Subsequent Endocrine Research Articles

Abstract 2401: Evaluation of circulating serum Amphiregulin levels in patients with breast cancer.

Abstract Amphiregulin (AREG), a ligand for Epidermal Growth Factor Receptor (EGFR), has been implicated as an effector of ERα signaling in mammary gland development and as a candidate ERα effector in human breast cancers. Analysis of 13 luminal subtype breast cancer cell lines and human breast tumors showed a strong correlation between ERα status and high AREG levels. A pilot study using healthy and breast cancer women's serum showed that circulating AREG levels were higher in the ERα positive patients as compared to healthy individuals. Therefore we hypothesized that Amphiregulin is a potential biomarker and/or therapeutic target for ERα positive breast cancers. To test our hypothesis, we are currently evaluating AREG as a potential serum biomarker of breast cancer progression and as an indicator of response to treatment by analyzing a cohort of breast cancer patients (n=225) stratified by stage of disease and subtypes (hormone receptor status). In this study, we want to determine if tumor-derived AREG is released into the systemic circulation and whether it may be a useful serum biomarker for the presence of breast cancer and for response to therapy. In the first phase, serum Amphiregulin was measured by an ELISA assay to establish the reference range in 125 healthy females. Fifty-five percent of the healthy women had no detectable circulating AREG (n=69), and only ten women had levels exceeding 500 pg/mL. Serum AREG levels did not vary significantly during the menstrual cycle. We determined that the 95th and 90th percentile was >1575 pg/ml and >471 pg/ml, respectively, to use as a comparison against the AREG levels of the breast cancer patients. We are analyzing serum AREG levels in breast cancer patient serum samples of three different cohorts: women with no evidence of disease after more than 1 year post-surgery (Cohort 1), women with locally advanced or stage IV with disease progression (Cohort 2) and women with operable disease that will have surgery and subsequent chemotherapy and/or endocrine therapy (Cohort 3). Each cohort was further stratified by hormone receptor status. In addition to determining the baseline AREG levels, for Cohort 3, AREG levels will be measured post-surgery and at different timepoints during treatment. Interim analysis of the different cohorts showed a significance difference (p<0.05) between healthy individuals and patients with ERα+ breast tumors when comparing detectable versus undetectable AREG levels (threshold of detection: 20 pg/ml). Interestingly, longitudinal sampling of one patient with very high levels (18,300 pg/ml at diagnosis) showed a 37% decline following tumor resection and a 60% decline after 9 months of endocrine therapy. In summary, determining the potential role of AREG as predictive biomarker for therapy and/or as therapeutic target by the completion of this clinical study, will contribute to the quest for better predictive biomarkers in breast cancer and better management of the disease. Citation Format: Esther A. Peterson, Paraic A. Kenny. Evaluation of circulating serum Amphiregulin levels in patients with breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2401. doi:10.1158/1538-7445.AM2013-2401

Abstract P2-10-10: Clinical implications of molecular heterogeneity in highly proliferative, ER-positive, HER2-negative breast cancer

Abstract Objectives: Different clinical behaviors are observed in tamoxifen-treated and untreated ER-positive, HER2-negative highly-proliferative breast cancer (BC) that demonstrate either high (highERS) or low (lowERS) expression of estrogen-related genes (Bianchini SABCS 2011). LowERS tumors are intrinsically endocrine resistant and at significant risk of relapse in the first 5 yrs after diagnosis. We studied lowERS and highERS BC in pts treated with neoadjuvant chemotherapy (NAC) and examined prognostic and predictive markers in the highest risk group of lowERS BC. Methods: We examined affymetrix gene expression data from 193 ER+/HER2−, high proliferation BC from pts treated with taxane-anthracycline-based NAC followed by endrocrine therapy. Previously defined cut-offs for markers of proliferation (MKS), and estrogen-related genes were applied (Bianchini SABCS 2011). Within the lowERS group, we examined pts treated with no systemic adjuvant therapy (n = 137; 50 events); adjuvant tamoxifen-only (n = 141; 36 events); and NAC (n = 127, 27 RCB0/I). We performed gene enrichment analysis for 2617 gene sets with known biological function (by 5000 random permutations). Primary endpoints were distant event free survival (DEFS) with follow-up censored at 5-yrs and pathological response (pathR) using the residual cancer burden (RCB) (Symmans JCO 2007). Results: The median follow-up of the NAC series was 3.1yrs. The DEFS at 4yrs was 0.94 [0.87–1.00] and 0.70 [0.60–0.81] in the high and low ERS groups, respectively (p = 0.004) (despite the higher rate of pathR (RCB0/I) to NAC in the low ERS group (9.5% and 21.9%; p = 0.04)). The pathR was prognostic in the lowERS group [HR 9.1 (CI 1.23–67.4); p = 0.009] but not in highERS (p = 0.485). In contrast, a different outcome was observed in BC with RCBII-III, were the 4-yrs DEFS was 0.93 [0.86–1.00] and 0.61 [0.49–0.76] in high and low ERS group, respectively (p = 0.0007). In the lowERS group there was substantial overlap in biological functions associated with prognosis in both tamoxifen-treated and untreated pts. At a conservative threshold of p < 0.0005, 38 gene sets were significant (31 good-prognosis involved in adaptive immune function, inflammation and chemotaxis and 7 poor prognosis gene sets involved in regulation of nuclear division and cell polarity). Only proliferation-related gene sets were predictive of RCB0/I. MKS as a continuous variable was predictive of pathR beyond clinical variables [OR 5.43 (2.04–16.1); p = 0.001]. Conclusions: Among ER+/HER2−, high proliferation BC the highERS group showed a low pathR rate with excellent prognosis even if there was residual disease. The lowERS group showed a higher rate of pathR which was significantly prognostic for good outcome. Lack of pathR in this group predicted for very poor prognosis despite subsequent adjuvant endocrine treatment. The clinical behaviour and aggressiveness of this subgroup is similar to triple negative tumors. The prognostic relevance of immune function provides a rationale for testing immunotherapeutic strategies in this subgroup. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-10.

Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized ‘FIRST’ study

Fulvestrant fIRst-line Study comparing endocrine Treatments is a phase II, randomized, open-label study comparing fulvestrant 500 mg with anastrozole 1 mg as first-line endocrine therapy for postmenopausal women with hormone receptor-positive (HR+) advanced breast cancer. At data cut-off, only 36 % of patients had progressed and the median time to progression (TTP) had not been reached for fulvestrant. Here, we report follow-up data for TTP for fulvestrant 500 mg versus anastrozole 1 mg. Key inclusion criteria were postmenopausal women with estrogen receptor-positive and/or progesterone receptor-positive locally advanced or metastatic breast cancer and no prior endocrine therapy. Key exclusion criteria were presence of life-threatening metastases and prior treatment with a non-approved drug. Fulvestrant was administered 500 mg/month plus 500 mg on day 14 of month 1; anastrozole was administered 1 mg/day. TTP was defined by modified Response Evaluation Criteria in Solid Tumors v1.0 before data cut-off for the primary analysis, and investigator opinion after data cut-off. Best overall response to subsequent therapy and serious adverse events are also reported. In total, 205 patients received fulvestrant 500 mg (n = 102) or anastrozole (n = 103). Follow-up analysis was performed when 79.5 % of patients had discontinued study treatment. Median TTP was 23.4 months for fulvestrant versus 13.1 months for anastrozole; a 34 % reduction in risk of progression (hazard ratio 0.66; 95 % confidence interval: 0.47, 0.92; P = 0.01). Best overall response to subsequent therapy and clinical benefit rate for subsequent endocrine therapy was similar between the treatment groups. No new safety concerns for fulvestrant 500 mg were documented. These longer-term, follow-up results confirm efficacy benefit for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for HR+ advanced breast cancer in terms of TTP, and, importantly, show similar best overall response rates to subsequent endocrine therapy.

Response to subsequent endocrine therapy in patients treated with fulvestrant 500mg or anastrozole: results from FIRST

Response to subsequent endocrine therapy in patients treated with fulvestrant 500mg or anastrozole: results from FIRST

Abstract P3-14-03: Combining or Sequencing Targeted Therapies in ER+/HER2 Amplified Breast Cancer (BC): In Vitro and In Vivo Studies of Letrozole and Lapatinib in an ER+/HER2+ Aromatase-Transfected BC Model

Abstract Rationale: ER+/HER2+ BC may be resistant to endocrine therapies, but sensitive to HER2 inhibitors such as lapatinib. There is evidence that lapatinib may reactivate ERα expression1,2 raising the possibility that lapatinib may sensitize BC to subsequent endocrine therapy. Whether targeting the ER and HER2 in combination or in sequence in ER+/HER2+ BC may enhance anti-tumour effect is unknown. Aims: (1) To determine in ER+/HER2+ aromatase-expressing breast cancer models in vitro and in vivo.whether the combination of lapatinib with letrozole or tamoxifen is synergistic, and (2) to investigate whether using lapatinib and letrozole in sequence rather than in combination may provide a superior strategy. Methods: ER+/HER2+ BT474 cells were stably transfected with aromatase (BTArom). Combination growth studies, immunoblots and gene expression assays were conducted in BTArom cells. BTArom xenograft studies were performed over 18 weeks under androstenedione support and mice randomized to daily treatment with vehicle, lapatinib, letrozole, or lapatinib and letrozole (L+L). In addition, mice in the lapatinib alone arm, were randomized at 6 weeks to continued lapatinib, vs. switch to letrozole, vs switch to L+L. Results: Formal combination studies in aromatase-transfected BT474 (BTArom) cells demonstrated synergy between lapatinib and letrozole (combination index, CI=0.4, p<10-5), but antagonism between lapatinib and 4-OH-tamoxifen (CI=1.34, p=0.05). In BTArom cells, lapatinib increased ESR1 2.8-fold (P<0.0001) and ERα protein expression 2- fold. As expected, androstenedione upregulated both ER-controlled genes, PGR and GREB1, however lapatinib treatment increased PGR and GREB1 further, by 4.6- and 1.8—fold over androstenedione alone (p=0.0001 and p=0.045, respectively). In long-term BTArom xenografts the combination of lapatinib and letrozole was no more effective at controlling tumour growth than either treatment alone (Kruskall-Wallis comparing treatment arms, P>0.05). However for the group of mice treated with lapatinib for 6 weeks followed by the combination of lapatinib and letrozole for 12 weeks, tumour volume increased only 2.2-fold, compared to 4.5-fold for those continuing on lapatinib, 5.7-fold for those switching to letrozole and 5.2-fold for those on lapatinib and letrozole from the start. Conclusion: We have demonstrated that HER2 targeted therapy enhanced responsiveness to aromatase inhibition in an ER+/HER2+ breast cancer model in vitro and in vivo. In contrast, the interaction between lapatinib and 4-OH-tamoxifen was antagonistic. Lapatinib increased ER expression and function, and the most effective tumour control was achieved with lapatinib alone followed by the combination of lapatinib and letrozole. Maximizing benefit from ER and HER2 targeted therapies in ER+/HER2+ BC may involve sequential rather than concurrent treatment to exploit lapatinib-induced ER reactivation. 1 Leary et al, Clin Canc Res 2010 2Xia et al, PNAS 2006 Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-03.

Rational management of endocrine resistance in breast cancer

Endocrine therapy for breast cancer was introduced more than 100 years ago. In the last 30 years, it has been demonstrated that tamoxifen significantly improves outcomes for patients with hormone-responsive breast tumors. Aromatase inhibitors, which suppress the production of estrogen, are recognized today as an effective alternative for estrogen-receptor-positive breast cancer in postmenopausal women. However, despite an initial response to treatment, many tumors eventually recur or progress. When selecting subsequent endocrine therapy, it is helpful to understand the mechanisms of hormone resistance, consider the goals of treatment, and evaluate the clinical potential of each available drug. The objective of this article was to review the underlying mechanisms of action and resistance for each type of hormone therapy, evaluate the most recent data regarding the use of endocrine agents after disease progression or recurrence, and explore potential combinations of hormone therapies with novel molecules that target key growth factor signaling pathways.

Pathway decision-making strategies for generating pancreatic β-cells: systems biology or hit and miss?

Method selection strategies to achieve beta-cell differentiation from human embryonic stem cells are reviewed. Expectations are high for an embryonic stem cell derived cellular replacement method to cure diabetes, and recent observations indicate that mature beta-cells can be derived from human embryonic stem cells. In terms of the translational setting, however, we are not there yet; conversion of embryonic stem cells to fully mature beta-cells is not effective and does not provide an exclusive beta-cell population as the end-product. Studies emphasize that expecting development of a 'magic media bullet' that promotes endocrine fate is rather optimistic; consecutive administration of signaling inducers, carefully provided to mimic normal development, is more likely to succeed. To accomplish this task we need better understanding of the extracellular signaling pathways that drive progressive endodermal fate choices throughout development. Knowledge of cell-intrinsic control of fate assignments in pancreas is growing rapidly. Nevertheless, insufficient information regarding morphogen codes that operate in endoderm and pancreas is hindering development of better, directed differentiation schema of uncommitted embryonic stem cells toward endodermal, pancreatic, and subsequent endocrine specific fates. A systematic approach to defining morphogen codes in developing endoderm and pancreas appears timely and justified.

Endocrine response after prior treatment with fulvestrant in postmenopausal women with advanced breast cancer: experience from a single centre

The pure anti-oestrogen fulvestrant has now been licensed for use in advanced breast cancer which has progressed on an anti-oestrogen. Optimal sequencing of various endocrine agents becomes very important in the therapeutic strategy. We report our experience of further endocrine response with another endocrine agent after prior fulvestrant treatment. Among all patients with advanced breast cancer who had been entered into five phase II/III trials using fulvestrant as first- to ninth-line endocrine therapy in our Unit since 1993, 54 patients who fulfilled the following criteria were studied for their subsequent endocrine response: (i) oestrogen receptor positive or unknown; (ii) having been on a subsequent endocrine therapy for > or =6 months unless the disease progressed before; and (iii) with disease assessable for response according to International Union Against Cancer criteria. Eleven patients had received an aromatase inhibitor prior to fulvestrant, which resulted in five CBs (clinical benefit = objective remission/stable disease (SD)) for > or =6 months). Twenty-eight patients achieved CB on fulvestrant. They went on subsequent endocrine therapy with two partial responses, 11 SDs and 15 PDs (progressive disease) at 6 months. The median survival from starting fulvestrant and subsequent endocrine therapy was respectively 46.6 and 18.2 months. Among the remaining 26 patients who progressed at 6 months on fulvestrant, there were three SDs and 23 PDs at 6 months on subsequent endocrine therapy. The median survival from starting fulvestrant and subsequent endocrine therapy was respectively 12.5 and 9.3 months. Of all these 54 patients, 30% (n = 16) therefore achieved CB using another (second- to tenth-line) endocrine agent (anastrozole = 26; tamoxifen = 12; megestrol acetate = 11; others = 5). It would thus appear that further endocrine response can be induced in a reasonable proportion of patients after failing fulvestrant.

Sensitivity to further endocrine therapy is retained following progression on first-line fulvestrant

There is a need for new endocrine agents that lack cross-resistance with currently available treatments to extend the endocrine treatment window and delay the need for cytotoxic chemotherapy. This retrospective analysis evaluated the response of postmenopausal patients with previously untreated metastatic/locally advanced breast cancer to further endocrine treatment following progression on first-line fulvestrant or tamoxifen. Patients received fulvestrant 250 mg (intramuscular injection every 28 days) plus matching tamoxifen placebo (once daily), or tamoxifen 20 mg (orally once daily) plus matching fulvestrant placebo (every 28 days) in a double-blind, randomized, phase III trial. Treatment continued until disease progression or withdrawal, when further endocrine therapy was initiated (at the treating physician's discretion). Information regarding subsequent therapies and responses was obtained by follow-up questionnaire. Two-hundred-and-forty-five questionnaires were returned (from 587 patients), 149 of which yielded follow-up data on patients receiving second-line endocrine therapy following fulvestrant (n=83) and tamoxifen (n=66). Second-line therapy produced objective responses (OR) in 6/44 (13.6%) and clinical benefit (CB) in 25/44 (56.8%) patients who had CB with fulvestrant and produced OR in 5/41 (12.2%) patients and CB in 27/41 (65.8%) patients who had CB with first-line tamoxifen. For patients deriving no CB from trial therapy, second-line therapy produced OR in 3/39 (7.7%) and CB in 15/39 (38.5%) patients in the fulvestrant group and OR in 4/25 (16.0%) and CB in 12/25 (48.0%) patients in the tamoxifen group. Results from this questionnaire-based study suggest that postmenopausal women with advanced breast cancer who respond to first-line fulvestrant or tamoxifen retain sensitivity to subsequent endocrine therapy.

Long‐term Follow‐up after Adrenalectomy for Primary Aldosteronism

The objective of this study was to assess the long-term effects of adrenalectomy on the blood pressure and antihypertensive medication in patients with primary aldosteronism (PA). Twenty-four patients (15 female and 9 male) with a mean age of 48.3 +/- 10.8 years underwent surgery for PA in our institution between 1988 and 2001. All subjects were re-examined with a complete clinical work-up after a mean follow-up period of 86 +/- 48 months, including blood pressure readings (<140/90 mmHg defined as normal), endocrine adrenal function, and specific medication. All patients suffered from hypertension (onset 8.5 +/- 5.5 years prior to surgery). In 92% of the patients, hypokalemia was present (onset 2.0 +/- 2.6 years prior to surgery). The histopathologic examinations revealed unilateral adenomas in 23 patients and a bilateral hyperplasia in one patient. At follow-up, 33% (8) of the patients were completely cured (normal blood pressure and no antihypertensive treatment), with seven of these eight patients being under 50 years of age at the time of surgery. One patient revealed a contralateral aldosterone-secreting adrenal adenoma during the subsequent endocrine and imaging examination 44 months after the first operation. Despite normalized plasma-aldosterone concentration (PAC), plasma-renin-activity (PRA) and serum potassium levels, a long-lasting insufficiently treated hypertension due to the delayed diagnosis in patients with PA may explain the persistent blood pressure elevation, indicating the necessity of a life-long, regular control of the blood pressure and antihypertensive medication.

The Prognostic Value of Neuroendocrine Differentiation in Adenocarcinoma of the Prostate in Relation to Progression of Disease After Endocrine Therapy

Purpose We evaluated the prognostic impact of neuroendocrine differentiation in prostate cancer with regard to the onset of endocrine therapy failure. Materials and Methods A retrospective study was performed on 72 transurethral resection specimens from patients who subsequently underwent endocrine therapy for prostate cancer and were followed for 44 to 95 months. Progression-free interval was recorded. Distribution pattern and proportion of neuroendocrine cells were examined in transurethral resection specimens. Neuroendocrine cells were identified based on immunoreactivity for chromogranin A. Results Of 32 patients with progressive disease 27 died of prostate cancer. Chromogranin A positive cells were found in 40 of the 72 prostate cancers (55%). In a Cox proportional hazards analysis neuroendocrine differentiation of the tumor showed a negative correlation with progression-free survival (p = 0.022), which proved to be independent of the Gleason score (p <0.001). Conclusions Our results support the view that neuroendocrine differentiation in prostatic adenocarcinomas is a prognostic factor for progressive disease under subsequent endocrine therapy. This prognosticator acts independently of tumor grade.

Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy.

Up to 30% to 40% of metastases from hormone receptor-positive primary breast cancer do not respond to endocrine therapy. We studied how often hormone receptor status changes between primary and recurrent tumors and whether such a change might explain unresponsiveness to endocrine therapy. Primary breast cancer samples and matched asynchronous recurrences were studied from 50 patients who had not received any adjuvant therapy. Estrogen receptor (ER) and progesterone receptor (PR) status was determined immunohistochemically from histologically representative formalin-fixed paraffin-embedded tumor samples. ER status was ascertained by mRNA in situ hybridization. Thirty-five (70%) of 50 primary tumors were positive for ER and 30 (60%) for PR. Hormone receptor status of the recurrent tumor differed from that of the primary tumor in 18 cases (36%). Discordant cases were due to the loss of ER (n = 6), loss of PR (n = 6), or loss of both receptors (n = 6). Receptor-negative primary tumors were always accompanied by receptor-negative recurrences. Among 27 patients with ER-positive primary tumors, loss of ER was a significant predictor (P = .0085) of poor response to subsequent endocrine therapy. Only one of eight patients (12.5%) with lost ER expression responded to tamoxifen therapy, whereas the response rate was 74% (14 of 19) for patients whose recurrent tumors retained ER expression. Loss of ER expression in recurrent breast cancer should be considered as a cause for poor response to endocrine therapy in primarily ER-positive patients. We conclude that analysis of recurrent tumor samples may improve the predictive value of ER and PR assays.

Primary endocrine therapy for advanced breast cancer: To start with tamoxifen or with medroxyprogesterone acetate?

The availability of compounds effective against metastatic disease and at the same time excellently tolerated even in long-term administration has determined the choice of tamoxifen as primary treatment for palliation in metastatic breast cancer. Other drugs or other hormonal approaches were hardly tested against tamoxifen, especially as first-line treatment. 119 patients with metastatic breast cancer and no prior endocrine therapy were randomized to receive either tamoxifen (TAM) 20 mg/day orally (64 patients), or medroxyprogesterone acetate (MAP) 1g/day i.m. 5 days/week for 4 weeks and then 500 mg twice a week (55 patients). The subsequent endocrine therapy was also prospectively defined at study entry. A total of 111 events, contributing to the endpoint 'time to progression' have so far been observed: a study of similar size would have a 90% power to detect a hazard ratio of 1.85. Initial MAP was associated with a significantly higher remission rate (50% versus 30% for tamoxifen; p = 0.023) and a marginally significantly longer median time to progression (8.8 versus 5.4 months; p = 0.051). Overall survival was also longer for the MAP group (28 versus 20 months; p = 0.384). The use of MAP was associated with a significantly higher toxicity, mainly hypertension, weight gain and tremor. The implications of these results are that initial endocrine therapy in postmenopausal patients with metastatic disease should be MAP if the patient is willing to accept the side effects of high-dose progestins. Progestins should be tested in the adjuvant setting for postmenopausal women, especially those with no tendency to hypertension or obesity.

Effects of the peri-pubertal rearing environment on endocrine and behavioural responses to oestrous female exposure in the mature bull

The objective of this study was to determine the impact of the peri-pubertal rearing environment upon subsequent endocrine and behavioural responses of the bulls to oestrous female exposure. Thirty Angus bulls were allotted to one of three rearing environments at 10–11 months of age: on pasture (male contact only, CON); on pasture with male contact and female contact for 2 h at 28-day intervals (female-exposed treatment, EXP); or penned individually which restricted direct physical contact with other animals (IND). Environmental conditions were maintained for 8 months after which bulls were observed during a single 30-min exposure to an oestrous female with concurrent blood sampling. Significantly elevated serum cortisol concentrations were a result of the female contact period in CON, EXP and IND bulls. Detectable increases in growth hormone were evident during oestrous female exposure in IND bulls ( P<0.01). This observation was absent in CON and EXP bulls. Increased mean testosterone levels were measured subsequent to the period of female exposure in all bulls. Of the behavioural events recorded, only the elapsed time to first mounting was different between environmental rearing groups. The CON bulls were slower to initiate mounting than EXP and IND bulls ( P<0.07). These results suggest that the rearing environment, at or near the time of puberty, can alter subsequent endocrine responses during mating with little or no effect on behavioural parameters during the post-pubertal period of the bull.

Phase I/II study of the anti-oestrogen zindoxifene (D16726) in the treatment of advanced breast cancer. A Cancer Research Campaign Phase I/II Clinical Trials Committee study

We report a phase I/II study of the indole derivative, zindoxifene, an anti-oestrogen with intrinsic oestrogenic activity. We have treated 28 women with advanced breast cancer of whom 26 had received prior endocrine therapy. Oral zindoxifene doses ranged from 10 to 100 mg daily; doses were escalated in some patients. Twenty-five patients were assessed for response; the remaining three patients completed less than 3 weeks of treatment. There were no objective responses; disease stabilised in seven patients for up to 5 months and progressed in the remaining 18. Five patients (including three treated with tamoxifen) responded to subsequent endocrine therapy. Nausea, which was dose-limiting, affected half of the patients treated with 80 mg daily. Metabolites of zindoxifene were detectable in serum at all doses used, and sex hormone binding globulin (SHBG) levels showed a strong tendency to rise at the higher doses, indicating that zindoxifene is absorbed and has biological activity. We conclude that zindoxifene in the doses used in this study has only marginal therapeutic activity in the treatment of advanced breast cancer.

TREATMENT OF DISSEMINATED BREAST CANCER WITH TAMOXIFEN, AMINOGLUTETHIMIDE, HYDROCORTISONE, AND DANAZOL, USED IN COMBINATION OR SEQUENTIALLY

222 patients with disseminated breast cancer have been randomised to receive either a combination of hormone therapies using tamoxifen, aminoglutethimide with hydrocortisone, and danazol (TAD), or tamoxifen alone. The response to the combination was significantly better (43%) than that to tamoxifen alone (31%). Patients who relapsed after response or failed to respond to tamoxifen were subsequently treated with aminoglutethimide and then, if possible, with danazol. Some patients who received TAD were subsequently treated with alternative endocrine therapy, which was usually medroxyprogesterone acetate. Of the 111 patients who initially received tamoxifen, 43 responded to the tamoxifen and/or subsequent endocrine therapy. Of the 111 patients who initially received TAD, 50 responded. Although the duration of response to TAD was the same as for tamoxifen, the TAD patients achieved remission more quickly. The total time in endocrine remission for patients receiving TAD is 303 months to date, compared with 264 months for patients receiving tamoxifen. Survival for patients randomised to receive TAD or tamoxifen is the same.

Endocrine and behavioral changes in depression after Thyrotropin-Releasing Hormone (TRH): Alteration by pretreatment with thyroid hormones

The effects of pretreatment with a single dose of thyroid hormones (TH) on the subsequent endocrine and behavioral response to TRH was evaluated in unipolar depressed women. TH pretreatment altered neither serum levels of thyroid hormones nor the TRH-induced TSH response. It antagonized, however, the behavioral response to THR. This was apparent in 2 self-assessment scales but not in an objective rating scale. Taken together the data suggest that (a) there is an impaired pituitary response to TH feedback in depressed patients; (b) TH pretreatment may effect self-assessment of behavioral effects of TRH in depression.

Estrogen receptor status: an important variable in predicting response to endocrine therapy in metastatic breast cancer

The influence of estrogen receptor status on response rate to endocrine therapy in 85 patients with metastatic breast cancer was determined in a retrospective study. The specific purpose of this study was to assess the role of estrogen receptor determinations in the light of a host of clinical variables known or suspected to influence response rates to endocrine therapy. Thirty-four of 52 patients whose tumors contained significant amounts of estrogen receptor (> 10 fmole/mg cytoplasmic protein) had objective responses to endocrine therapy while only 3 33 patients whose tumors did not possess estrogen receptor (< 10 fmole/mg cytoplasmic protein) responded ( P < 0.0001). A quantitative relationship was found between the amount of estrogen receptor and response rate. The quantity of estrogen receptor was not associated with the duration of response. The predictive value of the estrogen receptor assay was not associated with the receptor dissociation constant. Prior treatment with endocrine or chemotherapy did not diminish the ability of estrogen receptor determinations to predict response to subsequent endocrine therapy. Response rate in estrogen receptor positive tumors was not affected by extent of disease, site of involvement with metastatic tumor, or prior therapy. We conclude that these negative prognostic factors are less important in predicting response to endocrine therapy than estrogen receptor values.

The radiological demonstration of osseous metastases. Experimental observations

The efficiency of conventional radiological methods in detecting osseous destruction has been investigated. Using human lumbar vertebrae, detection of a defect on lateral x-ray was only possible when between 50% and 75% of the cancellous bone thickness had been removed, whilst on A.P. view a greater deficit was necessary. The practical implications of these observations to initial radical therapy of certain cancers and also to subsequent endocrine and chemotherapy is discussed. The need for an alternative more sensitive method for detecting changes in bone structure is obvious. The efficiency of conventional radiological methods in detecting osseous destruction has been investigated. Using human lumbar vertebrae, detection of a defect on lateral x-ray was only possible when between 50% and 75% of the cancellous bone thickness had been removed, whilst on A.P. view a greater deficit was necessary. The practical implications of these observations to initial radical therapy of certain cancers and also to subsequent endocrine and chemotherapy is discussed. The need for an alternative more sensitive method for detecting changes in bone structure is obvious.