Months Of Tamoxifen Research Articles

EFFECT OF TAMOXIFEN ON FASTING SERUM LIPID PROFILE IN BREAST CANCER PATIENTS

Background:Tamoxifen acts as a selective estrogen receptor modulator by binding to the estrogenreceptors on mammary epithelium andblockingtheproliferative action of estrogen on mammaryepithelium. In contrast to that it has a weak estrogen agonistic effect on bone, liver and endometrium.Tamoxifen therapy has favorable effects on serum lipid profile by decreasing serum levels of Total cholesterol and low density lipoprotein (LDL), while its effect on high density lipoprotein (HDL) and triglyceride (TG)is still controversial. So this study is to evaluate the effects of tamoxifenTherapy on fasting serum lipid profile in patients with breast cancer. Results: Mean age was 43.56±3.53yrs , most common BMI was 30-34.9. Patient serum TG levels were raised from baseline after 3 months of tamoxifen with p values of (0.000) which was statistically significant while HDL levels were raised but with p value of (0.008 ) which was statistically insignificant. Serum LDL and total cholesterol were reduced from baseline after 3 month with p value of (0.000) and (0.000) respectively. Conclusion: This study concludes that tamoxifen has effects on serum lipid profile by increasing TG levels and lowering TC and LDL levels so this should be in consideration while prescribing tamoxifen to the patients having other risk factors for cardiovascular abnormalities.

Abstract P3-12-03: Impact of genetic polymorphisms on plasma levels of tamoxifen and its metabolites and toxicity: 6-months results of the adjuvant breast cancer longitudinal PHACS study (NCT01127295)

Abstract Supported by a PHRC grant (#09-18-005) Background: The role of CYP2D6 genetic polymorphisms and plasma levels of active metabolites of tamoxifen (TAM) on clinical response and occurrence of side effects remains controversial. We conducted a prospective, adjuvant, multicentre, 3-year follow-up study of breast cancer patients in order to evaluate the relationships between pharmacogenetics, pharmacokinetics and toxicity of TAM and its metabolites (n=879) or aromatase inhibitors (AI, n=1098). The present report focuses on the evaluation at 6 months after inclusion of 864 patients treated with 20 mg/day TAM.The clinical results and the AI PG/PK analyses are described elsewhere (abstracts #851544 and #851525). Methods: Residual plasma concentrations for tamoxifen and its 6 major metabolites (endoxifen ENDO, 4-hydroxy-tamoxifen 4-OH-TAM, N-desmethyl TAM, TAM-N-oxyde, 4'-OH-TAM and Z'ENDO) at 6 months after start of treatment were measured by UPLC-MS/MS in 789 patients. Nine patients with TAM concentrations below the limit of quantification were excluded for non-compliance. SNP genotyping of 95 selected SNPs was performed on the Biomark (Fluidigm) in a microfluidic multiplex 96 dynamic array chip with Taqman assays and was available for 857 patients. Patients were classified according to their CYP2D6 metaboliser status (MS) (PM, IM, EM and UM) based on presence of functional, decreased function or no functional alleles (*4, *6, *7, *9, *10, *17, *41) and number of CYP2D6 copies (*5 or duplication). Metabolic ratios (MR) were calculated for TAM/4-OH-TAM, TAM/N-desmethyl tamoxifen (NDT), NDT/ENDO and 4-OH-TAM/ENDO. Anti-estrogenic activity score (AAS) was calculated according to a recently proposed algorithm (De Vries Schultink et al.,Breast Cancer Res Treat. 2017).Toxicity was measured as a binary outcome (first occurrence or worsening of hot flushes, fatigue, depression, pain, arthralgia, vaginal dryness). All genetic associations were adjusted for multiple testing. Results: ENDO concentration and AAS increased significantly with CYP2D6 MS (p<0.001). The presence of a CYP3A4*22 allele was significantly associated with endoxifen concentrations; this association remained significant after adjusting for CYP2D6 MS. TAM/4-OH-TAM MR was significantly influenced by the presence of CYP3A4*22, CYP2C19*2 and *17, and CYP2D6 status. The percentage of patients having an AAS>=1798 (i.e., threshold previously associated with recurrence-free survival RFS by De Vries et al. 2017) was 6%, 50%, 84% and 91% of patients respectively classified as PM, IM, EM and UM. Side effects were not significantly associated with higher levels of TAM metabolites concentrations. After correction for multiple testing, SNPs or CYP2D6 MS were not significantly associated with occurrence or worsening of adverse events, premature treatment discontinuations or switch due to toxicity within the first 6 months. Conclusions: In this large prospective study, we quantified the impact of PG on TAM PK and AAS, previously shown to predict RFS. Although the toxicity observed after 6 months of TAM does not seem correlated with PK or PG, these relationships need to be re-evaluated during the 3-year follow-up. Citation Format: White-Koning M, Arellano C, Le Morvan V, Evrard A, Puzskiel A, Vachoux C, Dauba J, Houyau P, Poublanc M, Robert J, Boyer J-C, Roché H, Thomas F, Chatelut E. Impact of genetic polymorphisms on plasma levels of tamoxifen and its metabolites and toxicity: 6-months results of the adjuvant breast cancer longitudinal PHACS study (NCT01127295) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-03.

Abstract OT2-1-05: Prospective multicenter study evaluating the effect of impaired tamoxifen metabolization on efficacy in breast cancer patients receiving tamoxifen in the neo-adjuvant or metastatic setting - The CYPTAM-BRUT 2 trial

Abstract Background Tamoxifen is commonly used to treat and prevent hormone receptor positive breast cancers. This drug is metabolized into more active metabolites by liver enzymes such as cytochrome P450 (CYP) enzymes. Endoxifen is considered to be the principal active metabolite of tamoxifen. As CYP enzymes are highly polymorphic in humans, endoxifen plasma levels are modulated by the patient’s genotype. It, however, is not yet clear if lowered endoxifen plasma levels have an effect on tamoxifen efficacy. This is the first prospective study where the association between endoxifen plasma concentrations, multiple CYP-genotypes and clinical outcome in postmenopausal patients treated with tamoxifen is investigated. Trial Design CYPTAM-BRUT 2 is a prospective multi-center open label, single-arm, non-randomized observational study. Postmenopausal women with measurable, estrogen receptor positive breast cancer receiving tamoxifen as neo-adjuvant or as first-line metastatic treatment are included in this study. The objective treatment response and clinical benefit are observed to investigate the efficacy of 20 mg tamoxifen daily. Patients are allowed to have started tamoxifen before inclusion but not more than three months. Further, if more than twelve months have passed after completion of the adjuvant therapy prior endocrine therapy in the adjuvant setting is allowed. Patients receiving neo-adjuvant tamoxifen will be assessed no more than four months after starting with tamoxifen. The primary endpoint is a statistical association between steady-state endoxifen plasma concentrations and the objective response rate (ORR) after 3-6 months of tamoxifen, under the assumption that the relationship is linear with an odds ratio (OR) of 1.49 per 10 nmol/L. Using available data on endoxifen concentrations, this OR is chosen to reflect an improvement from 10% ORR in the lowest endoxifen quartile to 30% in the highest endoxifen quartile when the overall ORR is around 18%. To have 90% power at a 5% significance level, 180 patients have to be included into the study. The main secondary study endpoint is the relation between endoxifen plasma concentrations and clinical benefit (CR+PR+SD at 6 months). The study has to include 270 patients to detect a statistically significant association with endoxifen with 90% power at a 5% significance level, assuming an OR of 1.28 per 10 nmol/L. This OR is chosen to reflect an improvement of clinical benefit at 6 months from 30% in the lowest endoxifen quartile to 50% in the highest endoxifen quartile (overall clinical benefit around 39%). For both endpoints the RECIST criteria are used. Other endpoints are progression-free survival, tolerability of tamoxifen treatment and the association between CYP2D6 genotype and clinical outcome. Patient accrualPatients from 22 participating centers in Belgium and Switzerland are included in this trial. In May 2014, the predefined sample size of 270 patients was reached. Follow-up of the last patients will continue until all required data are obtained (i.e blood samples and response evaluation). Citation Format: Kathleen Van Asten, Lynn Jongen, Anne-Sophie Dieudonné, Anneleen Lintermans, Chantal Blomme, Olivier Brouckaert, Diether Lambrechts, Hans Wildiers, Marie-Rose Christiaens, Dirk Timmerman, Ben Van Calster, Jan Decloedt, Patrick Berteloot, Didier Verhoeven, Markus Joerger, Khalil Zaman, Vincent Dezentjé, Patrick Neven. Prospective multicenter study evaluating the effect of impaired tamoxifen metabolization on efficacy in breast cancer patients receiving tamoxifen in the neo-adjuvant or metastatic setting - The CYPTAM-BRUT 2 trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-1-05.

Radiation recall dermatitis induced by tamoxifen during adjuvant breast cancer treatment

Tamoxifen and radiotherapy are used in breast cancer treatment worldwide. Radiation recall dermatitis (RRD), induced by tamoxifen, has been rarely reported. Herein, we report a RRD case induced by tamoxifen. A 47-year-old woman had a right quadrantectomy and an axillary lymph node dissection due to breast cancer. The tumor was staged pT2N0; it was hormone receptor positive, and human epidermal growth factor receptor 2 negative. The patient received adjuvant chemotherapy followed by tamoxifen and radiotherapy. After 22 months of tamoxifen, the patient developed a localized heating sensation, tenderness, edema, and redness at the irradiated area of the right breast. The symptoms improved within 1 week without treatment. Three weeks later, however, the patient developed similar symptoms in the same area of the breast. She continued tamoxifen before and during dermatitis, and symptoms resolved within 1 week.

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.

Cognitive function after adjuvant treatment for early breast cancer: a population-based longitudinal study

The purpose of this study was to examine cognitive function in patients with early breast cancer before and after adjuvant chemotherapy or 6 months of tamoxifen. We performed a population-based study in the county of North Jutland, Denmark, including 120 women aged <60 years who received adjuvant chemotherapy with seven cycles of cyclophosphamide, epirubicin and fluoruracil or adjuvant tamoxifen for 6 months for early breast cancer from 2004 to 2006. They were compared with an aged-matched group of 208 women without previous cancer selected randomly from the same population. Data were collected before start of adjuvant treatment and after 6 months by neuropsychological tests and questionnaires to evaluate cognitive function, quality of life and psychological distress. Neuropsychological tests did not reveal any differences in cognitive function between breast cancer patients after chemotherapy and healthy controls. Patients rated their own cognitive functions as improved after 6 months, and patients, who did not receive adjuvant medical treatment, reached the same level as controls within 6 months. Patients receiving chemotherapy or tamoxifen were up to three times more likely than controls to rate themselves as impaired at 6 months. Our results do not support that adjuvant chemotherapy is associated with cognitive side effects in breast cancer patients.

A study of the effects of the aromatase inhibitors anastrozole and letrozole on bone metabolism in postmenopausal women with estrogen receptor-positive breast cancer

ALIQUOT (Anastrozole vs. Letrozole, an Investigation of Quality Of Life and Tolerability) was a prospective, open-label, randomized pharmacodynamic study designed to assess the effects of aromatase inhibitors (AIs) on bone turnover in healthy postmenopausal women with estrogen receptor-positive breast cancer. Ninety-four patients were randomized to receive either 12 weeks of letrozole (2.5 mg; n = 42) followed by 12 weeks of anastrozole (1 mg), or 12 weeks of anastrozole (1 mg; n = 42) followed by 12 weeks of letrozole (2.5 mg). After completion of the study period, patients in the immediate adjuvant group were either switched to tamoxifen (n = 38) or continued on anastrozole or letrozole. In the beginning of the study, 42 patients had taken tamoxifen within 3 months. Patients taking drugs likely to affect bone metabolism, including bisphosphonates, were excluded. Eighty-four patients had complete sample measurements and were included in the analysis. Prior tamoxifen therapy resulted in a significantly lower mean baseline procollagen type 1 N-terminal propeptide (PINP) compared with patients with no prior tamoxifen. There were no significant differences in bone markers between AIs at any time. By 6 months, significant increases were seen in PINP, C-terminal telopeptides (CTX), bone specific alkaline phosphatise (ALP), and urinary N-terminal telopeptides (NTX). Patients with prior tamoxifen had significantly greater increases than patients with no prior tamoxifen. Patients treated with 3 months of tamoxifen following 6 months of an AI showed a significant decrease in markers of bone resorption, serum CTX and urinary NTX. In conclusion, AI-induced bone turnover increases over time. Anastrozole and letrozole produce similar effects on bone metabolism and turnover. Stopping tamoxifen therapy and starting AIs results in a significantly greater increase in bone turnover compared with commencing AIs in tamoxifen-naïve patients. Patients given tamoxifen following AI therapy showed a decrease in markers of bone resorption.

Treatment of hyper-IgG4 disease with sequential corticosteroids and tamoxifen – case report and review of the literature

We report a patient with multifocal fibrosclerosis presenting as sialadenitis, hepatic fibrosis, and retroperitoneal fibrosis with renal failure. His medical management consisted of prednisone (4 months at 40 mg daily, then tapered down to 5 mg daily for another 14 months) and 18 months of tamoxifen. He responded clinically and radiographically to this regimen, and remains in clinical remission 10 months after discontinuing medical therapy. Subsequent histologic examination of submandibular gland tissue revealed strong staining for IgG4-positive plasma cells. To our knowledge, this is the first case of confirmed multifocal hyper-IgG4 disease to be successfully treated with sequential corticosteroids and tamoxifen.

Estrogen Receptor Genotypes Influence Hot Flash Prevalence and Composite Score Before and After Tamoxifen Therapy

Hot flashes are common and frequently lead to drug discontinuation among women prescribed tamoxifen. We determined whether genetic polymorphisms in estrogen receptors (ESRs) alpha and beta (ESR1 and ESR2, respectively) are associated with tamoxifen-induced hot flashes. We determined ESR1 PvuII and XbaI and ESR2-02 genotypes in 297 women who were initiating tamoxifen. One-week hot flash diaries were collected to calculate a hot flash score (frequency x severity) before and 1, 4, 8, and 12 months after starting tamoxifen. Approximately 80% of 297 participants reported hot flashes before or during the first year of tamoxifen. After 4 months of tamoxifen, premenopausal women who did not receive adjuvant chemotherapy had a four-fold increase in hot flash score (from 5.9 to 23.6; P = .003) compared with a 1.17-fold increase (from 19.6 to 23; P = .34) in those who received chemotherapy. In premenopausal women, increased number of ESR1 PvuII and XbaI CG alleles was associated with higher baseline hot flash scores compared with those who had other haplotypes (P = .0026). At 4 months, postmenopausal women with ESR1 PvuII CC and ESR2-02 GG genotypes had 4.6 times increases in hot flash scores than other postmenopausal women (56 v 12; P = .0007). Women who had the ESR2-02 AA genotype were significantly less likely to experience tamoxifen-induced hot flashes than women who carried at least one ESR-02 G allele (hazard ratio, 0.26; 95% CI, 0.10 to 0.63; P = .001). Knowledge of menopausal status, prior chemotherapy, and ESR genotype may help predict which women are most likely to suffer hot flashes during tamoxifen treatment.

Do Aromatase Inhibitors Increase Hemoglobin in Women with Breast Cancer?

Aromatase inhibitors (AI) block the conversion of testosterone and androstenedione to the estrogen estrone by inhibiting the aromatase enzyme complex. AI are used to treat estrogen receptor positive (ER+) breast cancer in postmenopausal women. With AI therapy, estrogen levels decrease to 85–95% of baseline. In women with metastatic disease, androstenedione levels do not increase. We have evaluated 2 women for polycythemia during AI therapy. Case 1 is 52 years old with stage II breast cancer treated with lumpectomy, TAC × 6 and radiation. Tamoxifen was started 4 months later. The mean hemoglobin during 6 months of tamoxifen was 14.0±0.1 gm/dl. When switched to exemestane, the mean hemoglobin over the next 24 months was 16.1±0.5 gm/dl (Mann-Whitney, p<0.003). Case 2 is an 80 year old with stage I breast cancer treated with lumpectomy followed by radiation. Her baseline hemoglobin was 13.8 gm/dl. 26 months after starting exemestane, her hemoglobin reached 18.0 gm/dl. After extensive evaluation, neither patient met the criteria for polycythemia vera and no etiology for secondary polycythemia was found. The presumption was that the temporal increase in hemoglobin may be due to AI therapy. Previous clinical trials have not reported an increase in hemoglobin in women receiving AI therapy for breast cancer. However, given the dramatic increase in hemoglobin in our 2 patients, we wished to test the hypothesis that inhibition of aromatase may lead to an increase in hemoglobin in postmenopausal women receiving AI therapy for breast cancer. The Cooper University Hospital Tumor Registry was used as a source of potential subjects. Women over the age of 50 years, diagnosed with ER+ nonmetastatic breast cancer between 2002 and 2006 were identified. Women included for study were postmenopausal, and treated with breast surgery +/− local radiation. Women receiving chemotherapy were excluded because of the potential effect of chemotherapy or therapeutic erythropoietin on the hemoglobin level. In order to be included for study, women needed to have a hemoglobin prior to surgery or prior to starting anti-estrogen therapy and at least 3 hemoglobin measurements over a minimum of 12 months after starting anti-estrogen therapy. AI included anastrozole and exemestane. Of 123 charts available for review, 82 had inadequate data for analysis. 27 evaluable women received only an AI. The mean age was 67±8 years and 67% were stage I. The mean hemoglobin before and during AI therapy was 13.7±0.4 and 13.2±1.1 gm/dl, respectively (Mann Whitney, p<0.09). 3/27 had an increase in hemoglobin after starting AI therapy by linear regression analysis (r ≥ 0.60). The increase in hemoglobin ranged from 0.9 to 1.1 gm/dl. As a control group, 11 women received tamoxifen rather than an AI. Mean age was 59±8 years and 54% were stage I. The mean hemoglobin before and during tamoxifen therapy was 13.0±1.0 and 12.8±0.8 gm/dl, respectively (Mann Whitney, p=0.53). 0/11 had an increase in hemoglobin by linear regression analysis (r > 0.60). 2 additional women received tamoxifen which was subsequently changed to an AI, 1 of whom had a mean hemoglobin of 12.9±0.3 gm/dl on tamoxifen which increased to 14.9±0.4 gm/dl on exemestane (Mann Whitney, p<0.05). 1 additional woman had a rise in hemoglobin of > 1 gm/dl while on AI therapy which decreased back to baseline when switched to tamoxifen. In conclusion, although the numbers are small and the data retrospective, these data suggest that AI therapy may be associated with an increase in hemoglobin in a subgroup of women treated with AI therapy for localized breast cancer. Given that AI have not been shown to significantly increase the systemic androgen level, the mechanism for the increase in hemoglobin remains unclear. A well designed, prospective study is needed to determine if AI have an effect on hemoglobin in women being treated for breast cancer.

Stabilization of Hypomania Following Initiation of Tamoxifen

Back to table of contents Previous article Next article Letters to the EditorFull AccessStabilization of Hypomania Following Initiation of TamoxifenJENNIFER TEITELBAUM PALMER M.D.JENNIFER L. PAYNE M.D.,JENNIFER TEITELBAUM PALMER M.D.Search for more papers by this authorJENNIFER L. PAYNE M.D.Search for more papers by this author,Published Online:1 May 2008https://doi.org/10.1176/appi.ajp.2007.07071165AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To The Editor: Tamoxifen, an antiestrogen agent used in breast cancer treatment, inhibits protein kinase C and may have antimanic properties (1 – 3) . We present the case of a patient with bipolar disorder who became depressed while receiving tamoxifen. A 55-year-old Caucasian woman with bipolar disorder presented in December 2006 for evaluation of depression after starting tamoxifen for the treatment of breast cancer. While she was in her 20s, the patient’s bipolar disorder was characterized primarily by hypomania. Beginning in her 30s, depressive episodes predominated. She was subjectively euthymic but at times hypomanic, and she was medication free for 3 years before starting tamoxifen. In December 2004, at age 53, she was diagnosed with stage I breast cancer and treated with lumpectomy and radiation, followed by 18 months of tamoxifen. The patient had no other conditions that present with depression. Two antidepressant trials plus stimulants had little effect until tamoxifen was discontinued by her oncologist in June 2006 when a mixed state ensued. Subsequently, lithium was started, which precipitated worsening mood. We feel that tamoxifen, then lithium, “stabilized” her mood in the depressed phase of the illness. We recommended increased dosing of lithium, antidepressant taper, avoidance of stimulants, and the addition of lamotrigine. Mood stabilizers have been anecdotally associated with stabilization in the depressed phase of bipolar disorder. There is only indirect evidence for this phenomenon in that anticonvulsants, including valproate, are associated with risk of depression (4) . Evidence for an association between tamoxifen and depression is conflicting (3 , 5 , 6) . One possible explanation for these clinical observations is that the pathophysiology of bipolar disorder may involve protein kinase C. Chronic administration of lithium and valproate has been shown to reduce protein kinase C isoenzymes in the frontal cortex and hippocampus in rats, and increased protein kinase C activity has been observed in postmortem brain tissue in bipolar disorder patients (7) . Tamoxifen was antimanic in three small clinical studies (1 – 3) , supporting evidence for a possible role of protein kinase C in bipolar disorder. Our case supports the need for larger studies of protein kinase C-inhibiting agents in hypomania. Because tamoxifen is widely used in the treatment of breast cancer, understanding its potential effect on mood regulation is also clinically important. Limitations of this report include the episodic nature of bipolar disorder and unavailable follow-up data, making the association between tamoxifen use and depression tentative. We therefore advise careful consideration of risks and benefits before discontinuing tamoxifen for symptoms of depression.Baltimore, Md.Dr. Payne receives research support from NIH, the Stanley Medical Research Institute, and Novartis; she has also received a speaker’s honorarium from AstraZeneca and has served as a consultant to Wyeth and AstraZeneca. Dr. Palmer reports no competing interests.This letter (doi: 10.1176/appi.ajp.2007.07071165) was accepted for publication in October 2007.

Phase III Randomized Placebo-Controlled Trial of Two Doses of Megestrol Acetate as Treatment for Menopausal Symptoms in Women With Breast Cancer: Southwest Oncology Group Study 9626

Prior progestin studies treating hot flashes in women have been short duration and single dose. This study tests the progestin megestrol acetate (MA) at two doses versus placebo over 6 months. Patients with T1-3, N0-1, M0 breast cancer were eligible after completion of surgery and chemotherapy and at least 4 months of tamoxifen (if prescribed). Women were required to have at least 10 hot flashes of any severity or at least five severe episodes per week. Patients were randomly assigned to placebo, MA 20 mg, or MA 40 mg for 3 months. Success at 3 months was defined as completion of treatment with a >or= 75% reduction in hot flashes from baseline. If success was achieved, drug treatment for another 3 months was given on the same blinded arm; if not, open-label MA 20 mg was added to blinded study drug and continued for 3 months. Other menopausal symptoms were also assessed. Two hundred eighty eight eligible women were randomly assigned (286 eligible), of whom 85% were on tamoxifen, 40% had over 63 hot flashes/week, and 75% had vasomotor symptoms for >or= 6 months. Success at 3 months was 14% on placebo, 65% on 20 mg, and 48% on 40 mg (both MA doses superior to placebo; P < .0001). Most successes at 3 months were maintained at 6 months (77% on 20 mg and 81% on 40 mg). MA significantly reduced vasomotor symptoms with durable benefit over 6 months. MA 20 mg/d is the preferred dose. There was no significant impact on other menopausal symptoms.

Tamoxifen for one year versus two years versus 6 months of Tamoxifen and 6 months of megestrol acetate: A randomized comparison in postmenopausal patients with high-risk breast cancer (DBCG 89C)

From January 1, 1990 to December 31, 1994, DBCG conducted a randomised trial in 1 615 postmenopausal women with operable, high-risk, receptor-positive or -unknown breast cancer. The patients were after surgery randomised to Tamoxifen for 1 year (TAM1), Tamoxifen for 2 years (TAM 2) or Tamoxifen for 6 months followed by megestrol acetate for 6 months (TAM/MA). When the preplanned sample size of 1 500 patients was reached it was decided to continue randomisation to TAM1 or TAM2 and the study was finally closed December 31, 1996. With a median follow-up of more than 10 years, there was no difference in disease-free survival (DFS) or overall survival (OS) among the three treatment arms. Similar results were obtained in the original and extended comparisons of Tamoxifen for 1 versus 2 years. A multivariate analysis in the per-protocol treated patients did not show significant differences in hazard ratios for DFS or OS among the three arms. Side-effects were rare but more common in the TAM2 and TAM/MA arms.

Changes on Bone Mineral Density after Adjuvant Treatment in Women with Non-metastatic Breast Cancer

. Adjuvant therapies have prolonged survival of non-metastatic breast cancer (NMBC) patients, but they also decrease bone mineral density (BMD). We have analyzed the effects of chemotherapy, hormone therapy with tamoxifen or both, on BMD of women with NMBC. We prospectively included 168 women with NMBC (stage I-III) referred to the Medical Oncology Service of University Hospital of Canary Islands between 1997 and 2001 (55 +/- 12 years; 37% premenopausal; 43 +/- 13 months of follow-up). We measured lumbar and hip BMD (g/cm2) at diagnosis, after chemotherapy and after 12 months of tamoxifen. If a low BMD was detected, women were treated with bisphosphonates. BMD after chemotherapy (n = 83) significantly decreased at lumbar (1.014 +/- 0; 0.995 +/- 0, p = 0.0001), trochanter (0.701 +/- 0; 0.690 +/- 0, p = 0.001), intertrochanter (1.095 +/- 0; 1.078 +/- 0, p = 0.0001) and total hip (0.924 +/- 0; 0.915 +/- 0, p = 0.046) areas. Although 60% of the premenopausal women suffered amenorrhea after chemotherapy, there were not significant differences in BMD between them and women who retained menses. BMD of women who received 12 months of tamoxifen after chemotherapy increased--total hip (0.907 +/- 0; 0.922 +/- 0, p = 0.005) and intertrochanter (1.071 +/- 0; 1.091 +/- 0, p = 0.003)--or remained stable--lumbar, femoral neck, trochanter, and Ward's triangle (n = 39). When tamoxifen was the only adjuvant treatment, BMD after 12 months (n = 22) increased in trochanter area (0.644 +/- 0; 0.663 +/- 0, p = 0.011), and remained stable in all other sites. 50 (30%) patients were treated with bisphosphonates because of osteopenia. Women with NMBC are affected by early bone loss after adjuvant chemotherapy. This bone loss is attenuated by one year of tamoxifen treatment.

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.

Effect of tamoxifen on plasma lipids and lipoproteins in postmenopausal women with breast cancer

Adjuvant tamoxifen therapy is given to large and increasing numbers of women with early-stage breast cancer. The effects of this drug on plasma lipids and lipoprotein profiles are important, because cardiovascular disease also develops over time in a large percentage of tamoxifen-treated postmenopausal women. The purpose of the study was to evaluate the effects of tamoxifen on plasma lipid and lipoprotein profiles in postmenopausal Indian women who were disease-free after primary treatment for breast cancer. A short-term evaluation of 6 months of tamoxifen therapy (10 mg twice a day) in 45 postmenopausal women was conducted. The plasma lipids and lipoprotein levels were evaluated before and after 3 and 6 months of tamoxifen treatment. At 3 and 6 months' evaluation, patients receiving tamoxifen showed significantly decreased levels of total cholesterol, free cholesterol, and low-density lipoprotein cholesterol (P < 0.001 for each) and increased levels of plasma triglycerides, free fatty acids, very low density lipoprotein cholesterol, and high-density lipoprotein cholesterol. The results suggest that tamoxifen therapy benefits postmenopausal patients with breast cancer, with likely reduction in the risk of cardiovascular disease.