An exploratory analysis of alkaline phosphatase, lactate dehydrogenase, and prostate-specific antigen dynamics in the phase 3 ALSYMPCA trial with radium-223.

Background: Baseline clinical variables are prognostic for overall survival (OS) in patients with castration-resistant prostate cancer (CRPC). Their prognostic and predictive value with agents targeting bone metastases, such as radium-223, is not established. Patients and methods: The radium-223 ALSYMPCA trial enrolled patients with CRPC and symptomatic bone metastases. Prognostic potential of baseline variables was assessed using Cox models. Percentage changes in biomarker levels from baseline were evaluated during the trial period; changes from baseline to week 12 were evaluated for association with OS and surrogacy. Results: Eastern Cooperative Oncology Group performance status, total alkaline phosphatase (tALP), lactate dehydrogenase (LDH), and prostate-specific antigen (PSA) at baseline were associated with OS (P ≤ 0.0003) in the intent-to-treat population (radium-223, N = 614; placebo, N = 307). tALP declined from baseline within 4 weeks after beginning radium-223, by week 12 declining in 87% of radium-223 and 23% of placebo patients (P < 0.001). LDH declined in 51% and 34% (P = 0.003), whereas PSA declined in 27% and 14% (P = 0.160). Mean tALP change from baseline was 32.2% decrease with radium-223 and 37.2% increase with placebo. Radium-223 patients with tALP decline from baseline to week 12 (confirmed ≥3 weeks from week 12) had 55% lower risk of death (hazard ratio = 0.45; 95% CI 0.34-0.61) versus those with no confirmed tALP decline. Proportional treatment effect (PTE) values for tALP, LDH, and PSA changes from baseline at week 12 as OS surrogate markers were 0.34 (95% CI: 0-0.746), 0.07 (95% CI: 0-0.211), and 0 (95% CI: 0-0.082), respectively. Conclusions: Significant tALP declines (versus placebo) occurred as early as 4 weeks after beginning radium-223 therapy. tALP or LDH declines at 12 weeks correlated with longer OS, but did not meet statistical surrogacy requirements. Dynamic changes in tALP and LDH during radium-223 treatments may be useful to monitor, but do not serve as surrogates for survival.

Alpha emitter radium-223 and survival in metastatic prostate cancer.

BACKGROUND: Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. METHODS: In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. RESULTS: At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. CONCLUSIONS: In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).

Effects of tamoxifen and octreotide LAR on the IGF-system compared with tamoxifen monotherapy.

The insulin-like growth factor (IGF)-system was evaluated in 150 breast cancer patients participating in a randomised phase III trial comparing octreotide pamoate and tamoxifen with tamoxifen+placebo. Alterations in the IGF-system in the two treatment arms and individual changes with respect to outcome were compared. Serum IGF-I and -II, free IGF-I, and insulin-like growth factor binding protein 1-3 (IGFBP1-3) were measured by radioimmmunoassay (RIA)/immunoradiometric assay (IRMA) and IGFBPs by Western ligand blots (WLB) before and during treatment. Combined treatment caused a higher increase in IGFBP-1 and larger suppression of total and free IGF-I, IGF-II, and IGFBP-3 (P<0.01 for all), but less suppression of IGFBP-2 (P<0.05) compared with tamoxifen monotherapy. An increase in IGFBP-2 25% was associated with decreased progression-free survival (PFS) in the total patient population and combined treatment group. Similar response rates and time to progression in the treatment arms suggests moderate suppression of circulating IGF-I has no influence on clinical outcome.

Plasma insulin-like growth factor binding protein-3 proteolysis is increased in primary breast cancer.

Fasting blood samples were obtained before definitive surgery or biopsy in 128 patients referred to the department of surgery with suspected or manifest breast cancer. Insulin-like growth factor (IGF)-I, IGF-II and free IGF-I were measured by radioimmunoassay/immunoradiometric assay, while IGFBP-3 proteolysis was evaluated by Western immunoblot. 12 patients had ductal carcinoma in situ benign conditions, while staging revealed metastatic disease in 15 of 16 patients with invasive cancers. IGFBP-3 proteolysis above the normal range was recorded in 19 patients with invasive cancers, but in none of the patients suffering from DCIS/benign conditions. Increased IGFBP-3 proteolysis was most frequently recorded in patients harbouring large tumours and metastatic disease (Stage I: 0/19, 0%; Stage II: 3/45, 7%, Stage III: 9/37, 24%, and Stage IV: 7/15, 47%). IGFBP-3 proteolysis was significantly higher in Stage III (P =0.01) and IV (P< 0.001) patients compared to the other stage groups (P = 0.001). IGF-I and IGF-II correlated negatively to IGFBP-3 proteolysis and age. Plasma levels of IGF-I and -II were significantly lower in patients with elevated IGFBP-3 proteolysis compared to those within the normal range. Our findings reveal alterations in the IGF-system among a substantial number of patients with large primary breast cancers.

Alterations in the insulin-like growth factor system during treatment with diethylstilboestrol in patients with metastatic breast cancer.

Alterations in the insulin-like growth factor (IGF)-system were evaluated in 16 patients treated with diethylstilboestrol 5 mg 3 times daily. Fasting blood samples were obtained before treatment and after 2 weeks, 1 month and/or 2-3 months on therapy. Insulin-like growth factor (IGF)-I, IGF-II, free IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-2 and IGFBP-3 were measured by radioimmuno-/immunoradiometric-assays. All samples were subjected to Western ligand blotting as well as immunoblotting for IGFBP-3. We observed a significant decrease (percentage of pretreatment levels with 95 confidence intervals of the mean) in IGF-I [2 weeks 63% (49-79); 1 month 56% (44-73); 2-3 months 66% (53-82)], IGF-II [2 weeks 67% (56-80); 1 month 60% (52-68); 2-3 months 64% (55-75)], free IGF-I [2 weeks 29% (19-42); 1 month 25% (18-36); 2-3 months 31% (21-46)], IGFBP-2 [2 weeks 53% (18-156); 1 month 69% (61-78); 2-3 months 66% (57-78)], IGFBP-3 [2 weeks 74% (63-85); 1 month 69% (62-76); 2-3 months 71% (63-80)], as well as IGFBP-3 protease activity [2 weeks 71% (54-95); 1 month 78% (64-94); 2-3 months 71% (54-93)]. Contrary, the plasma levels (percentage of pretreatment levels with 95 confidence intervals of the mean) of IGFBP-1 [2 weeks 250% (127-495); 1 month 173% (138-542); 2-3 months 273% (146-510)] and IGFBP-4 [2 weeks 146% (112-192); 1 month 140% (116-169); 2-3 months 150% (114-198)] increased significantly. While this study confirms previous observations during treatment with oral oestrogens in substitution doses, the reduction in plasma IGF-II, free IGF-I, IGFBP-2 and -3 are all novel findings. A profound decrease in free IGF-I suggests a reduced bioavailability of IGFs from plasma to the tissues. These observations may be of significance to understand the mechanisms of the antitumour effect of diethylstilboestrol in pharmacological doses.

The insulin-like growth factor system in human immunodeficiency virus infection: relations to immunological parameters, disease progression, and antiretroviral therapy.

Endocrine dysfunctions have previously been reported in human immunodeficiency virus (HIV) infection. In this study we evaluated the relation of immunological parameters, virus load, clinical stage, and wasting to several parameters of the insulin-like growth factor (IGF) system in 76 patients with HIV infection, of whom 37 had developed acquired immune deficiency syndrome (AIDS). A subgroup of 26 untreated patients was followed during longitudinal testing, while the effects of antiretroviral therapy were evaluated in 34 patients (nucleoside analogs in 9, nucleoside analogs in combination with protease inhibitors in 25). Twenty healthy sex- and age-matched controls were analyzed for comparison. IGF-II was decreased (P = 0.03) and IGF-binding protein-2 (IGFBP-2) and IGFBP-3 protease activity were increased (P < 0.001) in AIDS patients compared with other HIV-infected individuals and controls. Plasma levels of IGFBP-2 and IGFBP-3 protease activity correlated positively to virus load (P < 0.001) and tumor necrosis factor-alpha (P < 0.025) and negatively to CD4(+) and CD8(+) cell counts (P < 0.001). AIDS patients with wasting (n = 13) had lower IGF-II levels (P = 0.001) and higher IGFBP-2 levels (P = 0.001) than other AIDS patients. Although no significant change in any of the IGF-parameters was observed in patients during antiretroviral therapy, patients with elevated IGFBP-3 protease activity before therapy (5 of 34) all had a decrease during treatment. During longitudinal testing in patients followed without antiretroviral therapy, disease progression was associated with increases in IGFBP-3 protease activity and IGFBP-2 levels. Our results reveal several alterations in the IGF system during HIV infection with decreased IGF-II levels, increased concentration of IGFBP-2, and an increased IGFBP-3 protease activity in advanced disease.

Effects of treatment with megestrol acetate on the insulin-like growth factor system: time and dose dependency.

This study was designed to evaluate time and dose dependency of alterations in insulin-like growth factor (IGF)-I, free IGF-I and the functional status of IGF-binding protein (IGFBP)-3 in breast cancer patients during treatment with megestrol acetate (MA). In 16 patients receiving MA 160 mg daily, total IGF-I levels increased gradually (significant after 3 days on treatment) by a maximum of 2.66-fold after 5-6 months on treatment. However, free (readily dissociable) IGF-I levels increased to a smaller extent (1.23-2.15-fold). This discrepancy may be due to an increase in intact IGFBP-3 determined by Western ligand blotting (WLB). Similar findings were observed in 12 patients treated with MA in escalating doses from 40-800 mg daily. A dose-dependent increase in IGF-I was observed up to a dose level of 120 mg daily. We conclude that treatment with MA caused a profound increase in plasma levels of total IGF-I accompanied by a moderate increase in free IGF-I. This may explain the anabolic effects of MA in patients suffering from cachexia, but refute the hypothesis that alterations in the IGF-system may contribute to the antitumour effects of MA in breast cancer patients.

Plasma oestrogen fractions in postmenopausal women receiving hormone replacement therapy: influence of route of administration and cigarette smoking.

The aim of this study was to determine the impact of the administration route and cigarette smoking on plasma oestrogen levels during oral and parenteral oestrogen replacement therapy (ERT). Fourteen healthy postmenopausal women (six smokers and eight non-smokers) were recruited for a prospective, randomised, crossover study at a private outpatient medical centre in Oslo, Norway. All patients were randomised to receive cyclic therapy with oestradiol and norethisterone orally or by the transdermal route each for a 6-month period. Plasma levels of oestrone (Oe(1)), oestradiol (Oe(2)) and oestrone sulphate (Oe(1)S) were determined using highly sensitive RIA methods before and during hormone replacement therapy given by the oral and transdermal route. Comparing smokers and non-smokers, plasma levels of Oe(1), Oe(2) and Oe(1)S were all found to be 40-70% lower in smokers compared with non-smokers when ERT was given orally (Oe(1)S, P<0.05; Oe(1) and Oe(2), P<0.01 for both). Oe(2) given orally caused a higher Oe(1)S/Oe(2) ratio but also a higher Oe(1)/Oe(2) ratio compared with parenteral therapy in smokers (40.2 versus 7(.)0, P<0.01; and 3.2 versus 0.8, P<0.05 respectively). No significant differences in these parameters in the different test-situations were seen in non-smokers. Except for a lower level of Oe(1)S in smokers (non-significant), no difference in plasma oestrogen levels between smokers and non-smokers was observed during parenteral therapy. In conclusion, cigarette smoking has been shown to have major impact on plasma oestrogen levels during oral but not during parenteral Oe(2) replacement.

Prognostic value of plasma prostate specific antigen after megestrol acetate treatment in patients with metastatic breast carcinoma.

BACKGROUND: Prostate specific antigen (PSA) is an established tumor marker of prostate adenocarcinoma that recently also was found in breast tumors. Minute amounts of PSA are found in female plasma. It is known from cell culture studies that PSA expression can be up-regulated by androgens and progestins but not estrogens. In this study, the authors examined whether plasma PSA in women with breast carcinoma changes after the therapeutic administration of the progestin megestrol acetate (MA) and whether these changes have any prognostic value. METHODS: Plasma PSA was measured by a highly sensitive immunofluorometric procedure that can measure within 1 ng/L of PSA. Serial plasma levels from women with metastatic breast carcinoma who received either MA (N = 52) or other treatments (N = 24) were evaluated. PSA changes in plasma were correlated with patient outcomes. RESULTS: The study found that approximately 50% of the patients receiving MA had a significant increase in their plasma PSA concentration after the treatment and that this increase was rapid (starting within 1 week) and dose-dependent. PSA levels declined when treatment was withdrawn. Further comparisons with similar groups of patients receiving tamoxifen or doxorubicin have shown that the plasma PSA increases are specific to the MA treatment. The plasma PSA increases reflect the stimulation of the tumor by MA to produce PSA and the secretion of PSA into the general circulation. There is a statistically significant association between the plasma PSA changes after MA treatment and overall patient survival; patients with increased plasma PSA have an approximate threefold increase in their relative risk of death during the follow-up period. Multivariate analysis has shown that the increased risk of death in this group is associated, at least in part, with the frequent presence of distant metastasis. CONCLUSIONS: The measurement of plasma PSA after treatment with MA allows for patient classification into two groups. The group that did not demonstrate any changes in their plasma PSA level after MA treatment (approximately 50% of the patients) had a significantly better prognosis. The group that did demonstrate an increase in their plasma PSA level after MA treatment represented a subset of patients who may benefit more from MA withdrawal and the initiation of alternative regimens. However, these data need further confirmation with a larger pool of patients.

Influence of treatment with onapristone on the IGF-system in breast cancer patients.

The influence of the novel antiprogestin onapristone on the serum insulin-like growth factor (IGF) system was studied in a group of 13 postmenopausal women with metastatic breast cancer. Blood samples were obtained before treatment and subsequently after 1, 2 and 3 months on therapy. IGF-I, IGF-II and IGF-binding protein (IGFBP)-2 were measured by radioimmunoassay (RIA). In addition, the IGFBP profile was evaluated by Western ligand blotting (WLB), and IGFBP-3 fragmentation determined by immunoblotting. A moderate (29%) but significant increase in IGF-I was observed after 3 months on treatment (p < 0.05). IGFBP-2 showed a significant, progressive increase during treatment when evaluated both by WLB (44% increase over baseline at 3 months) and by RIA (33% increase over baseline at 3 months). There was a non-significant trend towards an initial decrease in IGFBP-3 fragmentation. No significant alterations were observed in IGF-II or any of the binding proteins (except IGFBP-2) determined by Western ligand blotting. Due to the observation that onapristone treatment caused a moderate suppression of serum cortisol and androstenedione, we postulate the observed increase in IGF-I to be due to a slight glucocorticoid agonistic effect of the drug. On the contrary, the increase in IGFBP-2 may be related to disease progression as has been observed in patients suffering from prostatic cancer.

Microencapsulated octreotide pamoate in advanced gastrointestinal and pancreatic cancer: a phase I study.

Fourteen patients suffering from advanced colorectal (n = 7), pancreatic (n = 4) or gastric (n = 3) carcinomas received treatment with microencapsulated octreotide pamoate 90 mg i.m. every 4 weeks (n = 4), 160 mg i.m. every 4 weeks (n = 4) or 160 mg i.m. every 2 weeks (n = 6). Two patients had stable disease, one for 4 and one for 6 months. Plasma insulin-like growth factor (IGF)-I decreased by 49-53%, IGF-II by 27-37% and total IGF-binding protein (IGFBP)-3 by 16-19%, whereas IGFBP-1 increased by 35-55%. Insulin and C-peptide levels decreased by 29-38% and 41-46% respectively. A non-significant decrease in urinary GH secretion and an increase in the ratio of fragmented to intact IGFBP-3 as well as IGFBP-3 protease activity was seen. The increase in IGFBP-3 fragmentation correlated negatively with alterations in IGF-I and IGF-II (P < 0.05). We conclude that microencapsulated octreotide administered in doses up to 160 mg every 2 weeks is well tolerated and has pronounced effects on several components of the IGF system in plasma. In addition, changes in IGFBP-3 protease activity because of cancer may contribute to alterations in IGF-I and -II, indicating the importance of measuring this parameter in addition to IGFs and IGFBPs when evaluating alterations in IGF-I.

Alterations in the insulin-like growth factor system during the menstrual cycle in normal women.

OBJECTIVES: To evaluate the effects of endogenous estrogens and progestins on the IGF-system during the normal menstrual cycle in healthy premenopausal women not using contraceptive drugs. METHODS: Nine women had fasting blood samples obtained at 2-3 days intervals during a 5 week study period. Plasma levels of IGF-I, IGF-II, IGFBP-I, IGFBP-3, estradiol and progesterone were measured by radioimmunoassay (RIA) in each sample. IGFBP-3 was also evaluated by Western ligand blot (WLB) and immunoblot. Any differences between the menstrual phase (defined as day 1-5), follicular and luteal phases (separation based on plasma estradiol and progesterone values) were evaluated by the Friedman test. RESULTS: A small but significant difference in plasma levels of IGF-I (P < 0.01) and IGFBP-d (P < 0.05) measured by RIA between the three phases were seen with the highest levels found during the follicular phase. No change in plasma levels of IGFBP-1 and IGF-II was found and immunoblots did not reveal any alteration in the ratio of fragmented to intact IGFBP-3 during the menstrual cycle. A positive correlation between plasma levels of IGF-I and estradiol was seen in 8 out of 9 patients (P = 0.012). CONCLUSIONS: The finding of a slight but significant higher level of plasma IGF-I in the follicular and luteal phases compared with the menstrual phase suggests plasma estradiol may influence the level of this growth factor. This hypothesis is further supported by the finding of a correlation between plasma levels of IGF-I and estradiol but not progesterone in individual patients at different times during the menstrual cycle.

Effects of oral and transdermal oestrogen replacement therapy on plasma levels of insulin-like growth factors and IGF binding proteins 1 and 3: a cross-over study.

OBJECTIVE: Conflicting results have been reported on the effects of oral and transdermal oestrogen replacement therapy on IGF-I, while little information exists regarding the effects on IGFBP -1 and -3. In this study we evaluated the effects of oral and transdermal oestrogens on these parameters in post-menopausal women in a randomized cross-over study. PATIENTS: A group of 14 post-menopausal women were randomized to receive progestin-opposed oestrogen replacement therapy administered orally (Trisekvens Novo: 17 beta-oestradiol 2 mg daily on days 1-22 and 1 mg daily on days 23-28, norethisterone 1 mg days 13-22) or transdermally (Estracomb CIBA: oestradiol 50 micrograms/24 h on days 1-28, norethisterone 250 micrograms/24 h on days 15-28) for 6 months after which they were crossed over to the alternative treatment option. Fasting blood samples were obtained before treatment, and after 3, 6, 9 and 12 months on treatment. MEASUREMENTS: IGF-I, IGF-II, IGFBP-1, IGFBP-3, oestradiol and norethisterone were analysed by radioimmuno-assays. In addition, IGFBPs were evaluated with Western ligand blots (WLB) in a subgroup of 12 patients. RESULTS: Plasma levels of oestradiol were not significantly different during oral and transdermal treatment. Norethisterone levels were below the detection limit in all situations in 8 patients, while 6 patients had detectable levels in one or several samples during treatment. Oral treatment caused a significant decrease (16%, P < 0.005) in IGF-I and a non-significant decrease in IGFBP-3. A similar effect was observed when samples containing detectable levels of norethisterone were excluded from the analysis. No significant effect on IGFBP-1 was observed when all samples were included in the analysis. However, when samples with detectable norethisterone were excluded IGFBP-1 increased by 46% (P < 0.01) during oral therapy. Contrary, transdermal treatment with oestrogens did not influence any of the parameters measured. None of the treatments had any effect on plasma IGF-II levels or IGFBP profile evaluated by WLB. CONCLUSIONS: Treatment with oral hormone replacement therapy significantly suppresses plasma IGF-1 levels and increases plasma IGFBP-1 while transdermal treatment had no influence. This may be due to the route of administration, as plasma oestradiol levels showed little difference between the groups. The effect of oral oestrogens on IGFBP-1 seems to be attenuated by progestins.

Profound suppression of plasma estrogens by megestrol acetate in postmenopausal breast cancer patients.

Twelve postmenopausal women suffering from advanced breast cancer had plasma estrogens, androgens, cortisol, and gonadotropins determined before therapy and during treatment with megestrol acetate (MA) in oral doses escalated from 40 to 160 mg. The plasma clearance and production rate of estrone and estrone sulfate were determined before treatment and after 4 weeks of therapy with 160 mg MA. Treatment with MA suppressed plasma levels of dehydroepiandrosterone sulfate, androstenedione, and cortisol in a dose-dependent manner to <10% of pretreatment values. Plasma testosterone, estradiol, estrone, and estrone sulfate were suppressed to 18-29% of pretreatment values, whereas the gonadotropins were suppressed to 35-52%. The plasma clearance rates of estrone and estrone sulfate were increased by a mean value of 23.7% (P < 0.01) and 23.5% (P < 0.025), whereas the production rates were reduced by 76.7% (P < 0.0005) and 76.1% (P < 0.0005), respectively. Our findings indicate that MA causes profound suppression of adrenal steroid production but in addition suppresses ovarian secretion of androgens in postmenopausal breast cancer patients. The reduction in plasma estrogens is comparable to values obtained with commonly used aromatase inhibitors and may be responsible for its antitumor effects in breast cancer.

Influence of treatment with tamoxifen and change in tumor burden on the IGF-system in breast cancer patients.

Plasma levels of IGF-I, IGFBP-I and IGFBP-3 were measured before and during treatment with tamoxifen up to 19+ months in 34 post-menopausal patients with advanced breast cancer. In 28 patients, pro-IGF-IIE (IGF-IIE) levels were determined and IGFBP-3 was evaluated by immunoblot in 27 patients. Tamoxifen suppressed plasma levels of IGF-I by a mean value of 25.5%-37.7% at different times. This effect was fully developed after 1-2 months of treatment. IGF-IIE was decreased by a mean value of 7.7-23.2% at different time intervals during treatment with tamoxifen, but this effect was significant after long-term treatment (19 months +) only. Plasma IGFBP-I increased by a mean value varying between 48.6% and 190.1%. Tamoxifen had no significant effect on total IGFBP-3 levels. However, patients responding to treatment had a 28% reduction in fragmentation of IGFBP-3, while patients with progressive disease had a 36% increase in fragmentation. The difference between responders and non-responders was highly significant. These findings confirm and extend previous observations regarding the effects of treatment with tamoxifen on IGF-I and IGFBP-I. The finding that patients responding to tamoxifen achieve a reduction in the ratio of fragmented to intact IGFBP-3, while patients progressing on therapy experience an increase in the IGFBP-3 fragmentation ratio, suggest that the tumor burden influences IGFBP-3 protease activity in breast- cancer patients.

Effects of treatment with megestrol acetate, aminoglutethimide, or formestane on insulin-like growth factor (IGF) I and II, IGF-binding proteins (IGFBPs), and IGFBP-3 protease status in patients with advanced breast cancer.

The effects of treatment with the aromatase inhibitors aminoglutethimide (AG) and formestane or the synthetic progestin megestrol acetate (MA) on plasma levels of insulin-like growth factor I (IGF-1), IGF-II, IGF-binding proteins (IGFBPs), and IGFBP-3 protease status were investigated in 39 patients suffering from advanced breast cancer. Treatment with AG and MA elevated plasma levels of IGF-I by mean values of 27% (n = 15; P < 0.025) and 81% (n = 7; P < 0.025), respectively, whereas treatment with formestane had no effect (n = 13). Treatment with AG increased plasma levels of IGFBP-2, as evaluated by Western blotting (P < 0.01). MA caused a significant reduction in IGFBP-3 protease activity (mean reduction, 69%; P < 0.05). These alterations in plasma IGF-I and IGFBP-3 protease activity were reversed 4 weeks after terminating MA therapy (n = 8; P < 0.025). Taken together, 13 of 15 patients had reduced IGFBP-3 protease activity during treatment with MA compared to the control situation (P < 0.0025). Total levels of IGFBP-3 as measured by RIA were moderately elevated by treatment with MA (mean increase, 19%; P < 0.05), and Western immunoblotting revealed an increase in the amount of intact IGFBP-3 and reduced amounts of IGFBP-3 in the modified form. None of the treatment modalities had any influence on plasma levels of IGF-II. The increase in the plasma IGF-I concentration seen during treatment with MA may be secondary to an increased level of intact IGFBP-3. This could reflect an alteration in IGF availability that contributes to the antitumor effect of MA.

Influence of droloxifene on plasma levels of insulin-like growth factor (IGF)-I, Pro-IGF-IIE, insulin-like growth factor binding protein (IGFBP)-1 and IGFBP-3 in breast cancer patients.

The influence of the novel anti-estrogen droloxifene on the insulin-like growth factor (IGF) system in plasma was studied in two groups of breast cancer patients receiving droloxifene 40 mg o.d. (group 1, n = 6) or 100 mg o.d. (group 2, n = 7). Fasting blood samples were obtained from all patients before treatment and after 3 months (group 1) or 6 months (group 2) on droloxifene treatment, except for two patients in group 2 from whom the second sample was obtained following 2 months on treatment when the drug was to be terminated due to progressive disease. Insulin-like growth factor (IGF)-I, insulin-like growth factor binding protein (IGFBP)-1, IGFBP-3 and pro-IGF-IIE (IGF-IIE) were measured by radioimmunoassay. In patients in group 1, plasma lGF-I levels decreased by a mean value of 20% (P < 0.05) on treatment with droloxifene, while IGFBP-1 increased by a mean value of 45% (P > 0.1). In group 2 we observed a 42% decrease in IGF-I during treatment (P < 0.025), while the level of IGFBP-1 increased by a mean value of 70% (P < 0.025). No significant effect on IGF-IIE or IGFBP-3 was noted in any of the groups. The change in plasma lGF-I and IGFBP-1 observed during treatment with droloxifene resembles what is found in patients treated with tamoxifen. As IGF-I is a potent mitogen for breast cancer cells in vitro, a decrease in the plasma level of this growth factor with an increase in the concentration of IGFBP-1 may contribute to the anti-tumour effects of droloxifene.

Influence of plasma estrogen levels on the length of the disease-free interval in postmenopausal women with breast cancer.

The influence of plasma estrogen levels on disease-free interval (time from primary treatment to first relapse, DFI) in breast cancer patients is not known. Any relation between plasma estrogens and the outcome in breast cancer patients may have implications considering use of hormone replacement therapy (HRT) in patients treated for breast cancer. We measured plasma estradiol (E2), estrone (E1), and estrone sulfate (E1S) in 92 postmenopausal women with breast cancer relapse and correlated plasma estrogen levels to the length of their disease-free interval (DFI1) and the length of the DFI in the subgroup of patients in whom this extended a time period of more than 2 years (DFI2). The length of DFI2 correlated negatively to plasma level of E1S (p < 0.025) and E2 (p < 0.05) and to the E2/E1 and E1S/E1 ratios (p < 0.05), while the length of DFI1 correlated negatively to plasma level of E1S (p < 0.025) and the E1S/E1 ratio (p < 0.005). We also analyzed for possible correlations between DFIs and plasma estrogen levels in subgroups based on tumor stage at diagnosis and previous therapy. In general, these subgroup analyses revealed negative correlations of statistical significance or borderline significance between the DFI1 and DFI2 and E2 and the E2/E1 ratio and non-significant negative correlations between plasma levels of E1S and DFI1 and DFI2. In particular, strong negative correlations between plasma estrogen levels and the length of DFI1 and DFI2 were found among patients responding to first line endocrine treatment for relapse and among patients with primar stage III tumors. Our findings suggest plasma E2 and E1S to stimulate the growth of micrometastases in patients treated for breast cancer.

Insulin-like growth factors in breast cancer.

Insulin-like growth factor (IGF)-I is one of the most potent mitogens to many breast cancer cell lines in vitro. Effective growth inhibition in vitro may be achieved by antibodies to the type I IGF receptor (IGF-IR) or by using antisense strategies. Most human breast cancers express IGF-IR in vivo. Thus, different therapeutic strategies aimed at inhibiting ligand stimulation of the IGF-IR may be an attractive treatment option against breast cancer. Several drugs commonly used in breast cancer influence the IGF system both in vitro and in vivo. While antioestrogens such as tamoxifen and droloxifene reduce the expression of IGF-IR in vitro and suppress plasma levels of IGF-I but elevate IGF-binding protein-1 in vivo, megestrol acetate may reduce the delivery of IGFs to the tissues by inhibition of IGFBP-3 protease activity.

Relations between sex hormones, sex hormone binding globulin, insulin-like growth factor-I and insulin-like growth factor binding protein-1 in post-menopausal breast cancer patients.

OBJECTIVE: Oestrogens, androgens and anti-endocrine drugs such as tamoxifen and aminoglutethimide influence plasma insulin-like growth factor-I (IGF-I). IGF-I, in turn, has been found to stimulate the peripheral aromatase in vitro. The aim of this study was to examine relations between sex hormones, IGF-I and insulin-like growth factor binding protein-1 (IGFBP-1) in post-menopausal women with breast cancer. DESIGN: To measure plasma sex steroids, sex hormone binding globulin (SHBG), IGF-I, IGFBP-1, insulin and urinary oestrogen metabolites in post-menopausal women with breast cancer not receiving any endocrine therapy. PATIENTS: Thirty-two patients had fasting blood samples obtained between 0800 and 1000 h. A sub-group of 10 patients had 24-hour urine oestrogen metabolites determined. MEASUREMENTS: Plasma steroids and proteins were measured by radioimmunoassays. Urinary oestrogens were measured by GC-MS. RESULTS: SHBG correlated negatively with plasma androstenedione (P < 0.001), insulin (P < 0.001), IGF-I, height and plasma oestrone sulphate (P < 0.025 for all), but positively with plasma IGFBP-1 (P < 0.025). IGFBP-1 correlated negatively with IGF-I (P < 0.001) and the testosterone/SHBG ratio (P < 0.05). Neither IGF-I nor IGFBP-1 correlated with any of the plasma or urinary sex hormones or with the oestrone/androstenedione and oestradiol/testosterone ratios. Multivariate analysis revealed plasma SHBG to correlate positively with IGFBP-1 (P = 0.029) and negatively with insulin (P = 0.031). Plasma IGFBP-1 correlated negatively with IGF-I (P < 0.0001) but not with insulin. CONCLUSION: Our results do not suggest any influence of plasma sex steroids in physiological concentrations on IGF-I or IGFBP-1 in post-menopausal breast cancer patients, nor do they indicate IGF-I at physiological concentrations influences the ratios between plasma oestrogens and their androgen precursors.