the primary tumor. Tamoxifen appeared ineffective among ER negative patients, and the greatest effect was seen among those with high levels of ER. The results indicate that the main mechanism of action of adjuvant tamoxifen is similar to that suggested in advanced disease, i.e. an interaction with the estrogen receptor.     

A combination chemoendocrine therapy of mitoxantrone, doxifluridine, and medroxyprogesterone acetate for anthracycline-resistant advanced breast cancer

Between January 1993 and October 1995, 34 patients with anthracycline-resistant advanced breast cancer were treated with a combination chemoendocrine therapy of mitoxantrone (MIT), doxifluridine (5′-DFUR) and medroxyprogesterone acetate (MPA). Of 34 patients, 28 were evaluable for efficacy of this combination therapy, and 30 including 2 for whom data were incomplete were assessed for adverse drug reactions. Adriamycin (ADM) was used for pretreatment in 12 patients, 4′-epi-ADM in 6, and THP-ADM in 12. In the eligible patients, 8.0 mg/m² MIT was administered intravenously every 4 weeks, and 600 mg MPA and 600 mg 5′-DFUR were given orally every day. The median follow-up period was 25 weeks (range 2–90 weeks). The median cumulative dose of mitoxantrone was 66 mg (range 12–121 mg). Of the 28 patients, 11 (39.3%) responded to this combination therapy. As for response in relation to predominant site of lesion, 1 of 5 soft tissue lesions (20%) and 8 of 12 bone metastases (66.7%) showed a partial response, and one complete response and one partial response (25.0%) were seen in eight lung lesions. None of three pleural lesions responded to this therapy. The median duration of response was 31 ± weeks (range 12–82 weeks). Adverse drug reactions were controllable or tolerable. Combined chemoendocrine therapy with a low dose of MIT is a well-tolerated and moderately effective regimen for the treatment of anthracycline-resistant advanced breast cancer. Received: 20 September 1996 / Accepted: 12 May 1997