Double blind randomized controlled trial of efficacy of ormeloxifene for the treatment of fibroadenoma (The FIBROCENT study).

BACKGROUND: We evaluated the effectiveness of Ormeloxifene (Centchroman) on regression of Fibroadenoma in a double-blind randomized controlled trial. METHODS: Patients with biopsy proven Fibroadenoma were enrolled between March 2023 and October 2023 and divided in two arms- Ormeloxifene group and Placebo group. Effectiveness of the treatment was evaluated using USG. No residual mass was defined as complete regression and more than 30% decrease in size was considered as partial regression. RESULTS: A total of 130 consecutive patients with Fibroadenoma were randomized to Ormeloxifene group (n = 65) and Placebo Group (n = 65). Complete regression was observed in 9% (6/65) patients in Ormeloxifene group and 10.8% (7/65) in Placebo Group at the end of 12 weeks (p = 0.49). Twenty one patients taking Ormeloxifene reported adverse events as compared to none in the other group. CONCLUSION: In our study Ormeloxifene was not found to be effective in treatment of fibroadenoma and had concerning side effects.

Metformin as a new option in the medical management of breast fibroadenoma; a randomized clinical trial.

BACKGROUND: Fibroadenoma (FA) is the most common benign solid breast mass in women, with no definite method of management. Because fibroadenoma is dependent on female sex hormones and comprises hypertrophic changes at cellular levels, we investigated the effects of metformin (MF), a safe hypoglycemic agent with anti-estrogenic and anti-proliferative properties, in the management of fibroadenoma. METHODS: In this randomized clinical trial study, eligible women with fibroadenomas were assigned randomly to the metformin (1000 mg daily for six months) or the placebo group. Breast physical and ultrasound exam was performed before and after the intervention, and the changes in the size of fibroadenomas were compared in the two groups. RESULTS: Overall, 83 patients in the treatment, and 92 in the placebo group completed the study. A statistically significant difference in changing size between the two groups was observed only in the smallest mass. In the largest FAs, the rate of size reduction was higher in the treatment group (60.2 % vs. 43.5 %); while a higher rate of enlargement was observed in the placebo group (38 % vs. 20.5 %). In the smallest FAs, the rate of the masses that got smaller or remained stable was about 90 % in the treatment group and 50 % in the placebo group. We categorized size changes of FAs into < 20 % enlargement and ≥ 20 % enlargement. The odds ratio (OR) for an elargemnt less than 20% was 1.48 (95 % CI = 1.10-1.99) in the treatment group in comparison with the placebo group; the odds for an enlargement less than 20% was higher in women with multiples fibroadenomas (OR = 4.67, 95 % CI: 1.34-16.28). In our study, no serious adverse effect was recorded, and the medicine was well-tolerated by all users. CONCLUSIONS: This is the first study that evaluates the effect of MF on the management of fibroadenoma, and the results suggest a favorable effect. Larger studies using higher doses of MF and including a separate design for patients with single or multiple FAs are suggested in order to confirm this effect. TRIAL REGISTRATION: This trial (IRCT20100706004329N7) was retrospectively registered on 2018-10-07.

[A Case of Lobular Carcinoma In Situ Occurring in a Fibroadenoma of the Breast].

The patient was a 43-year-old premenopausal woman with a 14×11 mm tumor in upper outer quadrant of the left breast, diagnosed as a fibroepithelial lesion using core needle biopsy. Resection was performed. Histopathologically, the resected specimen was diagnosed as a fibroadenoma with lobular carcinoma in situ(LCIS). Tamoxifen was administered as endocrine therapy to reduce recurrence risk. We report a case of LCIS accidentally discovered by surgical resection of a benign tumor.

Single cell profiling of female breast fibroadenoma reveals distinct epithelial cell compositions and therapeutic targets.

Fibroadenomas (FAs) are the most common breast tumors in women. No pharmacological agents are currently approved for FA intervention owing to its unclear mechanisms and a shortage of reproducible human models. Here, using single-cell RNA sequencing of human FAs and normal breast tissues, we observe distinct cellular composition and epithelial structural changes in FAs. Interestingly, epithelial cells exhibit hormone-responsive functional signatures and synchronous activation of estrogen-sensitive and hormone-resistant mechanisms (ERBB2, BCL2 and CCND1 pathways). We develop a human expandable FA organoid system and observe that most organoids seem to be resistant to tamoxifen. Individualized combinations of tamoxifen with ERBB2, BCL2 or CCND1 inhibitors could significantly suppress the viability of tamoxifen-resistant organoids. Thus, our study presents an overview of human FA at single-cell resolution that outlines the structural and functional differences between FA and normal breast epithelium and, in particular, provides a potential therapeutic strategy for breast FAs.

Expression of Ki-67 and Bcl-2 biomarkers in normal breast tissue from women of reproductive age treated with raloxifene.

OBJECTIVE: To evaluate the effect of raloxifene on antigen expression of Ki-67 and Bcl-2 in normal breast tissue. MATERIALS AND METHODS: A randomized, double-blind study was conducted with 40 premenopausal women aged 18-40 years who had been diagnosed with fibroadenoma of the breast. The patients were divided into two groups: Group A (placebo, n = 20), and Group B (raloxifene 60 mg, n = 20).The medication was taken for 22 days initiating from the first day of the menstrual cycle. An excisional biopsy was performed on the 23rd day. At the time of biopsy, a sample of normal breast tissue was collected to evaluate protein expression of Ki-67 and Bcl-2. The Student's t test and Chi-square test were used for statistical data analysis and the significance level was established at 5%. RESULTS: The mean percentage of nuclei stained for Ki-67 was 22.16 ± 1.91 (p < 0.001) and 2.161 ± 0.181 in the control group and the raloxifene group. The expression of Bcl-2 was similar in both groups (p = 0.8888). CONCLUSIONS: Raloxifene treatment significantly reduced antigen expression of Ki-67, but failed to have any significant results on the Bcl-2 expression. Further studies are warranted to evaluate the mechanism of raloxifene on apoptosis in normal breast tissue.

Evaluation of estrogen and progesterone receptors in non-neoplastic breast tissue of women of reproductive age exposed to tamoxifen and raloxifene: a randomized, double-blind study.

The objective of the present study was to compare the effects of tamoxifen and raloxifene in non-neoplastic breast epithelium. A randomized, double-blind study was carried out in 57 ovulatory, premenopausal women of 18-40 years of age, who had been diagnosed with fibroadenoma of the breast. The patients were divided into three groups: Group A: placebo, n=20; Group B: tamoxifen 20 mg/day, n = 21; and Group C: raloxifene 60mg/day, n=16. The study medication was given for 22 days starting on the first day of the menstrual cycle. On the 23rd day, the fibroadenoma was removed and a sample of non-neoplastic breast tissue was collected for immunohistochemical evaluation of estrogen and progesterone receptors. Comparison between the mean percentages of stained nuclei in the three groups was performed by analysis of variance and multiple comparisons, using Tukey's method to compare pairwise means, with significance established at P < 0.05. Exposition to tamoxifen or raloxifene resulted in a significant and similar reduction in the mean percentage of stained nuclei for estrogen and progesterone receptors (P<0.0001). Tamoxifen and raloxifene reduce progesterone and estrogen receptor alpha expression significantly and to a similar extent in the non-neoplastic breast tissue of women of reproductive age.

Expression of nm23, MMP-2, TIMP-2 in breast neoplasm in Zhengzhou Center Hospital, China.

BACKGROUND: In recent years, the carcinoma of the breast threatens to women's health heavily. Invasion and metastasis is the main reason that results in the patients death. OBJECTIVE: A prospective study is made in the center hospital of zhengzhou, in order to approach the expression of nm23, MMP-2 (Matrix metallo-proteinase-2), TIMP-2 (it's tissue-inhibitor of the metalloproteinase-2) in the breast neoplasm and the relationship with invasion and metastasis. METHODOLOGY: This study applied the immunohistochemistry technique SP method RESULTS: In fibroadenoma, ductal carcinoma in situ and invasive ductal carcinoma of the breast 4 groups, the positive immunostaining rate of nm23, MMP-2 and TIMP-2 have significant difference among 4 groups (p < 0.05). In the breast invasive ductal carcinoma, the expression of nm23 and TIMP-2 decreased or the expression of MMP-2 increased CONCLUSION: This suggested that invasion and metastasis is ability of the neoplasm. MMP-2 in the breast ductal carcinoma in situ appears of high expression and this suggested that the positive expression of this onco-proteins was the early incident in the genetic course of the breast cancer The unite detection of nm23, MMP-2 and TIMP-2 expression would contribute to the early diagnosis and prognostic assessment of the carcinoma of the breast.

Effect of oral contraceptive with and without associated estriol on ultrasound measurements of breast fibroadenoma: randomized clinical trial.

CONTEXT AND OBJECTIVE: Fibroadenomas are the most common benign tumors of the female breast. The aim of this study was to evaluate the proliferative activity of breast fibroadenoma as shown by ultrasound measurements, following administration of oral contraceptives with and without associated estriol. DESIGN AND SETTING: This was a randomized, double-blind, placebo-controlled clinical trial carried out in the Mastology Sector, Department of Gynecology, Universidade Federal de São Paulo. METHODS: We studied 33 women with fibroadenomas. Ten were placed in group 1 and took an oral contraceptive consisting of levonorgestrel and ethinyl estradiol together with placebo material in the same capsule, for four consecutive cycles with a seven-day interval between them. The other 23 patients constituted group 2 and took the oral contraceptive as above together with estriol in the same capsule, in the same way as done by the group 1 patients. We took ultrasound measurements of their tumors (in three dimensions) before and after the intake of medication. At the end of the study, all the patients had their tumors removed by surgery. RESULTS: We observed decreased fibroadenoma width among the users of oral contraceptives with placebo, and this decrease was statistically significant. In the other group, we did not observe any changes (in width, length or height). CONCLUSION: The results confirm that estriol may block the protective effect of oral contraceptives on fibroadenomas, since we observed decreased fibroadenoma width among the group 1 patients but not the group 2 patients.

A randomized trial of Boswellia in association with betaine and myo-inositol in the management of breast fibroadenomas.

OBJECTIVE: Breast fibroadenoma is a common finding in young women and actually accounts for the majority of benign breast lumps. Fibroadenoma does not require any treatment unless clinical symptoms (mostly mastalgia) or histological markers of cancer risk (atypia) impose specific medical or surgical intervention. In symptomatic fibroadenoma, anti-estrogenic treatments provided evidence of success. Yet, these therapies are often associated with relevant side effects that lead to drug treatment discontinuation. Additionally, in such cases, relapse is a frequent issue. Therefore, an optimal strategy is still warranted. Boswellia, betaine and myo-inositol have already been proved to modulate different pathways - inflammatory, metabolic, oxidative and endocrine processes - in a wide array of human tissues. Based on that background, we hypothesized that these substances can effectively synergize in inducing the regression of fibroadenoma. PATIENTS AND METHODS: We included 64 patients ≤ 30 years of age with fibroadenoma. The patients were randomized into two groups. The experimental group was treated with an association of Boswellia, betaine, myo-inositol, B-group vitamins and N-acetylcysteine for 6 months; otherwise, the placebo group was treated only with B-group vitamins and N-acetylcysteine. Patients were monitored at the enrollment and the end of the study for evaluating the clinical response. RESULTS: A significant clinical improvement was observed in the experimental arm. Fibroadenoma median volume reduction averaged 17.86% in the experimental group and 5.96% in the placebo group. Moreover, 14 out of 36 (38.88%) patients showed a reduction of fibroadenoma volume compared to 5/28 (17.85%) observed in the placebo group (p = 0.005). CONCLUSIONS: A supplementation with Boswellia, betaine and myo-inositol reduces fibroadenoma dimension in young women. No relevant side effects have been recorded.

[Investigation of the drug "Mamoclam" for the treatment of patients with fibroadenomatosis of the breast].

The clinical trial of a new drug "mamoclam" was carried out in patients with benign breast disease. The drug contains omega-3 polyunsaturated fatty acids, iodine and chlorophyll derivatives and is produced from the brown sea alga laminaria. The study involved 33 patients (mean age 42.5 +/- 1.1 yrs). Two tablets were administered thrice a day for three months. Examination included clinical evaluation of symptoms of mastopathy and dysalgomenorrhea, breast sonography and mammography. Therapeutic response presented as reduced mastalgia, premenopausal syndrome, dysmenorrhea and algomenorrhea, breast cyst regression as well as attenuated pain associated with benign breast disease and palpation. Positive response was reported in 94%. The drug should be recommended for benign breast disease treatment.

Effects of low dose tamoxifen on normal breast tissue from premenopausal women.

The aim of this study was to determine the effects of low doses of tamoxifen (5 and 10mg/day) for 50 days compared with the standard dose (20 mg/day) on breast biomarkers measured in normal breast tissue from premenopausal patients. A randomised double-blind study was performed using tissue from 56 premenopausal women with a diagnosis of fibroadenoma of the breast. Excisional biopsy was performed on the 50th day of therapy. Normal breast tissue samples were collected during surgery. The patients were divided in groups: A (placebo, n=11); group B (5 mg, n=16), group C (10 mg, n=14) and group D (20 mg, n=15). In this cross-sectional study, differences in the expression of Oestrogen Receptor alpha (ERalpha), Progesterone Receptor (PR), Ki-67, apoptotic bodies and mitotic index between the different groups after treatment can be seen on the normal breast tissue. We believe that a lower dose of tamoxifen could reduce the side-effects associated with treatment without affecting its chemopreventive activity in the breast.

Effects of a progestogen on normal human breast epithelial cell apoptosis in vitro and in vivo.

Many investigators have reported cyclic proliferation of normal human breast epithelial cells. A delicate balance between proliferation and apoptosis (programmed cell death) ensures breast homeostasis. Both the follicular and luteal phases of the menstrual cycle are characterized by proliferation, whereas apoptosis occurs only at the end of the latter phase. In this study, we observed that the withdrawal of a synthetic progestin (nomegestrol acetate or NOMAC), but not continuous treatment with it, induced apoptosis of normal human breast epithelial cells in vitro and in women who applied NOMAC gel to their breasts. Furthermore, this apoptotic response was specific to normal breast cells, since withdrawal of NOMAC did not induce apoptosis of tumoral T47D cells in vitro or of fibroadenoma cells in women. These observations open up new perspectives in the prevention of hyperplasia and breast cancer.

Effect of a half dose of tamoxifen on proliferative activity in normal breast tissue.

OBJECTIVES: To investigate the proliferative activity of the mammary gland epithelium and plasma levels of progesterone, estradiol, prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) in premenopausal women treated with 10 and 20 mg of tamoxifen (TAM) for 22 days. PATIENTS AND METHODS: A randomized double-blind study was performed with 43 premenopausal women with a diagnosis of fibroadenoma of the breast. The patients were divided into three groups: A (n = 15, placebo); B (n = 15, TAM 10 mg/day) and C (n = 13, TAM 20 mg/day). They started taking an oral dose of TAM or placebo on the very first day of the menstrual cycle. Lumpectomy was performed on the 22nd day of therapy. Normal breast tissue samples were collected during surgery, immediately immersed in 10% buffered formalin, processed for routine histology and immunohistochemistry for proliferating cell nuclear antigen (PCNA) detection. Two peripheral blood samples were collected, both on the 22nd day of the menstrual cycle, in order to evaluate the hormone levels. PCNA expressing epithelial cells were quantified by using a digital program Kontron Image System KS-300 in 1000 cells (400 x ). RESULTS: The percentage of cells expressing PCNA was significantly higher in the group receiving placebo (group A, 50.3%) when compared to groups receiving TAM 10 or 20 mg/day (group B, 24.1%; and group C, 23.2%, respectively) (P < 0.001). Differences between groups B and C were not significant. Levels of progesterone, estradiol and SHBG were significantly higher in B and C groups compared to group A. Increasing concentrations of FSH (P < 0.0045) and lower levels of prolactin (P < 0.0055) were only found in the group receiving 20 mg/day of TAM (group C). CONCLUSIONS: A 22-day TAM therapy, either with 10 or 20 mg/day, significantly reduced the PCNA expression and therefore the proliferative activity of the normal human breast tissue. Increasing levels of estradiol, progesterone and SHBG were associated with TAM therapy at 10 or 20 mg/day. However, a significant change of the level of FSH and prolactin was reached only with a 20-mg/day dose.

A reactive acrosyringeal proliferation in a patient with ectodermal dysplasia: eccrine syringofibroadenoma-like lesion.

A 33-year-old man with ectodermal dysplasia (ED) has suffered from keratotic, exudative, erythematous plaques on the genital area, thighs, and soles since age 17. Verrucous soft nodules in a cobblestone arrangement developed on the erythematous plaque on his left thigh when he was 31 years old. Histologic examination of the verrucous nodules demonstrated that they were composed of anastomosing thin cords of uniform, cuboidal, epithelial cells and a fibrovascular stroma. The changes are indicative of eccrine syringofibroadenoma of Mascaro (ESFA), which has been reported as a neoplasm, a hamartoma, or a nevus. With etretinate treatment, the verrucous nodules completely disappeared within two months. Similar, but much flatter, verrucous lesions recurred and disappeared twice during the subsequent two years period. These verrucous lesions were likely induced by irritation from urine, stool, and/or mechanical friction. This case of ESFA in a patient with ED clearly showed a reactive process which was successfully managed with oral etretinate.

Treatment of fibroadenomatous hyperplasia in cats with aglépristone.

Fibroadenomatous hyperplasia (FAH) is characterized by a rapid proliferation of mammary stroma and duct epithelium of 1 or more glands and predominantly affects younger female cats. Endogenous progesterone and exogenous progestogens play an important role in the genesis of FAH. The presence of progesterone receptors in fibroadenomatous tissue allows for targeted endocrine therapy with progesterone receptor blockers. We report on 22 young cats with FAH, none of which had responded to the withdrawal of progestogens or ovariectomy. The common signs were tachycardia (11 cats); skin ulceration, painful mammary glands, or both (16 cats); lethargy (8 cats); and anorexia (4 cats). The cats were treated with subcutaneous injections of the progesterone receptor blocker aglépristone on 1 (7 cats, 20 mg/kg) or 2 consecutive days (15 cats, 10 mg/kg/d) once weekly. All but 1 cat responded with a complete and lasting remission of signs after 1-4 weeks of treatment. Two cats had a short-term skin irritation at the site of the aglépristone injection. Two pregnant cats with FAH aborted after treatment with aglépristone and subsequently developed endometritis. In conclusion, the results of this study demonstrate that FAH in cats can be treated successfully with the progesterone receptor blocker aglépristone.

Evaluation of the ultrasonographic volume of breast fibroadenomas in women treated with tamoxifen.

BACKGROUND: Fibroadenomas are the most frequent benign breast neoplasias. Although they are hormone-dependent, no hormonal treatment of proven effectiveness is available for these neoplasias. The objective of the present study was to evaluate the ultrasonographic volume of fibroadenomas in premenopausal women treated with tamoxifen at the doses of 5, 10, 20 mg/day or with placebo for 50 days, starting on the 1st day of the menstrual cycle. METHODS: A prospective and randomized study was conducted on 62 eumenorrheic women aged 15 to 45 years with no hormonal treatment or pregnancy during the last 12 months, with a clinical, cytologic and ultrasonographic diagnosis of fibroadenoma, later followed by a biopsy diagnosis. The patients were divided at random into 4 groups: A (n=15; placebo), B (n= 16; 5 mg/day tamoxifen), C (n=16; 10 mg/day tamoxifen), and D (n=15; 20 mg/day tamoxifen). Fibroadenoma volume was measured by ultrasound at 3 different times: on the 22nd day of the cycle that preceded the beginning of tamoxifen treatment, after 1 month of treatment, and on the day of the biopsy (50th day). The mean volume obtained for groups A, B, C and D was 3, 3.3, 1.9, and 2.3 cm3, respecti-vely. RESULTS: Statistical analysis revealed a significant reduction in nodule size only in group D (p=0.0024). CONCLUSIONS: We conclude that tamoxifen significantly reduced fibroadenoma volume when administered for 50 days at the dose of 20 mg/day. Further clinical studies are needed using the drug for a longer period of time, and in order to exclude the need for unnecessary treatment in some women.

Tamoxifen down-regulates CaMKII messenger RNA levels in normal human breast tissue.

Tamoxifen was proven to reduce the incidence of breast cancer by 49% in women at increased risk of the disease in the Breast Cancer Prevention Trial. In order to identify potential candidates to explain the preventive effect induced by tamoxifen on breast cancer, normal breast tissue obtained from 42 fibroadenoma patients, randomly assigned to receive placebo or tamoxifen, was analyzed by the reverse Northern blot and RT-PCR techniques. The cDNA fragments used on Northern blot membranes were generated by the Human Cancer Genome Project funded by the Ludwig Institute for Cancer Research and FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil). Total RNA was obtained from normal breast tissue from patients with clinical, cytological and ultrasound diagnosis of fibroadenoma. After a 50-day treatment with tamoxifen (10 or 20 mg/day) or placebo, normal breast tissue adjacent to the tumor was collected during lumpectomy with local anesthesia. One differentially expressed gene, Calcium/calmodulin-dependent protein kinase II (CaMKII), was found to be down-regulated during TAM treatment. CaMKII is an ubiquitous serine/threonine protein kinase that has been implicated in the diverse effects of hormones utilizing Ca2+ as a second messenger as well as in c-fos activation. These results indicate that the down-regulation of CaMKII induced by TAM might represent alternative or additional mechanisms of the action of this drug on cell cycle control and response to hormones in normal human breast tissue.

[The goals and possibilities of drug therapy in mastopathies (results of a questionnaire addressed to oncologists in various regions of Russia)]. / Zadachi i vozmozhnosti lekarstvennogo lecheniia i dispanserizatsii bol'nykh mastopatiei (rezul'taty oprosa onkologov raznykh regionov Rossii).

The results of a questionnaire-based investigation involving 126 oncologists who treat mastopathy are presented. The study failed to establish any significant decrease in breast cancer morbidity as a result of treating mastopathy by medication. It was found that the whole problem of treatment and follow-up of dibraodenoma mammae needs to be re-considered.

[Study of an antioxidant dietary supplement "Karinat" in patients with benign breast disease]. / Izuchenie antioksidantnoi biologicheski aktivnoi dobavki k pishche "Karinat" u bol'nykh s fibroadenomatozom molochnykh zhelez.

A randomized double blind placebo-controlled trial of efficiency of a dietary supplement "Karinat" in patients with benign breast disease was carried out. Karinat contains beta-carotene 2.5 mg, alpha-tocopherol 5 mg, ascorbic acid 30 mg and garlic powder 150 mg per one tablet. Out of 66 patients, 33 patients were given karinat, 33 were given placebo. The patients reccived a tablet of karinal or placebo twice a day during 6 months. Examinations of the patients included clinical estimation of symptoms of mastopathy and dysalgomenorrhea, breast sonography and mammography. It was found that karinat reduced the severity of mastalgia, premenstrual syndrome, dysmenorrhea and algomenorrhea and caused regression of palpable symptoms of the breast fibromatosis. On the whole karinat had positive action in 75.8% that was significantly greater by 45.5% as compared with placebo. Karinat may be useful for the treatment of patients with benign breast disease.