Early findings on the use of tamoxifen or raloxifene as prophylaxis against breast cancer have been mixed; we update available data and overview the combined results.
All five randomised prevention trials comparing tamoxifen or raloxifene with placebo were included. Relevant data on contralateral breast tumours and side-effects were included from an overview of adjuvant trials of tamoxifen versus control.
The tamoxifen prevention trials showed a 38% (95% CI 28-46; p<0.0001) reduction in breast-cancer incidence. There was no effect for breast cancers negative for oestrogen receptor (ER; hazard ratio 1.22 [0.89-1.67]; p=0.21), but ER-positive cancers were decreased by 48% (36-58; p<0.0001) in the tamoxifen prevention trials. Age had no apparent effect. Rates of endometrial cancer were increased in all tamoxifen prevention trials (consensus relative risk 2.4 [1.5-4.0]; p=0.0005) and the adjuvant trials (relative risk 3.4 [1.8-6.4]; p=0.0002); no increase has been seen so far with raloxifene. Venous thromboembolic events were increased in all tamoxifen studies (relative risk 1.9 [1.4-2.6] in the prevention trials; p<0.0001) and with raloxifene. Overall, there was no effect on non-breast-cancer mortality; the only cause showing a mortality increase was pulmonary embolism (six vs two).
The evidence now clearly shows that tamoxifen can reduce the risk of ER-positive breast cancer. New approaches are needed to prevent ER-negative breast cancer and to reduce the side-effects of tamoxifen. Newer agents such as raloxifene and the aromatase inhibitors need to be evaluated. Although tamoxifen cannot yet be recommended as a preventive agent (except possibly in women at very high risk with a low risk of side-effects), continued follow-up of the current trials is essential for identification of a subgroup of high-risk, healthy women for whom the risk-benefit ratio is sufficiently positive.
"Given that this injury occurs predominantly in pre-and postmenopausal  women and that breast intraductal papillary lesions are usually hormone-dependent  (in our series more than 85% estrogens positive), these patients may be susceptible to receive an chemoprevention with hormone inhibitors. It has been demonstrated in different studies that the inhibition of both estrogen receptors (tamoxifen and raloxifene)    and aromatase pathway (exametasane )  reduces contralateral breast cancer relapse. The major problem of these therapies is the election of patients to receive treatment, we propose that COL11A1 positive biopsy should be a new factor to ponder besides a Gail 5- year risk score greater than 1.66% and prior preneoplastic lesion  to select candidates for this chemoprevention as these lesions have a high susceptibility to malignant relapse. "
[Show abstract][Hide abstract] ABSTRACT: Despite the progress achieved in the treatment of breast cancer, there are still many unsolved clinical issues, being the diagnosis, prognosis, and treatment of papillary diseases, one of the highest challenges. Because of its unpredictable clinical behavior, treatment of intraductal papilloma has generated a great controversy. Even though considered as a benign lesion, it presents high rate of malignant recurrence. This is the reason why there are clinicians supporting a complete excision of the lesion, while others support an only expectant follow-up. Previous results of our group suggested that procollagen 11 alpha 1 (pro-COL11A1) expression correlates with infiltrating phenotype in breast lesions. We analyzed the correlation between expression of pro-COL11A1 in intraductal papilloma and their risk of malignant recurrence. Immunohistochemistry of pro-COL11A1 was performed in 62 samples of intraductal papilloma. Ten out 11 cases relapsed as carcinoma presents positive staining for COL11A1, while just 17 out of 51 cases with benign behaviour present immunostaining. There were significant differences (
) when comparing patients with malignant recurrence versus nonmalignant relapse patients. These data suggest that pro-COL11A1 expression is a highly sensitive biomarker to predict malignant relapse of intraductal papilloma and it can be used as indicative factor for prevention programs.
"To date, an alternative strategy in preventing the progression of ER-dependent breast tumors is represented by drugs that inhibit the aromatase enzyme and interfere with the biosynthesis of estrogens, leading to a drastic reduction of circulating estrogen levels (5). Accordingly, clinical trials have suggested that aromatase inhibitors (AIs) are highly effective in preventing invasive ER-positive breast tumors in high-risk women (6, 7), even though significant side-effects have been observed in follow-up studies (8). The aforementioned observations indicate that SERMs and AIs are not able to prevent the development of ER-negative breast cancer, hence suggesting the need of additional prognostic and predictive factors beyond ERα (9), toward more comprehensive therapeutic strategies particularly in these types of tumors. "
[Show abstract][Hide abstract] ABSTRACT: The G-protein-coupled estrogen receptor-1 (GPER, formerly known as GPR30) has attracted increasing interest, considering its ability to mediate estrogenic signaling in different cell types, including the hormone-sensitive tumors like breast cancer. As observed for other GPCR-mediated responses, the activation of the epidermal growth factor receptor is a fundamental integration point in the biological action triggered by GPER. A wide number of natural and synthetic compounds, including estrogens and anti-estrogens, elicit stimulatory effects in breast cancer through GPER up-regulation and activation, suggesting that GPER function is associated with breast tumor progression and tamoxifen resistance. GPER has also been proposed as a candidate biomarker in triple-negative breast cancer, opening a novel scenario for a more comprehensive assessment of breast tumor patients.
Frontiers in Endocrinology 05/2014; 5:66. DOI:10.3389/fendo.2014.00066
"Tamoxifen is the main drug that is able to reduce breast cancer (BC) risk, but its adverse events have so far precluded the uptake as a preventive agent . The Food and Drug Administration (FDA) has approved raloxifene for the same indications as tamoxifen, though only for postmenopausal women. "
[Show abstract][Hide abstract] ABSTRACT: We previously demonstrated that 1 or 5 mg per day of tamoxifen (T) given for 4 weeks before surgery reduces Ki-67 in breast cancer (BC) patients to the same extent as the standard 20 mg/d. Given the long half-life of T, a weekly dose (10mg/w) may be worth testing. Also, raloxifene (R) has shown Ki-67 reduction in post menopausal patients in a preoperative setting, but data in premenopausal women are limited. We conducted a randomized trial testing T 10mg per week (w), vs R 60 mg/d vs placebo in a pre-surgical model.
Out of 204 screened subjects, 57 were not eligible, 22 refused to participate and 125 were included in the study. The participants were all premenopausal women with estrogen receptor-positive BC. They were randomly assigned to either T 10mg/w or R 60 mg/d or placebo for 6 weeks before surgery. The primary endpoint was tissue change of Ki67. Secondary endpoints were modulation of estrogen and progesterone receptors and several other circulating biomarkers.
Ki-67 was not significantly modulated by either treatment. In contrast, both selective estrogen receptor modulators (SERMs) significantly modulated circulating IGF-I/IGFBP-3 ratio, cholesterol, fibrinogen and anti-thrombin III. Estradiol was increased with both SERMs. Within the tamoxifen arm, CYP2D6 polymorphism analysis showed a higher concentration of N-desTamoxifen, one of the tamoxifen metabolites, in subjects with reduced CYP2D6 activity. Moreover, a reduction of Ki67 and a marked increase of sex hormone banding protein (SHBP) were observed in the active phenotype.
A weekly dose of tamoxifen and a standard dose of raloxifene did not inhibit tumor cell proliferation, measured as Ki67 expression, in premenopausal BC patients. However in the tamoxifen arm women with an extensive phenotype for CYP2D6 reached a significant Ki67 modulation.
Breast cancer research: BCR 06/2013; 15(3):R47. DOI:10.1186/bcr3439 · 5.49 Impact Factor
Francesco Dentali, Gianluca Di Micco, Matteo Giorgi Pierfranceschi, Gualberto Gussoni, Giovanni Barillari, Maria Amitrano, Andrea Fontanella, Corrado Lodigiani, Anna Guida, Adriana Visonà, Manuel Monreal, Pierpaolo Di Micco
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