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Chemoprevention and endocrine therapy of endometrial carcinoma
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
Besides progestins and oral contraceptives, selective estrogen receptor modulators (SERMs) have recently been assessed as chemopreventive agents. These structurally diverse non-steroidal compounds, that bind to estrogen receptors and produce estrogen agonist effects in some tissues and estrogen antagonist effects in others, are being assessed for several estrogen-related diseases including hormone-dependent malignancies33. Experimental animal data suggest that raloxifene does not stimulate the endometrium as tamoxifen does, while having similar antiestrogenic effects on breast tissue, and clinical studies have revealed that raloxifene causes no hyperplasia and no increase in endometrium thickness or polyp formation34. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial showed that, among postmenopausal women with osteoporosis, the risk of endometrial cancer was not increased (RR 0.8, 95% CI 0.2–2.7) during 3 years of treatment with raloxifene35. A prevention study of tamoxifen and raloxifene (STAR) is currently assessing the effect of tamoxifen or raloxifene on the incidence of breast cancer, endometrial cancer, ischemic heart disease and bone fractures in postmenopausal women at increased risk of invasive breast cancer36. Other compounds that display a SERM profile are currently in clinical development, including other triphenylethylenes (droloxifene, idoxifene) and benzothiophenes (LY353381 hydrochloride), benzopyrans (EM-800) and naphthalenes (CP-336, 156)33.
Clinical cancer genetics
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
The role of chemoprevention is much less certain, but includes a reduction of ovarian cancer risk in users of the combined oral contraceptive pill.92 Data on the role of tamoxifen in the prevention of breast cancer in high-risk women appeared initially to be conflicting. A large American study (NSABP1) has suggested a 45% reduction in breast cancer risk in women at increased risk who took tamoxifen chemoprevention.93 However, the effect was not replicated by two European studies.94,95 Tamoxifen also has potentially life-threatening side effects (pulmonary emboli, endometrial cancer, etc.), which has resulted in its use being patchy, even in the United States. More recent evidence, (that for women who are BRCA1/2 gene mutation carriers, tamoxifen significantly reduces the risk of breast cancer in both pre-menopausal and post-menopausal women;95) led to the establishment of the Study of Tamoxifen and Raloxifene (STAR) trial in the United States, involving tamoxifen and raloxifene, to determine which drug is most effective in preventing breast cancer.
Individualization of Endocrine Therapy in Breast Cancer
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Amelia B. Zelnak, Ruth M. O’Regan, Clodia Osipo
New drug discovery for selective ER modulators (SERMs) is currently driven by the known side effects of tamoxifen, which include an increase in the incidence of endometrial cancer, development of resistance, and the recent report of the negative effects of hormone replacement therapy (HRT) on coronary heart disease (42). Several approaches are being pursued by altering the antiestrogenic side chain or improving the pharmacokinetics of existing molecules. Several novel antiestrogen compounds have been developed to replace tamoxifen for ERα-positive breast cancer without the agonist actions. These compounds have the potential to be more effective than tamoxifen, having the advantage of reducing the incidence of endometrial cancer and possibly acquired resistance during therapy. Two groups of antiestrogenic drugs exist today with the potential to replace tamoxifen: (1) The SERMs that include tamoxifen-like compounds (triphenylethylenes) such as toremifene, idoxifene, and GW 5638 and fixed-ring compounds (benzothiophenes) such as raloxifene, arzoxifene, EM 652, and CP 336,156, and (2) selective ER downregulators (SERDs and pure antiestrogen) such as ICI 182,780 (Fulvestrant®). In phase II trials in patients with tamoxifen-resistant metastatic breast cancer, the new SERMs showed low response rates (0–15%) (43,44), suggesting crossresistance to tamoxifen. No difference in outcome was noted between tamoxifen and toremifene in patients with metastatic or early-stage breast cancer (45,46). In contrast, few clinical trials exist today evaluating the effectiveness of the fixed-ring compounds to tamoxifen. The Study of Tamoxifen and Raloxifene (STAR) trial compared the efficacy of raloxifene over tamoxifen as a chemopreventive for women at high risk for breast cancer. Both drugs reduced the risk of invasive breast cancer by approximately 50%. Tamoxifen also lowered the incidence of lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS) by about 50 percent; however, raloxifene did not have an effect on the incidence of LCIS and DCIS (47). Of note, the incidence of uterine cancer was 36% lower, and the incidence of thromboembolic events was 29% lower in the raloxifene arm (47). Fulvestrant and other SERDs have been shown to have high affinity for ERs compared with tamoxifen with none of the agonist activities. In clinical trials, fulvestrant initially showed significant promise for the treatment of advanced breast cancer (48,49). However, in a phase III clinical trial versus tamoxifen for first-line therapy of advanced breast cancer, fulvestrant was not superior to tamoxifen in terms of time-to-treatment failure (50). Therefore, more work is needed to evaluate the efficacy of SERDs in comparison with SERMs for ERα-positive breast cancer.
Assessment and management of B3 breast lesions with atypia: a focused review
Published in Climacteric, 2020
M. U. Ugurlu, T. Yoldemir, B. M. Gulluoglu
The efficacy of chemoprevention with tamoxifen, raloxifene, and exemestane has been established in large prospective randomized controlled trials63–66. In the National Surgical Adjuvant Breast and Bowel Project P-1 trial, the numbers of invasive and non-invasive breast cancers were significantly reduced after 5 years of tamoxifen by about 50% compared with placebo63. When subgroup analysis was performed, risk was reduced by 86% in women with a history of atypical hyperplasia and reduced by 56% among women with a history of LCIS63. The National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene trial showed that 5 years of raloxifene was almost as efficacious as tamoxifen among postmenopausal women while decreasing the invasive and non-invasive breast cancer risk by about 38%65.
Beyond estrogen: advances in tissue selective estrogen complexes and selective estrogen receptor modulators
Published in Climacteric, 2019
Hot flushes have been reported bothersome enough to seek treatment in clinical trials in 16% of participants20. The effect of tamoxifen on the vagina is mixed, with some estrogenic effects but also adverse reports of dyspareunia, leukorrhea, or vaginal dryness5. Tamoxifen use is associated with an increased risk of endometrial polyps, hyperplasia and adenocarcinoma of the endometrium (rare reports of mixed mesodermal sarcoma), venous thromboembolic events, pulmonary embolism, and stroke in women over 50 years old21–23. The risk of endometrial cancer in postmenopausal tamoxifen users in the Study of Tamoxifen and Raloxifene (STAR) was increased, with a relative risk (RR) of 2.54, and a higher RR of 5.4 for women over 50 years old, particularly those with longer durations of use or prior endometrial thickening on ultrasound21.
Selective estrogen receptor modulators and bone health
Published in Climacteric, 2022
Finally, in 2009, the US Food and Drug Administration (FDA) approved raloxifene for ‘reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis’ as well as ‘postmenopausal women at high-risk for invasive breast cancer’ [12,p.1]. This was based on the Study of Tamoxifen and Raloxifene (STAR) trial [15] that involved almost 20,000 postmenopausal women deemed at high risk for breast cancer (mean Gail score = 4.01%) who were randomized to tamoxifen 20 mg versus raloxifene 60 mg daily for 5 years. Raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer and had a lower risk of thromboembolic events and cataracts.