56 research outputs found
Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy. Menopause 11
ABSTRACT Objective: There is now convincing evidence that usual hormone therapy for ovarian failure increases the risk for breast cancer. We have previously shown that ovarian androgens normally protect mammary epithelial cells from excessive estrogenic stimulation, and therefore we hypothesized that the addition of testosterone to usual hormone therapy might protect women from breast cancer. Design: This was a retrospective, observational study that followed 508 postmenopausal women receiving testosterone in addition to usual hormone therapy in South Australia. Breast cancer status was ascertained by mammography at the initiation of testosterone treatment and biannually thereafter. The average age at the start of follow-up was 56.4 years, and the mean duration of follow-up was 5.8 years. Breast cancer incidence in this group was compared with that of untreated women and women using usual hormone therapy reported in the medical literature and to age-specific local population rates. Results: There were seven cases of invasive breast cancer in this population of testosterone users, for an incidence of 238 per 100,000 woman-years. The rate for estrogen/progestin and testosterone users was 293 per 100,000 woman-years-substantially less than women receiving estrogen/progestin in the Women's Health Initiative study (380 per 100,000 woman-years) or in the "Million Women" Study (521 per 100,000 woman-years). The breast cancer rate in our testosterone users was closest to that reported for hormone therapy never-users in the latter study (283 per 100,000 woman-years), and their age-standardized rate was the same as for the general population in South Australia. Conclusions: These observations suggest that the addition of testosterone to conventional hormone therapy for postmenopausal women does not increase and may indeed reduce the hormone therapy-associated breast cancer risk-thereby returning the incidence to the normal rates observed in the general, untreated population
Co-expression of estrogen receptor-alpha and targets of estrogen receptor action in proliferating monkey mammary epithelial cells
INTRODUCTION: Failure to detect co-expression of estrogen receptor-alpha (ERα) and proliferation 'markers' such as Ki67 in human mammary epithelium led to the view that estrogen acts indirectly to stimulate mammary epithelial proliferation. The mitotic index was so low in prior studies, however, that transient co-expression of ERα and Ki67 during the cell cycle could have been below detection limits. METHODS: Immunohistochemistry was used on mammary tissue sections from estrogen treated rhesus monkeys to investigate co-expression of ERα and the proliferation antigen Ki67. Using the same methods, we investigated the cell localization of proteins involved in estrogen-induced proliferation, including cyclin D1, stromal cell-derived factor (SDF)-1, and MYC. RESULTS: ERα was co-expressed with the proliferation marker Ki67 as well as with SDF-1, MYC and cyclin D1 in mammary epithelial cells from estrogen-treated monkeys. CONCLUSION: ERα is expressed in proliferating mammary epithelial cells together with the estrogen-induced proteins MYC, cyclin D1 and SDF-1, consistent with a direct mitogenic action by estrogen in primate mammary epithelium
Androgens and the breast
Androgens have important physiological effects in women while at the same time they may be implicated in breast cancer pathologies. However, data on the effects of androgens on mammary epithelial proliferation and/or breast cancer incidence are not in full agreement. We performed a literature review evaluating current clinical, genetic and epidemiological data regarding the role of androgens in mammary growth and neoplasia. Epidemiological studies appear to have significant methodological limitations and thus provide inconclusive results. The study of molecular defects involving androgenic pathways in breast cancer is still in its infancy. Clinical and nonhuman primate studies suggest that androgens inhibit mammary epithelial proliferation and breast growth while conventional estrogen treatment suppresses endogenous androgens. Abundant clinical evidence suggests that androgens normally inhibit mammary epithelial proliferation and breast growth. Suppression of androgens using conventional estrogen treatment may thus enhance estrogenic breast stimulation and possibly breast cancer risk. Addition of testosterone to the usual hormone therapy regimen may diminish the estrogen/progestin increase in breast cancer risk but the impact of this combined use on mammary gland homeostasis still needs evaluation
Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from Greece
<p>Abstract</p> <p>Background</p> <p>Inheritance of a mutation in either <it>BRCA1 </it>or <it>BRCA2 </it>accounts for approximately 5% of all breast cancer cases, but varies by country. Investigations into the contribution of <it>BRCA </it>mutations to breast cancer incidence in Greece have been, for the most part, limited by small sample sizes and by the use of cases selected for their family history of cancer. The aim of the current study was to estimate <it>BRCA </it>mutation frequencies in breast cancer patients unselected for family history.</p> <p>Methods</p> <p>To do so, we enrolled 127 unselected women with breast cancer from the Alexandra Hospital in Athens, Greece, a large public hospital in the city. Mutations in <it>BRCA1 </it>and <it>BRCA2 </it>were detected using a combination of techniques and were confirmed by direct sequencing. Two large genomic deletions were sought using mutation-specific assays. A detailed family history of cancer was obtained from each patient.</p> <p>Results</p> <p>We were able to successfully complete testing on samples from 127 women. Among these, six mutations were identified (four in <it>BRCA1 </it>and two in <it>BRCA2</it>) representing 4.7% of the total or 9.5% of cases diagnosed before age forty. None of the mutation carriers had a family history of breast or ovarian cancer. Three of the four <it>BRCA1 </it>mutations were in exon 20: two were a G5331A mutation and the third was a 3.2 kb deletion. The fourth <it>BRCA1 </it>mutation was the 3819delGTAAA in exon 11. The two <it>BRCA2 </it>mutations were in exon 11 (3782del10 and 4512insT).</p> <p>Conclusions</p> <p>The G5331A mutation in <it>BRCA1 </it>appears to be a founder mutation in the Greek population.</p
Androgens and Breast Cancer in Men and Women
Abundant clinical evidence suggests that androgens normally inhibit
mammary epithelial proliferation and breast growth. Clinical and
nonhuman primate studies support the notion that androgens inhibit
mammary proliferation and, thus, may protect from breast cancer. On the
other hand, administration of conventional estrogen treatment suppresses
endogenous androgens and may, thus, enhance estrogenic breast
stimulation and possibly breast cancer risk. Addition of testosterone to
the usual hormone therapy regimen may diminish the estrogen/progestin
increase in breast cancer risk, but the impact of this combined use on
mammary gland homeostasis still needs evaluation
Androgens and the breast
Androgens have important physiological effects in women while at the
same time they may be implicated in breast cancer pathologies. However,
data on the effects of androgens on mammary epithelial proliferation
and/or breast cancer incidence are not in full agreement. We performed a
literature review evaluating current clinical, genetic and
epidemiological data regarding the role of androgens in mammary growth
and neoplasia. Epidemiological studies appear to have significant
methodological limitations and thus provide inconclusive results. The
study of molecular defects involving androgenic pathways in breast
cancer is still in its infancy. Clinical and nonhuman primate studies
suggest that androgens inhibit mammary epithelial proliferation and
breast growth while conventional estrogen treatment suppresses
endogenous androgens. Abundant clinical evidence suggests that androgens
normally inhibit mammary epithelial proliferation and breast growth.
Suppression of androgens using conventional estrogen treatment may thus
enhance estrogenic breast stimulation and possibly breast cancer risk.
Addition of testosterone to the usual hormone therapy regimen may
diminish the estrogen/progestin increase in breast cancer risk but the
impact of this combined use on mammary gland homeostasis still needs
evaluation
Reduced breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: A prospective, observational study
Objectives: There is evidence that androgens are breast protective and
that testosterone therapy treats many symptoms of hormone deficiency in
both pre and postmenopausal patients. However, unlike estrogen and
progestins, there is a paucity of data regarding the incidence of breast
cancer in women treated with testosterone therapy. This study was
designed to investigate the incidence of breast cancer in women treated
with subcutaneous testosterone therapy in the absence of systemic
estrogen therapy.
Study design: This is a 5-year interim analysis of a 10-year,
prospective, observational, IRB approved study investigating the
incidence of breast cancer in women presenting with symptoms of hormone
deficiency treated with subcutaneous testosterone (T) implants or, T
combined with the aromatase inhibitor anastrozole (A), i.e., T+A
implants. Breast cancer incidence was compared with that of historical
controls reported in the literature, age specific Surveillance
Epidemiology and End
Results (SEER) incidence rates, and a representative, similar age group
of our patients used as a ‘control’ group. The effect of adherence to T
therapy was also evaluated. Results: Since March 2008, 1268 pre and post
menopausal women have been enrolled in the study and eligible for
analysis. As of March 2013, there have been 8 cases of invasive breast
cancer diagnosed in 5642 person-years of follow up for an incidence of
142 cases per 100 000 person-years, substantially less than the
age-specific SEER incidence rates (293/100 000), placebo arm of Women’s
Health Initiative Study (300/100000), never users of hormone therapy
from the Million Women Study (325/100 000) and our control group
(390/100 000). Unlike adherence to estrogen therapy, adherence to T
therapy further decreased the incidence of breast cancer (73/100 000).
Conclusion: T and/or T+A, delivered subcutaneously as a pellet implant,
reduced the incidence of breast cancer in pre and postmenopausal women.
Evidence supports that breast cancer is preventable by maintaining a T
to estrogen ratio in favor of T and, in particular, by the use of
continuous T or, when indicated, T+A. This hormone therapy should be
further investigated for the prevention and treatment of breast cancer.
(C) 2013 The Authors. Published by Elsevier Ireland Ltd. All rights
reserved
Rapid response of breast cancer to neoadjuvant intramammary testosterone-anastrozole therapy: neoadjuvant hormone therapy in breast cancer
Objective: Experimental and clinical data support the inhibitory effect
of testosterone on breast tissue and breast cancer. However,
testosterone is aromatized to estradiol, which exerts the opposite
effect. The aim of this study was to determine the effect of
testosterone, combined with the aromatase inhibitor anastrozole, on a
hormone receptor positive, infiltrating ductal carcinoma in the
neoadjuvant setting.
Methods: To determine clinical response, we obtained serial ultrasonic
measurements and mammograms before and after therapy. Three combination
implants-each containing 60 mg of testosterone and 4 mg of
anastrozole-were placed anterior, superior, and inferior to a 2.4-cm
tumor in the left breast. Three additional testosterone-anastrozole
implants were again placed peritumorally 48 days later.
Results: By day 46, there was a sevenfold reduction in tumor volume, as
measured on ultrasound. By week 13, we documented a 12-fold reduction in
tumor volume, demonstrating a rapid logarithmic response to intramammary
testosterone-anastrozole implant therapy, equating to a daily response
rate of 2.78% and a tumor half-life of 23 days. Therapeutic systemic
levels of testosterone were achieved without elevation of estradiol,
further demonstrating the efficacy of anastrozole combined with
testosterone.
Conclusions: This novel therapy, delivered in the neoadjuvant setting,
has the potential to identify early responders and to evaluate the
effectiveness of therapy in vivo. This may prove to be a new approach to
both local and systemic therapies for breast cancer in subgroups of
patients. In addition, it can be used to reduce tumor volume, allowing
for less surgical intervention and better cosmetic oncoplastic results
Testosterone implants in women: Pharmacological dosing for a physiologic effect
Objectives: The objectives of this study were to determine therapeutic
serum testosterone (T) levels/ranges and inter-individual variance in
women treated with subcutaneous T implants.
Study design: In study group 1, T levels were measured at two separate
time intervals in pre- and postmenopausal women treated with
subcutaneous T for symptoms of androgen deficiency: (i) four weeks after
pellet insertion, and (ii) when symptoms of androgen deficiency
returned.
In a separate pharmacokinetic study (study group 2), 12 previously
untreated postmenopausal women each received a 100 mg T implant. Serum T
levels were measured at baseline, 4 weeks and 16 weeks following T
pellet implantation.
In study ‘group’ 3, serial T levels were measured throughout a 26 h
period in a treated patient.
Results: In study group 1, serum T levels measured at ‘week 4’ (299.36
+/- 107.34 ng/dl, n = 154), and when symptoms returned (171.43 +/- 73.01
ng/dl, n = 261), were several-fold higher compared to levels of
endogenous T. There was significant inter-individual variance in T
levels at ‘week 4’ (CV 35.9%) and when symptoms returned (CV 42.6%).
Even with identical dosing (study group 2), there was significant
inter-individual variance in T levels at ‘week 4’ (CV 41.9%) and ‘week
16’ (CV 41.6%). In addition, there was significant intra-individual
circadian variation (CV 25%).
Conclusions: Pharmacologic dosing of subcutaneous T, as evidenced by
serum levels on therapy, is needed to produce a physiologic effect in
female patients. Safety, tolerability and clinical response should guide
therapy rather than a single T measurement, which is extremely variable
and inherently unreliable. (c) 2012 Elsevier Ireland Ltd. All rights
reserved
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