Adjuvant Tamoxifen For Breast Cancer Research Articles

Can the levonorgestrel intrauterine system improve outcomes in women taking adjuvant tamoxifen for breast cancer?

Can the levonorgestrel intrauterine system improve outcomes in women taking adjuvant tamoxifen for breast cancer?

Can the levonorgestrel intrauterine system improve outcomes in women taking adjuvant tamoxifen for breast cancer?

Can the levonorgestrel intrauterine system improve outcomes in women taking adjuvant tamoxifen for breast cancer?

Randomized trial of medroxyprogesterone acetate for the prevention of endometrial pathology from adjuvant tamoxifen for breast cancer: SWOG S9630.

The proliferative effect of adjuvant tamoxifen on the endometrium can potentially result in endometrial abnormalities, including cancer in postmenopausal women. We conducted a randomized, controlled trial to assess endometrial pathological diagnoses in postmenopausal women with early stage, ER-positive breast cancer without endometrial pathology at baseline. They were assigned to tamoxifen alone versus tamoxifen plus cyclical medroxyprogesterone acetate (MPA 10 mg for 14 days every 3 months) for 5 years. Endovaginal sonograms (EVS) +/− endometrial biopsies (EMB) were required at baseline, 2 and 5 years. Of 313 patients registered, 296 were eligible and 169 (57%; 89, tamoxifen; 80, tamoxifen+MPA) were evaluable (completed year-2 EVS, with an EMB if stripe width was ⩾5 mm). Sixty (67%) of these in the tamoxifen arm had an endometrial stripe width ⩾5 mm (and underwent subsequent EMB) compared with 48 (60%) in the tamoxifen+MPA arm (P=0.40). There were four cases of proliferative endometrium and one simple hyperplasia on the tamoxifen arm (6% (95% confidence interval (CI): 2–13%) among evaluable patients and one proliferative endometrium on the tamoxifen+MPA arm (P=0.11). The overall fraction with benign endometrial abnormalities at year 2 was 3.6% (6/169; 95% CI: 1.3–7.6%), with only 1 (of 102) new benign proliferative event at year 5. The event rate in both arms was much lower than projected, making treatment arm comparisons less informative. A normal endometrium prior to tamoxifen may provide reassurance regarding future endometrial events. However, validation in a larger trial is needed before changing practice in asymptomatic, postmenopausal women.

Randomized trial of medroxyprogesterone acetate for prevention of endometrial pathology from adjuvant tamoxifen for breast cancer: SWOG S9630.

547Background: Tamoxifen provides significant survival benefit in the adjuvant treatment of estrogen receptor-positive (ER+) breast cancer. However, its proliferative effect on the endometrium pote...

Association Between CYP2D6 Genotypes and the Clinical Outcomes of Adjuvant Tamoxifen for Breast Cancer: A Meta-Analysis

Tamoxifen is one of the most commonly used endocrine therapeutic agents for breast cancer. Although many studies have examined whether the treatment outcomes of tamoxifen for breast cancer differ according to CYP2D6 genotype, the study results have been inconsistent, and the role of CYP2D6 in the prediction of patient outcomes from tamoxifen therapy remains controversial. This study evaluated the association between CYP2D6 genotypes and postoperative tamoxifen treatment outcome in patients with breast cancer, using the available previous study results. We performed a meta-analysis of ten previous clinical reports (n = 5183) to evaluate the association between CYP2D6 genotype and hazard ratios for the recurrence risk of breast cancer after postoperative tamoxifen treatment. Pooled estimates of hazard ratios were computed using R and NONMEM® software. A significantly increased risk of breast cancer recurrence in patients carrying variant CYP2D6 genotypes was found in this investigation. The mean hazard ratios and 95% CI were 1.60 (1.04-2.47) in the random effect model implemented in R and 1.63 (1.01-2.62) in the random effect model in NONMEM. The bootstrap result (2000 replicates) of NONMEM was 1.64 (1.07-2.79). Our present findings suggest that genetic polymorphisms of CYP2D6 may be important predictors of the clinical outcomes of adjuvant tamoxifen treatment for the patients with breast cancer. A large-scale, prospective, randomized, well-controlled trial is warranted to confirm our findings.

Personalized medicine in breast cancer: tamoxifen, endoxifen, and CYP2D6 in clinical practice

Tamoxifen is metabolized into endoxifen, a potent antagonist of the estrogen receptor, in part through cytochrome p450 (CYP) 2D6. Genotypic variation in CYP2D6 affects endoxifen levels, and some have argued that patients who do not efficiently metabolize tamoxifen might wish to consider alternative hormonal treatments. This study evaluated an algorithm in which endoxifen levels and CYP2D6 genotypes were used to make hormonal therapy recommendations for patients on adjuvant tamoxifen for breast cancer. Patients with stage I-III breast cancer who had been taking adjuvant tamoxifen for 8-56weeks were eligible. At enrollment, baseline whole blood and serum were sent for genotyping by Amplichip and endoxifen measurement, respectively, and endoxifen levels were also measured 3weeks later. Results were returned to oncologists along with an algorithm-generated treatment recommendation. The algorithm recommended that participants with poor metabolizer genotype and/or baseline endoxifen level <6ng/mL consider alternative endocrine therapy. A medical record review evaluated actual treatment decisions. Of 99 patients on study, 18 (18%) had findings that triggered algorithm-based recommendations to consider a change in endocrine therapy due to endoxifen <6ng/mL (all 18 patients) and/or poor metabolizer CYP2D6 genotype (2 of the 18). Endoxifen levels were ≥6ng/mL in four of them 3weeks later. Seven (39% of 18) switched to a different treatment (one based on toxicity, not the algorithm). Hot flash burden was not found to be significantly associated with endoxifen <6ng/mL or genotype. Prospective testing of tamoxifen metabolism as gauged by CYP2D6 genotype and serum endoxifen levels is feasible. Future studies of tamoxifen metabolism and efficacy should consider including measurement of serial endoxifen levels. Although clinical evidence at present is insufficient to warrant routine CYP2D6 or endoxifen testing, some clinicians and patients did utilize this predefined algorithm to inform clinical decisions regarding optimal adjuvant endocrine therapy.

Prophylactic Use of Levonorgestrel-Releasing Intrauterine System in Women With Breast Cancer Treated With Tamoxifen

To estimate the rate of endometrial pathology with the prophylactic use of levonorgestrel-releasing intrauterine system in women with breast cancer treated with tamoxifen. This was a randomized contro-lled trial of 129 Chinese women who attended a university hospital in Hong Kong and required adjuvant tamoxifen for breast cancer after the completion of postoperative radiotherapy and chemotherapy. Women were randomized to treatment (prophylactic levonorgestrel-releasing intrauterine system insertion before the commencement of tamoxifen) or control group. The uterine cavity was examined by hysteroscopy and endometrial sampling before the commencement of tamoxifen and at 12, 24, 45, and 60 months afterward. Any endometrial polyps or submucosal fibroids were resected through hysteroscopy at each assessment and specimens were sent for histologic confirmation. A total of 94 women completed 5-year follow-up. There was no significant difference in the occurrence of submucosal fibroids (1 [1.8%] compared with 2 [3.4%]) and endometrial hyperplasia (both 0) in the treatment and control groups, respectively. Levonorgestrel-releasing intrauterine system significantly reduced de novo endometrial polyps (hazard ratio 0.19, 95% confidence interval 0.07-0.48) over the course of 5 years on an intention-to-treat basis. There was no statistically significant increase in breast cancer recurrence rate (10 [17.2%] compared with 6 [10.0%]) or cancer-related deaths (6 [10.3%] compared with 5 [8.3%]) in the treatment group, but the study was underpowered in this regard. Prophylactic levonorgestrel-releasing intrauterine system prevents de novo endometrial polyps in women using tamoxifen. However, its role in the prevention of endometrial hyperplasia and adenocarcinoma as well as its effect on risk of breast cancer recurrence remain uncertain. Chinese Clinical Trial Registry, http://www.chictr.org/en/, ChiCTR-TRC-09000625. I.

Factor V Leiden mutation and thromboembolism risk in women receiving adjuvant tamoxifen for breast cancer.

Tamoxifen use has been associated with increased risk of thromboembolic events (TEs) in women with breast cancer and women at high risk for the disease. Factor V Leiden (FVL) is the most common inherited clotting factor mutation and also confers increased thrombosis risk. We investigated whether FVL was associated with TE risk in women with early-stage breast cancer who took adjuvant tamoxifen. A case-control study was conducted among 34 Cancer and Leukemia Group B (CALGB) institutions. We matched each of 124 women who had experienced a documented TE while taking adjuvant tamoxifen for breast cancer (but who were not necessarily on a CALGB treatment trial) to two control subjects (women who took adjuvant tamoxifen but did not experience TE) by age at diagnosis (+/-5 years). DNA from blood was analyzed for FVL mutations. Conditional logistic regression was used to estimate odds ratios (ORs) and to evaluate other potential factors associated with TE and tamoxifen use. All P values are based on two-sided tests. FVL mutations were identified in 23 (18.5%) case and 12 (4.8%) control subjects (OR = 4.66, 95% confidence interval = 2.14 to 10.14, P < .001). In the multivariable model, FVL mutation was associated with TE (OR = 4.73, 95% confidence interval = 2.10 to 10.68, P < .001). Other statistically significant factors associated with TE risk were personal history of TE and smoking. Among women taking adjuvant tamoxifen for early-stage breast cancer, those who had a TE were nearly five times more likely to carry a FVL mutation than those who did not have a TE. Postmenopausal women should be evaluated for the FVL mutation before prescription of adjuvant tamoxifen if a positive test would alter therapeutic decision making.

Factor V Leiden Mutation and Thromboembolism Risk in Women Receiving Adjuvant Tamoxifen for Breast Cancer

Factor V Leiden Mutation and Thromboembolism Risk in Women Receiving Adjuvant Tamoxifen for Breast Cancer

CYP-2C19*2 Predicts Favorable Outcome of Tamoxifen Treatment for Advanced Breast Cancer.

Abstract Tamoxifen is metabolised by cytochrome P450 (CYP) enzymes to active metabolites. CYP2D6 and CYP2C19 genotypes have been reported to be associated with therapy outcome of adjuvant tamoxifen for breast cancer. Effects, however, were inconsistent and no data for advanced disease is available.We studied the association of functional polymorphisms in CYP2C19 and CYP2D6 with outcome of tamoxifen for advanced breast cancer.This multicenter study was performed on genomic DNA of 499 estrogen receptor (ER)-positive, retrospectively collected, primary breast tumor specimens of patients treated with first-line tamoxifen therapy for advanced disease.Primary endpoint was the time to treatment failure (TTF). Genomic DNA was analysed with Taqman allele-discrimination assays.A pooled analysis of three independent patient cohorts showed a longer TTF for CYP2C19*2 carriers, encoding lower enzymatic activity, compared to non-carriers (Hazard ratio (HR) (95% Confidence Interval (CI)): 0.71 (0.57-0.90), p=0.004). Neither the ultra-active CYP2C19*17 nor the inactive CYP2D6*4 allele were associated with TTF.In a pooled multivariable analysis, stratified for centre and time between primary diagnosis and occurrence of metastases, corrected for menopausal status at treatment start, adjuvant chemotherapy and CYP2D6*4 status, CYP2C19*2 was independently associated with TTF (HR (95% CI): 0.73 (0.58-0.91), p=0.007).CYP2D6*4 and CYP2C19*2 gene status were not prognostic for breast cancer outcome.In conclusion, CYP2C19*2 is associated with a longer time to treatment failure in breast cancer patients treated with tamoxifen for advanced disease.Our finding on the involvement of CYP2C19 in tamoxifen metabolism opens new avenues for further treatment individualisation and new management strategies. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4036.

A randomised controlled trial of prophylactic levonorgestrel intrauterine system in tamoxifen‐treated women

To study the prophylactic use of levonorgestrel intrauterine system (LNG-IUS) in the prevention of endometrial pathology in women having breast cancer treated with tamoxifen. Randomised controlled trial. A tertiary teaching hospital. One hundred and thirteen women (66 premenopausal/47 postmenopausal) who required adjuvant tamoxifen for breast cancer after the completion of postoperative radiotherapy and chemotherapy. Women were randomised to treatment group (prophylactic LNG-IUS insertion before the commencement of tamoxifen) or control group. Uterine cavity was examined by outpatient hysteroscopy and endometrial biopsy before and at 12 months after commencement of tamoxifen. De novo endometrial pathology at 1 year of tamoxifen. Women in the treatment group had a much lower incidence of endometrial polyp (1.8 versus 15.5%, P= 0.017) (relative risk: 0.12; 95% CI: 0.02-0.91) at 12 months. There was no significant difference in the incidence of submucosal fibroid between the two groups (1.8 versus 3.4%, P= 1.0). LNG-IUS was retained in 95% women in the treatment group at 1 year. LNG-IUS reduces the occurrence of de novo endometrial polyp in women treated with tamoxifen for breast cancer.

Pitavastatin ameliorates severe hepatic steatosis in aromatase-deficient (Ar-/-) mice.

Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Impaired hepatic FA beta-oxidation in peroxisomes, microsomes, and mitochondria results in progression of massive hepatic steatosis in estrogen deficiency. This impairment, although latent, is potentially serious: About 3% of the general population in the United States is now suffering from nonalcoholic steatohepatitis associated with obesity and hyperlipidemia. Therefore, in the present study we tried to restore impaired hepatic FA beta-oxidation by administering a novel statin, pitavastatin, to aromatase-deficient (Ar-/-) mice defective in intrinsic estrogen synthesis. Northern blot analysis of Ar-/- mice liver revealed a significant restoration of mRNA expression of essential enzymes involved in FA beta-oxidation such as very long fatty acyl-CoA synthetase in peroxisome, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase. Severe hepatic steatosis observed in Ar-/- mice substantially regressed. Consistent findings were obtained in the in vitro assays of FA beta-oxidation activity. These findings demonstrate that pitavastatin is capable of restoring impaired FA beta-oxidation in vivo via the peroxisome proliferator-activated receptor-alpha-mediated signaling pathway and is potent enough to ameliorate severe hepatic steatosis in mice deficient in intrinsic estrogen.

Aromatase-deficient (ArKO) mice are retrieved from severe hepatic steatosis by peroxisome proliferator administration

Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Recently, aromatase-deficient (ArKO, Ar−/−) mice lacking intrinsic estrogen was developed and the molecular mechanism involved in progression of massive hepatic steatosis in estrogen-deficiency was elucidated; impairment in hepatic fatty acid β-oxidation of peroxisomes, microsomes and mitochondria. This impairment is latent, but is potentially serious, because hepatic energy supply depends greatly on fatty acid β-oxidation. Therefore in the present study, we tried to conquer impaired hepatic fatty acid β-oxidation by administrating bezafibrate, a potent peroxisome proliferator, to Ar−/− mice through activating fatty acid β-oxidation via the peroxisome proliferator activated receptor-α mediated signaling pathway. Northern blot analysis of Ar−/− mice liver revealed a significant restoration of mRNA expression of very long fatty acyl-CoA synthetase in peroxisome, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase in mitochondria, essential enzymes in fatty acid β-oxidation by administration of bezafibrate. Severe hepatic steatosis observed in Ar−/− mice regressed dramatically. Consistent findings were obtained in the in vitro assays of fatty acid β-oxidation activity. These findings demonstrate that bezafibrate is capable of restoring impaired fatty acid β-oxidation in vivo via the peroxisome proliferator-activated receptor-α mediated signaling pathway and is potent enough to regress severe hepatic steatosis in mice deficient in intrinsic estrogen.

Clear Cell Ovarian Carcinoma Following Long-Term Tamoxifen Use.

A case of clear cell ovarian cancer and endometriosis in a postmenopausal patient following adjuvant tamoxifen for breast cancer is presented. Immunohistochemistry demonstrated the tumor to be positive for progesterone receptor protein but not estrogen receptor protein; the endometriosis was positive for both proteins. Literature review reveals this to be the first report of both clear cell ovarian cancer and endometriosis following tamoxifen use, and the third report of epithelial ovarian cancer associated with tamoxifen.

Tamoxifen and Cardiovascular Morbidity

The increasing use of adjuvant tamoxifen for breast cancer has led to more careful investigation of its side effects -- particularly its cardiovascular

Does long-term administration of tamoxifen affect bone mineral density?

A retrospective study was performed to determine whether the long-term (5 years or more) administration of tamoxifen is detrimental to bone mineral density (BMD). 19 patients taking adjuvant tamoxifen for breast cancer were paired with 19 controls comparable in age, time since menopause and performance status. BMD was measured at the femoral neck, lumbar spine and total body by dual energy X-ray absorptiometry (DEXA). There was no detrimental effect on BMD at any site. There was a trend towards an increase in BMD at the femoral neck. There were minor decreases in the serum calcium, phosphate and alkaline phosphatase.

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