Background
We investigated the association between body mass index (BMI) and breast cancer risk in women at increased risk of breast cancer receiving tamoxifen or anastrozole compared with placebo ...using data from the International Breast Cancer Intervention Studies IBIS-I (tamoxifen) and IBIS-II (anastrozole).
Methods
Baseline BMI was calculated from nurse assessed height and weight measurements for premenopausal (
n
= 3138) and postmenopausal (
n
= 3731) women in IBIS-I and postmenopausal women in IBIS-II (
n
= 3787). The primary endpoint was any breast cancer event (invasive and ductal carcinoma in situ). We used Cox proportional hazards regression to calculate hazard ratios (HRs) for risk after adjustment for covariates.
Results
There were 582 (IBIS-I) and 248 (IBIS-II) breast cancer events median follow-up = 16.2 years (IQR 14.4–17.7) and 10.9 years (IQR 8.8–13.0), respectively. In adjusted analysis, women with a higher BMI had an increased breast cancer risk in both IBIS-I HR = 1.06 per 5 kg/m
2
(0.99–1.15),
p
= 0.114 and in IBIS-II HR per 5 kg/m
2
= 1.21 (1.09–1.35),
p
< 0.001. In IBIS-I, the association between BMI and breast cancer risk was positive in postmenopausal women adjusted HR per 5 kg/m
2
= 1.14 (1.03–1.26),
p
= 0.01 but not premenopausal women adjusted HR per 5 kg/m
2
= 0.97 (0.86–1.09),
p
= 0.628. There was no interaction between BMI and treatment group for breast cancer risk in either IBIS-I (
p
= 0.62) or IBIS-II (
p
= 0.55).
Conclusions
Higher BMI is associated with greater breast cancer risk in postmenopausal women at increased risk of the disease, but no effect was observed in premenopausal women. The lack of interaction between BMI and treatment group on breast cancer risk suggests women are likely to experience benefit from preventive therapy regardless of their BMI.
Trial registration
Both trials were registered IBIS-I: ISRCTN91879928 on 24/02/2006, retrospectively registered (
http://www.isrctn.com/ISRCTN91879928
); IBIS-II: ISRCTN31488319 on 07/01/2005, retrospectively registered (
http://www.isrctn.com/ISRCTN31488319
)
Purpose At least 94 common single nucleotide polymorphisms (SNPs) are associated with breast cancer. The extent to which an SNP panel can refine risk in women who receive preventive therapy has not ...been directly assessed previously. Materials and Methods A risk score on the basis of 88 SNPs (SNP88) was investigated in a nested case-control study of women enrolled in the International Breast Intervention Study (IBIS-I) or the Royal Marsden study. A total of 359 women who developed cancer were matched to 636 controls by age, trial, follow-up time, and treatment arm. Genotyping was done using the OncoArray. Conditional logistic regression and matched concordance indices (mC) were used to measure the performance of SNP88 alone and with other breast cancer risk factors assessed using the Tyrer-Cuzick (TC) model. Results SNP88 was predictive of breast cancer risk overall (interquartile range odds ratio IQ-OR, 1.37; 95% CI, 1.14 to 1.66; mC, 0.55), but mainly for estrogen receptor-positive disease (IQ-OR, 1.44; 95% CI, 1.16 to 1.79; P for heterogeneity = .10) versus estrogen receptor-negative disease. However, the observed risk of SNP88 was only 46% (95% CI, 19% to 74%) of expected. No significant interaction was observed with treatment arm (placebo IQ-OR, 1.46; 95% CI, 1.13 to 1.87; tamoxifen IQ-OR, 1.25; 95% CI, 0.96 to 1.64; P for heterogeneity = .5). The predictive power was similar to the TC model (IQ-OR, 1.45; 95% CI, 1.21 to 1.73; mC, 0.55), but SNP88 was independent of TC (Spearman rank-order correlation, 0.012; P = .7), and when combined multiplicatively, a substantial improvement was seen (IQ-OR, 1.64; 95% CI, 1.36 to 1.97; mC, 0.60). Conclusion A polygenic risk score may be used to refine risk from the TC or similar models in women who are at an elevated risk of breast cancer and considering preventive therapy. Recalibration may be necessary for accurate risk assessment.
Carpal tunnel syndrome (CTS) is a condition in which the median nerve is compressed, leading to pain and muscle weakness in the fingers and hand. Aromatase inhibitors lead to profound estrogen ...suppression and may be expected to increase the risk of CTS in postmenopausal women receiving adjuvant therapy for early breast cancer.
The current analyses were based on the 100-month median follow-up data in postmenopausal women in the two monotherapy arms (anastrozole, n = 3,092; tamoxifen, n = 3,094). Here, we investigate the natural history of patients who presented with CTS during adjuvant treatment for breast cancer and the relative importance of a range of known risk factors for CTS.
After 100 months of follow-up, 80 cases (2.6%) of CTS were reported in the anastrozole arm, compared with 23 cases (0.7%) in the tamoxifen arm (P < .0001). The majority of CTS cases were reported as mild to moderate intensity and occurred early. None of the women stopped treatment medication as a result of CTS. CTS was significantly increased for women who used prior hormone replacement therapy (P = .007) or received prior chemotherapy (P = .01). Those who were 60 years of age or older at entry were at lower risk of CTS compared with their counterparts (P = .002).
Although the use of anastrozole is associated with a greater incidence of CTS, it is rare, and most cases were of mild to moderate intensity and short duration. CTS has little impact on the overall risk-to-benefit ratio for the use of anastrozole in postmenopausal women with early breast cancer.
Studies in the adjuvant setting have shown that endocrine therapy related side effects predict breast cancer recurrence risk. Here, we assess the relationship between early reported side effects and ...incidence of breast cancer in women randomised to tamoxifen for cancer prevention in the International Breast Intervention Study (IBIS)–I trial.
Women randomised to tamoxifen in the IBIS-I trial and for whom side effect status was known at the 6-month follow-up visit were included in this analysis. Side effects included in this analysis were hot flushes, vaginal discharge, and vaginal dryness. The primary endpoint was all breast cancer and secondary endpoint was oestrogen receptor (ER) positive breast cancer. Cox proportional hazard models were used to investigate breast cancer incidence in the tamoxifen group with and without side effects reported within 6 months of randomisation.
Women randomised to tamoxifen and reporting hot flushes at the 6-month follow-up visit had a non-statistically significant increase in breast cancer compared to those without hot flushes (HR = 1.26 (0.98–1.62), P = 0.08). A significant higher breast cancer risk was observed for postmenopausal women who reported hot flushes at the 6-month follow-up visit compared to those without hot flushes (HR = 1.59 (1.12–2.26), P = 0.01). A higher risk was observed for ER-positive breast cancer in postmenopausal women (HR = 1.81 (1.19–2.74), P = 0.01). No significant associations between gynaecological side effects and breast cancer occurrence was observed.
Overall, no association between side effects reported at 6 months and subsequent breast cancer occurrence was observed. Some side effects might be useful markers for breast cancer occurrence in postmenopausal women.
Summary Background Aromatase inhibitors prevent breast cancer in postmenopausal women at high risk of the disease but are associated with accelerated bone loss. We assessed effectiveness of oral ...risedronate for prevention of reduction in bone mineral density (BMD) after 3 years of follow-up in a subset of patients in the IBIS-II trial. Methods The double-blind IBIS-II trial recruited 3864 healthy, postmenopausal women at increased risk of breast cancer and randomly allocated them oral anastrozole (1 mg/day) or matched placebo. 1410 (36%) postmenopausal women were then enrolled in a bone substudy and stratified at baseline according to their lowest baseline T score at spine or femoral neck (stratum I: T score at least −1·0; stratum II: T score at least −2·5 but less than −1·0; stratum III: T score less than −2·5 but greater than −4·0). Women in stratum I were monitored only; women in stratum III were all given risedronate (35 mg/week). Women in stratum II were randomly assigned (1:1) to risedronate (35 mg/week) or matched placebo by use of a block randomisation schedule via a web-based programme. The primary outcome of this per-protocol analysis (done with all women with a baseline and 3 year DXA assessment) was the effect of risedronate versus placebo for osteopenic women in stratum II randomly allocated to anastrozole (1 mg/day). Secondary outcomes included effect of anastrozole (1 mg/day) on BMD in women not receiving risedronate (strata I and II) and in osteoporotic women who were all treated with risedronate (stratum III). The trial is ongoing, but no longer recruiting. This trial is registered, number ISRCTN31488319. Findings Between Feb 2, 2003, and Sept 30, 2010, 150 (58%) of 260 women in stratum II who had been randomly allocated to anastrozole and either risedronate or placebo had baseline and 3 year assessments. At the lumbar spine, 3 year mean BMD change for the 77 women receiving anastrozole/risedronate was 1·1% (95% CI 0·2 to 2·1) versus −2·6% (−4·0 to −1·3) for the 73 women receiving anastrozole/placebo (p<0·0001). For the total hip, 3 year mean BMD change for women receiving anastrozole/risedronate was −0·7% (−1·6 to 0·2) versus −3·5% (−4·6 to −2·3) for women receiving anastrozole/placebo (p=0·0001). 652 (65%) of 1008 women in strata I and II who were not randomly allocated to risedronate had both baseline and 3 year assessments. Women not receiving risedronate in stratum I and II who received anastrozole (310 women) had a significant BMD decrease after 3 years of follow-up compared with women who received placebo (342 women) at the lumbar spine (−4·0% –4·5 to −3·4 vs −1·2% −1·7 to −0·7, p<0·0001) and total hip (−4·0% –4·4 to −3·6 vs −1·8% −2·1 to −1·4, p<0·0001). 106 (79%) of 149 women in stratum III had a baseline and a 3 year assessment. The 46 women allocated to anastrozole had a modest BMD increase of 1·2% (−0·1 to 2·6) at the spine compared with a 3·9% (2·6 to 5·2) increase for the 60 women allocated to placebo (p=0·006). For the total hip, a small 0·3% (−0·9 to 1·5) increase was noted for women allocated anastrozole compared with a 1·5% (0·5 to 2·5) increase for women allocated placebo, but the difference was not significant (p=0·12). The most common adverse event reported was arthralgia (stratum I: 94 placebo and 114 anastrozole; stratum II: 39 placebo/placebo, 25 placebo/risedronate, 34 anastrozole/placebo, and 34 anastrozole/risedronate; stratum III: 21 placebo/risedronate, 17 anastrozole/risedronate). Other adverse events included hot flushes, alopecia, abdominal pain, and back pain. Interpretation Risedronate counterbalances the effect of anastrozole-induced bone loss in osteopenic and osteoporotic women and might be offered in combination with anastrozole treatment to provide an improved risk–benefit profile. Funding Cancer Research UK (C569/A5032), National Health and Medical Research Council Australia (GNT300755, GNT569213), Sanofi-Aventis, and AstraZeneca.
Obesity is a risk factor for postmenopausal breast cancer (BC), and evidence suggests a role for adiponectin in the relationship between obesity and BC. We investigated whether adiponectin or other ...biomarkers mediate the effect of body mass index (BMI) on postmenopausal BC risk in a cohort study nested in the IBIS-II Prevention Trial. We measured adiponectin, leptin, IGF-I, IGFBP-1, high-sensitivity C-reactive protein, glycemia, insulin, HOMA-IR index, and SHBG in baseline and 12-month serum samples from 123 cases and 302 matched controls in the placebo arm of the IBIS-II Prevention trial. We conducted the main mediation analysis considering baseline BMI as an exposure and the 12-month adiponectin increase as a mediator after adjustment for the Tyrer–Cuzick score and the lipid-lowering medications/supplements use. In the multivariable Cox model, both the 12-month adiponectin increase (HR, 0.60; 95%CI, 0.36–1.00) and BMI were associated with BC risk (HR, 1.05; 95%CI, 1.00–1.09), with a 40% reduction in women with a 12-month increase in adiponectin. A significantly higher cumulative hazard of BC events was observed in obese women (BMI > 30) with decreased adiponectin (p = 0.0087). No mediating effect of the adiponectin increase on the total effect of BMI on BC risk was observed (natural indirect effect: HR, 1.00; 95%CI, 0.98–1.02). Raising adiponectin levels might be an attractive target for postmenopausal BC prevention.
There is growing consensus that genomic assays provide useful complementary information to clinicopathological features in oestrogen receptor-positive breast cancers. Here, ongoing research with ...multigene tests used for postmenopausal breast cancer and new emerging prognostic and predictive markers for pre and postmenopausal women are summarised.
Results of the TAILORx trial have shown that women with an intermediate risk score do not benefit from adjuvant chemotherapy. Prosgina has been further investigated in a contemporary patient population in postmenopausal women and its use has been extended for premenopausal women. The EndoPredict was extensively used in decision-impact studies showing that its use can potentially reduce the need for adjuvant chemotherapy. Several new genomic assays have been developed, with some of them showing promising use for women with early oestrogen receptor-positive breast cancer.
New areas of research for prediction of recurrence and risk stratification involve the development of immune gene signatures that carry modest but significant prognostic value. The recent expansion of high-throughput technology platforms including circulating tumour DNA/RNA and microRNA offer new opportunities to improve prediction models, particularly in women with oestrogen receptor-negative disease and premenopausal women. Genomic assays have clearly improved prognostication of early oestrogen receptor-positive breast cancer but it is clear that standard clinicopathological parameters are still very important when identifying patient for adjuvant chemotherapy.
The Arimidex, Tamoxifen Alone or in Combination (ATAC) study was a double-blind randomized trial in which postmenopausal women with early-stage breast cancer were assigned to receive anastrozole, ...tamoxifen, or the combination. We have conducted a retrospective analysis to examine the effects of comorbidities and age on treatment received, breast cancer-related mortality, and competing causes of mortality.
The current analyses were based on 10-year median follow-up data in the two monotherapy arms (anastrozole, n = 3,092; tamoxifen, n = 3,094) of the ATAC study. Baseline comorbidities and tumor and treatment characteristics were compared between women age less than 70 years and women age ≥ 70 years. The cumulative incidence of breast cancer-related and non-breast cancer-related mortality was assessed according to age and comorbidities.
One thousand six hundred sixty-two patients (27%) were age ≥ 70 years at study entry. Older women were more likely to undergo mastectomy (odds ratio OR, 1.92; 95% CI, 1.71 to 2.16) and less likely to receive radiotherapy (OR, 0.49; 95% CI, 0.44 to 0.55) or chemotherapy (OR, 0.24; 95% CI, 0.18 to 0.29). Women age ≥ 70 years had an increased risk of recurrence compared with women age less than 70 years (hazard ratio HR, 1.21; 95% CI, 1.08 to 1.37) and a substantially increased risk of death without recurrence (HR, 4.13; 95% CI, 3.53 to 4.83). The risk of death without recurrence increased with comorbidity score (10-year estimates of 8.4%, 20.0%, and 30.4% for Satariano score 0, 1, and 2+, respectively; P < .001).
Age influences the risk of recurrence, and age and comorbidities significantly influence the risk of death without recurrence. Formal assessment of comorbidities should be incorporated into decisions regarding adjuvant therapies.
To identify the individual genes or gene modules that lead to the OncoptypeDx 21-gene recurrence score's reduced performance after 5 years and thereby identify indices of residual risk that may guide ...selection of patients for extended adjuvant therapy.
We conducted a retrospective assessment of the relationship between (i) the individual genes and gene modules of the Recurrence Score and (ii) early (0-5 years) and late (5-10 years) recurrence rates in 1,125 postmenopausal patients with primary estrogen receptor-positive breast cancer treated with anastrozole or tamoxifen in the Arimidex, Tamoxifen, Alone or Combined (ATAC) randomized clinical trial.
In the HER2-negative population (n = 1,009), estimates of recurrence risk were similar between years 0-5 and 5-10 for proliferation and invasion modules but markedly different for the estrogen module and genes within it (all split at the median): for low estrogen module, annual recurrence rates were similar across the two time windows (2.06% vs. 2.46%, respectively); for high estrogen module, annual rates were 1.14% versus 2.72%, respectively (P interaction = 0.004). Estrogen receptor transcript levels showed inverse prediction across the time windows: HR, 0.88 (0.73-1.07) and 1.19 (0.99-1.43), respectively (P interaction = 0.03). Similar time-, module-, and estrogen-dependent relationships were seen for distant recurrence.
Patients with tumors with high estrogen receptor transcript levels benefit most from 5 years' endocrine therapy but show increased recurrence rates after 5 years and may benefit from extended therapy. Improved prognostic profiles may be created by considering period of treatment and follow-up time.
Abstract Background Breast cancer prevention with tamoxifen in high-risk women is limited due to concerns of endometrial cancer and thromboembolism. We report the risk of endometrial cancer, deep ...vein thrombosis and pulmonary embolism in women <50 years given tamoxifen for breast cancer prevention. Methods We searched the Cochrane Central Register of Controlled Trials and National Library of Medicine for published data from January 1970 to December 2010. We contacted principal investigators of clinical trials, and searched Grey literature and conference proceedings for unpublished data. We reviewed three breast cancer prevention trials comparing tamoxifen (20 mg per day) with placebo for five years in high-risk women <50 years. The absolute risk and relative risk (RR) for each outcome were estimated. Results The RR for endometrial cancer in women <50 years given tamoxifen is 1.19 (95% CI, 0.53–2.65; p = 0.6) as compared to the placebo. The RR for deep vein thrombosis with tamoxifen is 2.30 (95% CI, 1.23–4.31; p = 0.009) in the active phase of treatment. The risk decreases to 1.00 (95% CI, 0.38–2.67; p = 0.9) in the follow-up phase. The RR for pulmonary embolism with tamoxifen is 1.16 (95% CI, 0.55–2.43; p = 0.6). Interpretation The risk of endometrial cancer, deep vein thrombosis and pulmonary embolism is low in women <50 years who take tamoxifen for breast cancer prevention. The risk decreases from the active to follow-up phase of treatment. Education and counseling are the cornerstones of breast cancer chemoprevention.
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