Obgyn News 

OBGYN NEWS is a service that the EMAS President, Serge Rozenberg, intends to share with you in EMAS' efforts to exchange research and knowledge. The selection of the articles is arbitrary, but there are no commercial interests involved and no conflict of interest. 

n° 711  Topic: Breast Cancer, Women’s health

Statin prescriptions and breast cancer recurrence risk: a danish nationwide prospective cohort study.
Ahern TP, et al (J Natl Cancer Inst. 2011 Oct 5;103(19):1461-8. Epub 2011 Aug 2) conducted a nationwide, population-based prospective cohort study of all female residents in Denmark diagnosed with stage I-III invasive breast carcinoma who were reported to the Danish Breast Cancer Cooperative Group registry between 1996 and 2003 (n = 18 769). Women were followed for a median of 6.8 years after diagnosis. Prescriptions for lipophilic and hydrophilic statins were ascertained from the national electronic pharmacy database. Associations between statin prescriptions and breast cancer recurrence were estimated with generalized linear models and Cox proportional hazards regression with adjustment for age and menopausal status at diagnosis; histological grade; estrogen receptor status; receipt of adjuvant therapy; type of primary surgery received; pre-diagnosis hormone replacement therapy; and co-prescriptions of aspirin, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or anticoagulants. Most prescriptions for lipophilic statins in the study population were for simvastatin. Exclusive simvastatin users experienced approximately 10 fewer breast cancer recurrences per 100 women after 10 years of follow-up (adjusted 10-year risk difference = -0.10, 95% confidence interval = -0.11 to -0.08), compared with women who were not prescribed a statin. Exclusive hydrophilic statin users had approximately the same risk of breast cancer recurrence as women not prescribed a statin over follow-up (adjusted 10-year risk difference = 0.05, 95% confidence interval = -0.01 to 0.11). Conclusions Simvastatin, a highly lipophilic statin, was associated with a reduced risk of breast cancer recurrence among Danish women diagnosed with stage I-III breast carcinoma, whereas no association between hydrophilic statin use and breast cancer recurrence was observed. 

N° 710 Topic: menopause, symptoms

Aedo S, et al (Climacteric. 2011 Aug 24. [Epub ahead of print]) evaluated the efficacy of sertraline (50 mg/day) versus placebo in the management of somatic and psychological complaints of the climacteric syndrome using a RCT involving 44 women with moderate to severe complaints. A reduction of 50% or more in the score was considered as a successful response Thirty-three patients finished the trial showing an odds ratio of 7.94 (95% confidence interval 1.3-57.3), p = 0.0038 for the sertraline group, in spite of the prominent effect of placebo.

N° 709 Topic: Breast cancer

Effect of the Gonadotropin-Releasing Hormone Analogue Triptorelin on the Occurrence of Chemotherapy-Induced Early Menopause in Premenopausal Women With Breast Cancer : a RCT.
Lucia Del Mastro, et al (JAMA. 2011;306(3):269-276. doi: 10.1001/jama.2011.991 determined the effect of the temporary ovarian suppression obtained by administering the gonadotropin-releasing hormone analogue triptorelin during chemotherapy on the incidence of early menopause in young patients with breast cancer undergoing adjuvant or neoadjuvant chemotherapy. They enrolled 281 premenopausal women with stage I through III breast cancer who were candidates for adjuvant or neoadjuvant chemotherapy. Twelve months after the last cycle of chemotherapy, the rate of early menopause was 25.9% in the chemotherapy-alone group and 8.9% in the chemotherapy plus triptorelin group, an absolute difference of −17% (95% confidence interval, −26% to −7.9%; P < .001). The odds ratio for treatment-related early menopause was 0.28 (95% confidence interval, 0.14 to 0.59; P < .001).

N° 707 Topic: Breast cancer

Goss et al (N Engl J Med. 2011 Jun 4. [Epub ahead of print]) conducted a randomized, placebo-controlled, double-blind trial of exemestane designed to detect a 65% relative reduction in invasive breast cancer, in postmenopausal women at increased breast cancer risk. A total of 4560 women (median age 62.5 years, median Gail risk score was 2.3%) were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%; HR, 0.35; 95% [CI], 0.18 to 0.70; P=0.002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (HR, 0.47; 95% CI, 0.27 to 0.79; P=0.004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P=0.003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatment-related deaths. Minimal quality-of-life differences were observed.

Conclusions: Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer.

N° 706 Topic: Menopause, Women’s health, Quality of life

Duration of Menopausal Hot Flushes and Associated Risk Factors
Freeman, et al (Obstetrics & Gynecology. 117(5):1095-1104, May 2011. doi: 10.1097/AOG.0b013e318214f0de)

Freeman, et al. estimated the duration of moderate-to-severe menopausal hot flushes and identified potential risk factors for hot flush duration using “The Penn Ovarian Aging Study cohort”, which was monitored for 13 years. Hot flushes were evaluated at 9-month to 12-month intervals through in-person interviews. The primary outcome was the duration of moderate-to-severe hot flushes estimated by survival analysis (n=259). Potential risk factors included menopausal stage, age, race, reproductive hormone levels, body mass index (BMI), and current smoking. A secondary analysis included women who reported any hot flushes (n=349). The median duration of moderate-to-severe hot flushes was 10.2 years and was strongly associated with menopausal stage at onset. Hot flushes that started near entry into the menopause transition had a median duration greater than 11.57 years; onset in the early transition stage had a median duration of 7.35 years (95% CI 4.94–8.89; P<.001); and onset in the late transition to postmenopausal stages had a median duration of 3.84 years (95% CI 1.77–5.52; P<.001). The most common ages at onset of moderate-to-severe hot flushes were 45–49 years (median duration, 8.1 years; 95% CI 5.12–9.28). African American women had a longer duration of hot flushes than white women in adjusted analysis. They concluded that median duration of hot flushes considerably exceeded the timeframe that is generally accepted in clinical practice. The identified risk factors, particularly menopausal stage, race, and BMI, are important to consider in individualizing treatment and evaluating the risk-to-benefit ratio of hormones and other therapies.

N° 705 Topic: Women’s health, prolapse, incontinence

Anterior Colporrhaphy versus Transvaginal Mesh for Pelvic-Organ Prolapse
Daniel Altman, et al for the Nordic Transvaginal Mesh Group (N Engl J Med 2011; 364:1826-1836May 12, 2011)

Daniel Altman, et al. conducted a multicenter, parallel-group, randomized, controlled trial, comparing the use of a trocar-guided, transvaginal polypropylene-mesh repair kit with traditional colporrhaphy in women with prolapse of the anterior vaginal wall (cystocele). The primary outcome was a composite of the objective anatomical designation of stage 0 (no prolapse) or 1 (position of the anterior vaginal wall more than 1 cm above the hymen), according to the Pelvic Organ Prolapse Quantification system, and the subjective absence of symptoms of vaginal bulging 12 months after the surgery. Of 389 women who were randomly assigned to a study treatment, 200 underwent prolapse repair with the transvaginal mesh kit and 189 underwent traditional colporrhaphy. At 1 year, the primary outcome was significantly more common in the women treated with transvaginal mesh repair (60.8%) than in those who underwent colporrhaphy (34.5%) (absolute difference, 26.3 percentage points; 95% confidence interval, 15.6 to 37.0). The surgery lasted longer and the rates of intraoperative hemorrhage were higher in the mesh-repair group than in the colporrhaphy group (P<0.001 for both comparisons). Rates of bladder perforation were 3.5% in the mesh-repair group and 0.5% in the colporrhaphy group (P=0.07), and the respective rates of new stress urinary incontinence after surgery were 12.3% and 6.3% (P=0.05). Surgical reintervention to correct mesh exposure during follow-up occurred in 3.2% of 186 patients in the mesh-repair group. As compared with anterior colporrhaphy, use of a standardized, trocar-guided mesh kit for cystocele repair resulted in higher short-term rates of successful treatment but also in higher rates of surgical complications and postoperative adverse events.

N° 704 Topic: Osteoporosis

Bisphosphonate Use and Atypical Fractures of the Femoral Shaft
Jörg Schilcher, et al (N Engl J Med 2011; 364:1728-1737May 5, 2011)

Jörg Schilcher, et al reviewed radiographs of 1234 of the 1271 women who had a subtrochanteric or shaft fracture and identified 59 patients with atypical fractures. Data on medications and coexisting conditions were obtained from national registries. The relative and absolute risk of atypical fractures associated with bisphosphonate use was estimated by means of a nationwide cohort analysis. The 59 case patients were also compared with 263 control patients who had ordinary subtrochanteric or shaft fractures The age-adjusted relative risk of atypical fracture was 47.3 (95% CI, 25.6 to 87.3) in the cohort analysis. The increase in absolute risk was 5 cases per 10,000 patient-years (95% CI, 4 to 7). A total of 78% of the case patients and 10% of the controls had received bisphosphonates, corresponding to a multivariable-adjusted odds ratio of 33.3 (95% CI, 14.3 to 77.8). The risk was independent of coexisting conditions and of concurrent use of other drugs with known effects on bone. The duration of use influenced the risk (odds ratio per 100 daily doses, 1.3; 95% CI, 1.1 to 1.6). After drug withdrawal, the risk diminished by 70% per year since the last use (odds ratio, 0.28; 95% CI, 0.21 to 0.38). The authors concluded that these population-based nationwide analyses may be reassuring for patients who receive bisphosphonates. Although there was a high prevalence of current bisphosphonate use among patients with atypical fractures, the absolute risk was small. (Funded by the Swedish Research Council.)

N° 703 Topic: menopause, whi and breast cancer

Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy 
(LaCroix et al. April 6, 2011 JAMA. 2011;305(13):1305-1314. doi: 10.1001/jama.2011.382)

WHI Investigators published a recent update of the RCT in (hysterectomied women) treated with conjugated equine estrogens after a mean of 10.7 years of follow-up through August 2009. The postintervention risk (annualized rate) for coronary hearth disease (CHD) among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (HR, 0.97; 95%CI, 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00; 95% CI, 0.84-1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27; 95% CI, 0.88-1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62-0.95). Health outcomes were more favorable for younger compared with older women for CHD (P = .05 for interaction), total myocardial infarction (P = .007 for interaction), colorectal cancer (P = .04 for interaction), total mortality (P = .04 for interaction), and global index of chronic diseases (P = .009 for interaction). 

Conclusions: Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted.

N° 702 Topic: Breast cancer

Preventive therapy for breast cancer: a consensus statement (Jack Cuzick et al The Lancet Oncology, Early Online Publication, 28 March 2011 doi:10.1016/S1470-2045(11)70030-4)(doi:10.1016/S0140-6736(08)61345-8)

A group of breast cancer experts met to develop a consensus statement on breast cancer prevention. They agreed that the term chemoprevention is inappropriate and suggested that the term preventive therapy better represents this feature of management. Two selective oestrogen-receptor modulators—tamoxifen and raloxifene—are so far the only medical options approved by the US Food and Drug Administration for preventive therapy. Of these tamoxifen has greater efficacy and can be used in premenopausal women, but raloxifene has fewer side-effects. Two newer drugs in this class, lasofoxifene and arzoxifene, also show efficacy and possibly a better overall risk-benefit profile, but need further assessment. Aromatase inhibitors might be more efficacious, and results of prevention trials are eagerly awaited. Newer agents, notably bisphosphonates and metformin, have shown promise in observational studies and need to be assessed in randomised prevention trials. Other agents, such as aspirin, other non-steroidal anti-inflammatory drugs, COX-2 inhibitors, retinoids, rexinoids, and dietary components have limited effects or are in the early phases of investigation. New contralateral tumours in women with breast cancer might be generally useful as a model for prevention, as has been seen for tamoxifen. If valid such a model would facilitate the design of simpler, cheaper, and better-focused trials for assessing new agents.

N° 701 Topic: Vitamin D and Women’s health

Vitamin D and Prevention of Cancer — Ready for Prime Time? (JE. Manson, ST. Mayne, SK. Clinton. March 23, 2011 (10.1056/NEJMp1102022)
Despite biologic plausibility and widespread enthusiasm, the American Institute of Medicine (IOM) committee found that the evidence that vitamin D reduces cancer incidence and related mortality was inconsistent and inconclusive as to causality. Indeed, for instance 3 vitamin D trials, including one trial comparing a combination of vitamin D with calcium to calcium alone, have assessed the occurrence of newly diagnosed cancers or cancer mortality as secondary outcomes, but the results were null. New trials assessing moderate-to-high-dose vitamin D supplementation for cancer prevention are in progress and should provide additional information within 5 to 6 years. Although future research may demonstrate clear benefits of vitamin D related to cancer and other nonskeletal health outcomes, and possibly support higher intake requirements, the existing evidence falls short.

N° 700 Topic: Women’s health, Breast Cancer, Smoking

Cigarette Smoking and the Incidence of Breast Cancer
Fei Xue, et al ( Arch Intern Med. 2011;171(2):125-133. doi:10.1001/archinternmed.2010.503) evaluated the effect of smoking on breast cancer (BC) incidence in the prospective cohort study of 111 140 participants of the Nurses' Health Study from 1976 to 2006 for active smoking and 36 017 women from 1982 to 2006 for passive smoking. During 3 005 863 person-years of follow-up, 8772 incident cases of invasive BC were reported. After adjustment for potential confounders, the HR of BC was 1.06% (95%CI, 1.01%-1.10%) for ever smokers relative to never smokers. Breast cancer incidence was associated with a higher quantity of current (P for trend = .02) and past (P for trend = .003) smoking, younger age at smoking initiation (P for trend = .01), longer duration of smoking (P for trend = .01), and more pack-years of smoking (P for trend = .005). Premenopausal smoking was associated with a slightly higher incidence of BC (HR, 1.11; 95% CI, 1.07-1.15 for every increase of 20 pack-years), especially smoking before first birth (1.18; 1.10-1.27 for every increase of 20 pack-years). Conversely, the direction of the association between postmenopausal smoking and BC was inverse (0.93; 0.85-1.02 for every increase of 20 pack-years). Passive smoking in childhood or adulthood was not associated with BC risk.
Conclusion Active smoking, especially smoking before the first birth, may be associated with a modest increase in the risk of BC.  

N° 699 Topic: Breast Cancer

Axillary Dissection vs No Axillary Dissection in Women With Invasive Breast Cancer and Sentinel Node Metastasis: A Randomized Clinical Trial
Giuliano, et al (JAMA. 2011;305(6):569-575. doi: 10.1001/jama.2011.90) determined the effects of complete axillary lymph node dissection (ALND) on survival of patients with sentinel lymph node (SLN) metastasis of breast cancer in a phase 3 noninferiority multicenter involving women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases identified by frozen section, touch preparation, or hematoxylin-eosin staining on permanent section. All patients underwent lumpectomy and tangential whole-breast irradiation. Those with SLN metastases identified by SLND were randomized to undergo ALND or no further axillary treatment. Those randomized to ALND underwent dissection of 10 or more nodes. Clinical and tumor characteristics were similar between 445 patients randomized to ALND and 446 randomized to SLND alone. However, the median number of nodes removed was 17 with ALND and 2 with SLND alone. At a median follow-up of 6.3 years (last follow-up, March 4, 2010), 5-year overall survival was 91.8% (95% CI, 89.1%-94.5%) with ALND and 92.5% (95% CI, 90.0%-95.1%) with SLND alone; 5-year disease-free survival was 82.2% (95% CI, 78.3%-86.3%) with ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone. The hazard ratio for treatment-related overall survival was 0.79 (90% CI, 0.56-1.11) without adjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy.
The authors concluded that among patients with limited SLN metastatic breast cancer treated with breast conservation and systemic therapy, the use of SLND alone compared with ALND did not result in inferior survival.

N° 697 Topic: Breast Cancer

Gulisa Turashvili et al (Modern Pathology (2011) 24, 64–81; doi:10.1038/modpathol.2010.189; published online 17 September 2010) http://www.nature.com/modpathol/journal/v24/n1/full/modpathol2010189a.html reported an analysis of P-cadherin expression as a prognostic biomarker in a 3992 case tissue microarray series of breast cancer. P-cadherin expression was evaluated using immunohistochemistry. Median follow-up was 12.5 years. P-cadherin was expressed in 34.8% of cases. P-cadherin staining was strongly associated with HER2+ and basal carcinoma subtypes (P<0.0005). P-cadherin-positive patients showed significantly poorer short-term (0–10 years) overall survival, disease-specific survival, distant relapse-free interval, and locoregional relapse-free interval in univariable models (P<0.05). In multivariable Cox models containing standard clinical covariates and cancer subtypes, P-cadherin did not show independent prognostic value. P-cadherin expression was positively associated with histological grade, chemotherapy, Ki-67, EGFR, CK5/6, p53, YB-1, and HER2 expression (P<0.002), and negatively associated with age at diagnosis, ER, PR, and Bcl-2 expression (P<0.0005). This study shows the value of P-cadherin as a marker of poor prognosis. The large sample size of this series clarifies contradictory findings of many smaller studies. P-cadherin positivity is associated with high-grade tumor subtypes and well-established markers of poor prognosis, and may represent a promising antibody therapeutic target.

N° 696 Topic: endometrial cancer, screening, Postmenopausal bleeding

Sensitivity of transvaginal ultrasound screening for endometrial cancer in postmenopausal women: a case-control study within the UKCTOCS cohort
In this paper, Ian Jacobs et al from United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) (The Lancet Oncology, Early Online Publication, 13 December 2010 doi:10.1016/S1470-2045(10)70268-0) analysed whether Transvaginal ultrasound (TVS) is a possible screening test for endometrial cancer. They did a nested case-control study of postmenopausal women who underwent (TVS) between April 17, 2001, and Sept 29, 2005. Endometrial thickness and endometrial abnormalities were recorded, and follow-up, through national registries and a postal questionnaire, documented the diagnosis of endometrial cancer. The primary outcome measure was endometrial cancer and atypical endometrial hyperplasia (AEH). Performance characteristics of endometrial thickness and abnormalities for detection of endometrial cancer within 1 year of TVS were calculated. Epidemiological variables were used to develop a logistic regression model and assess a screening strategy for women at higher risk. 48 230 women underwent TVS in the UKCTOCS prevalence screen. 9078 women were ineligible because they had undergone a hysterectomy and 2271 because their endometrial thickness had not been recorded; however, 157 of these women had an endometrial abnormality on TVS and were included in the analysis. Median follow-up was 5•11 years (IQR 4•05—5•95). 136 women with endometrial cancer or AEH within 1 year of TVS were included in the primary analysis. The optimum endometrial thickness cutoff for endometrial cancer or AEH was 5•15 mm, with sensitivity of 80•5% (95% CI 72•7—86•8) and specificity of 86•2% (85•8—86•6). Sensitivity and specificity at a 5 mm or greater cutoff were 80•5% (72•7—86•8) and 85•7% (85•4—86•2); for women with a 5 mm or greater cutoff plus endometrial abnormalities, the sensitivity and specificity were 85•3% (78•2—90•8) and 80•4% (80•0—80•8), respectively. For a cutoff of 10 mm or greater, sensitivity and specificity were 54•1% (45•3—62•8) and 97•2% (97•0—97•4). When our analysis was restricted to the 96 women with endometrial cancer or AEH who reported no symptoms of postmenopausal bleeding at the UKCTOCS scan before diagnosis and had an endometrial thickness measurement available, a cutoff of 5 mm achieved a sensitivity of 77•1% (67•8—84•3) and specificity of 85•8% (85•7—85•9). The logistic regression model identified 25% of the population as at high risk and 39•5% of endometrial cancer or AEH cases were identified within this high risk group. In this high-risk population, a cutoff at 6•75 mm achieved sensitivity of 84•3% (71•4—93•0) and specificity of 89•9% (89•3—90•5).
Interpretation
These findings show that TVS screening for endometrial cancer has good sensitivity in postmenopausal women. The burden of diagnostic procedures and false-positive results can be reduced by limiting screening to a higher-risk group. The role of population screening for endometrial cancer remains uncertain, but these findings are of immediate value in the management of increased endometrial thickness in postmenopausal women undergoing pelvic scans for reasons other than vaginal bleeding.

N° 695 Topic: Cancer, Women’s health

Detection of lung, breast, colorectal, and prostate cancers from exhaled breath using a single array of nanosensors
G Peng et al (British Journal of Cancer (2010) 103, 542–551. doi:10.1038/sj.bjc.6605810 www.bjcancer.com) investigated the ability of a nanosensor array to discriminate between the emission of volatile organic compounds (VOCs) (breath VOCs) that characterise healthy states and the most widespread cancer states in the developed world: lung, breast, colorectal, and prostate cancers. Exhaled alveolar breath was collected from 177 volunteers aged 20–75 years (patients with lung, colon, breast, and prostate cancers and healthy controls). The healthy population was healthy according to subjective patient's data. The breath of volunteers was examined by a tailor-made array of cross-reactive nanosensors based on organically functionalised gold nanoparticles and gas chromatography linked to the mass spectrometry technique (GC-MS). The results showed that the nanosensor array could differentiate between ‘healthy’ and ‘cancerous’ breath, and, furthermore, between the breath of patients having different cancer types. Moreover, the nanosensor array could distinguish between the breath patterns of different cancers in the same statistical analysis, irrespective of age, gender, lifestyle, and other confounding factors. The GC-MS results showed that each cancer could have a unique pattern of VOCs, when compared with healthy states, but not when compared with other cancer types.

N° 694 Topic: women's health

Baer et al Am J Epidemiol. 2010 Dec 6. [Epub ahead of print] examined associations of lifestyle and dietary factors with all-cause and cause-specific mortality among 50,112 participants in the Nurses' Health Study. There were 4,893 deaths between 1986 and 2004: 1,026 from cardiovascular disease, 931 from smoking-related cancers, 1,430 from cancers not related to smoking, and 1,506 from all other causes. Age, body mass index at age 18 years, weight change, height, current smoking and pack-years of smoking, glycemic load, cholesterol intake, systolic blood pressure and use of blood pressure medications, diabetes, parental myocardial infarction before age 60 years, and time since menopause were directly related to all-cause mortality, whereas there were inverse associations for physical activity and intakes of nuts, polyunsaturated fat, and cereal fiber. Moderate alcohol consumption was associated with decreased mortality. A model that incorporated differences in the associations of some risk factors with specific causes of death had a significantly better fit compared with a model in which all risk factors had common associations across all causes. In the future, this new model may be used to identify individuals at increased risk of mortality.

N° 693 Topic: osteoporosis and breast cancer

Two studies published today in Nature show how progestin can cause breast cancer in mice by activating the protein RANKL. The studies highlight a potential role for RANKL inhibition in the management of proliferative breast disease.

Daniel Schramek et al (Nature 468, 98-102, 4 November 2010) observed that the in vivo administration of MPA triggers massive induction of the key osteoclast differentiation factor RANKL (receptor activator of NF-κB ligand) in mammary-gland epithelial cells. Genetic inactivation of the RANKL receptor RANK in mammary-gland epithelial cells prevents MPA-induced epithelial proliferation, impairs expansion of the CD49fhi stem-cell-enriched population, and sensitizes these cells to DNA-damage-induced cell death. Deletion of RANK from the mammary epithelium results in a markedly decreased incidence and delayed onset of MPA-driven mammary cancer. These data show that the RANKL/RANK system controls the incidence and onset of progestin-driven breast cancer.

Eva Gonzalez-Suarez (Nature 468, 103-107 (4 November 2010) | doi:10.1038/nature09495) showed that RANK and RANKL are expressed within normal, pre-malignant and neoplastic mammary epithelium, and using complementary gain-of-function (mouse mammary tumour virus (MMTV)-RANK transgenic mice) and loss-of function (pharmacological inhibition of RANKL) approaches, define a direct contribution of this pathway in mammary tumorigenesis. Accelerated pre-neoplasias and increased mammary tumour formation were observed in MMTV-RANK transgenic mice after multiparity or treatment with carcinogen and hormone (progesterone). Reciprocally, selective pharmacological inhibition of RANKL attenuated mammary tumour development not only in hormone- and carcinogen-treated MMTV-RANK and wild-type mice, but also in the MMTV-neu transgenic spontaneous tumour model. The reduction in tumorigenesis upon RANKL inhibition was preceded by a reduction in pre-neoplasias as well as rapid and sustained reductions in hormone- and carcinogen-induced mammary epithelial proliferation and cyclin D1 levels. Collectively, these results indicate that RANKL inhibition is acting directly on hormone-induced mammary epithelium at early stages in tumorigenesis, and the permissive contribution of progesterone to increased mammary cancer incidence is due to RANKL-dependent proliferative changes in the mammary epithelium. 
 

N° 692 Topic: osteoporosis

Effect of Music-Based Multitask Training on Gait, Balance, and Fall Risk in Elderly People
Andrea Trombetti, et al (Arch Intern Med. Published online November 22, 2010. doi:10.1001/archinternmed.2010.446) conducted a 12-month RCT involving 134 community-dwelling individuals older than 65 years, who are at increased risk of falling. They were randomly assigned to an intervention group (n = 66) or a delayed intervention control group scheduled to start the program 6 months later (n = 68). The intervention was a 6-month multitask exercise program performed to the rhythm of piano music. Change in gait variability under dual-task condition from baseline to 6 months was the primary end point. Secondary outcomes included changes in balance, functional performances, and fall risk.
At 6 months, Balance and functional tests improved compared with the control group. And there were fewer falls in the intervention group (incidence rate ratio, 0.46; 95%CI, 0.27-0.79) and a lower risk of falling (RR, 0.61; 95% CI, 0.39-0.96). Similar changes occurred in the delayed intervention control group during the second 6-month period with intervention. The benefit of the intervention on gait variability persisted 6 months later.  

N° 691 Topic: breast cancer

Cuzick et al (The Lancet Oncology, Early Online Publication, 17 November 2010
doi:10.1016/S1470-2045(10)70257-6) report the long-term outcomes after a median follow-up of 120 months of the The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial comparing the efficacy and safety of anastrozole (1 mg) with tamoxifen (20 mg), both given orally every day for 5 years, as adjuvant treatment for postmenopausal women with early-stage breast cancer.

The primary endpoints were the disease-free survival, and the secondary endpoints: time to recurrence, time to distant recurrence, incidence of new contralateral breast cancer, overall survival, and death with or without recurrence in all randomised patients (anastrozole n=3125, tamoxifen n=3116) and hormone-receptor-positive patients (anastrozole n=2618, tamoxifen n=2598). After treatment completion, they continued to collect data on fractures and serious adverse events in a masked fashion (safety population: anastrozole n=3092, tamoxifen n=3094).

There were 24 522 woman-years of follow-up in the anastrozole group and 23 950 woman-years in the tamoxifen group. In the full study population, there were significant improvements in the anastrozole group compared with the tamoxifen group for disease-free survival (HR] 0•91, 95% CI 0•83—0•99; p=0•04), time to recurrence (0•84, 0•75—0•93; p=0•001), and time to distant recurrence (0•87, 0•77—0•99; p=0•03). For hormone-receptor-positive patients, the results were also significantly in favour of the anastrozole group for disease-free survival (HR 0•86, 95% CI 0•78—0•95; p=0•003), time to recurrence (0•79, 0•70—0•89; p=0•0002), and time to distant recurrence (0•85, 0•73—0•98; p=0•02). In hormone-receptor-positive patients, absolute differences in time to recurrence between anastrozole and tamoxifen increased over time (2•7% at 5 years and 4•3% at 10 years) and recurrence rates remained significantly lower on anastrozole than tamoxifen after treatment completion (HR 0•81, 95% CI 0•67—0•98; p=0•03), although the carryover benefit was smaller after 8 years. There was weak evidence of fewer deaths after recurrence with anastrozole compared with tamoxifen treatment in the hormone-receptor-positive subgroup (HR 0•87, 95% CI 0•74—1•02; p=0•09), but there was little difference in overall mortality (0•95, 95% CI 0•84—1•06; p=0•4).
Fractures were more frequent during active treatment in patients receiving anastrozole than those receiving tamoxifen (451 vs 351; OR 1•33, 95% CI 1•15—1•55; p<0•0001), but were similar in the post-treatment follow-up period (110 vs 112; OR 0•98, 95% CI 0•74—1•30; p=0•9). Treatment-related serious adverse events were less common in the anastrozole group than the tamoxifen group (223 anastrozole vs 369 tamoxifen; OR 0•57, 95% CI 0•48—0•69; p<0•0001), but were similar after treatment completion (66 vs 78; OR 0•84, 95% CI 0•60—1•19; p=0•3). No differences in non-breast cancer causes of death were apparent and the incidence of other cancers was similar between groups (425 vs 431) and continue to be higher with anastrozole for colorectal (66 vs 44) and lung cancer (51 vs 34), and lower for endometrial cancer (six vs 24), melanoma (eight vs 19), and ovarian cancer (17 vs 28). No new safety concerns were reported.

Interpretation
These data confirm the long-term superior efficacy and safety of anastrozole over tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer.

N° 690 Topic: Osteoporosis, breast cancer

Chlebowski et al (J Clin Oncol. 2010 Aug 1;28(22):3582-90. Epub 2010 Jun 21) evaluated the association between oral bisphosphonate use and invasive breast cancer was in postmenopausal women enrolled onto the WHI. Of the 154,768 participants, 2,816 were oral bisphosphonate users at entry (90% alendronate, 10% etidronate). As calculated hip fracture risk score was significantly associated with both BMD (regression line = 0.79 to 0.0478 log predicted fracture; P < .001; r = 0.43) and breast cancer incidence (P = .03), this variable was incorporated into regression analyses to adjust for BMD difference between users and nonusers of bisphopshonate. After 7.8 mean years of follow-up (standard deviation, 1.7), invasive breast cancer incidence was lower in bisphosphonate users (hazard ratio [HR], 0.68; 95% CI, 0.52 to 0.88; P < .01) as was incidence of estrogen receptor (ER) -positive invasive cancers (HR, 0.70; 95% CI, 0.52 to 0.94, P = .02). A similar but not significant trend was seen for ER-negative invasive cancers. The incidence of ductal carcinoma in situ was higher in bisphosphonate users (HR, 1.58; 95% CI, 1.08 to 2.31; P = .02). 

N° 689 Topic: osteoporosis

Leslie, et al (Ann Intern Med November 2, 2010 vol. 153 no. 9 580-586) assessed the changes in physician prescribing behavior after introduction of absolute 10-year fracture risk reporting in Manitoba, Canada. Absolute fracture risk reporting reclassified more women (32.7%) into lower-risk categories than into higher-risk categories (10%). This effect was more prominent in women younger than 65 years. Fewer women per physician were prescribed osteoporosis drugs after introduction of absolute fracture risk reporting. The absolute fracture risk reporting system was associated with an overall reduction in osteoporosis medications dispensed (adjusted absolute reduction, 9.0 percentage points [95% CI, 3.9 to 14.2 percentage points]; relative reduction, 21.3% [CI, 9.2% to 33.5%]; P < 0.001). The reduction was attributed to fewer drugs dispensed to women at low and moderate risk for fracture.

N° 688 Topic: POI

Schmidt  et al J Clin Endocrinol Metab.2010 Nov 3. [Epub ahead of print] characterized the prevalence of psychiatric disorders and the timing of onset of clinically significant depression relative to both the diagnosis of primary ovarian insufficiency (POI) and the onset of menstrual irregularity in women with POI. They conducted a cross-sectional clinic-based study: A total of 174 women with spontaneous 46, XX POI and 100 women with Turner syndrome participated in the study. Lifetime histories of depression in POI exceeded rates of depression reported in women with Turner syndrome and community-based samples of women (P < 0.001). The onset of depression frequently preceded the diagnosis of POI but occurred after the onset of menstrual irregularity. Analyses standardizing the periods of risk for depression showed that similar numbers of depressions occurred before and after these events. The authors concluded that POI is associated with an increased lifetime risk for major depression. Attention to the presence of depression in POI should become an important part of the care for these women. The onset of depression frequently occurs after signs of altered ovarian function but before the diagnosis of POI. Thus, in some women the association between POI and depression suggests an overlapping pathophysiology rather than a causal relationship.