Decrease In Breast Cancer Incidence Research Articles

Abstract P1-09-02: Pilot study of a 1-year intervention of high-dose vitamin D in women at high risk for breast cancer.

Abstract Background: Selective estrogen receptor modulators (SERMs) have been shown to decrease breast cancer incidence among high-risk women, but uptake for prevention has been poor. Observational studies have demonstrated that serum 25-hydroxyvitamin D (25-OHD) is inversely related to breast cancer risk, such that levels >40 ng/ml are associated with about a 40% reduction in breast cancer risk compared to women who are vitamin D deficient (25-OHD <20 ng/ml). Uncertainty remains about whether vitamin D supplementation will reduce breast cancer risk, the optimal dose of vitamin D, and the target level of serum 25-OHD. We examined the safety of high dose vitamin D and the effects on serum 25-OHD in women at high risk for breast cancer. Methods: Forty high-risk women (defined as a 5-year Gail risk ³1.67%, lobular or ductal carcinoma in situ [LCIS/DCIS], BRCA1/BRCA2 mutation carrier, or stage I/II invasive breast cancer in remission for >5 years) were assigned to a 1-year intervention of vitamin D3 20,000 or 30,000 IU weekly. Other eligibility criteria included baseline mammographic density (MD) ≥25%, serum 25-OHD ≤32 ng/ml, no current SERM use and no history of kidney stones. Women underwent a digital mammogram at baseline and 12 months, and serial blood draws every 3 months. In addition, random core breast biopsies were conducted in premenopausal women, whereas postmenopausal women underwent a breast MRI at baseline and 12 months. Participants were monitored for toxicity, particularly hypercalcemia and hypercalciuria, every 3 months. The primary objective is to determine the safety and feasibility of high-dose vitamin D in this study population. Secondary objectives are to determine changes in breast density and blood-based biomarkers (25-OHD, 1,25(OH)D, PTH, IGF-I, IGFBP-3). Serum 25-OHD was measured by Diasorin radioimmunoassay. Results: From November 2007 to January 2011, 292 women were screened and 142 were ineligible. Main reasons for ineligibility (%) included 25-OHD >32 ng/ml (27), opted for SERM (23), prior kidney stones (11), and MD <25% (9). Of the 40 enrolled participants: median age 50 years (range, 37–73); pre/postmenopausal: 20/20; white/hispanic/black/asian: 19/14/6/1; median body mass index 26.6 kg/m2 (20–39.6); elevated Gail risk/LCIS/DCIS/stage I or II breast cancer: 20/10/8/2; mean baseline serum 25-OHD 20.2 ng/ml (9–31). Currently, 1 participant is on-study, 31 completed the intervention, 6 were lost to follow-up, 1 withdrew due to hypercalciuria (spot urine Ca/Cr >0.37) and 1 withdrew due to dyspepsia. Mean serum 25-OHD rose to 47 ng/ml at 3 months, 49.1 ng/ml at 6 months, and 53.7 ng/ml (range, 26–77) at 12 months. No significant hypercalcemia (serum Ca >10.5 mg/dl) occurred at either dose level. Imaging and biomarker analyses are ongoing. Discussion: We have demonstrated that a 1-year intervention of high-dose vitamin D3 is well tolerated and can increase serum 25-OHD above a target level of 40 ng/ml. This preliminary data has informed an ongoing phase IIb randomized placebo-controlled trial (SWOG 0812) of high-dose vitamin D in 200 high-risk premenopausal women and highlights the importance of early phase breast cancer chemoprevention trials with intermediate biomarker endpoints to test novel agents. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-09-02.

Metformin Inhibits Advanced Glycation End Products (AGEs)-induced Growth and VEGF Expression in MCF-7 Breast Cancer Cells by Suppressing AGEs Receptor Expression via AMP-activated Protein Kinase

Metformin use has been reported to decrease breast cancer incidence and mortality in diabetic patients. We have previously shown that advanced glycation end products (AGEs) and their receptor (RAGE) interaction stimulate growth and/or migration of pancreatic cancer and melanoma cells. However, effects of metformin on AGEs-RAGE axis in breast cancers remain unknown. We examined here whether and how metformin could block the AGEs-induced growth and vascular endothelial growth factor (VEGF) expression in MCF-7 breast cancer cells. Cell proliferation was measured with an electron coupling reagent WST-1 based colorimetric assay. Gene expression level was evaluated by real-time reverse-transcription polymerase chain reactions. AGEs significantly increased cell proliferation of MCF-7 cells, which was completely prevented by the treatment with 0.01 or 0.1 mM metformin or anti-RAGE antibodies. Furthermore, metformin at 0.01 mM completely suppressed the AGEs-induced upregulation of RAGE and VEGF mRNA levels in MCF-7 cells. An inhibitor of AMP-activated protein kinase, compound C significantly blocked the growth-inhibitory and RAGE and VEGF suppressing effects of metformin in AGEs-exposed MCF-7 cells. Our present study suggests that metformin could inhibit the AGEs-induced growth and VEGF expression in MCF-7 breast cancer cells by suppressing RAGE gene expression via AMP-activated protein kinase pathway. Metformin may protect against breast cancer expansion in diabetic patients by blocking the AGEs-RAGE axis.

238. Localized and metastatic breast cancer. Role of polymorphonuclear CD64 index measurement as marker of monocyte activation

Background: A number of patients with small breast cancer (BC) may develop aggressive disease, and thus the traditional histopathological characteristics are unable to correctly evaluate the biological behavior of BC. The decrease in use of hormone replacement therapy among postmenopausal women has been suggested as an explanation for the decrease in BC incidence registered in recent years, while the higher detection rate of small lesions without lymph node involvement or invasive growth should be attributed to screening programs.

59P Mammary Duct Endoscopy with Saline Lavage for Breast Cancer Prevention and Homeostasis Maintenance in Middle Aged Women

ABSTRACT Background Our previous report has demonstrated that mammary duct endoscopy plays important role for breast cancer screening in patients with spontaneous nipple discharge (SND). From our large quantity of mammary duct endoscopy data pool and regular follow up, we found that patients underwent mammary duct endoscopy plus saline lavage not only had decreased breast cancer incidence rate, but also greatly improved symptoms of hypothyroidism which subsequently improved their life quality. Objectives The objective of current study was to compare mammary duct endoscopy with or without saline lavage in the context of decreasing breast cancer incidence rate and improving clinical presentations of hypothyroidism. Material and methods 1000 of patients with normal initial mammary duct endoscopy were randomly divided into two groups. Group L patients underwent mammary duct lavage during the procedure; group C patients without any further intervention. For both groups of patients, questionnaires to screen symptoms of hypothyroidism were given; and a baseline TSH was recorded. Patients were followed up for physical examination and TSH level. The second time mammary duct endoscopy was performed 3 years after the initial exam. Results 2% of patients in group L had ductal hyperplasia compared to 25% in the group C; breast cancer was found in 3% in group C and none in group L. 28% of patients previously with more than two hypothyroidism symptoms became asymptomatic in group L; while in group C, 3% of patients without hypothyroidism symptoms during the initial screening became symptomatic three years later. Blood TSH level changed from 0.3 µIU/ml to 1.8 µIU/ml for group L patients and decreased from 0.4 µIU/ml to 0.3 µIU/ml for group C patients. Conclusion From this study we find that mammary duct lavage through endoscopy played significant role on prevention of breast cancer by removing mechanical blockage and subsequently decreased PRL secretion. This indirectly recovered the pituitary TSH secretion through inhibition of thyrotroph transdifferentiation into lactotroph and improved patients' life quality by homeostasis rebalance. Disclosure All authors have declared no conflicts of interest.

A Modest Proposal for a Clinical Trial on Single-Bundle Versus Double-Bundle Anterior Cruciate Ligament Reconstruction

A Modest Proposal for a Clinical Trial on Single-Bundle Versus Double-Bundle Anterior Cruciate Ligament Reconstruction

P3-11-02: Changing Paradigms for Breast Cancer Chemoprevention?

Abstract The SERMs tamoxifen and raloxifene are approved for breast cancer risk reduction but their acceptance in clinical practice has been poor largely related to rare but potentially life threatening side effects which requires identification of populations at higher breast cancer risk and careful risk benefit discussion (Visvanathan 2009). Recent findings from randomized placebo-controlled clinical trials suggest potential alternative approaches. In the MAP.3 placebo-controlled trial including 4,650 postmenopausal women, exemestane decreased breast cancer incidence by 65% (P=0.002) (Goss 2011) with no significant difference between groups for fractures, CVD events, other cancers or treatment-related deaths. While the median Gail 5-yr risk score of participants was 2.3, eligibility factors included age alone (≥ 60 years) regardless of calculated breast cancer risk and accounted for 49% of entries. With extended follow-up from the Women's Health Initiative (WHI) randomized, placebo-controlled trial evaluating estrogen alone in 10,739 postmenopausal women with prior hysterectomy, a statistically significant decrease in breast cancer incidence of 23% was seen with estrogen use (P=0.02) (LaCroix 2011). Younger postmenopausal women (age 50–59 years at entry) randomized to estrogen alone had lower risk of myocardial infarction (HR 0.54, 95% CI 0.34−0.86) and death (HR 0.73, 95% CI 0.53−1.00). These findings contrast to those in the WHI trial evaluating combined estrogen plus progestin in 16,608 postmenopausal women with an intact uterus where breast cancers were increased 25% (P=0.004) as was breast cancer mortality (increased by 96%, P=0.049) (Chlebowski 2010). The apparently paradoxical findings that in postmenopausal women estrogen addition, as conjugated equine estrogen, lowers breast cancer incidence and estrogen reduction, by aromatase inhibitor use, also lowers breast cancer incidence are consistent with preclinical studies indicating condition dependent change in estrogen influence on mammary cancers (Jordan 2011). Major eligibility for the WHI trials included anticipated 3-yr survival regardless of breast cancer or CVD risk. The findings from the MAP.3 and WHI trials highlight the complex relationships between estrogen and breast cancer and suggest potential strategies for chronic disease risk reduction in select populations of postmenopausal women which may not require formal breast cancer risk assessment. Visvanathan K, Chlebowski RT, et al. J Clin Oncol 2009;27:3235–3258. Goss PE, Ingle JN, Ales-Martinez J, Cheung A, Chlebowski RT, et al. The NCIC CTG MAP.3 Trial. N Engl J Med 10.1056/NEJMos 1103507. Chlebowski RT, Anderson GL, et al. JAMA 2010;304(15):1684–1692. LaCroix AZ, Chlebowski, RT, et al. JAMA 2011;305(13):1305–14. Jordan VC, Ford LG. Cancer Prev Res. 4:633–7 (2011). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-11-02.

OT2-04-03: Uptake of a Randomized Breast Cancer Prevention Trial Comparing Letrozole to Placebo in BRCA1/2 Mutations Carriers: The FNCLCC ONCO-03/LIBER Trial.

Abstract Background: Women with germline BRCA1or BRCA2 (BRCA1/2) mutations are an extreme risk population for developing breast cancer, with a life-time risk of 56–80%. Prophylactic mastectomy provides a valid option to reduce such risk, but it considerably affects the quality of life. Medical prevention by aromatase inhibitor that has been recently shown to have preventive effect may thus be an alternative. LIBER is an ongoing, double-blind, randomized phase III trial to evaluate the efficacy of five-years letrozole versus placebo to decrease breast cancer incidence in post-menopausal BRCA1/2 mutation carriers (NCT00673335). We present data on the uptake of this trial. Methods: To evaluate theoretical feasibility, we compared inclusion criteria of women in the LIBER trial (n=113) to characteristics of women entered in the prospective ongoing national GENEPSO cohort (n=1505). Uptake was evaluated through a survey sent to all active centres, with responses obtained from 17 of the 20 (85%) centres. Results: According to characteristics of the women included in GENEPSO cohort (n=1505) and the survey, approximately one third of BRCA1/2 mutation carriers are eligible for this study. From november 2009 to may 2010, 534 women eligible from chart review have been informed by mail of the trial and were invited to an oral information by participating centres. Of them, 44% of women came to the dedicated medical visit. Uptake of drug prevention trial was 32 % of orally informed women and 15 % of overall eligible women. Main reasons of refusal were: potential side effects, probability to receive the placebo and lack of support from the women's physicians. Prior prophylactic oophorectomy and history ***of previous unilateral breast cancer were more frequent in women enrolled in the ONCO-03/LIBER trial than in the French cohort (93% versus 60% and 50 % versus 39 %, respectively), suggesting a higher motivation for medical prevention in these subgroups of patients. Conclusion: One third of women with a BRCA1/2 mutation are eligible to the ONCO-03/LIBER prevention trial. 32 % of orally informed women and, only 15% of overall eligible women entered the trial. To reach accrual objective (n=308), a greater information of the trial should be offered to women with BRCA1/2 mutation and the trial has been proposed to other countries. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-04-03.

Uptake of a randomized breast cancer prevention trial comparing letrozole to placebo in BRCA1/2 mutations carriers: the LIBER trial

Women with germline BRCA1 or BRCA2 (BRCA1/2) mutations are considered as an extreme risk population for developing breast cancer. Prophylactic mastectomy provides a valid option to reduce such risk, impacting however, the quality of life. Medical prevention by aromatase inhibitor that has also recently shown to have preventive effect may thus be considered as an alternative. LIBER is an ongoing double-blind, randomized phase III trial to evaluate the efficacy of 5-year letrozole versus placebo to decrease breast cancer incidence in post-menopausal BRCA1/2 mutation carriers (NCT00673335). We present data on the uptake of this trial. We compared characteristics of women in the LIBER trial (n=113) to those of women enrolled in the prospective ongoing national GENEPSO cohort (n=1,505). Uptake was evaluated through a survey sent to all active centres, with responses obtained from 17 to the 20 (85%) centres. According to the characteristics of the women enrolled in the GENEPSO cohort and the survey, approximately one-third of BRCA1/2 mutation carriers were eligible for the trial. Five hundred and thirty-four women eligible from chart review have been informed by mail about the prevention trial and were invited to an oral information by participating centres. Forty-four percentage of them came to the dedicated medical visit. Uptake of drug prevention trial was 32% among women informed orally and 15% of all the eligible women. The main reasons of refusal were: potential side effects, probability to receive the placebo and lack of support from their physicians. Additionally, we noticed that prior prophylactic oophorectomy and previous unilateral breast cancer were more frequent in women enrolled in the LIBER trial than in the French cohort (93% vs. 60% and 50% vs. 39%, respectively). Based on an overall 15% uptake among all eligible subjects, greater and wider information of the trial should be offered to women with BRCA1/2 mutation to improve recruitment. Women with previous unilateral breast cancer or prior prophylactic oophorectomy are more likely to enter a medical prevention trial.

Abstract S5-6: Steroid Hormone Regulation of Mammary Stem Cell Function

Abstract Background: The ovarian hormones estrogen and progesterone profoundly influence breast cancer risk, underpinning the benefit of endocrine therapies in the treatment of breast cancer. Modulation of their effects through ovarian ablation or chemoprevention strategies also significantly decreases breast cancer incidence. Conversely, there is an increased risk of breast cancer associated with pregnancy in the short-term. The cellular mechanisms underlying these observations, however, are poorly defined. We and others recently isolated mammary epithelial populations enriched for mammary stem cells (MaSCs), committed luminal progenitor and mature luminal cells from both mouse and human mammary glands. Unexpectedly, MaSCs exhibited a receptor-negative phenotype for ERα , PR and ErbB2. Given the central important of estrogen and progesterone signaling to mammary gland development and cancer, we sought to determine whether these hormones could indirectly modulate MaSC function. Methods and Results: We utilized mouse models to directly study the effects of steroid hormones on the in vivo repopulating ability of MaSCs. Ovariectomy markedly diminished MaSC number and the extent of ductal outgrowth in vivo. The relative contribution of estrogen and progesterone to the regulation of MaSC activity was next examined using hormone pellets or antagonists. MaSC activity increased in animals treated with both estrogen and progesterone. Remarkably, even three weeks of treatment with the aromatase inhibitor letrozole was sufficient to reduce the MaSC pool. The outgrowth potential of these cells was again affected, suggesting that MaSCs retain a ‘memory’ of estrogen deprivation, perhaps through perturbation of their cycling status. Indeed, cell cycle analysis revealed an increase in the percentage of MaSC-enriched cells in G0/G1 in ovariectomized glands compared to controls. This was accompanied by a profound reduction in the expression of cell cycle genes including Cyclin D1. We further evaluated the effect of the hormonal environment on MaSC function during pregnancy, where progesterone (and prolactin) have prominent roles. Pregnancy led to a transient 11-fold increase in MaSC numbers. This was accompanied by marked elevation in the expression of the progesterone target gene RANK ligand in luminal cells, together with its receptor RANK in the MaSC-containing population. To determine whether MaSC activity is in part mediated through paracrine signals from RANK ligand, inhibitors of RANK signaling were evaluated. Treatment of virgin or pregnant mice with an anti-RANK ligand monoclonal antibody in vivo significantly impaired the clonogenic activity of the MaSC-enriched but not luminal subpopulation. Discussion: Despite lacking the steroid hormone receptors ERα and PR, MaSCs appear to be exquisitely sensitive to hormone signaling, presumably via paracrine signaling that includes the RANK signaling pathway. The augmented MaSC pool during pregnancy suggests a cellular basis for the short-term increase in breast cancer incidence following pregnancy. Our findings further indicate that breast cancer chemoprevention may in part be achieved through suppression of MaSC function. We speculate that inhibitors of RANK and other stem cell signaling pathways could represent potential chemoprevention agents. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S5-6.

Abstract P2-07-05: Age-Related Changes in ERK5 Signaling and Crosstalk with ERK1/2 and PI3K in Breast Cancer

Abstract Increasing age is a main risk factor for breast cancer. By the year 2040, the number of Americans age 65 or older is expected to more than double to nearly 80 million. Therefore, the need to define the underlying mechanisms involved in breast tumor proliferation with aging is crucial. Previous studies have shown that mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 5 (ERK5) expression and activity increase with age in breast cancer patients. Furthermore, patients with increased levels of ERK5 have been found to have a poorer prognosis than those with lower levels. The MAPK and phosphatidylinositol 3-kinase (PI3K) signaling cascades play essential roles in several cellular processes including proliferation, survival, and apoptosis. In breast cancer cells, crosstalk between the MAPK extracellular signal-regulated kinase 1/2 (ERK1/2) and PI3K pathways has been found to play an important role in cellular proliferation and chemoresistance. Therefore, our hypothesis is that as ERK5 activity increases, ERK1/2 and PI3K activities decrease, and vice versa, to promote the proliferation of breast cancer cells with aging. The human breast cancer BT-474 and MDA-MB-231 cell lines and the murine cancer, MMC, cell line were utilized for our in vitro studies of ERK and Akt expression and activation. To mimic aging in vitro, cells were maintained in culture out to 36 passages with intermittent lysates collected at every third passage. In the BT-474 (ER+/PR+/HER2high) cell line, increased ERK5 activity was observed in the middle passages; ERK1/2 activation and expression remained unchanged between the different passages collected. Conversely, no ERK5 activity was observed in the MDA-MB-231 (ER-/PR-/HER2low) cell line, while ERK1/2 activity and expression again remained unchanged throughout the different passages. These observations suggest the potential of age-related and hormonal influences on ERK5 activation and require further investigation. To confirm our findings in vivo, the MMTV-neu transgenic mouse model was employed. These female mice spontaneously develop mammary tumors thereby mimicking the development of human breast cancers. Tumors were extracted from young (3 mo), middle-aged (9 mo), and old (15 mo) mice. Data from our in vivo studies suggest that ERK5 activity increases at middle-age, confirming our observations in vitro. Interestingly, ERK1/2 activation decreased in the middle-age group. Such findings suggest the presence of a compensatory mechanism between the MAPKs. Ongoing studies are examining the crosstalk between these pathways and the PI3K pathway. Specific inhibitors of the pathways and small interfering RNA (siRNA) will be used to selectively decrease ERK1/2, ERK5 and PI3K signaling. Cell proliferation will then be assessed to evaluate the relative roles of these kinases. The data obtained from these studies may lead to the identification of ERK5 as a therapeutic target in middle-aged and elderly patients thereby providing more individualized therapies that may lead to decreased breast cancer incidence and mortality. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-07-05.

Decline in breast cancer incidence in the Flemish region of Belgium after a decline in hormonal replacement therapy

BackgroundBreast cancer incidence rate in Belgian women was as high as 152.7 for 100 000 in 2003 (adjusted on European population). We made an estimation of the contribution of hormone replacement therapy (HRT) on breast cancer incidence from 1999 to 2005 in women aged 50–69 years in Flanders. MethodsBreast cancer data were extracted from the Belgium Cancer Registry. Drug consumption was computed from drug sales data. The fraction of breast cancers attributable to HRT was calculated by year, using the relative risks of the Million Women Study in the UK. ResultsThe proportion of women aged 50–69 years using HRT in Flanders increased since 1992, peaked at 20% in 2001, then decreased to 8% in 2008. The incidence of breast cancer in 100 000 women aged 50–69 years in Flanders increased from 332.8 in 1999 to 407.9 in 2003, then decreased to 366.1 in 2005; the variations were mostly noticeable for tumors <20 mm in size. The fraction of breast cancers attributed to HRT peaked at 11% in 2001 and decreased afterward. ConclusionThe high level of breast cancer observed in the years 2001–2003 in Flanders can be partly attributed to the use of HRT. Since participation to mammography screening of Flemish women aged 50–69 years was still on the rise in 2003 and never exceeds 62%, the decrease in breast cancer incidence was likely to be due to the decrease in HRT use and not to screening saturation.

Parity is associated with an expanded macrophage population in the mammary gland

Pregnancy is a well established protective factor against breast cancer. One explanation for protection is the increased differentiation status of the parous epithelium. However, this does not explain the association of parity with increased aggressiveness of breast cancers, particularly cancers that occur soon after pregnancy. Because tumor aggressiveness can be influenced by the cell population that surrounds the mammary epithelium, we examined the potential role of the immune system in establishing a long-term difference between the mammary glands of primiparous and virgin animals. Specific mRNA levels, enzyme activities and antigen expressing cells were quantified in primiparous and virgin mammary glands from Sprague-Dawley rats in diestrous. Our results show that macrophages, but not neutrophils or B-cells, are specifically increased in fully involuted glands compared with age-matched virgin mammary glands. Macrophages play a dual role in tumor progression, both opposing and supporting the process. Our finding of an increased macrophage population in the primiparous mammary gland could explain the dichotomy of the reported association of parity with decreased breast cancer incidence and increased breast cancer aggressiveness.

Could Recent Decreases in Breast Cancer Incidence Really Be Due to Lower HRT Use? Trends in Attributable Risk for Modifiable Breast Cancer Risk Factors in Canadian Women

Objectives: Recent downward trends in breast cancer incidence have been attributed to declining use of hormone replacement therapy (HRT). To determine whether this is a credible conclusion, this study calculated population attributable risk (PAR) for HRT and other modifiable breast cancer risk factors. Methods: PAR calculation needs both the prevalence of a risk factor, and the relative risk (RR) for breast cancer incidence for that risk factor. Prevalences were calculated for Canadian women, aged 50-69, participating in the National Population Health Survey, 1994-2006. RR were derived from published research: 1.4 for HRT use, 1.4 for excessive alcohol use, 1.15 for physical inactivity, 1.25 for smoking, 1.4 for BMI over 30 kg/m2. Trends for PAR were calculated for the risk factors separately, as well as combined. Age-adjusted breast cancer incidence rates were calculated for Canadian women aged 50-69 for the years 1994-2004. Results: Between 1998 and 2004, PAR for HRT decreased by 50%. PAR for other risk factors showed only small changes, and the combined PAR decreased by 18.6%. Age-adjusted breast cancer incidence for women aged 50-69 peaked in 2000 at 330.0/100,000, then dropped by 17.2% by 2004. Conclusion: Patterns of PAR for HRT use in Canada are consistent with the noticeable decrease in breast cancer incidence observed for women of the same age group. Combining PAR for all risk factors indicated that changes in HRT use overpowered any trends of other risk factors. The combined PAR suggest that alterations in lifestyle could have considerable impact on breast cancer incidence. Key words: Breast cancer incidence; population attributable risk; hormone replacement therapy; alcohol; physical activity; obesity

Control of mammary stem cell function by steroid hormone signalling

The ovarian hormones oestrogen and progesterone profoundly influence breast cancer risk, underpinning the benefit of endocrine therapies in the treatment of breast cancer. Modulation of their effects through ovarian ablation or chemoprevention strategies also significantly decreases breast cancer incidence. Conversely, there is an increased risk of breast cancer associated with pregnancy in the short term. The cellular mechanisms underlying these observations, however, are poorly defined. Here we demonstrate that mouse mammary stem cells (MaSCs) are highly responsive to steroid hormone signalling, despite lacking the oestrogen and progesterone receptors. Ovariectomy markedly diminished MaSC number and outgrowth potential in vivo, whereas MaSC activity increased in mice treated with oestrogen plus progesterone. Notably, even three weeks of treatment with the aromatase inhibitor letrozole was sufficient to reduce the MaSC pool. In contrast, pregnancy led to a transient 11-fold increase in MaSC numbers, probably mediated through paracrine signalling from RANK ligand. The augmented MaSC pool indicates a cellular basis for the short-term increase in breast cancer incidence that accompanies pregnancy. These findings further indicate that breast cancer chemoprevention may be achieved, in part, through suppression of MaSC function.

Sustained lower rates of breast cancer incidence in France in 2007

We previously reported a decrease in breast cancer incidence between 2003 and 2006 for only women aged 50 or above in France [1]. The magnitude and timing of decrease varied by age [2]. This was in the context of a substantial reduction in hormonal replacement therapy (HRT) prescriptions after 2001. In this update we report that, this decrease has been maintained into 2007 only for the women 55–64 years old. We used the same national data sources on HRT prescribing and on breast cancer in France up to 2007 [2]. The number of HRT users has dropped by 64% between 2001 and 2007, and remained low after 2004 compared to 2001. The largest decrease was observed in women 55– 64 years old, the group in which the prevalence of HRT use has been highest and the decrease most pronounced: 32% in 2001, 19% in 2004, and 11% in 2007. Recent publication from Sweden also reported a significant decrease in incidence confined to women 50– 59 years of age, in the same context of dramatic decline in the use of HRT [3]. Figure 1 shows that breast cancer incidence rates in France in women aged 55–59 and 60–64 years old decreased 14.7% [95% CI 12.2 to 17.2%] and 12.6% [95% CI 10.1 to 15.1%] from 2003 to 2007. No significant change was observed in the age groups 50–54 and 65–69. The slight decline observed in those age groups between 2003 and 2006 (0.7 and 2.1%, respectively) was followed by an increase in 2007. Mammography use increased continuously in France between 1990 and 2005, and was stable in 2006 and 2007 after the implementation of the National Breast Cancer Screening Programme in 2004. Participation rates for French women aged 50–74 years were 40.2% in 2004 increasing to 50.8% in 2007. The upward trend concerned all age groups. Digital mammography was allowed in the screening programme from 2008. Gradual development of screening and change in technology cannot account for the reduction in breast cancer incidence. Breast cancer trends in France are thus broadly similar to those of Western countries where prevalence of HRT use was high [4–9]. Differences between countries may be the reflect of different types of HRT and duration of use. In France the range of HRT preparations differs from what is found in the United States, but our results indicate also in France a striking correlation between fall in HRT use and the decline in incidence of breast cancer, in women older than 55 years.

Screening mammography intervals among postmenopausal hormone therapy users and nonusers

The recent decline in US breast cancer incidence rates has been attributed to the marked reduction in use of postmenopausal hormone therapy (HT). An alternative explanation is that women who are not routinely seeking medical care to renew HT prescriptions may be less adherent to recommendations for mammographic screening. To investigate the latter possibility, we compared mammographic intervals according to HT use. Using data (1995-2007) from the New Hampshire Mammography Network (NHMN), a state-based mammography registry, we assessed mammographic intervals corresponding to HT use or nonuse among postmenopausal women. We used linear mixed effects models to assess whether the length of screening mammogram intervals differed according to HT use. A total of 310,185 mammograms, representing 76,192 postmenopausal women and 319,353 person-years of screening, were included in the analysis. The median screening interval corresponding to HT use overall was 13.0 months (interquartile range: 12.4-15.1) and for nonuse was 13.1 (interquartile range: 12.4-15.8). Virtually, all screening mammograms occurred within a 2-year interval regardless of HT use or nonuse (98.5 and 98.1%, respectively). Our findings indicate that screening mammography intervals are similar whether or not women are using HT. Thus, reduced utilization of screening mammography is unlikely to account for the decrease in breast cancer incidence seen soon after the WHI report.

Decrease in breast cancer incidence following a rapid fall in use of hormone replacement therapy in Australia

Decrease in breast cancer incidence following a rapid fall in use of hormone replacement therapy in Australia

Decrease in breast cancer incidence following a rapid fall in use of hormone replacement therapy in Australia

Decrease in breast cancer incidence following a rapid fall in use of hormone replacement therapy in Australia

Postmenopausal hormone drugs and breast and colon cancer: Nordic countries 1995–2005

ObjectivesThe purpose of this study was to utilize the variation in the level and timing of the change in postmenopausal hormone therapy (HT) use between the Nordic countries to assess the population-level impact of decline in HT use on the breast and colon cancer incidences. MethodsNationwide HT-sales data in defined daily doses (DDDs) per 1000 inhabitant in 1995–2005 in Finland, Iceland, Norway and Sweden were obtained from drug control authorities. Breast and colon cancer incidence data by 5-year age-groups were obtained from the National Cancer Registers. By time series analysis we estimated in each age-group and country how much a change in HT-sales changes cancer incidence. ResultsThe decline of HT-sales varied; the decline from the highest sales was 61% in Sweden, 51% in Norway, 43% in Iceland and 25% in Finland. With the exception of Finland, the breast cancer incidence increased from 1995 to the year following the year with maximum HT-sales and decreased after that year. In the model combining countries and years, changes in HT-sales predicted the change in breast cancer incidence, an average 7% for each 10 DDD units of HT-sales. No clear association between HT-sales and colon cancer incidence was found. ConclusionsThe time and country specific data suggest, that on the population level, a notable drop from high level of HT use somewhat decreases breast cancer incidence or breaks its increasing trends. The suggested protective effect of HT for colon cancer was not seen.

Sustained lower rates of breast cancer in the United States

We have previously reported that, a sharp decrease in breast cancer incidence rates had occurred in 2003 among women C50 years of age in the United States [1]. This decrease seemed temporally related to a decrease in the use of hormone replacement therapy. In this update (Fig. 1) we report that, this decrease has been maintained into 2005. Comparing incidence from years 2000 through 2002 to years 2003 through 2005 significant decreases of 12.0% (se 0.8) and 7.8% (se 1.0) are seen for women 50–69 and [70 years of age, respectively. No significant decrease occurred in women less than 50. This reanalysis using the most recently released data from SEER [2] shows that, the decrease occurred primarily in ER positive breast cancers, with the rate of ER positive breast cancer in women 50– 69 years of age decreasing 14.5% and ER negative breast cancers decreasing 2.1%. Because the SEER data does not include information about the use of mammography or hormonal therapy by individual patients, we are unable to unambiguously attribute the decrease in breast cancer rates to a decrease in the use of hormonal therapy. However, other epidemiologic studies have reported decreased breast cancer incidence after a decrease in the use of hormone therapy in settings where there were no significant changes in screening mammography, suggesting that a change in screening mammography is unlikely to be the cause of the decrease [3, 4]. The women’s health initiative combined hormone therapy trial recently reported results for women stopping combined therapy, and a clear decrease in breast cancer rates was not seen [5]. Thus, the etiology of the sudden drop in ER positive breast cancer in the general population is unclear, but it has clearly occurred and has been maintained.