Prognostic and predictive value of low estrogen receptor expression in breast cancer.

PURPOSE: Anti-hormonal therapy (tamoxifen) is recommended for estrogen receptor (er)-positive breast cancer (bca); however, its effect on low-receptor cancers is unclear. We retrospectively evaluated the effect of adjuvant tamoxifen in patients with weakly er-positive bca. METHODS: We identified 2221 bca patients who had been er-tested by ligand-based assay (lba) during 1976-1995 and who had been treated and followed until 2008. Cox proportional hazards models adjusted for age, body mass index, tumour size, nodal status, surgery, and chemotherapy were used to assess the effect of er level on bca survival in patients who received tamoxifen. RESULTS: Overall, 17% (383) of patients were within 0-3 fmol/mg cytosol protein, and 12% (266) were within 4-9 fmol/mg cytosol protein. Patients with er levels of 0-3, 4-9, 10-19, 20-49, and 50 fmol/mg or more cytosol protein had 20-year bca survival rates of 56%, 56%, 63%, 71%, and 60% respectively. Of the 2221 patients studied, 661 (29.8%) received anti-hormonal therapy. Within the latter group, er levels of 0-3, 4-9, 10-19, 20-49, and 50 fmol/mg or more cytosol protein were associated with a hazard ratio for lower bca mortality: respectively, 1.00 (reference), 0.59 (p = 0.09), 0.19 (p < 0.0001), 0.26 (p < 0.0001), and 0.31 (p < 0.0001)-the risk reduction being significant only for er levels of 10 fmol/mg or more cytosol protein. CONCLUSIONS: Tamoxifen use in bca patients with a weakly positive er status (4-9 fmol/mg cytosol protein), compared with those having higher er levels (≥10 fmol/mg cytosol protein), is not associated with a significantly lower bca-specific mortality. Our results do not support treatment with anti-hormonal therapy for bca patients with a weakly positive er status as identified by lba.

Final efficacy and updated safety results of the randomized phase III BEATRICE trial evaluating adjuvant bevacizumab-containing therapy in triple-negative early breast cancer.

BACKGROUND: The purpose of this analysis was to assess the long-term impact of adding bevacizumab to adjuvant chemotherapy for early triple-negative breast cancer (TNBC). METHODS: Patients eligible for the open-label randomized phase III BEATRICE trial had centrally confirmed triple-negative operable primary invasive breast cancer (pT1a-pT3). Investigators selected anthracycline- and/or taxane-based chemotherapy for each patient. After definitive surgery, patients were randomized 1:1 to receive ≥4 cycles of chemotherapy alone or with 1 year of bevacizumab (5 mg/kg/week equivalent). Stratification factors were nodal status, selected chemotherapy, hormone receptor status, and type of surgery. The primary end point was invasive disease-free survival (IDFS; previously reported). Secondary outcome measures included overall survival (OS) and safety. RESULTS: After 56 months' median follow-up, 293 of 2591 randomized patients had died. There was no statistically significant difference in OS between treatment arms in either the total population (hazard ratio 0.93, 95% confidence interval [CI] 0.74-1.17; P = 0.52) or pre-specified subgroups. The 5-year OS rate was 88% (95% CI 86-90%) in both treatment arms. Updated IDFS results were consistent with the primary IDFS analysis. Five-year IDFS rates were 77% (95% CI 75-79%) with chemotherapy alone versus 80% (95% CI 77-82%) with bevacizumab. From 18 months after first study dose to study end, new grade ≥3 adverse events occurred in 4.6% and 4.5% of patients in the two arms, respectively. CONCLUSION: Final OS results showed no significant benefit from bevacizumab therapy for early TNBC. Late-onset toxicities were rare in both groups. Five-year OS and IDFS rates suggest that the prognosis for patients with TNBC is better than previously thought. CLINICALTRIALS.GOV: NCT00528567.

Is clinical breast examination important for breast cancer detection?

BACKGROUND: Screening clinical breast examination (cbe) is controversial; the use of cbe is declining not only as a screening tool, but also as a diagnostic tool. In the present study, we aimed to assess the value of cbe in breast cancer detection in a tertiary care centre for breast diseases. METHODS: This retrospective study of all breast cancers diagnosed between July 1999 and December 2010 at our centre categorized cases according to the mean of detection (cbe, mammography, or both). A cbe was considered "abnormal" in the presence of a mass, nipple discharge, skin or nipple retraction, edema, erythema, peau d'orange, or ulcers. RESULTS: During the study period, a complete dataset was available for 6333 treated primary breast cancers. Cancer types were ductal carcinoma in situ (15.3%), invasive ductal carcinoma (75.7%), invasive lobular carcinoma (9.0%), or others (2.2%). Of the 6333 cancers, 36.5% (n = 2312) were detected by mammography alone, 54.8% (n = 3470) by mammography and cbe, and 8.7% (n = 551) by physician-performed cbe alone (or 5.3% if considering ultrasonography). Invasive tumours diagnosed by cbe alone were more often triple-negative, her2-positive, node-positive, and larger than those diagnosed by mammography alone (p < 0.05). CONCLUSIONS: A significant number of cancers would have been missed if cbe had not been performed. Compared with cancers detected by mammography alone, those detected by cbe had more aggressive features. Clinical breast examination is a very low-cost test that could improve the detection of breast cancer and could prompt breast ultrasonography in the case of a negative mammogram.

Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial.

BACKGROUND: The optimal regimen for adjuvant breast cancer chemotherapy is undefined. We compared sequential to concurrent combination of doxorubicin and cyclophosphamide with docetaxel chemotherapy in women with node-positive non-metastatic breast cancer. We report the final, 10-year analysis of disease-free survival (DFS), overall survival (OS), and long-term safety. PATIENTS AND METHODS: A total of 3298 women with HER2 nonamplified breast cancer were randomized to doxorubicin and cyclophosphamide every 3 weeks for four cycles followed by docetaxel (AC → T) every 3 weeks for four cycles or docetaxel, doxorubicin, and cyclophosphamide (TAC) every 3 weeks for six cycles. The patients received standard radiotherapy and endocrine therapy and were followed up for 10 years with annual clinical evaluation and mammography. RESULTS: The 10-year DFS rates were 66.5% in the AC → T arm and 66.3% in the TAC arm (P = 0.749). OS was 79.9% in the AC → T arm and 78.9% in the TAC arm (P = 0.506). TAC was associated with higher rates of febrile neutropenia, although G-CSF primary prophylaxis greatly reduced this risk. AC → T was associated with a higher rate of myalgia, hand-foot syndrome, fluid retention, and sensory neuropathy. CONCLUSION: This 10-year analysis of the BCIRG-005 trial confirmed that the efficacy of TAC was not superior to AC → T in women with node-positive early breast cancer. The toxicity profiles differ between arms and were consistent with previous reports. The TAC regimen with G-CSF support provides shorter adjuvant treatment duration with less toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00312208.

Recommendations on breast cancer screening and prevention in the context of implementing risk stratification: impending changes to current policies.

In recent years, risk stratification has sparked interest as an innovative approach to disease screening and prevention. The approach effectively personalizes individual risk, opening the way to screening and prevention interventions that are adapted to subpopulations. The international perspective project, which is developing risk stratification for breast cancer, aims to support the integration of its screening approach into clinical practice through comprehensive tool-building. Policies and guidelines for risk stratification-unlike those for population screening programs, which are currently well regulated-are still under development. Indeed, the development of guidelines for risk stratification reflects the translational aspects of perspective. Here, we describe the risk stratification process that was devised in the context of perspective, and we then explain the consensus-based method used to develop recommendations for breast cancer screening and prevention in a risk-stratification approach. Lastly, we discuss how the recommendations might affect current screening policies.

Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study.

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.

No effect of scalp cooling on survival among women with breast cancer.

Scalp cooling can prevent chemotherapy-induced alopecia in some cancer patients. It is not used in all countries. No data are available regarding its impact, if any, on survival. The aim of this study was to compare overall survival according to whether or not scalp cooling was used during neoadjuvant or adjuvant chemotherapy for non-metastatic breast cancer. We conducted a retrospective cohort study of 1,370 women with non-metastatic invasive breast carcinoma who received chemotherapy in the neoadjuvant or adjuvant setting. A total of 553 women who used scalp cooling came from a tertiary breast cancer clinic in Quebec City (diagnosed between 1998 and 2002) and 817 were treated in other hospitals in the province of Quebec (between 1998 and 2003) where scalp cooling was not routinely available. Overall survival of women who used scalp cooling and those who did not was compared using Cox proportional hazards models. Median follow-up for the scalp-cooled and the non-scalp-cooled groups was 6.3 years and 8.0 years, respectively. Overall mortality was no different (adjusted hazard ratio 0.89, 95 % confidence interval: 0.68-1.17, p = 0.40) among scalp-cooled women, compared to those not getting scalp cooling. Among women getting neoadjuvant or adjuvant chemotherapy for non-metastatic breast cancer, scalp cooling used to prevent chemotherapy-induced alopecia had no negative effect on survival. To our knowledge, this is the first study to compare survival of women who used scalp cooling to that of women who did not.

Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2†.

BACKGROUND: The BOLERO-2 study previously demonstrated that adding everolimus (EVE) to exemestane (EXE) significantly improved progression-free survival (PFS) by more than twofold in patients with hormone-receptor-positive (HR(+)), HER2-negative advanced breast cancer that recurred or progressed during/after treatment with nonsteroidal aromatase inhibitors (NSAIs). The overall survival (OS) analysis is presented here. PATIENTS AND METHODS: BOLERO-2 is a phase III, double-blind, randomized international trial comparing EVE 10 mg/day plus EXE 25 mg/day versus placebo (PBO) + EXE 25 mg/day in postmenopausal women with HR(+) advanced breast cancer with prior exposure to NSAIs. The primary end point was PFS by local investigator assessment; OS was a key secondary end point. RESULTS: At the time of data cutoff (3 October 2013), 410 deaths had occurred and 13 patients remained on treatment. Median OS in patients receiving EVE + EXE was 31.0 months [95% confidence interval (CI) 28.0-34.6 months] compared with 26.6 months (95% CI 22.6-33.1 months) in patients receiving PBO + EXE (hazard ratio = 0.89; 95% CI 0.73-1.10; log-rank P = 0.14). Poststudy treatments were received by 84% of patients in the EVE + EXE arm versus 90% of patients in the PBO + EXE arm. Types of poststudy therapies were balanced across arms, except for chemotherapy (53% EVE + EXE versus 63% PBO + EXE). No new safety concerns were identified. CONCLUSIONS: In BOLERO-2, adding EVE to EXE did not confer a statistically significant improvement in the secondary end point OS despite producing a clinically meaningful and statistically significant improvement in the primary end point, PFS (4.6-months prolongation in median PFS; P < 0.0001). Ongoing translational research should further refine the benefit of mTOR inhibition and related pathways in this treatment setting. TRIAL REGISTRATION NUMBER: NCT00863655.

Biomarker results from the AVADO phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer.

BACKGROUND: Combining bevacizumab with first-line chemotherapy significantly improves progression-free survival (PFS) in HER2-negative metastatic breast cancer (mBC). However, identification of patients benefitting most from bevacizumab remains elusive. The AVADO trial included an extensive optional exploratory biomarker programme. METHODS: Patients with HER2-negative mBC were randomised to receive docetaxel with placebo or bevacizumab. The primary end point was PFS. Plasma samples were analysed using a multiplex ELISA. Blood mRNA expression was assessed using quantitative PCR. Tumour tissue samples were analysed by immunohistochemistry. Single-nucleotide polymorphisms (SNPs) involved in the VEGF pathway were analysed in germline DNA. RESULTS: Samples for biomarker analysis were available from 24-54% of the 736 treated patients (depending on specimen type). The most consistent potential predictive effect was observed with plasma VEGF-A and VEGFR-2; high baseline concentrations were associated with greater treatment effect. Blood mRNA analyses suggested a greater bevacizumab effect in patients with high VEGF121. No consistent predictive effect was seen for tumour neuropilin or other candidate tumour markers by immunohistochemistry, or for any of the SNPs investigated. CONCLUSION: Plasma VEGF-A and VEGFR-2 are potential predictive markers for bevacizumab efficacy, supporting findings in gastric and pancreatic cancers. Plasma VEGF-A is being evaluated prospectively in mBC in the MERiDiAN trial.

Endocrine therapy for postmenopausal women with hormone receptor-positive her2-negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement.

Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2-) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients-efect, sofea, confirm, and bolero-2-have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2- advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient's age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged.

Cardiac safety of adjuvant pegylated liposomal doxorubicin with concurrent trastuzumab: a randomized phase II trial.

BACKGROUND: The cardiac safety of trastuzumab concurrent with pegylated liposomal doxorubicin (PLD) in an adjuvant breast cancer treatment regimen is unknown. PATIENTS AND METHODS: Women with resected node-positive or intermediate-risk node-negative HER2 overexpressing breast cancer and baseline left ventricular ejection fraction (LVEF)≥55% were randomized (1:2) to doxorubicin 60 mg/m2 (A)+cyclophosphamide 600 mg/m2 (C) every 21 days (q21d) for four cycles or PLD 35 mg/m2+C q21d+trastuzumab 2 mg/kg weekly (H) for 12 weeks. Both groups then received paclitaxel (Taxol, T) 80 mg/m2 with H for 12 weeks followed by H to complete 1 year. The primary end point was cardiac event rate or inability to administer 1 year of trastuzumab. RESULTS: Of 181 randomized patients, 179 underwent cardiac analysis. The incidence of cardiac toxicity or inability to administer trastuzumab due to cardiotoxicity was 18.6% [n=11; 95% confidence interval (CI) 9.7% to 30.9%] with A+C→T+H and 4.2% (n=5; 95% CI 1.4% to 9.5%) with PLD+C+H→T+H (P=0.0036). All events, except one, were asymptomatic systolic dysfunction or mildly symptomatic heart failure. Mean absolute LVEF reduction at cycle 8 was greater with doxorubicin (5.6% versus 2.1%; P=0.0014). CONCLUSION: PLD+C+H→T+H is feasible and results in lower early cardiotoxicity rates compared with A+C→T+H.

Emerging trends in the treatment of triple-negative breast cancer in Canada: a survey.

Triple-negative breast cancer (TNBC) has a poor prognosis compared to other subtypes and lacks common therapeutic targets, including HER 2 and the estrogen and progesterone receptors. The clinicopathological heterogeneity of the disease and limited treatment options make clinical management particularly challenging. Here we present the results of a survey of Canadian clinical oncologists regarding treatment of TNBC, and review recent and ongoing clinical research in this area. Our survey results show that the majority of respondents use a combination of anthracyclines-taxanes as adjuvant therapy for early TNBC. For the first-line treatment of metastatic TNBC, most clinicians recommend taxanes, while single agent capecitabine and platinum-based therapies are more common for subsequent lines of therapy. Despite the ongoing development of novel targeted therapies, chemotherapy remains the mainstay of treatment for TNBC.

Optimizing the management of HER2-positive early breast cancer: the clinical reality.

Breast cancer positive for HER2 (human epidermal growth factor receptor 2) is associated with a poor prognosis for patients with both early-stage and metastatic breast cancer. Trastuzumab has been shown to be effective and is now considered the standard of care for early-stage patients with HER2-positive breast cancer. In that population, trastuzumab has been studied in six randomized clinical trials. Overall, use of this agent leads to a significant reduction in risk of disease recurrence and improvement in overall survival. Despite the strong evidence for the use of trastuzumab in managing HER2-positive early breast cancer (EBC), a number of clinical controversies remain. The authors of this paper undertook a review of the available scientific literature on adjuvant trastuzumab to produce practical considerations from Canadian oncologists. The panel focused their discussion on five key areas: Management of node-negative disease with tumours 1 cm or smaller in size. Management of HER2-positive EBC across the spectrum of the disease (that is, nodal and steroid hormone receptor status, tumour size) Timing of trastuzumab therapy with chemotherapy for early-stage disease: concurrent or sequential. Treatment duration of trastuzumab for EBC. The role of non-anthracycline trastuzumab-based regimens.

The role of neoadjuvant (HER)2-targeted therapies in (HER)2-overexpressing breast cancers.

Women receiving neoadjuvant systemic therapy for primary operable or inoperable breast cancer can potentially benefit in a number of ways, but the main advantage, which has been consistently demonstrated, is improved tumour resectability. Given the improvement in outcomes with the adjuvant use of trastuzumab in patients with early-stage breast cancer positive for the human epidermal growth factor receptor 2 (HER2), questions have been raised about the use of trastuzumab in the neoadjuvant setting. The present paper reviews the currently available data and outlines suggestions from a panel of Canadian oncologists about the use of trastuzumab and other HER2-targeted agents in the neoadjuvant setting.The panel focussed on the use of trastuzumab and other HER2-targeted agents as neoadjuvant therapy in primary operable, locally advanced, and inflammatory breast cancer; and possible choices of chemotherapeutic regimens with trastuzumab.The suggestions described here will continue to evolve as data from current and future trials with trastuzumab and other HER2-targeted agents emerge.

The role of HER2-targeted therapies in women with HER2-overexpressing metastatic breast cancer.

The role of targeted therapies in the treatment of women with breast cancer has been rapidly evolving. Trastuzumab, a monoclonal antibody against the human epidermal growth factor receptor 2 (HER2), was the first HER2-targeted therapy that clearly demonstrated a significant clinical benefit for women with HER2-overexpressing metastatic breast cancer (mbc). However, in recent years it has become increasingly apparent that, when trastuzumab is used in the first-line setting in combination with chemotherapy, most women eventually develop progressive disease. Determining the treatment options available to women who have progressed while on trastuzumab therapy has been hampered by a paucity of high-quality published data. In addition, with the standard use of trastuzumab in the adjuvant setting (for eligible HER2-positive patients), the role of anti-HER2 agents for patients who experience a breast cancer relapse has become a clinically relevant question. This manuscript reviews current available data and outlines suggestions from a panel of Canadian oncologists about the use of trastuzumab and other HER2-targeted agents in two key mbc indications:Treatment for women with HER2-positive mbc progressing on trastuzumab (that is, treatment beyond progression)Treatment for women with HER2-positive mbc recurring following adjuvant trastuzumab (that is, re-treatment)The suggestions set out here will continue to evolve as data and future trials with trastuzumab and other HER2-targeted agents emerge.

Cardiac management during adjuvant trastuzumab therapy: recommendations of the Canadian Trastuzumab Working Group.

Trastuzumab has been shown to be an effective therapy for women with breast cancer that overexpresses the human epidermal growth factor receptor 2 (her2) protein. In the pivotal metastatic breast cancer trials, cardiac dysfunction was observed in women treated with trastuzumab and chemotherapy. The incidence and severity of cardiac dysfunction was greatest among patients who received trastuzumab in combination with anthracycline-based therapy. Those findings influenced the design of subsequent trastuzumab trials to include prospective evaluations of cardiac effects and protocols for cardiac monitoring and management. The risk of cardiotoxicity has also driven efforts to develop non-anthracycline-based regimens for women with her2-positive breast cancers.With the increasing use of trastuzumab, particularly in the curative adjuvant setting, the need for a rational approach to the treatment and cardiac management of the relevant patient population is clear. The mandate of the Canadian Trastuzumab Working Group was to formulate recommendations, based on available data, for the assessment and management of cardiac complications during adjuvant trastuzumab therapy. The panel formulated recommendations in four areas: Risk factors for cardiotoxicity, Effects of various regimens, Monitoring, Management. The recommendations published here are expected to evolve as more data become available and experience with trastuzumab in the adjuvant setting grows.

Sucrose export defective1 encodes a novel protein implicated in chloroplast-to-nucleus signaling.

The Sucrose export defective1 (Sxd1) gene of maize was cloned and shown to encode a novel protein conserved between plants and cyanobacteria. The structure of the Sxd1 locus was determined in wild-type plants and two independent sxd1 alleles. Expression analysis demonstrated that the gene was transcribed in all green tissues, with highest levels in maturing leaf blades. In situ hybridization studies revealed high levels of Sxd1 mRNA in bundle sheath cells, with lower levels within the mesophyll. The SXD1 protein was localized to chloroplasts, in both bundle sheath and mesophyll cells. Levels of sucrose, glucose, and fructose were compared between wild-type and sxd1 plants. Mutant plants were fully capable of producing sucrose and accumulated all three sugars at concentrations above those measured in wild-type plants. Despite these increased sugar concentrations, photosynthetic gene expression was not significantly downregulated in affected areas of sxd1 leaf blades. These results are consistent with photosynthate being trapped within anthocyanin-accumulating regions of sxd1 leaves due to plasmodesmal occlusion at the bundle sheath-vascular parenchyma boundary of the minor veins. A model for SXD1 function is proposed in which the protein is involved in a chloroplast-to-nucleus signaling pathway necessary for proper late-stage differentiation of maize bundle sheath cells, including the developmentally regulated modification of plasmodesmata.

Comparison of the effects of the new orally active antiestrogen EM-800 with ICI 182 780 and toremifene on estrogen-sensitive parameters in the ovariectomized mouse.

The nonsteroidal antiestrogen EM-800 is approximately 10-fold more potent than ICI 182 780, the most potent known steroidal antiestrogen, at inhibiting estrone-stimulated uterine weight in ovariectomized mice (half-maximal inhibitory daily s.c. doses of 0.2 and 2.0 microg, respectively). At maximal doses, however, both compounds lead to a similar maximal 90% inhibition of estrone-stimulated uterine weight. A 10-fold higher activity of EM-800 compared with ICI 182 780 was also observed on estrone-stimulated vaginal weight, with maximal inhibitions of 96% and 90%, respectively, achieved by the two compounds. In addition, EM-800 injected s.c. or administered orally led to a marked loss of uterine and vaginal estrogen receptor levels measured by binding assay, whereas ICI 182 780 exerted no inhibitory effect on this parameter under the experimental conditions used. Comparable effects were observed when estrogen receptor protein levels were measured by enzyme immunoassay. After oral administration, EM-800 exerted maximal 83% and 88% inhibitions of uterine and vaginal weight, respectively, whereas maximal inhibitions limited to 51% and 67% were achieved with toremifene. This limited inhibition by toremifene of the stimulatory effect of estrone on uterine and vaginal weight is probably due to the intrinsic estrogenic activity of the compound. The present data also show that the steroidal antiestrogen ICI 182 780 has less than 3% the activity of EM-800 when administered by the oral route. In fact, EM-800 administered orally is 2- to 3-fold more potent than ICI 182 780 injected s.c.

Binding characteristics of novel nonsteroidal antiestrogens to the rat uterine estrogen receptors.

Tamoxifen (TAM), the only antiestrogen currently available for the endocrine therapy of breast cancer behaves as a mixed agonist/antagonist of estrogen action, thus limiting its therapeutic potential. We report the binding characteristics of a novel series of nonsteroidal antiestrogens to the rat uterine estrogen receptor. As measured by competition studies, the affinity of EM-652, the active metabolite of the prodrug EM-800, for the estrogen receptor is 7-11 times higher than that of 17beta-estradiol (E2), ICI 182780, and hydroxy-tamoxifen (OH-TAM), the active metabolite of Tamoxifen. EM-652 is 20x more potent than ICI 164384 and Droloxifene while it is 400 times more potent than Toremifene in displacing [3H]E2 from the rat uterine estrogen receptor. On the other hand, the prodrug EM-800 and Tamoxifen have respectively 150-fold and 410-fold less affinity for the estrogen receptor than the pure antiestrogen EM-652. No significant binding of EM-652, EM-800, TAM or OH-TAM was observed to the rat uterine progesterone receptor at concentrations up to 10,000 nM except for TAM that caused a 50% displacement of labeled R5020 at 4000 nM. No significant binding of EM-652 or EM-800 was observed on the rat ventral prostate androgen receptor or the rat uterine progesterone receptor. The present data demonstrate the high affinity and specificity of the new antiestrogen, EM-652, for the rat uterine estrogen receptor. The antiestrogen EM-652 thus becomes the compound having the highest known affinity for the estrogen receptor. Due to its unique potency and its pure antiestrogenic activity already demonstrated in many systems, this antiestrogen could well offer an important advance for the endocrine therapy of breast cancer, uterine cancer, and other estrogen-sensitive diseases in women.

Comparative efficacy and safety of controlled-release morphine suppositories and tablets in cancer pain.

Although the oral route is the preferred method of opioid therapy in patients with cancer pain, many patients will require an alternate route of analgesic administration at some point during the trajectory of their illness. This study compared the efficacy and safety of a novel, controlled-release suppository of morphine (MSC-R) and controlled-release morphine tablets (MSC-T) in patients with cancer pain. In a double-blind crossover study, 27 patients with cancer pain were randomized to receive MSC-R or MSC-T every 12 hours for 7 days each, using a 1:1 analgesic equivalence ratio. Pain intensity was assessed using a visual analog scale (VAS) and the Present Pain Intensity Index of the McGill Pain Questionnaire. Nausea and sedation were also assessed with a VAS. Pharmacodynamic assessments were made by the patient at 8:00 AM, 12:00 PM, 4:00 PM, and 8:00 PM and rescue morphine use recorded in a daily diary. There were no significant differences between MSC-R and MSC-T in overall scores for pain intensity VAS, ordinal pain intensity, and sedation. There was a small but significant difference in overall nausea VAS score in favor of MSC-R. Mean daily rescue analgesic use did not differ significantly during between treatment with MSC-R and MSC-T. MSC-R provides pain control comparable to that provided by MSC-T when given every 12 hours at a 1:1 dose ratio, and represents a reliable alternative method of pain control for patients unable to take oral opioid agents.