Months Of Tamoxifen Treatment Research Articles

Health-related quality of life and productivity costs in breast cancer patients treated with tamoxifen in the Netherlands

The aim of this study was to describe health-related quality of life (HRQoL) and productivity in Dutch breast cancer patients treated with tamoxifen in an adjuvant setting. Patients who started treatment with a standard dose of tamoxifen and who gave written informed consent, were eligible for participation in this trial. A total of 145 patients were asked to complete a survey at 3 months (T1) and 6 months (T2) after initiation of tamoxifen. HRQoL was measured by the EQ-5D-5L and the FACT-B questionnaire, and productivity by using the iMTA Productivity Costs Questionnaire. At 3 months 137 (95%) and at 6 months 133 (92%) patients responded to the surveys. EQ-5D-5 L utility values for T1 and T2 were 0.81 ± 0.17 and 0.81 ± 0.18, respectively. FACT-B scores for T1 and T2 were 109 ± 17.9 and 108 ± 20.0, respectively. No differences in both EQ-5D-5 L utility and FACT-B scores were found between T1 and T2 (p > 0.05). Age and employment status were statistically significantly associated with FACT-B scores (p = 0.04 and p = 0.03, respectively), indicating that younger and unemployed respondents had lower FACT-B scores. Importantly, both short-term and long-term productivity improved during the first six months of tamoxifen treatment (p < 0.05). Here, short-term productivity losses (consisting of absenteeism, presenteeism and unpaid work) for T1 and T2 were estimated at € 855,- and € 396,-, respectively. Long-term productivity losses (consisting of absenteeism) for T1 and T2 were estimated at € 2876,- and € 1104,-, respectively. In conclusion, this study presents HRQoL scores using different instruments and detailed loss of productivity estimates for breast cancer patients treated with adjuvant endocrine therapy. The results presented here can be used to inform input parameters in health economic evaluations of interventions for patients with breast cancer in the Netherlands and other Western countries and ultimately support decision making.

Abstract P1-07-08: Endoxifen predicts early recurrence in breast cancer: A Brazilian prospective study

Abstract Tamoxifen is widely used in adjuvant therapy for breast cancer patients, but up to one-third of patients recur within 15 years after surgery even with its regular use. Low plasma levels of (Z)-endoxifen, the most active tamoxifen metabolite, have been studied as a possible predictor of treatment failure. Here, we evaluated plasma (Z)-endoxifen as a predictor of response to adjuvant treatment in breast cancer patients. Methods: One hundred forty nine patients were selected from a prospective cohort of consecutive newly diagnosed breast cancer patients recruited at a national referral center for treatment of cancer in Curitiba, Southern Brazil. Inclusion criteria were breast cancer women on stage I - III, positive hormone receptor tumors, operable, undergoing or not (neo)adjuvant chemotherapy, and signed for adjuvant tamoxifen for at least five years. At diagnosis, peripheral blood samples were collected for CYP2D6 genotyping for *1 *2, *3, *4, *5, *6, *7, *8, *9, *10, *17, *29 and *41 and subsequent metabolic activity scores according to phenotypes assigned for each allele (poor metabolizer PM; intermediate, IM; extensive, EM and ultrarapid metabolizer, UM). After the tamoxifen initiation, patients were evaluated at months 3, 6, and 12 for adherence and drug interactions, and plasma (Z)-endoxifen quantification. They were followed from April 2014 to April 2019. The study's primary objective was to evaluate whether (Z)-endoxifen plasma levels predict early recurrence in patients on adjuvant tamoxifen. The secondary aim was to evaluate an association between (Z)-endoxifen levels and clinical and phenotypic CYP2D6 metabolism variables. A Cox model estimated hazard ratios (HR) comparing recurrence free survival (RFS) according to (Z)-endoxifen plasma levels. The survival was compared using the Kaplan-Meier method and the log-rank test. Results: The median follow-up period was 52.3 months and at that point, there were 20 recurrences of 149 patients. At 3 months there were no cases of low adherence to tamoxifen. The (Z)-endoxifen levels were established by quartiles, with the first lower quartile being used as a cutoff (14.72nM). High (Z)-endoxifen levels at 3 months (&amp;gt;14.72nM) were detected in 75.8% (n = 113) of cases and low levels (≤14.72nM) in 24.2% (n = 36). There was no statistically significant difference between the groups with low or high (Z)-endoxifen levels regarding clinical and pathological variables, but there was a higher CYP2D6 PM/IM frequency in the low (Z)-endoxifen levels group (p&amp;lt;0.001). High (Z)-endoxifen levels were associated with lower RFS compared to low (Z)-endoxifen levels (HR 2.5, 95% CI 1.00-6.22, p=0.041). Low (Z)-endoxifen levels increased the recurrence risk even when adjusted for staging and molecular subtypes (HR 2.55, 95% CI 1.00-6.48, p&amp;lt;0.001) or staging and CYP2D6 phenotype (UM/EM vs IM/PM; HR 4.38, 95% CI 1.66-11.59, p=0.003), or prior chemotherapy exposure (HR 2.65, 95% CI 1.06-6.61, p=0.036). Conclusion: This is the first Brazilian prospective trial evaluating the association of plasma (Z)-endoxifen levels, with the clinical outcome in breast cancer women treated with adjuvant tamoxifen, controlled by predictable confounding factors of plasma (Z)-endoxifen levels, such as tamoxifen adherence, and drug interaction with CYP2D6 inhibitors. In our study, a low plasma level of (Z)-endoxifen (≤ 14.72nM) after 3 months of tamoxifen treatment was a predictor of early recurrence in patients under adjuvant tamoxifen (p=0.041). A longer follow-up and a larger cohort may be needed to confirm the (Z)-endoxifen cutoff value that is a predictor of long-term recurrence. Citation Format: Thais Almeida, Werner Schroth, Jeanine Marie Nardin, Thomas Mürdter, Solane Picolotto, Reiner Hoppe, Jenifer Primon Kogin, Elisa Daniele Gaio, Angela Dasenbrock, Raquel Cristina Skrsypcsak, Lucia Noronha, Hiltrud Brauch, José Claudio Casali-da-Rocha. Endoxifen predicts early recurrence in breast cancer: A Brazilian prospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-07-08.

Protective role of the lipid phosphatase Fig4 in the adult nervous system.

The signaling lipid phosphatidylinositol 3,5-bisphosphate, PI(3,5)P2, functions in vesicular trafficking through the endo-lysosomal compartment. Cellular levels of PI(3,5)P2 are regulated by an enzyme complex comprised of the kinase PIKFYVE, the phosphatase FIG4, and the scaffold protein VAC14. Mutations of human FIG4 cause inherited disorders including Charcot-Marie-Tooth disease type 4J, polymicrogyria with epilepsy, and Yunis-Varón syndrome. Constitutive Fig4-/- mice exhibit intention tremor, spongiform degeneration of neural tissue, hypomyelination, and juvenile lethality. To determine whether PI(3,5)P2 is required in the adult, we generated Fig4flox/-; CAG-creER mice and carried out tamoxifen-induced gene ablation. Global ablation in adulthood leads to wasting, tremor, and motor impairment. Death follows within 2 months of tamoxifen treatment, demonstrating a life-long requirement for Fig4. Histological examinations of the sciatic nerve revealed profound Wallerian degeneration of myelinated fibers, but not C-fiber axons in Remak bundles. In optic nerve sections, myelinated fibers appear morphologically intact and carry compound action potentials at normal velocity and amplitude. However, when iKO mice are challenged with a chemical white matter lesion, repair of damaged CNS myelin is significantly delayed, demonstrating a novel role for Fig4 in remyelination. Thus, in the adult PNS Fig4 is required to protect myelinated axons from Wallerian degeneration. In the adult CNS, Fig4 is dispensable for fiber stability and nerve conduction, but is required for the timely repair of damaged white matter. The greater vulnerability of the PNS to Fig4 deficiency in the mouse is consistent with clinical observations in patients with Charcot-Marie-Tooth disease.

Precocious puberty in McCune-Albright syndrome: a case report

McCune-Albright syndrome (MAS) is a rare disease characterized by a triad of fibrous dysplasia, cafe-au-lait spots and peripheral precocious puberty. We reported a 5-year- 8-month old girl with MAS who has been followed-up for 2 years and 8 months. She was referred to pediatric endocrinology clinic in our hospital for vaginal bleeding at age of 2 years 11 months. She had peripheral precocious puberty, i.e. increased estrogen level associated with very low gonadotropins, and cafe-au-lait spots on her face and was diagnosed as MAS. The patient was treated with estrogen receptor blocker (tamoxifen). She had no menses during the 2 years and 8 months of tamoxifen treatment. Her growth rate and bone maturation were also in normal ranges. However, at the end of tamoxifen treatment she had an episode of vaginal bleeding so that we had to change to other treatment modalities.

Precocious puberty in McCune-Albright syndrome: a case report

McCune-Albright syndrome (MAS) is a rare disease characterized by a triad of fibrous dysplasia, cafe-au-lait spots and peripheral precocious puberty. We reported a 5-year- 8-month old girl with MAS who has been followed-up for 2 years and 8 months. She was referred to pediatric endocrinology clinic in our hospital for vaginal bleeding at age of 2 years 11 months. She had peripheral precocious puberty, i.e. increased estrogen level associated with very low gonadotropins, and cafe-au-lait spots on her face and was diagnosed as MAS. The patient was treated with estrogen receptor blocker (tamoxifen). She had no menses during the 2 years and 8 months of tamoxifen treatment. Her growth rate and bone maturation were also in normal ranges. However, at the end of tamoxifen treatment she had an episode of vaginal bleeding so that we had to change to other treatment modalities.

Abstract 27: Loss of GATA4 in Kit Lineage-derived Endothelium Leads to Vascular Permeability and Increased Heterotypic Fusion

The treatment of cardiac ischemic injury using heart-derived c-Kit stem cells showed promising results in clinical trials with scar reduction and improved ejection fraction following coronary infusion. We previously developed a c-Kit lineage tracing mouse model showing that these cells very rarely convert into de novo cardiomyocytes and most lineage-derived cardiomyocytes are due to fusion. To potentially reduce this de novo rate to zero, and unequivocally evaluate the cellular fusion process in vivo , we deleted the essential cardiomyogenic transcription factor Gata4 in c-Kit cells using a Cre-loxP approach (Kit-Gata4 KO). Mice with the tamoxifen inducible Kit-MerCreMer allele crossed into a Gata4 homozygous LoxP targeted background with the Rosa26-eGFP reporter were fed tamoxifen at weaning to delete Gata4 in all c-Kit expressing cells and show them and their progeny as eGFP + . Unexpectedly, we observed a greater than 10-fold increase in Kit lineage-traced cardiomyocytes in Kit-Gata4 KO mice compared to Kit only controls with up to 4 months of tamoxifen treatment (90% v. 81% fusion in Kit-Gata4 KO v. controls). A 6-fold increase in leukocyte (CD45 + ) infiltration was observed suggesting the possibility for greater rates of fusion in the heart. However, bone marrow transplant studies revealed that Kit-Gata4 KO bone marrow does not exhibit increased cardiac infiltration or heterotypic fusion with cardiomyocytes. The reciprocal experiment, donating control bone marrow to recipient mice with Kit-Gata4 KO hearts, showed a 4-fold increase in fusion of control bone marrow showing that increases in fusion was intrinsic to the cells within the heart. Analysis of cardiac endothelial cells in Kit-Gata4 KO mice revealed that total CD31 + cells were increased by 30% with 2 months of tamoxifen treatment with a parallel increase in endothelial progenitor cells (CD133 + ) in the bone marrow. This endothelial phenotype was corroborated using endothelial-specific deletion of Gata4 in a Tie2-CreER mouse which showed a 5-fold increase in both CD31 + cells and vascular permeability after 1 month of tamoxifen. Currently, studies are underway to assess the mechanism of altered endothelial integrity and expansion in the absence of Gata4 in c-kit hemoangioblast progenitors.

DNA Damage Response and Inflammatory Signaling Limit the MLL-ENL-Induced Leukemogenesis In Vivo

Activation of the MLL-ENL-ERtm oncogene initiates aberrant proliferation of myeloid progenitors. Here, we show induction of a fail-safe mechanism mediated by the DNA damage response (DDR) machinery that results in activation of the ATR/ATM-Chk1/Chk2-p53/p21(CIP1) checkpoint and cellular senescence at early stages of cellular transformation caused by a regulatable MLL-ENL-ERtm in mice. Furthermore, we identified the transcription program underlying this intrinsic anticancer barrier, and DDR-induced inflammatory regulators that fine-tune the signaling toward senescence, thereby modulating the fate of MLL-ENL-immortalized cells in a tissue-environment-dependent manner. Our results indicate that DDR is a rate-limiting event for acquisition of stem cell-like properties in MLL-ENL-ERtm-mediated transformation, as experimental inhibition of the barrier accelerated the transition to immature cell states and acute leukemia development.

Massive hepatic angiomyolipoma in a young woman with tuberous sclerosis complex: Significant clinical improvement during tamoxifen treatment

Isolated liver angiomyolipomas (AMLs) occur in about 40% of TSC patients. Because of their slow growth, these tumors are often asymptomatic. Since AMLs express estrogen and progesteron receptors we suggest the possible benefits of tamoxifen for the treatment of liver AMLs. We report the case of a 26-year-old female affected by tuberous sclerosis (TSC2) with cerebral, renal and hepatic involvement admitted to the Liver Unit for severe malnutrition, anorexia and abdominal pain. MRI showed a grossly enlarged liver, causing severe gastric compression. The liver was entirely filled with multiple nodular lesions of different sizes. Liver biopsy showed tumoral tissue with microscopic and ultrastructural features of angiomyolipoma. All liver function tests were repeatedly normal. Prior to considering the patient for partial hepatectomy, she was administered tamoxifen (20mg b.i.d). After 6 months of tamoxifen treatment a greatly improved quality of life and a significant weight gain were observed. After 12 months the clinical conditions further improved and the MRI showed a significant reduction of the largest lesion with a liquid central area and a diminished compression of the stomach. This is to our knowledge the first report in which tamoxifen has been successfully used in a TSC patient with multiple liver angiomyolipomas.

Long-term “protective” effect of aromatase inhibitors on the endometrium of postmenopausal breast cancer patients

Decrement of endometrial thickness was recorded following short-term aromatase inhibitor treatment in breast cancer patients previously treated with tamoxifen. It is necessary to verify if long-term aromatase inhibitor treatment can maintain this phenomenon. Prospective long-term comparison of the last ultrasonographic endometrial thickness measurement taken before discontinuation of long-term tamoxifen treatment in 64 postmenopausal breast cancer patients, with further repeated measurements, performed following administration of aromatase inhibitors. There was a significant decrement of endometrial thickness, following 36.5 +/- 15.7 months of tamoxifen treatment, from a mean value of 8.7 +/- 5.2 mm, measured at the last ultrasonographic measurement performed before discontinuation of tamoxifen treatment, down to a mean value of 6.2 +/- 4.6 mm, measured following 5.3 +/- 4.8 months of aromatase inhibitor therapy (P < 0.001). Further ultrasonographic studies revealed the same significant trend. In the first ultrasonographic study performed during aromatase inhibitor treatment, five (7.8%) patients demonstrated a significant increase of endometrial thickness. Hysteroscopy revealed a benign endometrial polyp in three patients and atrophic endometrium in the other 2. In 35 patients (54.7%), endometrial thickness was reduced following the administration of aromatase inhibitors and in 24 patients (37.5%) there was no change in endometrial thickness. With longer duration of aromatase inhibitor therapy, more patients showed decrement of endometrial thickness. Reversal of endometrial thickening induced by long-term tamoxifen treatment in postmenopausal breast cancer patients is maintained throughout long-term aromatase inhibitor treatment.

Positive False Discovery Rate Estimate in Step-Wise Variable Selection

Selecting predictors to optimize the outcome prediction is an important statistical method. However, it usually ignores the false positives in the selected predictors. In this article, we advocate a conventional stepwise forward variable selection method based on the predicted residual sum of squares, and develop a positive false discovery rate (pFDR) estimate for the selected predictor subset, and a local pFDR estimate to prioritize the selected predictors. This pFDR estimate takes account of the existence of non null predictors, and is proved to be asymptotically conservative. In addition, we propose two views of a variable selection process: an overall and an individual test. An interesting feature of the overall test is that its power of selecting non null predictors increases with the proportion of non null predictors among all candidate predictors. Data analysis is illustrated with an example, in which genetic and clinical predictors were selected to predict the cholesterol level change after four months of tamoxifen treatment, and pFDR was estimated. Our method's performance is evaluated through statistical simulations.

Aromatase inhibitors reverse tamoxifen induced endometrial ultrasonographic changes in postmenopausal breast cancer patients

Aromatase inhibitors may decrease endometrial thickness in breast cancer patients previously having short-term tamoxifen treatment. There is a necessity to find out if aromatase inhibitors can also decrease endometrial thickness in patients previously treated with long-term tamoxifen treatment. Prospective comparison of the last ultrasonographic endometrial thickness measurement taken before discontinuation of long-term tamoxifen treatment in 36 postmenopausal breast cancer patients, with further measurements, performed following aromatase inhibitors administration. There was a significant decrement of endometrial thickness, following 36.2 +/- 16.8 months of tamoxifen treatment, from a mean value of 9.1 +/- 5.8 mm, measured at the last ultrasonographic measurement performed before discontinuation of tamoxifen treatment, down to a mean value of 6.0 +/- 5.0 mm, measured following 5.8 +/- 5.8 months of aromatase inhibitors therapy (P = 0.001). A second ultrasonographic measurement performed in 8 patients following of additional 7.5 +/- 4.0 months of aromatase inhibitors treatment revealed further decrement of mean endometrial thickness to 4.8 +/- 2.1 mm (P = 0.002 compared to baseline). In 28 patients (77.8%), endometrial thickness was reduced following the administration of aromatase inhibitors, in four patients (11.1%) there was no change in endometrial thickness and four (11.1%) patients demonstrated an increase of endometrial thickness. Aromatase inhibitors may reverse endometrial thickening induced by long-term tamoxifen treatment in postmenopausal breast cancer patients.

Estrogen receptor genotype is associated with platelet inhibition after tamoxifen treatment

Backgroud Tamoxifen therapy can cause a ~ 4% decrease in platelet count. We hypothesized that this decrease may lead to changes in platelet function, and that estrogen receptor (ESR) genotype may influence tamoxifen-induced changes in platelet function. METHODS Platelet aggregation tests were performed on blood drawn from 19 women before and after 4 months of tamoxifen treatment. ESR1 PvuII and XbaI and ESR2-02 genotypes were also determined. Differences in platelet aggregation were tested using student’s t test (SPSS, v12). Data expressed as mean ± SD. RESULTS Tamoxifen therapy led to a significant decrease in ADP (13.3±3.4 vs 11.5±2.0, P = 0.012) and collagen (15.0±5.7 vs 12.2±6.1, P=0.04) induced platelet aggregation. ESR1 PvuII genotype was associated with differences in baseline ADP-induced platelet aggregation and the change in ADP-induced platelet aggregation (table 1). CONCLUSION Platelet aggregation was inhibited after 4 months of tamoxifen treatment. ESR1 PvuII genotype was associated with changes in platelet aggregation after tamoxifen treatment. Table 1.. ADP-induced Platelet aggregation based on ESR1 PvuII genotype

Histopathologic behavior of endometrial hyperplasia during tamoxifen therapy for breast cancer

Objective. The purpose of the present study is to prospectively evaluate the effects of tamoxifen on the pathological behavior of endometrial hyperplasias without atypia, diagnosed before the start of adjuvant endocrine therapy, in menopausal patients suffering from breast cancer. Methods. Twenty-six patients suffering from estrogen–receptor positive breast cancer and candidate to receive adjuvant tamoxifen, were found to be affected by endometrial hyperplasias before the start of endocrine therapy. All women showed a baseline endometrial stripe, measured by transvaginal ultrasonography, thicker than 4 mm and the diagnosis of endometrial hyperplasia was made by hysteroscopy and endometrial biopsy. Two patients showing complex atypical hyperplasia underwent vaginal hysterectomy, whereas the remaining 24 patients, suffering from endometrial hyperplasia without atypia, were followed on a yearly basis during the period of tamoxifen intake, by hysteroscopy and endometrial biopsy. Results. Baseline histopathology showed simple and complex hyperplasia in 20 and in 4 patients, respectively. The median follow-up period was 38 months; in particular, all patients underwent endometrial assessment after 12 months, while 22, 16, 10 and 4 patients were followed-up after 24, 36, 48 and 60 months of tamoxifen therapy, respectively. Progression from complex hyperplasia to complex atypical hyperplasia (1 patient) and from complex and simple hyperplasia to adenocarcinomas (2 patients) was found within 24 months of tamoxifen intake in 3 patients (12.5%). In 2 patients (8.3%), a progression from simple to complex hyperplasia was detected within 36 months of tamoxifen treatment. In 13 patients (54.1%), stable histology of simple or complex hyperplasia was found, whereas 6 patients (25.0%), with focal hyperplasia harbored in an endometrial polyp, showed a normalization of endometrial histology after polyp resection. Conclusions. Endometrial hyperplasias without atypia diagnosed before endocrine therapy for breast cancer in menopausal patients show an early and high progression-rate to atypical lesions under tamoxifen influence.

K-ras mutation in the endometrium of tamoxifen-treated breast cancer patients, with a comparison of tamoxifen and toremifene

The putative presence of a mutation in codon 12 of the K-ras gene was investigated in the endometrium of tamoxifen (TAM) and toremifene (TOR)-treated breast cancer patients. DNA was extracted from fresh cytologic samples of the endometrium in 86 TAM and 21 TOR-treated breast cancer patients. Mutations were detected by enriched PCR and an enzyme-linked mini-sequence assay (ELMA). K-ras mutation was found in 35 TAM-treated endometrial samples, and in only one TOR-treated endometrium (P<0.003). In 24 premenopausal patients, K-ras mutation was found in seven (43.8%) of 16 patients with less than 47 months of TAM treatment, while none was found in eight patients with more than 48 months of TAM treatment (P<0.03). In 62 postmenopausal-amenorrheic patients, K-ras mutation was found in three (15.8%) of 19 patients with less than 23 months of TAM treatment, while it was found in 16 (61.5%) of 26 patients with 24–47 months of TAM treatment and nine (52.9%) of 17 patients with more than 48 months of TAM treatment (P=0.002). The presence of K-ras mutation is significantly influenced by the duration of TAM treatment and menstrual status of the patients. TOR may have a lower potential genotoxicity than TAM.

Tamoxifen related uterine sarcoma - A retrospective review

801 Background: Tamoxifen has been shown to significantly reduce the risk of tumor recurrence in women with receptor-positive breast cancer and has been used for chemoprevention in women with non-invasive cancer and women at high risk of developing breast cancer. One established and accepted risk with this treatment is the increased risk of uterine malignancy. Originally this was felt to be limited to endometrial adenocarcinoma, but recent evidence suggests an increased risk of uterine sarcoma as well. Methods: A 42-year retrospective review was performed at a rural tertiary care center. The charts of all patients with a diagnosis of uterine sarcoma were reviewed. 136 patients with uterine sarcoma were identifed. Any women with a primary diagnosis of breast cancer or use of tamoxifen for adjuvant or preventive therapy were substratified. Results: Of the 136 women with uterine sarcoma, ten patients had primary breast malignancies. Six of these ten women had received a five-year course of tamoxifen prior to the development of uterine sarsoma; four did not receive adjuvant hormonal therapy. Additionally, one of our patients enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial developed a malignant mixed mullerian tumor (MMMT) 27 months after completing a five-year course of tamoxifen. Conclusions: We therefore report seven cases of uterine sarcoma occurring subsequent to 60 months of tamoxifen treatment. This is compared to the report of 12 cases identifed from the NSABP treatment and prevention trials secondary malignancy data. We suggest that there may be a higher incidence of uterine sarcoma in tamoxifen-treated patients than that based on the NSABP data. Given the increased risk of uterine malignancy (both adenocarcinoma and sarcoma), as well as other potential complications of tamoxifen use, consideration needs to be taken before beginning hormonal therapy, especially in a prevention setting. No significant financial relationships to disclose.

Pharmacokinetics and pharmacogenetics predict the inhibitory effects of tamoxifen on platelet aggregation

Platelets play a central role in the pathogenesis of coronary artery disease. We tested ADP induced platelet aggregation with the Chrono-Log® whole blood aggregometer before and after four months of tamoxifen treatment in women with breast cancer. Steady state plasma concentrations of tamoxifen and its metabolites, and common genetic variants, including eNOS, ER α and β, CYP 2D6, and 3A5 were also determined. There was a trend toward reduction in ADP induced platelet aggregation after 4 months of tamoxifen therapy (from 14.16 + 3.6 ohms to 11.5±4.1 ohms, P= 0.07). We stratified the subjects into two groups based on the inhibitory effects on platelets by tamoxifen: the “responders” showed ≥ 4ohms (14.5±8.4) and the “non-responders” exhibited < 4 ohms (0.6±1.65) reduction in platelet aggregation (p=0.01 by 2-tailed t-test). The responders had significantly lower plasma endoxifen (4-OH-N-desmethyl tamoxifen) and 4-OH tamoxifen concentrations (14.18±7.75 vs 48.22±7 ng/ml for endoxifen, P=0.006; 2.95±1.3 vs 5.8±0.9 ng/ml for 4_OH tamoxifen, p=0.01); and were more likely to carry an ER β variant allele. Plasma endoxifen concentration had the strongest correlation with the amplitude of platelet inhibition (Spearman r2=0.61, p=0.03). In conclusion, tamoxifen significantly inhibited platelet aggregation in certain individuals, and low concentrations of endoxifen and 4-OH tamoxifen as well as ER β genetic variants appeared to predict these effects. Clinical Pharmacology & Therapeutics (2004) 75, P67–P67; doi: 10.1016/j.clpt.2003.11.251

Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial

Objective We undertook a 1-year multicenter trial of tamoxifen treatment for precocious puberty in girls with McCune-Albright syndrome (MAS).Study design Girls ≤10 years with classic or atypical MAS were recruited. Pretreatment history was collected for 6 months. Patients received 20 mg tamoxifen daily. Diaries were used to record bleeding. Evaluations included physical examination, bone age, pelvic ultrasound, hormone levels, and safety assessments.Results A total of 28 girls (2.9-10.9 years of age) were enrolled from 20 centers, of whom 25 completed 12 months of tamoxifen treatment. Compared with before the study, vaginal bleeding episodes decreased (3.42±3.36/year vs 1.17±1.41/year), growth velocity slowed (SDS 1.22±2.65 vs −0.59±3.06, P=.005), and rate of bone maturation decreased (1.21±0.78 vs 0.72±0.36, P=.02). Ovarian volumes were enlarged and asymmetric throughout the study, and uterine volumes were increased. No adverse events occurred.Conclusions Tamoxifen treatment of precocious puberty in MAS results in a reduction of vaginal bleeding and significant improvements in growth velocity and rate of skeletal maturation.

IGF status is altered by tamoxifen in patients with breast cancer

Aims—An increased concentration of insulin-like growth factor 1 (IGF-1) is an independent risk factor for premenopausal breast cancer. Tamoxifen is thought initially to reduce concentrations of IGF-1 and increase concentrations...

Risk factors of endometrial polyps resected from postmenopausal patients with breast carcinoma treated with tamoxifen.

Endometrial polyps are the most common endometrial pathology described in association with postmenopausal tamoxifen exposure. Up to 3% of these polyps may show malignant changes. However, to the authors' knowledge no one has described any risk factor for the development of this pathology in postmenopausal patients with breast carcinoma treated with tamoxifen. OBJECTIVE. The objective of this study was to evaluate whether risk factors can be identified for the development of endometrial polyps in postmenopausal patients with breast carcinoma treated with tamoxifen. The authors reviewed the medical records of 54 postmenopausal patients with breast carcinoma in whom endometrial polyps were resected by hysteroscopy after at least 6 months of tamoxifen treatment (Group I). Demographic characteristics, health habits, risk factors for endometrial carcinoma, and clinical factors related to the primary breast disease were examined. The results were compared with those obtained from 210 similar patients in whom hysteroscopy did not reveal any endometrial pathology (Group II). Age at menopause was significantly older, duration of breast disease was significantly longer, and body weight was significantly heavier among Group I patients compared with Group II patients (P = 0.0162, P = 0.0026, and P = 0.0364, respectively). Endometrial thickness, measured by transvaginal ultrasonography, was significantly thicker in Group I patients (16.3 +/- 7.2 mm) compared with that detected in Group II patients (11.8 +/- 6.3; P = 0.0001). Various factors, such as older age at menopause, longer duration of breast disease, heavier weight, and thicker endometrium may contribute to the prediction of increased risk of development of endometrial polyps in postmenopausal patients with breast carcinoma treated with tamoxifen.

Uterine side effects of treatment with tamoxifen

Objective: To assess a causal the relationship between endometrial lesions and tamoxifen therapy in patients with breast cancer. Design: Prospective longitudinal study and cross-sectional study. Setting: Cancer prevention unit at Basurto Hospital, Bilbao. Population and methods: Three populations of breast cancer were studied: 43 before the beginning of tamoxifen; 78 after 5–72 months of tamoxifen, and 34 before tamoxifen and after 12–24 months of tamoxifen treatment (PAIRED GROUP). All of them were systematically studied with CO 2 diagnostic hysteroscopy and endometrial biopsy by the same clinician. Results: Before tamoxifen, the following endometrial lesions were detected: endometrial polyps 9.3%; endometrial cysts 16.3%; synechiae 11.6%. In the paired group the ingestion of tamoxifen shows a direct causal effect with a significant increase in endometrial polyps (11.8% vs. 29.4%; OR=13; CI=7.9–18.1), in endometrial cysts (17.7% vs. 55.9%; OR=7.5; CI=5.9–9.1) and in synechiae (14.7% vs. 35.5%; OR=8; CI=4.7–11.3). In the group under tamoxifen for 5–72 months, one endometrial carcinoma was detected. Conclusions: Breast cancer patients have a number of endometrial lesions before undergoing any hormonal therapy. Tamoxifen significantly increased benign endometrial lesions, usually after less than one year of treatment. No cases of endometrial carcinoma was found in our series of 34 patients with 1–2 years of tamoxifen treatment, and 1/78 in patients with 5–72 months of tamoxifen.