Estrogen receptor in primary breast cancer estimated in paraffin-embedded tissue. A study of its usefulness compared to dextran-coated charcoal assay

Estrogen receptor (ER) was estimated immunohistochemically in formalin-fixed and paraffin-embedded tissue from the primary breast cancer in 349 postmenopausal patients with a high risk of recurrence and compared with the results of dextran-coated charcoal assay. There was a highly significant correlation between the ER classification obtained by the two methods (p less than 10(-6)). Patients ER positive according to immunohistochemical estimate had a significantly longer disease-free survival (p less than 0.001) and survival (p less than 0.001) than ER negative patients. The DCC assay showed an advantage of ER positive patients of the same magnitude. The patients, who were followed for a median of 86 months, were a subset of 1,700 patients participating in the Danish Breast Cancer Cooperative Group's randomized trial of adjuvant tamoxifen (TAM) treatment. In the presently analyzed subset of patients there were no statistically significant difference in disease-free survival (p = 0.52) or survival (p = 0.54) between patients who received adjuvant TAM and the controls. The same was true for receptor-defined subgroups regardless if the ER receptor was estimated in paraffin-embedded tissue or by the dextran-coated charcoal method. The analyzed subset might have been too small for demonstrating a positive effect of adjuvant TAM treatment.     

Prognostic significance of progesterone receptor levels in estrogen receptor-positive patients with metastatic breast cancer treated with tamoxifen: results of a prospective Southwest Oncology Group study.

PURPOSE: Southwest Oncology Group (SWOG) protocol 8228 is a prospective trial designed to investigate the prognostic significance of progesterone receptor (PgR) levels in estrogen receptor (ER)-positive breast cancer patients who were treated with tamoxifen. This study was undertaken because the value of PgR measurements in advanced breast cancer had been assessed previously only in studies that were small, retrospective, or included heterogeneously treated patients. METHODS: Receptor assays were performed only in the laboratories that met strict quality control guidelines. Of the 398 patients entered, 342 patients were eligible and assessable for the study end points of objective clinical response, time to treatment failure, and overall survival. RESULTS: Multivariate analysis shows that elevated PgR levels significantly and independently correlated with increased probability of response to tamoxifen, longer time to treatment failure, and longer overall survival. Overall response rate (defined as complete response [CR], partial response [PR], or stable disease [SD] for greater than 6 months) in this trial was 54%. Response rates to tamoxifen were 43%, 53%, and 61% in subsets of patients with less than 10, 10 to 99, and more than 100 fmol/mg PgR, respectively. Exploratory subset analysis using PgR and other prognostic variables identified ER-positive patient subsets with response rates to tamoxifen ranging from 24% (premenopausal patients) to 86% (postmenopausal patients with ER greater than 38 and PgR greater than 329 fmol/mg). No groups of ER-positive patients were identified who had such a low response rate as to absolutely preclude considering the use of tamoxifen. Multivariate analysis showed the independent, statistically significant predictors were: for response to tamoxifen, menopausal status, PgR, and ER; for time to treatment failure, menopausal status, disease-free interval (DFI), PgR, and ER; and for overall survival DFI, PgR, ER, site of disease, and history of adjuvant therapy. CONCLUSION: We conclude that knowledge of PgR levels together with other clinical information can improve the pretreatment assessment of ER-positive breast cancer patients with metastatic disease.     

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.     

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.     

Combination hormonal therapy with tamoxifen plus fluoxymesterone versus tamoxifen alone in postmenopausal women with metastatic breast cancer. An updated analysis

A randomized trial was performed to determine if therapy with tamoxifen (TAM) plus fluoxymesterone (FLU) was more efficacious than TAM alone for postmenopausal women with metastatic breast cancer. Patients failing TAM could subsequently receive FLU. The dose of both drugs was 10 mg orally twice daily. Objective responses were seen in 50 of 119 (42%) TAM patients and 64 of 119 (54%) TAM plus FLU patients (two-sided P = 0.07). Time to disease progression was better for TAM plus FLU (medians: 11.6 versus 6.5 months; Cox model, P = 0.03). Duration of response and survival were similar in the two treatment arms. Among 97 patients with estrogen receptor (ER) of 10 or greater and 65 years of age or older, there were highly significant advantages for treatment with TAM plus FLU in both response rate and time to progression. Of particular note is that in this patient group TAM plus FLU showed a survival advantage (Cox model, P = 0.05). Although these data require confirmation in a prospective randomized trial, they suggest that there is a substantive therapeutic advantage for TAM plus FLU over TAM alone in elderly women with ER of 10 fmol or greater.     

Significance of estrogen and progesterone receptors, disease-free interval, and site of first metastasis on survival of breast cancer patients

Estrogen and progesterone receptors (ER/PR) were measured in primary tumors and metastases of 397 breast cancer patients. Survival following mastectomy was significantly longer in patients with ER and PR positive tumors, as was survival after first recurrence. The prognostic value of ER and PR was compared with such clinical factors as disease-free interval (DFI) and the dominant site of first metastasis by Cox's regression analysis. With all the different therapy modalities long DFI was the best prognostic indicator. However, in the patient group treated with endocrine therapy, ER and PR positivity was the best prognostic indicator, suggesting that longer survival in receptor positive patients was related to the response to endocrine treatment.     

Combined modality therapy for first recurrence of breast cancer. A Southwest Oncology Group study

The Southwest Oncology Group has completed a study of 213 women with the first recurrence of breast cancer. Eligibility included a radical or modified radical mastectomy for cure and recurrence which had received no other form of therapy. Patients were started on tamoxifen (TAM) 20 mg daily (Phase I). Failures, or responders who subsequently failed, had an oophorectomy if the ovaries were intact, and TAM was continued (Phase II). During Phase III, eligible patients underwent an adrenalectomy, and lastly, in Phase IV, patients received chemotherapy. Responses to TAM were seen in 40% of 56 premenopausal patients, 46% of 95 postmenopausal women, and 44% of 62 patients without intact ovaries. Oophorectomy plus TAM gave responses only in premenopausal women who failed to respond on TAM or in postmenopausal patients who had a prior response to TAM. Adrenalectomy was successful in 7 of 21 patients. Chemotherapy resulted in 13% complete and 47% partial responses. Median overall survival was 108, 155, and 115 weeks, respectively, for the three patient groups. The authors believe that until results with chemotherapy improve significantly, hormonal therapy is the preferred first-line management of recurrent breast cancer.     

Phase III Randomized Trial of Toremifene vs Tamoxifen in Hormonodependant Advanced Breast Cancer

Purpose. Efficacy and safety of toremifene (TOR) 60mgs/dayly/o.r. was compared with tamoxifen (TAM) 40mgs/dayly/o.r. in a group of postmenopausal women with advanced breast cancer, without previous systemic therapy for advanced breast cancer. Material and methods. The study was a prospective double-blind randomized trial. All treated patients presented with positive estrogen receptors. Main end points were response rates, toxicity profile analysis, time to progression and survival. WHO and ECOG criteria were employed for response evaluation while toxicity was assesed according to WHO guidelines. Curves were constructed by means of Kaplan–Meier methodology and were compared by means of log-rank test. Results. From January 1996 to January 1999 a total of 217 patients were included in the study (106 in the TOR branch and 111 in the TAM arm). Both groups of patients were homogeneous regarding the main prognostic factors. A response rate of 64% (68/106) was observed in the TOR group as compared with a 52% (58/111) in the TAM group. Median times to progression and overall survival were not significantly different. A lower incidence of undesirable effects was apreciated in the TOR arm. Conclusions. Our data suggest that TOR is an efficient and well-tolerated agent for the therapy of postmenopausal women with hormonal positive receptors advanced breast cancer, and must be considered an alternative to TAM as first line therapy for ER+ advanced breast cancer patients and as well as an adjuvant treatment.     

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.     

Disparities in the survival improvement of recurrent breast cancer

Background

The therapeutic advances in breast cancer have improved the survival of patients with early disease; however, survival improvement of patients with recurrent disease remains ambiguous. In this retrospective study, we examined whether disparities in survival improvement exist in patients with recurrent breast cancer with distant metastasis.

Methods

The survival time of 126 patients who experienced recurrence at distant sites from 1990 through 1996 was compared to that of 195 patients who did from 1997 through 2003.

Results

A significant survival improvement was observed in the patients who experienced recurrence in the period of 1997–2003 in comparison to the other period in the subsets with estrogen receptor (ER)-positive disease, those who received adjuvant hormonal therapy, and those with a disease-free interval (DFI) of 24 months or more. However, no significant survival improvement was observed in each counterpart. The median survival time (MST) from the first relapse of patients with ER-positive disease in the recurrence period of 1997–2003 was 18.8 months longer than that in the recurrence period of 1990–1996 (46.6 months vs. 27.8 months). The MST of patients with a DFI of 24 months or more in 1997–2003 was 20.3 months longer than that in the other time period (47.2 months vs. 26.9 months).

Conclusion

The survival of recurrent breast cancer has improved with disparities. The ER status and the DFI are associated with a survival improvement of women with recurrent breast cancer with distant metastases.     

Chemohormonal therapy for advanced breast cancer with tamoxifen, adriamycin, and cyclophosphamide (TAC)

Combined chemohormonal therapy is an attractive therapeutic strategy for the treatment of Stage IV breast cancer. Between 1977 and 1979, the authors evaluated a new chemohormonal therapy program in 63 evaluable women with advanced breast cancer who previously had not received cytotoxic chemotherapy or tamoxifen. The chemohormonal therapy consisted of 21- to 28-day cycles of tamoxifen (10 mg orally twice daily), Adriamycin (doxorubicin) (40 mg/m2 intravenously on day 1) and cyclophosphamide (200 mg/m2 orally on days 3-6) (TAC). Objective responses were observed in 82% of the patients (22% complete response, 60% partial response). With a median follow-up of 104 weeks (2 years), the median relapse-free survival for the 52 responding patients was 80 weeks. The median survival for the entire group of 63 patients was 118 weeks. Eleven pretreatment patient characteristics were evaluated via univariate and multivariate analysis to determine their effect on response and survival. Prognostic factors with a significant association with longer survivals were as follows: a lack of soft tissue involvement, a lack of pleural involvement, and a long disease-free interval (DFI). Estrogen receptor (ER)-unknown patients, being composed primarily of postmenopausal patients with a long DFI and single-organ involvement (primarily bone), comprised 62% of the patient population and achieved a survival similar to the smaller number of ER-positive patients and was superior to the survival of ER-negative patients. Toxicities were recorded on all patients and overall the treatment was well tolerated. Combined chemohormonal therapy with TAC resulted in a high objective response rate and a long median survival. This study would support additional trials of chemohormonal therapy in patients with ER-positive tumors or in those whose tumors are likely to be ER-positive (e.g., postmenopausal patients with long DFIs).     

Results of two or five years of adjuvant tamoxifen correlated to steroid receptor and S-phase levels

A Swedish cooperative trial demonstrated that 5 years of adjuvant tamoxifen was more beneficial than 2 years of tamoxifen in the treatment of postmenopausal women with estrogen receptor (ER) positive, early stage, invasive breast cancer. The main aim of the present study was to investigate the importance of progesterone receptor (PgR) and ER concentration levels for patients participating in the trial and still distant recurrence free two years after the primary operation. Subgroup analyses revealed that only patients with ER positive and PgR positive breast cancer had improved distant recurrence free survival (DRFS) by prolonged tamoxifen therapy (p=0.0016). Patients with ER negative and PgR negative as well as ER positive and PgR negative tumors showed no significant effect of prolonged tamoxifen (p=0.53 and p=0.80, respectively). The percentage of ER negative and PgR positive breast cancers was too small (2.2%) for any meaningful subgroup analysis. There was a significant positive trend that the concentration level of PgR (high positive vs. low positive vs. negative) decreased the recurrence rate for those with prolonged therapy. No corresponding pattern was found for the ER content. S-phase fraction did not correlate to the recurrence rate of PgR positive breast cancers. Patients recurring during tamoxifen therapy had receptor negative tumors to a greater extent than those recurring after tamoxifen treatment.In conclusion, prolonged tamoxifen therapy for 5 years instead of 2 years was found to be beneficial for patients with ER positive and PgR positive breast cancer, whereas three extra years of tamoxifen had little or no effect for patients with ER positive but PgR negative tumors as well as for steroid receptor negative patients.     

Meta-analysis of trials comparing toremifene with tamoxifen and factors predicting outcome of antiestrogen therapy in postmenopausal women with breast cancer

Meta-analysis of all clinical data was conducted to compare toremifene 40-60 mg/day (TOR) with tamoxifen 20-40 mg/day (TAM) in postmenopausal women with estrogen receptor (ER) positive or ER unknown advanced breast cancer and assess factors predicting treatment outcome. Data from five randomized parallel group studies (all studies) were combined. Efficacy variables were the response rate in all studies and also the time to treatment failure and survival in the three major studies (pivotal studies). Of the 1421 patients, 725 received TOR and 696 TAM. Response rates were 24.0% and 25.3%, respectively (p = 0.675) with 95% confidence interval (95% CI) for the difference -5.3 to 3.4. Of the 1157 patients in the pivotal studies, 75% had progressed and 50% expired. Median treatment times were 4.9 months in TOR and 5.3 months in TAM groups (p = 0.762, hazard ratio 0.98 with 95% CI 0.87-1.11). Median survival times were 31.0 (TOR) and 33.1 (TAM) months (p = 0.758, hazard ratio 0.98 with 95% CI 0.83-1.15). All results are consistent with the criteria of statistical equivalence between TOR and TAM. More patients in TAM (20%) than in TOR (14%, p = 0.007) discontinued the treatment prematurely but overall the treatments were well tolerated. As the treatments were equally effective all data were analyzed together for predictive factors. High tumor ER concentration, long disease free time, soft tissue metastases, few metastatic sites, and good performance status all independently predicted longer survival (p<0.001). Previous adjuvant tamoxifen predicted shorter survival (p = 0.008). Objective response to treatment or disease stabilization for at least 12 months both predicted prolonged survival (p = 0.001). TOR 60 mg/day and TAM are equally effective and well tolerated in the treatment of advanced breast cancer in postmenopausal women. Probability of survival may be predicted based on patient characteristics and on the initial response to the treatment.     

Megestrol acetate versus tamoxifen in advanced breast cancer: 5-year analysis--a phase III trial of the Piedmont Oncology Association

One hundred thirty-eight patients with recurrent or metastatic breast cancer were randomized to receive megestrol acetate 40 mg orally four times daily or tamoxifen 10 mg orally twice a day. Upon treatment failure patients were crossed over to the alternate treatment. Eligibility required that either the estrogen receptor (ER) or progesterone receptor (PR) be positive or that both values be unknown, and that the patients be at least 2 years post-spontaneous menopause or over 50 years of age. Pretreatment characteristics including performance status (PS), disease-free interval (DFI), receptor status, and prior treatment were similar for both groups. Only three patients had previous hormonal therapy while one third had prior chemotherapy. Objective response was determined using strict International Union Against Cancer (UICC) criteria. Seventeen of 61 patients achieved complete response (CR) or partial response (PR) on megestrol (28%) while 20 of 64 patients achieved CR or PR on tamoxifen (31%). Responses of skin and bone lesions were similar for both agents; however, more patients with visceral disease responded to tamoxifen. Response did not correlate with the level of ER or PR but was correlated with age. Both unadjusted and adjusted analysis of time to progression and adjusted analysis (for pretreatment variables) of survival showed significant differences favoring tamoxifen. Six of 44 patients (14%) crossed from megestrol to tamoxifen achieved CR or PR while only two of 38 patients (5%) crossed from tamoxifen to megestrol achieved response. Only one of the original patients randomized to megestrol remains on study, while 12 patients still remain on tamoxifen. These data indicate similar response rates for megestrol and tamoxifen; however, time to progression and overall survival significantly favor tamoxifen when used as first-line therapy in this trial.     

Combined endocrine treatment of elderly postmenopausal patients with metastatic breast cancer; A randomized trial of tamoxifen vs. tamoxifen + aminoglutethimide and hydrocortisone and tamoxifen + fluoxymesterone in women above 65 years of age

The efficacy of combined endocrine therapy with tamoxifen (TAM), aminoglutethimide (AG), and hydrocortisone (H) or tamoxifen and fluoxymesterone (FLU) was evaluated against treatment with tamoxifen alone in 311 patients above 65 years of age with a first recurrence of a metastatic breast cancer. A total of 279 patients were eligible. The response rates were assessed for 258 fully evaluable patients and were the following for the TAM (N=94), the TAM+AG+H (N=83), and the TAM+FLU (N=81) groups, respectively, PR: 14, 18, and 21%, and CR: 20, 11, and 23%. The overall response rates are not statistically different (p=0.30). The 95% CL of difference in response rates for TAM vs. TAM+AG+H are –9–19% and for TAM vs. TAM+FLU –4–25%. Time to treatment failure was comparable with median values of 9.2, 7.7, and 9.2 months in the TAM, TAM+AG+H, and TAM+FLU group, respectively (p=0.17). The corresponding figures for survival are median times of 22.0, 24.1, and 21.1 months with a p-value of 0.62. Toxicity was more pronounced in both the combined treatment groups, and could in most instances be attributed to treatment with either AG+H or FLU. Currently, new specific aromatase inhibitors with lesser toxicity than AG are being evaluated in combination with TAM for treatment of primary and metastatic breast cancer. In conclusion, the simultaneous use of TAM and AG+H or FLU does not seem to improve the therapeutic efficacy in elderly postmenopausal patients with metastatic disease. So far, combined endocrine therapy in this group of patients should only be used in the context of clinical trials.     

Randomized comparison of the effects of tamoxifen, megestrol acetate, or tamoxifen plus megestrol acetate on treatment response and survival in patients with metastatic breast cancer

BACKGROUND:: The antioestrogen tamoxifen and progestins act via differentreceptors and may therefore have complementary effects againsthuman breast cancer. This possibility was tested in a randomizedstudy which compared the effects of tamoxifen, standard-dosemegestrol acetate, and these two agents in combination, in patientswith metastatic breast cancer. PATIENTS AND METHODS:: 184 post-menopausal patients with metastatic breast cancer wererandomized to initial treatment with either tamoxifen (TAM)40 mg daily, megestrol acetate (MA) 160 mgm daily, or the combinationof the two administered simultaneously. Patients crossed overto the alternative single agent on relapse or disease progression.Patients were evaluated for response, time to initial and ultimatetreatment failure, and survival. RESULTS:: There were no significant differences between the three groupswith respect to response rates, nor the other parameters. Patientsurvival was significantly associated with age >60 years,ER positive status, and the absence of visceral metastases. CONCLUSIONS:: TAM and MA are both equally effective in response inductionas initial treatments and the combination has no advantage.Sequential treatment is still optimal, TAM being the preferredinitial agent in view of the reported side effects with MA. breast, cancer, megestrol acetate, randomized, trial, tamoxifen     

Randomised study of anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women

A total of 668 patients (340 anastrozole and 328 tamoxifen) were randomised in a double-blind, double-dummy multicentre study. Anastrozole was given in a dose of 1 mg once daily and compared with tamoxifen 20 mg daily in postmenopausal patients with tumours that were hormone-receptor positive or of unknown receptor status. The efficacy and tolerability of anastrozole was compared with that of tamoxifen as first-line therapy for advanced breast cancer. The median time to progression was similar for both treatments (8.2 months in anastrozole patients and 8.3 months in tamoxifen patients). Anastrozole was also as effective as tamoxifen in terms of objective response-rate with 33% in the anastrozole group and 32.6% in the tamoxifen group achieving a complete or partial response. Both treatments were well tolerated. However, incidences of thromboembolic events and vaginal bleeding were reported in fewer patients treated with anastrozole than with tamoxifen. In conclusion, these findings indicate that anastrozole can be considered as first-line therapy for postmenopausal women with advanced breast cancer.     

A randomized trial of tamoxifen alone or combined with octreotide in the treatment of women with metastatic breast carcinoma

BACKGROUND: Tamoxifen (TAM) is generally considered the hormonal agent of choice for postmenopausal women with hormone receptor positive breast carcinoma. The somatostatin analogues, including octreotide, have demonstrated inhibition of breast carcinoma cell lines and multiple endocrinologic actions, including reduction of insulin-like growth factor I (IGF-I), a potent mitogen for breast carcinoma cells. In an attempt to improve the efficacy of TAM, this randomized trial was performed. METHODS: One hundred thirty-five eligible postmenopausal women with metastatic breast carcinoma were randomized to TAM (10 mg twice daily) alone or combined with octreotide 150 microg (administered subcutaneously thrice daily). The two groups were well balanced, except the TAM group had higher proportions of patients with visceral disease (50% vs. 37%) and a disease free interval longer than 5 years (47% vs. 34%). A cohort of 18 patients was evaluated for the impact of treatment on serum IGF-I, free IGF-I, IGF binding protein 3 levels, and total IGF binding capacity. RESULTS: The median time to progression was estimated to be 14.2 months with TAM and 10.3 months with TAM plus octreotide. The distribution of progression free survival times revealed no significant difference (P = 0.26), and the progression hazard ratio (TAM/TAM + octreotide) was 0.81 (95% confidence interval [CI], 0.56-1.17). The distribution of survival times revealed no significant difference (P = 0.92), and the death hazard ratio was 0.98 (95% CI, 0.62-1.55). When the 106 patients with measurable or evaluable disease were considered, the objective response rate was 49% with TAM alone and 43% with TAM plus octreotide (P = 0.70). Patients who received TAM plus octreotide had higher incidences of nausea, diarrhea, and steatorrhea. The percentage of decline in serum IGF-I, from pretreatment levels to those following 3-6 weeks of treatment, was significantly greater (P < 0.01) with TAM plus octreotide than with TAM alone. CONCLUSIONS: There is no indication that the combination of TAM plus octreotide as administered in this study is substantially more efficacious than TAM alone in the treatment of postmenopausal women with metastatic breast carcinoma. The limited cohort included in IGF-I studies suggests that TAM plus octreotide produces a significantly greater reduction in serum IGF-I levels.     

Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group.

PURPOSE: To analyze overall survival (OS) and update efficacy data for letrozole versus tamoxifen as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer. PATIENTS AND METHODS: This multicenter phase III trial randomly assigned 916 patients with hormone receptor-positive or unknown tumors letrozole 2.5 mg (n = 458) or tamoxifen 20 mg (n = 458) daily until disease progression. Optional cross-over was permitted at the treating physician's discretion. This report updates efficacy at a median follow-up of 32 months. RESULTS: The superiority of letrozole to tamoxifen was confirmed for time to progression (median, 9.4 v 6.0 months, respectively; P <.0001), time to treatment failure (median, 9 v 5.7 months, respectively; P <.0001), overall objective response rate (32% v 21%, respectively; P =.0002), and overall clinical benefit. Median OS was slightly prolonged for the randomized letrozole arm (34 v 30 months, respectively). Although this difference in OS is not significant, survival was improved in the randomized letrozole arm over the first 2 years of the study. Approximately one half of the patients in each arm crossed over. Total duration of endocrine therapy ("time to chemotherapy") was significantly longer (P =.005) for patients initially on letrozole (median, 16 months) than for patients initially on tamoxifen (median, 9 months). Time to worsening of Karnofsky performance score was significantly delayed with letrozole compared with tamoxifen (P =.001). CONCLUSION: This study documents the superiority of letrozole over tamoxifen in first-line endocrine therapy in postmenopausal women with advanced breast cancer.     

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.