Jean Wactawski-Wende

Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials.

IMPORTANCE Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. OBJECTIVE To report a comprehensive, integrated overview of findings from the 2 Womens Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up. DESIGN, SETTING, AND PARTICIPANTS A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. INTERVENTIONS Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010. MAIN OUTCOMES AND MEASURES Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death. RESULTS During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials. CONCLUSIONS AND RELEVANCE Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00000611.

Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women.

CONTEXT In the Womens Health Initiative randomized, placebo-controlled trial of estrogen plus progestin, after a mean intervention time of 5.6 (SD, 1.3) years (range, 3.7-8.6 years) and a mean follow-up of 7.9 (SD, 1.4) years, breast cancer incidence was increased among women who received combined hormone therapy. Breast cancer mortality among participants in the trial has not been previously reported. OBJECTIVE To determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (SD, 2.7) years, through August 14, 2009. DESIGN, SETTING, AND PARTICIPANTS A total of 16,608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were randomly assigned to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo pill. After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12,788 (83%) of the surviving participants. MAIN OUTCOME MEASURES Invasive breast cancer incidence and breast cancer mortality. RESULTS In intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow-up on March 31, 2005, estrogen plus progestin was associated with more invasive breast cancers compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46; P = .004). Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03). There were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04; P = .049) as well as more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P = .045) among women who received estrogen plus progestin compared with women in the placebo group. CONCLUSIONS Estrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive. Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00000611.

Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer

We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components. We identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 × 10−8; multiplicative per-allele odds ratio 1.20; 95% confidence interval 1.12–1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B.

Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative

BACKGROUND This study investigates whether the incidence of new-onset diabetes mellitus (DM) is associated with statin use among postmenopausal women participating in the Womens Health Initiative (WHI). METHODS The WHI recruited 161,808 postmenopausal women aged 50 to 79 years at 40 clinical centers across the United States from 1993 to 1998 with ongoing follow-up. The current analysis includes data through 2005. Statin use was captured at enrollment and year 3. Incident DM status was determined annually from enrollment. Cox proportional hazards models were used to estimate the risk of DM by statin use, with adjustments for propensity score and other potential confounding factors. Subgroup analyses by race/ethnicity, obesity status, and age group were conducted to uncover effect modification. RESULTS This investigation included 153,840 women without DM and no missing data at baseline. At baseline, 7.04% reported taking statin medication. There were 10,242 incident cases of self-reported DM over 1,004,466 person-years of follow-up. Statin use at baseline was associated with an increased risk of DM (hazard ratio [HR], 1.71; 95% CI, 1.61-1.83). This association remained after adjusting for other potential confounders (multivariate-adjusted HR, 1.48; 95% CI, 1.38-1.59) and was observed for all types of statin medications. Subset analyses evaluating the association of self-reported DM with longitudinal measures of statin use in 125,575 women confirmed these findings. CONCLUSIONS Statin medication use in postmenopausal women is associated with an increased risk for DM. This may be a medication class effect. Further study by statin type and dose may reveal varying risk levels for new-onset DM in this population.

Calcium Plus Vitamin D Supplementation and the Risk of Breast Cancer

BACKGROUND Although some observational studies have associated higher calcium intake and especially higher vitamin D intake and 25-hydroxyvitamin D levels with lower breast cancer risk, no randomized trial has evaluated these relationships. METHODS Postmenopausal women (N = 36 282) who were enrolled in a Womens Health Initiative clinical trial were randomly assigned to 1000 mg of elemental calcium with 400 IU of vitamin D(3) daily or placebo for a mean of 7.0 years to determine the effects of supplement use on incidence of hip fracture. Mammograms and breast exams were serially conducted. Invasive breast cancer was a secondary outcome. Baseline serum 25-hydroxyvitamin D levels were assessed in a nested case-control study of 1067 case patients and 1067 control subjects. A Cox proportional hazards model was used to estimate the risk of breast cancer associated with random assignment to calcium with vitamin D(3). Associations between 25-hydroxyvitamin D serum levels and total vitamin D intake, body mass index (BMI), recreational physical activity, and breast cancer risks were evaluated using logistic regression models. Statistical tests were two-sided. RESULTS Invasive breast cancer incidence was similar in the two groups (528 supplement vs 546 placebo; hazard ratio = 0.96; 95% confidence interval = 0.85 to 1.09). In the nested case-control study, no effect of supplement group assignment on breast cancer risk was seen. Baseline 25-hydroxyvitamin D levels were modestly correlated with total vitamin D intake (diet and supplements) (r = 0.19, P < .001) and were higher among women with lower BMI and higher recreational physical activity (both P < .001). Baseline 25-hydroxyvitamin D levels were not associated with breast cancer risk in analyses that were adjusted for BMI and physical activity (P(trend) = .20). CONCLUSIONS Calcium and vitamin D supplementation did not reduce invasive breast cancer incidence in postmenopausal women. In addition, 25-hydroxyvitamin D levels were not associated with subsequent breast cancer risk. These findings do not support a relationship between total vitamin D intake and 25-hydroxyvitamin D levels with breast cancer risk.

Patient level pooled analysis of 68,500 patients from seven major vitamin D fracture trials in US and Europe

Objectives To identify participants’ characteristics that influence the anti-fracture efficacy of vitamin D or vitamin D plus calcium with respect to any fracture, hip fracture, and clinical vertebral fracture and to assess the influence of dosing regimens and co-administration of calcium. Design Individual patient data analysis using pooled data from randomised trials. Data sources Seven major randomised trials of vitamin D with calcium or vitamin D alone, yielding a total of 68 517 participants (mean age 69.9 years, range 47-107 years, 14.7% men). Study selection Studies included were randomised studies with at least one intervention arm in which vitamin D was given, fracture as an outcome, and at least 1000 participants. Data synthesis Logistic regression analysis was used to identify significant interaction terms, followed by Cox’s proportional hazards models incorporating age, sex, fracture history, and hormone therapy and bisphosphonate use. Results Trials using vitamin D with calcium showed a reduced overall risk of fracture (hazard ratio 0.92, 95% confidence interval 0.86 to 0.99, P=0.025) and hip fracture (all studies: 0.84, 0.70 to 1.01, P=0.07; studies using 10 μg of vitamin D given with calcium: 0.74, 0.60 to 0.91, P=0.005). For vitamin D alone in daily doses of 10 μg or 20 μg, no significant effects were found. No interaction was found between fracture history and treatment response, nor any interaction with age, sex, or hormone replacement therapy. Conclusion This individual patient data analysis indicates that vitamin D given alone in doses of 10-20 μg is not effective in preventing fractures. By contrast, calcium and vitamin D given together reduce hip fractures and total fractures, and probably vertebral fractures, irrespective of age, sex, or previous fractures.

Serum 25-Hydroxyvitamin D Concentrations and Risk for Hip Fractures

Context Vitamin D supplementation may help prevent fractures, but the relationship between blood vitamin D concentrations and fracture risk is unclear. Contribution These authors observed an increased risk for hip fracture among women with lower serum 25-hydroxyvitamin D [25(OH) vitamin D] concentrations that was independent of measures of frailty, body mass index, physical function, and falls. Caution The authors did not measure bone mineral density (BMD), so they could not determine whether 25(OH) vitamin D concentrations give different information about fracture risk than that offered by BMD. Implication Low serum 25(OH) vitamin D concentrations seem to be associated with a higher hip fracture risk. The Editors Vitamin D deficiency is common in older adults, especially during the winter (1) and in homebound populations (2), general medical inpatients (3), and community-dwelling women admitted to the hospital with acute hip fracture (4). A recently published evidence-based report on vitamin D and bone health (5) found the level of evidence for an association between serum 25-hydroxyvitamin D [25(OH) vitamin D] concentrations and fracture risk to be inconsistent (5). Since publication of that review, 1 prospective study (6) reported no relationship between serum 25(OH) vitamin D concentrations and fractures, whereas another (7) reported a significantly lower risk for hip fracture with 25(OH) vitamin D concentrations greater than 60 nmol/L. Vitamin D concentration could be associated with fractures in several ways. It could influence muscle strength and balance, both of which contribute to falls and disability (810). The association between 25(OH) vitamin D concentrations and fracture may also be influenced by renal function, because renal insufficiency has been linked to fracture (11) and to vitamin D deficiency (12). Several interactions between vitamin D and estrogen receptors have been described (13); hormone therapy has been shown to reverse abnormalities in vitamin D metabolism (14), and low vitamin D concentrations have also been linked to higher bone turnover (15, 16). Thus, sex-steroid hormones and bone turnover could contribute to the association between 25(OH) vitamin D concentration and fractures. We conducted a nested casecontrol study within the WHI-OS (Womens Health Initiative Observational Study) among 400 case-patients with adjudicated incident hip fracture and 400 control participants. We tested whether low serum 25(OH) vitamin D concentrations are associated with a higher risk for hip fractures in community-dwelling women and whether this relationship may be mediated by poor physical functioning, frailty, falls, sex-steroid hormones, renal function, or bone turnover. Methods Study Population Our study population came from the WHI-OS, a prospective cohort study that enrolled 93676 women between 1994 and 1998 at 40 U.S. clinical centers (age range, 50 to 79 years). Study methods are described in detail elsewhere (17). In brief, women were eligible if they were postmenopausal, were unlikely to move or die within 3 years, were not enrolled in the WHI clinical trials, and were not currently participating in any other clinical trial. The human subjects review committees from each participating institution approved the study. Follow-up and Outcome Ascertainment We sent women questionnaires annually to report any hospitalization and other outcomes, including fractures. As of August 2004, median follow-up duration was 7.1 years (range, 0.7 to 9.3 years). At that time, 3.7% of participants had withdrawn or were lost to follow-up and 5.3% had died. We reviewed medical records to verify cases of hip fracture, and blinded central adjudicators confirmed the cases (18). We excluded patients with pathologic hip fractures. Nested CaseControl Study Design The present study is a casecontrol study nested within the prospective design of WHI-OS. We excluded women who had a history of hip fracture; were receiving hormone therapy up to 1 year before enrollment; or were currently receiving androgens, selective estrogen receptor modulators, antiestrogens, or other osteoporosis treatments (bisphosphonates, calcitonin, or parathyroid hormone). We also excluded women with insufficient serum stored or of unknown ethnicity, leaving 39793 eligible participants. Of these, 404 women had a hip fracture. We randomly selected 400 of these women to form the incident hip fracture group. For each case-patient, we selected 1 control participant who was within 1 year of the case-patients age at screening, was of matching race or ethnicity, and had their blood drawn within 120 days of the case-patients blood draw date; 99% of case-patients and control participants were matched within 30 days. Baseline Clinical Variables We divided clinical centers into 3 geographic regions on the basis of latitude: northern (>40 N), middle (35 to 40 N), and southern (<35 N). We ascertained all covariates at baseline. Clinic interviewers recorded current use of prescription medications by direct inspection of medicine containers. We entered prescription names into the WHI database and assigned drug codes by using Medispan software (First DataBank, San Bruno, California). Average amounts of elemental calcium and vitamin D preparations were entered directly from supplement containers. Dietary intakes of calcium and vitamin D were assessed by using a semiquantitative food-frequency questionnaire (19). Total calcium and vitamin D intake was defined as the sum of diet and supplements. We used questionnaires to ascertain date of birth, race or ethnicity, age at menopause, history of any fracture after age 55 years, smoking, parental history of hip fracture, self-rated health status, and alcohol consumption. We classfied physical activity on the basis of frequency and duration of walking and mild, moderate, and strenuous activities in the previous week. We calculated kilocalories of energy expended in 1 week as the metabolic equivalent (kcal hours/week per kg) (20). We measured physical function by using the RAND Short Form-36 physical function scale, which comprises 10 items measuring whether health now limits physical function in moderate or vigorous activity (2 items); strength to lift, carry, stoop, bend, or stair climb (4 items); ability to walk various distances without difficulty (3 items); and self-care (1 item) (21). The scale is scored from 0 to 100, with higher scores indicating better physical function. We compared women with a score greater than 90 versus those with a score less than or equal to 90, a cutoff value corresponding to the median score. We computed a frailty score, which included self-reported muscle weakness and impaired walking speed (RAND Short Form-36 physical function scale score <75), exhaustion (RAND Short Form-36 vitality scale score <55), low physical activity (lowest quartile of physical activity), and unintended weight loss between baseline and 3 years of follow-up (22). A woman was considered frail if she reported 3 or more of these indicators. Weight was measured on a balance-beam scale with the participant dressed in indoor clothing without shoes. Height was measured by using a wall-mounted stadiometer. Body mass index was calculated as weight (in kg) divided by height (in m2). Laboratory Procedures Laboratory personnel blinded to casecontrol status obtained a 12-hour fasting blood sample at the baseline visit, which was processed and stored at 80C according to strict quality control procedures (23). Serum 25(OH) vitamin D concentrations and sex-steroid hormone levels were measured at the Reproductive Endocrine Research Laboratory at the University of Southern California. 25-Hydroxyvitamin vitamin D was measured by using a radioimmunoassay with DiaSorin reagents (DiaSorin, Stillwater, Minnesota). The sensitivity of the assay was 3.75 nmol/L. The interassay coefficients of variation were 11.7%, 10.5%, 8.6%, and 12.5% at 14.0, 56.8, 82.5, and 122.5 nmol/L, respectively. Estradiol and testosterone concentrations were quantified by using sensitive and specific radioimmunoassays after organic solvent extraction and celite column partition chromatography (2427). The intra- and interassay coefficients of variation were 7.9% and 8% to 12%, respectively, for estradiol and 6% and 10% to 12%, respectively, for testosterone. We calculated bioavailable hormone concentrations by using mass action equations (2830). We measured sex hormonebinding globulin by using a solid-phase, 2-site chemiluminescent immunoassay. The intra- and interassay coefficients of variation were 4.1% to 7.7% and 5.8% to 13%, respectively. Serum cystatin C, a marker of renal function that is independent of age and weight, was measured at Medical Research Laboratories International, Highland Heights, Kentucky, by using the Dade Behring BN-II nephelometer and Dade Behring reagents (Dade Behring, Ramsey, Minnesota) in a particle-enhanced immunonepholometric assay. Serum C-terminal telopeptide of type I collagen and aminoterminal procollagen extensions propeptide were measured by immunoassay (Synarc, Lyon, France). Statistical Analysis We used chi-square and t tests to compare baseline characteristics between case-patients with hip fracture and matched control participants. We assigned 25(OH) vitamin D concentrations to quartile categories defined on the basis of the distribution in the control participants. To further assess confounding, we compared baseline characteristics across quartiles of 25(OH) vitamin D concentrations in case-patients and control participants combined. We calculated the P values for trend by using logistic regression and coding the variable of interest as a continuous variable. We assessed the association between serum 25(OH) vitamin D concentrations and incident hip fracture in conditional logistic regression models that retained the matched casecontrol design. We first examined the unadjusted associations and then adjusted for age, b

Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: Extended follow-up of the Women's Health Initiative randomised placebo-controlled trial

BACKGROUND By contrast with many observational studies, women in the Womens Health Initiative (WHI) trial who were randomly allocated to receive oestrogen alone had a lower incidence of invasive breast cancer than did those who received placebo. We aimed to assess the influence of oestrogen use on longer term breast cancer incidence and mortality in extended follow-up of this cohort. METHODS Between 1993 and 1998, the WHI enrolled 10,739 postmenopausal women from 40 US clinical centres into a randomised, double-masked, placebo-controlled trial. Women aged 50-79 years who had undergone hysterectomy and had expected 3-year survival and mammography clearance were randomly allocated by a computerised, permuted block algorithm, stratified by age group and centre, to receive oral conjugated equine oestrogen (0·625 mg per day; n=5310) or matched placebo (n=5429). The trial intervention was terminated early on Feb 29, 2004, because of an adverse effect on stroke. Follow-up continued until planned termination (March 31, 2005). Consent was sought for extended surveillance from the 9786 living participants in active follow-up, of whom 7645 agreed. Using data from this extended follow-up (to Aug 14, 2009), we assessed long-term effects of oestrogen use on invasive breast cancer incidence, tumour characteristics, and mortality. We used Cox regression models to estimate hazard ratios (HRs) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00000611. FINDINGS After a median follow-up of 11·8 years (IQR 9·1-12·9), the use of oestrogen for a median of 5·9 years (2·5-7·3) was associated with lower incidence of invasive breast cancer (151 cases, 0·27% per year) compared with placebo (199 cases, 0·35% per year; HR 0·77, 95% CI 0·62-0·95; p=0·02) with no difference (p=0·76) between intervention phase (0·79, 0·61-1·02) and post-intervention phase effects (0·75, 0·51-1·09). In subgroup analyses, we noted breast cancer risk reduction with oestrogen use was concentrated in women without benign breast disease (p=0·01) or a family history of breast cancer (p=0·02). In the oestrogen group, fewer women died from breast cancer (six deaths, 0·009% per year) compared with controls (16 deaths, 0·024% per year; HR 0·37, 95% CI 0·13-0·91; p=0·03). Fewer women in the oestrogen group died from any cause after a breast cancer diagnosis (30 deaths, 0·046% per year) than did controls (50 deaths, 0·076%; HR 0·62, 95% CI 0·39-0·97; p=0·04). INTERPRETATION Our findings provide reassurance for women with hysterectomy seeking relief of climacteric symptoms in terms of the effects of oestrogen use for about 5 years on breast cancer incidence and mortality. However, our data do not support use of oestrogen for breast cancer risk reduction because any noted benefit probably does not apply to populations at increased risk of such cancer. FUNDING US National Heart, Lung, and Blood Institute; Wyeth.

Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial.

BACKGROUND In the post-intervention period of the Womens Health Initiative (WHI) trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo. Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period. METHODS The WHI study was a randomised, double-blind, placebo-controlled trial undertaken in 40 centres in the USA. 16 608 postmenopausal women aged 50-79 years with an intact uterus were randomly assigned by a computerised, stratified, permuted block algorithm to receive a once-daily tablet of 0.625 mg conjugated equine oestrogen plus 2.5 mg medroxyprogesterone acetate (n=8506) or matching placebo (n=8102). We assessed incidence and mortality rates for all lung cancer, small-cell lung cancer, and non-small-cell lung cancer by use of data from treatment and post-intervention follow-up periods. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00000611. FINDINGS After a mean of 5.6 years (SD 1.3) of treatment and 2.4 years (0.4) of additional follow-up, 109 women in the combined hormone therapy group had been diagnosed with lung cancer compared with 85 in the placebo group (incidence per year 0.16%vs 0.13%; hazard ratio [HR] 1.23, 95% CI 0.92-1.63, p=0.16). 96 women assigned to combined therapy had non-small-cell lung cancer compared with 72 assigned to placebo (0.14%vs 0.11%; HR 1.28, 0.94-1.73, p=0.12). More women died from lung cancer in the combined hormone therapy group than in the placebo group (73 vs 40 deaths; 0.11%vs 0.06%; HR 1.71, 1.16-2.52, p=0.01), mainly as a result of a higher number of deaths from non-small-cell lung cancer in the combined therapy group (62 vs 31 deaths; 0.09%vs 0.05%; HR 1.87, 1.22-2.88, p=0.004). Incidence and mortality rates of small-cell lung cancer were similar between groups. INTERPRETATION Although treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, it increased the number of deaths from lung cancer, in particular deaths from non-small-cell lung cancer. These findings should be incorporated into risk-benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer. FUNDING National Heart, Lung and Blood Institute, National Institutes of Health.

Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development.

Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.