Efficacy of everolimus combined with endocrine therapy in HR-positive/HER-2-negativeadvanced breast cancer.

PURPOSE: To explore the efficacy and safety of everolimus combined with endocrine therapy in patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER-2)-negative advanced breast cancer. METHODS: The clinical information of 108 patients with HR-positive/HER-2-negative advanced breast cancer, who were admitted to and treated in our hospital from June 2014 to June 2016, was retrospectively analyzed. Of them, 54 patients were treated with everolimus combined with endocrine drugs (Everolimus group), while the other 54 patients underwent endocrine monotherapy (Control group). The clinical response rate and incidence of adverse reactions were compared between the two groups of patients, and the patients were followed up to record survival. Besides, the possible influencing factors for progression-free survival (PFS) were analyzed. RESULTS: The objective response rate (ORR) was 22.2% and 14.8%, respectively, in everolimus group and the Control group, while the clinical benefit rate (CBR) was 66.7% and 37.0%, respectively, in the two groups. There were statistically significant differences in the CBRs of the first-line and second-line therapies. The majority of adverse reactions were in grade I and II, with lower incidence rates of grade III and IV adverse reactions. The median PFS of the two groups of patients was 7.3±5.6 months and 6.7±5.1 months, respectively. The log-rank test revealed that there was a statistically significant difference in the PFS between the two groups of patients. According to the multivariate regression analysis results, progesterone receptor (PR)+, absence of visceral metastases, and sensitivity to endocrine therapy were the protective prognostic factors for PFS. CONCLUSION: Everolimus combined with endocrine therapy has significant clinical efficacy in patients with HR-positive/HER-2-negative advanced breast cancer, and can effectively improve the survival of patients with tolerable adverse reactions. PR+, absence of visceral metastases and sensitivity to endocrine therapy are the protective prognostic factors for PFS.

A prospective, randomized study of Toremifene vs. tamoxifen for the treatment of premenopausal breast cancer: safety and genital symptom analysis.

BACKGROUND: Toremifene (TOR) is a selective oestrogen receptor modulator (SERM) and has comparable efficacy to that of tamoxifen (TAM) in breast cancer patients. Herein, we compared the safety of TOR to that of TAM in the adjuvant treatment of premenopausal breast cancer. METHODS: This was a prospective randomized and open-label clinical study. Premenopausal patients with hormonal receptor (HR)-positive early breast cancer were randomly assigned (1:1) to receive TOR) or TAM treatment. The follow-up period was 1 year. The primary end point was the incidence of ovarian cysts, and secondary end points were the incidence of endometrial thickening, changes in female hormones, the incidence of fatty liver, changes in the modified Kupperman index (mKMI) and changes in quality of life. RESULTS: There were 92 patients in the final analysis. The incidences of ovarian cysts were 42.6% in the TOR group and 51.1% in the TAM group (p = 0.441). Forty-one patients (87.2%) in the TOR group and 36 patients (80.0%) in the TAM group experienced endometrial thickening (p = 0.348). The proportions of patients with fatty liver were 31.9% in the TOR group and 26.7% in the TAM group (p = 0.581). No significant differences in the mKMI or quality of life were observed between the two groups. CONCLUSIONS: TOR and TAM have similar side effects on the female genital system and quality of life in premenopausal early breast cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02344940. Registered 26 January 2015 (retrospectively registered).

Pharmacogenomic-pharmacokinetic study of selective estrogen-receptor modulators with intra-patient dose escalation in breast cancer.

BACKGROUND: An association between CYP2D6 polymorphisms and tamoxifen (TAM) efficacy has not been confirmed, partly due to unreliable prediction of active metabolite exposure solely by CYP2D6 activity. The efficacy of TAM dose escalation appears limited in poor TAM metabolizers. Since the chlorine atom on the side chain of toremifene (TOR) prevents 4-hydroxylation by CYP2D6, its contribution to active conversion of TOR is minor. We examined the role of TOR and its dose escalation among poor TAM metabolizers. METHODS: The pharmacokinetics (PK) and pharmacogenomics (PGx) of TAM and TOR were studied. Correlation between PK and CYP2D6 inhibitor use, smoking status, and PGx were examined by regression analysis. For patients showing low endoxifen levels, an intra-patient dose escalation of TOR was conducted, and TOR was increased from 40 to 120 mg for ≥ 24 weeks with PK sampling. Total activity was calculated as the sum of the concentration of each active metabolite adjusted by their respective in vitro activities. RESULTS: Fifty and 11 of the 273 participating patients had endoxifen levels < 15 and < 7.5 ng/mL, respectively. The CYP2D6 genotype was the major determinant for TAM activity (p < 0.01). Smoking status (p = 0.07) and the CYP2C19 phenotype (p = 0.07), but not the CYP2D6 genotype (p = 0.61), showed marginally significant effects on TOR activity. TOR activity increased significantly with dose escalation, even among poor TAM metabolizers, and was maintained for ≥ 24 weeks. CONCLUSION: TOR might be a valid alternative to TAM in patients predicted to be poor TAM metabolizers.

Differences between palpable and nonpalpable tumors in early-stage, hormone receptor-positive breast cancer.

BACKGROUND: We compared characteristics and outcomes of palpable versus nonpalpable, hormone-sensitive, early-stage breast cancers. METHODS: Patients from the North American Fareston vs. Tamoxifen Adjuvant (NAFTA) trial were divided into palpable (n = 513) and nonpalpable (n = 1063) tumor groups. Differences in pathological features, loco-regional therapy, disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: Patients with palpable tumors were older, had larger tumors, and higher rates of lymph-node involvement. The tumors were more likely to be poorly differentiated, of high nuclear grade, and display lymphovascular invasion. After mean followup of 59 months, DFS and OS were significantly lower for palpable than nonpalpable tumors (DFS 93.5% vs. 98.4%, p < 0.001, OS 88.5% vs. 95.6%, p < 0.001). Controlling for age, size and nodal status, palpability was an independent factor for DFS (OR = 2.56; 95%CI, 1.37-4.79, p = 0.003) and OS (OR = 2.12; 95%CI, 1.38-3.28, p < 0.001). CONCLUSIONS: In a group of hormone-sensitive, mostly postmenopausal early-stage breast cancer patients, palpable tumors were more likely to have more aggressive features and metastatic potential, which translated in to a higher incidence of breast cancer-related events and worse overall survival.

A Rapid Screening Assay Identifies Monotherapy with Interferon-ß and Combination Therapies with Nucleoside Analogs as Effective Inhibitors of Ebola Virus.

To date there are no approved antiviral drugs for the treatment of Ebola virus disease (EVD). While a number of candidate drugs have shown limited efficacy in vitro and/or in non-human primate studies, differences in experimental methodologies make it difficult to compare their therapeutic effectiveness. Using an in vitro model of Ebola Zaire replication with transcription-competent virus like particles (trVLPs), requiring only level 2 biosafety containment, we compared the activities of the type I interferons (IFNs) IFN-α and IFN-ß, a panel of viral polymerase inhibitors (lamivudine (3TC), zidovudine (AZT) tenofovir (TFV), favipiravir (FPV), the active metabolite of brincidofovir, cidofovir (CDF)), and the estrogen receptor modulator, toremifene (TOR), in inhibiting viral replication in dose-response and time course studies. We also tested 28 two- and 56 three-drug combinations against Ebola replication. IFN-α and IFN-ß inhibited viral replication 24 hours post-infection (IC50 0.038µM and 0.016µM, respectively). 3TC, AZT and TFV inhibited Ebola replication when used alone (50-62%) or in combination (87%). They exhibited lower IC50 (0.98-6.2µM) compared with FPV (36.8µM), when administered 24 hours post-infection. Unexpectedly, CDF had a narrow therapeutic window (6.25-25µM). When dosed >50µM, CDF treatment enhanced viral infection. IFN-ß exhibited strong synergy with 3TC (97.3% inhibition) or in triple combination with 3TC and AZT (95.8% inhibition). This study demonstrates that IFNs and viral polymerase inhibitors may have utility in EVD. We identified several 2 and 3 drug combinations with strong anti-Ebola activity, confirmed in studies using fully infectious ZEBOV, providing a rationale for testing combination therapies in animal models of lethal Ebola challenge. These studies open up new possibilities for novel therapeutic options, in particular combination therapies, which could prevent and treat Ebola infection and potentially reduce drug resistance.

Toremifene, a selective estrogen receptor modulator, significantly improved biochemical recurrence in bone metastatic prostate cancer: a randomized controlled phase II a trial.

BACKGROUNDS: Durability of androgen-deprivation therapy (ADT) for prostate cancer (PC) is limited. Additional selective estrogen receptor modulators (SERMs) may prolong the durability of ADT, because androgen and estrogen signaling drive PC progression. METHODS: Men with treatment-naïve bone metastatic PC were randomly assigned in 1:1:1 fashion to receive ADT, toremifene 60 mg plus ADT (TOPADT), or raloxifene 60 mg plus ADT (RAPADT). The primary endpoint was the biochemical recurrence (BCR) rate, and secondary endpoints were changes of scores of the visual analogue scale (VAS) and the functional assessment of cancer therapy (FACT). RESULTS: A total of 15 men, 5 each, were allocated to one of the three treatment arms. The basal serum prostate-specific antigen (PSA) level was 198 ng/mL (median, range; 30-8428). Bone metastases were graded as 1 (n = 11), 2 (n = 3), and 3 (n = 1) by the extent of disease. During the median follow-up period of 1370 days (range; 431-1983), BCR occurred in 3, 0 and 2 men in ADT, TOPADT and RAPADT group, respectively. The 5-year BCR-free rate was 30, 100 and 53 %, in ADT, TOPADT and RAPADT group, respectively (p = 0.04, ADT v.s. TOPADT, p = 0.48, ADT v.s. RAPADT and p = 0.12, TOPADT v.s. RAPADT). Scores of VAS improved in all groups and remained stable throughout the study. This analysis is limited as a preliminary result in a single center. CONCLUSIONS: Toremifene with conventional ADT significantly improved the BCR rate in treatment-naïve bone metastatic PC. Further clinical trials are warranted to confirm the promising clinical efficacy of this combination therapy. TRIAL REGISTRATION: The protocol was registered at the University Hospital Medical Information Network ( UMIN ID;0,000,064,000 ) in Sep 25, 2011.

Nano-Targeted Delivery of Toremifene, an Estrogen Receptor-α Blocker in Prostate Cancer.

PURPOSE: Estrogen Receptor-α (ERα) expression is increased in prostate cancer and acts as an oncogene. We propose that blocking of estrogen hormone binding to ERα using the ERα blocker toremifene will reduce the tumorigenicity of prostate cancer, and nano-targeted delivery of toremifene will improve anticancer efficacy. We report the synthesis and use in an orthotopic mouse model of PLGA-PEG nanoparticles encapsulating toremifene and nanoparticles encapsulating toremifene that are also conjugated to anti-PSMA for targeted prostate tumor delivery. METHODS: Human prostate cancer cell line PC3M and a nude mouse model were used to test efficacy of nano-targeted and nano-encapsulated toremifene versus free toremifene on the growth and differentiation of tumor cells. RESULTS: Treatment with free toremifene resulted in a significant reduction in growth of prostate tumor and proliferation, and its nano-targeting resulted in greater reduction of prostate tumor growth, greater toremifene tumor uptake, and enhanced tumor necrosis. Tumors from animals treated with nano-encapsulated toremifene conjugated with anti-PSMA showed about a 15-fold increase of toremifene compared to free toremifene. CONCLUSIONS: Our data provide evidence that blocking ERα by toremifene and targeting prostate cancer tissues with anti-PSMA antibody on the nanoparticles' surface repressed the tumorigenicity of prostate cancer cells in this mouse model.

Efficacy of high-dose toremifene therapy in postmenopausal patients with metastatic breast cancer resistant to aromatase inhibitors:a retrospective, single-institution study.

BACKGROUND: Aromatase inhibitors(AI)have established efficacy as first-line therapy in postmenopausal patients with hormone-sensitive metastatic breast cancer(MBC). However,the use of endocrine therapy has not yet been established for second-line and later therapy. Our study examined the efficacy of high-dose toremifene therapy(HD-TOR)in patients with MBC resistant to AIs. PATIENTS AND METHODS: A retrospective analysis was carried out to determine outcomes in 85 postmenopausal patients with MBC resistant to AIs who began HD-TOR between May 2001 and October 2011. The patients received toremifene 120 mg once daily on consecutive days. RESULTS: The objective response rate(ORR)was 21.2%,the clinical benefit rate(CBR)was 41.2%,and the median time to treatment failure(TTF)was 7.3 months. The CBR was high in patients with ER-positive status(p=0.045),no visceral metastasis(p=0.037),HD -TOR as first- or second-line therapy(p=0.007),no history of tamoxifen(TAM)therapy(p=0.019),and no history of chemotherapy(p=0.017). Multivariate analysis showed that ER-positive status(p=0.005, odds ratio: 0.064)and no visceral metastasis(p=0.034, odds ratio: 0.323)were independent predictors of efficacy. The TTF was significantly longer in patients with ER-positive status(p=0.019)and no history of TAM therapy(p=0.015). Multivariate analysis showed that ER-positive status(p=0.025, hazard ratio: 0.377)and no history of TAM therapy(p=0.002, hazard ratio: 0.422)were independent predictors of efficacy. No patient discontinued HDTOR therapy due to adverse events. CONCLUSION: HD-TOR is an effective endocrine therapy for patients with MBC who have failed AIs.

Clinical and laboratory patterns during immune stimulation in hormone responsive metastatic breast cancer.

This study clarifies the relationship between clinical and laboratory patterns, in endocrine-responsive metastatic breast cancer patients treated with a cyclic beta-interferon and interleukin-2 sequence added to anti-estrogens. In 31 patients, a regular laboratory and immunological assessment was made. During clinical benefit, as opposed to progression, a significant increase in the total number of lymphocytes, CD4+, CD8+, NK cells, CRP and IL-12 was confirmed. Also, a significant CEA, TPA, CA15.3 decrease occurred 24-72h after interleukin-2 administration. At the progression, both basally and after interleukin-2 stimulation, the mean values of CD4+ plus CD25+ cells were more than twice higher than during clinical benefit, with a decrease of CD4+ plus CD8+ (Teffector)/CD4+CD25+ (Treg) ratio. Moreover, a significant increase for CEA and for all 3 markers (standardized values) was found 24-72h after interleukin-2 administration. In patients who survived less than 5years, the Treg cell increase occurred at a significantly shorter time interval than in those who survived longer than 5years (20 vs 45.5months, respectively; P=0.001). These data show laboratory evidence of the effect of immunotherapy as well as that of hormone resistance occuring concomitantly with a laboratory pattern compatible with immune inhibition.

Toremifene and tamoxifen have similar efficacy in the treatment of patients with breast cancer: a meta-analysis of randomized trials.

A meta-analysis of randomized trials was performed to compare the efficacy of toremifene (TOR) with tamoxifen (TAM) in patients with breast cancer. A total of 4,768 intention-to-treat patients from nine randomized trials were identified, with 2,587 patients in TOR group and 2,181 patients in TAM group. The primary outcomes were objective response rate (ORR), time to progression (TTP), and overall survival (OS). The ORR for TOR group was 26.2 % (303/1,156), whereas the ORR for TAM group was 25.2 % (284/1,128). The pooled RR suggested that the ORR were not statistically different between the two therapeutic groups (RR 1.04, 95 % CI 0.91-1.20, P = 0.57). The median TTP was 6.7 months for the TOR group and 9.7 months for the TAM group. The median OS was 30.1 months for the TOR group and 31.7 months for the TAM group. There were no significant difference in TTP and OS between two therapeutic groups (for TTP: HR 0.91, 95 % CI 0.82-1.00; for OS: HR 1.02, 95 % CI 0.91-1.15). Adverse events were generally similar in two therapeutic groups, but TOR may cause fewer vaginal bleeding (4.0 vs. 6.7 %, P < 0.01), headache (0.2 vs. 3.1 %, P = 0.02) and thromboembolic events (4.7 vs. 7.0 %, P = 0.04). Sensitivity analyses were performed by deleting a single study each time; all the results were not materially altered. In summary, the results of this meta-analysis suggest that TOR and TAM have similar efficacy in the treatment of patients with breast cancer.

Phase II clinical trial of high-dose toremifene as primary hormone therapy in aromatase inhibitor-resistant breast cancer.

BACKGROUND: Third-generation aromatase inhibitors(AIs)are now common in adjuvant hormone therapy for breast cancer in postmenopausal women. However, a suitable treatment has yet to be established for patients who develop cancer recurrence during or after adjuvant AI therapy. PATIENTS AND METHODS: This prospective study evaluated the efficacy and safety of 120mg/day toremifene citrate(TOR-120)administered orally to 23 patients with recurrent breast cancer who were receiving or had received adjuvant AI therapy. Primary therapy for recurrence was TOR-120 monotherapy. RESULTS: The response rate was 13. 0%(partial response: three patients), the clinical benefit rate was 78. 3%(partial response: three patients; long-term stable disease: 15 patients), and median time to progression was 8. 1 months. Grade 1 adverse events such as loss of appetite, sweating, flushing and edema face were observed. CONCLUSION: TOR-120 monotherapy was effective and safe as a primary hormone therapy for recurrent breast cancer unresponsive to AIs.

The clinical benefit of high-dose toremifene for metastatic breast cancer.

INTRODUCTION: Toremifene(TOR)is a selective estrogen receptor modulator(SERM). A high dose of 120 mg TOR(HD-TOR) has been used for recurrent breast cancer in Japan, but there is still insufficient evidence regarding the efficacy of HD-TOR. PATIENTS AND METHODS: HD-TOR was administered for recurrent or metastatic breast cancer between January 2003 and May 2012. The primary end point of the study was the tumor response rate. Bone metastasis cases were excluded from the efficacy analysis, but were included in the safety population. RESULTS: A total of 21 patients registered in the study and the 2 patients with bone metastasis only were excluded from the efficacy analysis. The median follow-up period was 8. 3 months. None of the patients in the study had a CR, 4 had a PR(21. 1%), 9 had SD(47. 4%), and 6 had PD(31. 6%). Eight of the 9 SD cases had a long-term SD. The ORR was 21. 1% and the CB rate was 63. 2%. The median TTP of CB cases was 18. 3 months. None of the patients discontinued treatment because of a grade 3 or grade 4 adverse effects. CONCLUSION: In summary, the current study showed that HD-TOR may lead to a CB for recurrent breast cancer in first- or second-line treatment rather than thirdline. In particular, HD-TOR may give a benefit in highly endocrine-sensitive cases.

[A study of the efficacy of high-dose toremifene in advanced and recurrent breast cancer].

Recently, many patients have been treated with aromatase inhibitors(AI), either in an adjuvant setting or as a treatment for recurrence. The efficacy and safety of high-dose toremifene(HD-TOR)were evaluated in 18 patients with advanced/recurrent breast cancer. Twelve of the 18 patients had received AI just prior to the study treatment. The clinical benefit rate was 56%(PR: 28%, long SD: 28%). Progression-free median survival was 5. 5 months. Adverse events were mild and toremifene was well-tolerated. The results suggest that HD-TOR should be considered early on as a second-line treatment, or as a later treatment option for AI-resistant breast cancer.

[Efficacy of high-dose toremifene as a second-line hormone therapy in patients with advanced or metastatic breast cancer resistant to aromatase inhibitor].

BACKGROUND: Aromatase inhibitors(AIs)are frequently employed for advanced or metastatic postmenopausal breast cancer as first-line hormone therapy. However, it is unknown which hormonal agent is the most appropriate after AI has failed. PATIENTS AND METHODS: Five hormone-responsive postmenopausal women who used AI as a first-line hormone therapy for advanced or metastatic breast cancer, but AI failed, received high-dose toremifene therapy(HD-TOR: 120mg/day)in our hospital. Efficacy and safety were evaluated. RESULTS: Patients were all-hormone sensitive, and only one case had HER2 overexpression. All patients had received anastrozole(ANA)as first-line hormone therapy. Of a total of 5 cases, 3 were evaluated as partial responses(PR), 1 was a long stable disease(L-SD), and 1 was a progressive disease(PD). The overall response rate (RR)was 60. 0%(3/5 cases)and the clinical benefit rate(CB)was 80. 0%(4/5 cases). Grade 1 dry mouth was observed in one case as an adverse event. CONCLUSIONS: HD-TOR as a second-line therapy is optimal for advanced or metastatic AI resistance postmenopausal breast cancer.

Granulosa cell tumor of the ovary after long-term use of tamoxifen and toremifene.

The relation between the use of tamoxifen and gynecologic tumors has been documented. In this case, a 58-year-old postmenopausal woman had been treated with tamoxifen for 5 years followed by toremifene for 1.5 years due to the presence of stage II estrogen receptor-positive breast cancer. The patient was found to have a stage Ic granulosa cell tumor of the ovary despite undergoing annual gynecologic examinations. This report presents a case of granulosa cell tumor of the ovary after the long-term use of tamoxifen and toremifene.

Relevance of the selective oestrogen receptor modulators tamoxifen, toremifene and clomiphene in doping field: endogenous steroids urinary profile after multiple oral doses.

The present study was performed to investigate the influence of the intake of selective oestrogen receptor modulators on the urinary endogenous steroids profile. For this purpose the circadian variability of luteinizing hormone, follicle-stimulating hormone, testosterone, 5α-androstan-3α,17ß-diol, 5ß-androstan-3α,17ß-diol, epitestosterone, 4-androstenedione, androsterone and etiocholanolone were measured on eight subjects (four males and four females) by gas chromatography-mass spectrometry and chemiluminescent immunometric assay techniques before and after oral administration of multiple doses of either tamoxifen (80 mg for 2 days) or toremifene (120 mg for 2 days) or clomiphene (100 mg for 2 days). The individual baseline variability of the steroids studied was set up by collecting the urine samples every 3 h, for 3 days prior to the treatment; whereas the evaluation of the effects of the oral administration of multiple doses of selective oestrogen receptor modulators on the steroid urinary profile was assessed by collecting urine samples every three hours for at least five days from the first administration. The results of our measurements showed that, only in male subjects, the relative urinary concentrations of testosterone, epitestosterone and 4-androstenedione were significantly altered generally after the second day of drug administration. While no significant effects were recorded in both sexes on the luteinizing hormone, follicle-stimulating hormone, androsterone, etiocholanolone, 5α-androstan-3α,17ß-diol and 5ß-androstan-3α,17ß-diol urinary levels and on testosterone/epitestosterone, 5α-androstan-3α,17ß-diol/5ß-androstan-3α,17ß-diol and androsterone/etiocholanolone ratios.

[A retrospective study of high-dose toremifene treatment for patients with aromatase inhibitor refractory advanced or metastatic hormone receptor-positive breast cancer].

Aromatase inhibitors (AI) have largely replaced tamoxifen as the first-line of treatment for postmenopausal women with advanced or metastatic hormone-receptor-positive breast cancer. However, there is no established strategy for treating AI refractory cases. In this study, we investigated the efficacy of high-dose Toremifene therapy (HD-TOR). From January 2001 through April 2010, nineteen patients received 120 mg of TOR daily. The overall response rate was 36.8% (CR; 1, PR; 6), and the clinical benefit was 47.4%. The clinical benefit rate to each of the metastatic organs were: lung, 42.9%; bone, 13%; liver, 25%; and lymph node, 40%. A higher clinical benefit rate was observed in lung or lymph node metastases. The clinical benefit rate of HD-TOR as first to third-line therapy was 50%, which was more effective than that of fourth-line therapy. Our data suggests that HD-TOR may be one of the effective treatment strategies for patients with AI refractory advanced or metastatic hormone receptor-positive breast cancer.

[Regulation mechanism of breast cancer resistance protein by toremifene to reverse BCRP-mediated multidrug resistance in breast cancer cells].

OBJECTIVE: To explore the regulation mechanism of the reversal of breast cancer resistance protein-mediated multidrug resistance by toremifene. METHODS: Two recombinant plasmids (pcDNA3-promoter-BCRP and pcDNA3-CMV-BCRP) were designed to express the wild-type full-length BCRP cDNA enforced driven by its endogenous promoter containing a functional ERE and a CMV promoter as control, respectively. Two recombinant plasmids were transfected into ERα-positive MCF-7 and ERα-negative MDA-MB-231 breast cancer cell lines. Four kinds of BCRP expressing cell lines of MCF-7/Promoter-BCRP, MCF-7/CMV-BCRP, MDA-MB-231/Promoter-BCRP and MDA-MB-231/CMV-BCRP were established in which BCRP was promoted by the BCRP promoter and a CMV promoter as control, respectively. The drug resistant cells were treated with toremifene. Then RT-PCR, Western blot, mitoxantrone efflux assays and cytotoxicity assay were performed to detect the reversal function of BCRP by toremifene on the drug resistance cell lines. RESULTS: Toremifene significantly downregulated BCRP mRNA levels in a dose-dependent manner in ERα-positive MCF-7/Promoter-BCRP cells than that of untreated control cells. In MCF-7/Promoter-BCRP cells, toremifene at the dose of 0.1, 1 and 10 µmol/L decreased BCRP mRNA expression by 29.5% (P < 0.05), 68.1% (P < 0.01) and 97.4% (P < 0.01), respectively. After being treated with toremifene and 17ß-estradiol, the BCRP mRNA level in MCF-7/Promoter-BCRP cells was 64.2% ± 1.3%, significantly higher than that of toremifene treatment control cells (3.8% ± 0.2%,P < 0.01). Furthermore, the effect of toremifene on BCRP protein is similar in BCRP mRNA. Toremifene obviously increased the mitoxantrone fluorescence intensity and decreased the efflux activity by 47.3% (P < 0.05) in MCF-7/promoter-BCRP cells when compared with the untreated control, whereas intracellular accumulation of mitoxantrone obviously decreased and the efflux activity increased by 61.5% were observed in combination with 17ß-estradiol when compared with toremifene treatment alone. The results therefore suggested that toremifene reversed mitoxantrone resistance in MCF-7/Promoter-BCRP cells. However, in MCF-7/CMV-BCRP, MDA-MB-231/Promoter-BCRP and MDA-MB-231/CMV-BCRP cells, toremifene or in combination with 17ß-estradiol did not affect intracellular mitoxantrone uptake. CONCLUSION: Taken together, our findings indicate that expression of BCRP is downregulated by toremifene, via a novel transcriptional mechanism which might be involved in the ERE of BCRP promoter through ER-mediated to inactivate the transcription of BCRP gene.

Excellent outcomes with adjuvant toremifene or tamoxifen in early stage breast cancer.

BACKGROUND: Fareston (toremifene) and tamoxifen, both selective estrogen receptor modulators, are therapeutically equivalent treatments for metastatic breast cancer. We hypothesized that toremifene as compared with tamoxifen given as adjuvant therapy for early stage breast cancer would result in equivalent survival with an improved side effect profile, therefore, providing superior therapeutic efficacy. METHODS: The North American Fareston versus Tamoxifen Adjuvant trial assigned 1813 perimenopausal or postmenopausal women with hormone receptor (HR)-positive invasive breast cancer to adjuvant treatment with either tamoxifen or toremifene. The primary outcomes evaluated were disease-free survival (DFS) and overall survival (OS). RESULTS: Median follow-up was 59 months. The baseline characteristics of the 2 treatment groups were well-balanced. On the basis of intent-to-treat, 5-year actuarial DFS was not significantly different between tamoxifen and toremifene (91.2% [standard error of the mean [SE] 1.2%] vs 91.2% [SE 1.1%], respectively). Similarly, 5-year actuarial OS was not significantly different between tamoxifen and toremifene (92.7% [SE 1.1%] vs 93.7% [SE 1.0%], respectively). Controlling for patient age, tumor size, and tumor grade, a Cox multivariate survival analysis found no difference between patients randomized to toremifene versus tamoxifen in terms of OS (OR = 0.951; 95% confidence interval [CI], 0.623-1.451, P = .951) or DFS (OR = 1.037; 95% CI, 0.721-1.491, P = .846). Adverse events were similar in the 2 groups. CONCLUSIONS: Women treated with adjuvant hormonal therapy enjoyed excellent DFS and OS. No significant differences were found between treatment with either tamoxifen or toremifene. Treatment of HR-positive patients with either tamoxifen or toremifene is appropriate.

[Clinicopathological features of endometrial carcinoma in tamoxifen- and toremifene-treated breast cancer patients].

OBJECTIVE: Estrogen is involved in the development of breast and endometrial cancers, and tamoxifen, an antiestrogen, is associated with an increased risk of endometrial cancer. Recently, tamoxifen use is suggested to be associated with the development of aggressive endometrial tumors. We performed a retrospective study to clarify the effects of tamoxifen (TAM) and toremifene (TOR) on clinicopathological features of endometrial cancer subsequently developed in breast cancer patients. METHODS: Endometrial cancer patients diagnosed at our institution from 2000 through 2008 were studied. RESULTS: Of 194 patients with endometrial cancer, 18 (9.3%) developed breast cancer before endometrial cancer diagnosis. Mean age was 66 years, and the median time interval between breast and endometrial cancer diagnosis was 10 years (range, 1.5 -32 years). Nine patients developed aggressive tumors(serous, clear cell, small cell carcinoma, and carcinosarcoma), and the remaining nine developed endometrioid tumor. Patients with aggressive tumor had a lower 5-year disease-specific survival (0% vs 88%, p<0.01). Ten patients had used TAM and/or TOR, and six had not; aggressive tumors developed in six of 10 TAM/TOR users, and in one of six nonusers (p=0.15), and the 3-year disease-specific survival rate was not different between TAM/TOR users and nonusers (62% vs 53%, p=0.84). Time intervals from breast cancer and endometrial cancer diagnosis were 10-16 years for TAM users and 5-6 years for TOR users (p=0.02). CONCLUSION: Tamoxifen/toremifene use for breast cancer did not affect the prognosis of subsequent endometrial cancer in our small study; however, further studies were warranted. The use of toremifene may be associated with a shorter interval from breast cancer to endometrial cancer diagnosis compared to tamoxifen.