Mediation analysis of racial disparities in triple-negative breast cancer incidence among postmenopausal women

Breast Cancer Research and Treatment - Triple-negative breast cancer (TNBC) is disproportionately higher in Black women relative to White women. The objective of this study was to examine to what...     

Do adjuvant aromatase inhibitors increase the cardiovascular risk in postmenopausal women with early breast cancer

BACKGROUND: Despite the advantages from using aromatase inhibitors (AIs) compared with tamoxifen for early breast cancer, an unexpectedly greater number of grade 3 and 4 cardiovascular events (CVAE) (as defined by National Cancer Institute of Canada-Common Toxicity Criteria [version 2.0] was demonstrated. METHODS: Phase 3 randomized clinical trials (RCTs) comparing AI with tamoxifen in early breast cancer were considered eligible for this review. The event-based risk ratios (RRs) with 95% confidence intervals (95% CIs) were derived, and a test of heterogeneity was applied. Finally, absolute differences (ADs) in event rates and the number of patients needed to harm 1 patient (NNH) were determined. RESULTS: Seven eligible RCTs (19,818 patients) reported CVAE results. When considering all RCTs, the AD of the primary endpoint (CVAE) between the 2 arms (0.52%), tamoxifen versus AI, was statistically significant (RR, 1.31; 95% CI, 1.07-1.60; P= .007). This translated into an NNH value of 189 patients; when only third-generation AIs were considered, the difference (0.57%) remained significant (RR, 1.34; 95% CI, 1.09-1.63; P= .0038). Thromboembolic events were significantly more frequent in the tamoxifen arm, regardless of the strategy adopted (RR, 0.53; 95% CI, 0.42-0.65; P< .0001), without significant heterogeneity (P= .21). An AD of 1.17% and an NNH value of 85 patients were observed. CONCLUSIONS: According to the results from this meta-analysis, the risk of grade 3 and 4 CVAEs in patients who were receiving AIs was higher compared with the risk in patients who were receiving tamoxifen, and the difference reached statistical significance. However, the AD was relatively low, and from 160 to 180 patients had to be treated to produce 1 event.     

Awareness of breast cancer incidence and risk factors among healthy women.

The efficacy of early breast cancer detection programmes seems to be mainly influenced by the awareness of breast cancer in general among healthy women. This study aimed to provide information about women's understanding of breast cancer incidence and risk of disease. Based on a newly developed questionnaire 2108 healthy women were asked about their knowledge and perceptions in relation to breast cancer incidence, risk factors, risk perception and level of concern. Of these women 78.8% were well aware of breast cancer in general terms. However, there were major aspects such as incidence or risk factors that were poorly understood. Only one-third correctly estimated the incidence of breast cancer; 95% understood breast cancer in the familial history as a risk factor, but only 57% understood the age risk; 37.1% of women perceived hormonal contraceptives and 35.9% hormonal replacement therapy as risk factors of breast cancer. The latter estimation was significantly higher in women above 40 years. Recommendations for the improvement of cancer prevention programmes include targeting understanding of lifetime risk of breast cancer, age as a risk factor, survival from breast cancer or hormonal factors. There is a need to separately address the perceptions of women depending on age, social status and educational levels.     

Risk of early recurrence among postmenopausal women with estrogen receptor-positive early breast cancer treated with adjuvant tamoxifen

BACKGROUND: Adjuvant aromatase inhibitors (AIs), instead of or after tamoxifen, are effective in decreasing recurrence in postmenopausal women with estrogen receptor (ER)-positive breast cancer. An understanding of which patients are at risk of early recurrence while they are receiving tamoxifen may improve clinical decision making. METHODS: The patients who were included in this study were women aged >or= 50 years with early-stage, ER-positive breast cancer diagnosed between 1986 and 1999 and had been treated with tamoxifen. Characteristics of the patients with early recurrences (within 2.5 years of diagnosis), late recurrences (between 2.5 years and 5 years) and no recurrence within 5 years were compared. Logistic regression analyses were conducted to identify which groups were at risk of early recurrence. RESULTS: Among 3844 women, 304 women (7.9%) developed disease recurrence within 2.5 years. Higher than average rates of recurrence within 2.5 years were observed in cohorts with lymph node (N)-positive tumors (11.5%), grade 3 histology (14.3%), or low-positive ER levels, ie, 10-49 fmol/mg or 10%-20% staining (14.9%). In multivariate analyses, only pathologically N-positive tumors (1-3 vs 0 positive lymph nodes: odds ratio [OR], 1.6; 4-9 vs 0 positive lymph nodes: OR, 2.23 [P= .03]) and low-positive ER status (OR, 2.04; P= .01) were associated with recurrence within 2.5 years compared with recurrence between 2.5 years and 5 years. Other clinical and pathologic variables were not predictive of early recurrence. CONCLUSIONS: Subgroups of women with early ER-positive breast cancer may be identified who are at increased risk of recurrence within 2.5 years of diagnosis despite tamoxifen. It remains to be proven whether upfront AI therapy results in an advantage to these women.     

Anthropometric factors and risk of molecular breast cancer subtypes among postmenopausal Norwegian women

Adult height and body weight are positively associated with breast cancer risk after menopause, but few studies have investigated these factors according to molecular breast cancer subtype. A total of 18,562 postmenopausal Norwegian women who were born between 1886 and 1928 were followed up for breast cancer incidence from the time (between 1963 and 1975) height and weight were measured until 2008. Immunohistochemical and in situ hybridization techniques were used to subtype 734 incident breast cancer cases into Luminal A, Luminal B [human epidermal growth factor receptor 2 (HER2?)], Luminal B (HER2+), HER2 subtype, basal‐like phenotype (BP) and five‐negative phenotype (5NP). We used Cox regression analysis to assess adult height and body mass index (BMI) in relation to risk of these subtypes. We found a positive association of height with risk of Luminal A breast cancer (p_trend, 0.004), but there was no clear association of height with any other subtype. BMI was positively associated with risk of all luminal breast cancer subtypes, including Luminal A (p_trend, 0.002), Luminal B (HER2?) (p_trend, 0.02), Luminal B (HER2+) (p_trend, 0.06), and also for the HER2 subtype (p_trend, 0.04), but BMI was not associated with risk of the BP or 5NP subtypes. Nonetheless, statistical tests for heterogeneity did not provide evidence that associations of height and BMI differed across breast cancer subtypes. This study of breast cancer risk among postmenopausal women suggests that height is positively associated with risk of Luminal A breast cancer. BMI is positively associated with risk of all luminal subtypes and for the HER2 subtype.     

WCRF/AICR recommendation adherence and breast cancer incidence among postmenopausal women with and without non‐modifiable risk factors

Taller height, family history of breast cancer, greater number of years of potential fertility and nulliparity are established non‐modifiable risk factors for postmenopausal breast cancer. Greater adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) diet, physical activity and body weight recommendations has previously been shown to be associated with lower breast cancer risk. However, no prior studies have evaluated whether women with non‐modifiable risk factors receive similar benefits from recommendation adherence compared to women without these risk factors. In the Iowa Women's Health Study prospective cohort, we investigated whether associations of WCRF/AICR recommendation adherence differed by the presence/absence of non‐modifiable breast cancer risk factors. Baseline (1986) questionnaire data from 36,626 postmenopausal women were used to create adherence scores for the WCRF/AICR recommendations (maximum score = 8.0). Overall and single recommendation adherence in relation to breast cancer risk (n = 3,189 cases) across levels of non‐modifiable risk factors were evaluated using proportional hazards regression. Mean adherence score was 5.0 points (range: 0.5–8.0). Higher adherence scores (score ≥6.0 vs. ≤3.5, HR = 0.76, 95% CI = 0.67–0.87), and adherence to the individual recommendations for body weight and alcohol intake were associated with a lower breast cancer incidence. While not statistically significant among women with more non‐modifiable risk factors (score ≥6.0 vs. ≤3.5, HR = 0.76, 95% CI = 0.36–1.63), hazard ratios were comparable to women with the no non‐modifiable risk factors (score ≥6.0 vs. ≤3.5, HR = 0.74, 95% CI = 0.49–0.93) (p‐interaction = 0.57). WCRF/AICR recommendation adherence is associated with lower breast cancer risk, regardless of non‐modifiable risk factor status.     

Adipose organochlorine concentrations and risk of breast cancer among postmenopausal Danish women.

OBJECTIVE: Exposure to environmental organochlorines has been examined as a potential risk factor for human breast cancer with mixed results. Our purpose was to examine associations between organochlorines and the development of breast cancer in a large prospective study using stored adipose tissue. METHODS: We conducted a nested case-control study of 409 postmenopausal women who developed breast cancer and 409 controls selected from the 29,875 women enrolled in the Danish Diet, Cancer, and Health cohort between 1993 and 1997. We measured concentrations of 14 pesticides and 18 polychlorinated biphenyls in adipose tissue, collected upon enrollment, and estimated relative risk (RR) of breast cancer using conditional logistic regression. RESULTS: The results showed no higher risk of breast cancer among women with higher levels of any pesticides or polychlorinated biphenyls; the RR associated with the upper quartile of 1,1-dichloro-2, 2-bis(p-chlorophenyl)ethylene concentration was 0.7 [95% confidence interval (95% CI), 0.5-1.2] contrasting the lower quartile, and for the sum of polychlorinated biphenyls the similar risk was 1.1 (95% CI, 0.7-1.7). We observed a pattern of substantially lower risk of estrogen receptor-negative breast cancer in association with higher levels of most of the pesticides and polychlorinated biphenyls; the RR for the higher quartile of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene was 0.1 (95% CI, 0.0-0.5) and for the sum of polychlorinated biphenyls it was 0.3 (95% CI, 0.1-0.9). CONCLUSION: The results do not support that higher organochlorine body levels increase the risk of breast cancer in postmenopausal women. The interpretation of the inverse association for estrogen receptor-negative breast cancer is currently unclear.     

Effect of raloxifene on the incidence of invasive breast cancer in postmenopausal women with osteoporosis categorized by breast cancer risk.

PURPOSE: To assess the effect of raloxifene, indicated for osteoporosis treatment and prevention, on invasive breast cancer in subgroups of postmenopausal women defined by risk factors for breast cancer. EXPERIMENTAL DESIGN: Data from the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) trial (N=7,705) and a follow-up study, the 4-year Continuing Outcomes Relevant to Evista (CORE) trial (N=4,011), were analyzed. Prespecified subgroups were defined by age (>or=65 versus<65 years), age at menopause (>or=49 versus<49 years), body mass index (>or=25 versus<25 kg/m2), family history of breast cancer (yes/no), serum estradiol level (5-10 versus<5, >10 versus<5 pmol/L), prior estrogen therapy (yes/no), and bone mass at MORE baseline, and 5-year predicted risk, assessed using the modified Gail model (>or=1.67 versus<1.67%), at CORE baseline. Time-to-first invasive breast cancer was analyzed using Cox proportional hazards models. RESULTS: In the placebo group, older age, higher estradiol level, and a family history of breast cancer were associated with an increased breast cancer risk (P<0.05). Raloxifene therapy was associated with a reduced breast cancer risk in both women at lower and those at higher breast cancer risk. Hazard ratio point estimates were 0.11 to 0.67, corresponding to a 33% to 89% reduction in breast cancer risk with raloxifene versus placebo. The therapy by family history interaction was significant (P=0.04). CONCLUSIONS: Raloxifene therapy was associated with a reduced risk of invasive breast cancer in postmenopausal women irrespective of the presence/absence of risk factors; its effect was greater in women with a family history of breast cancer.     

Oral bisphosphonate use and lung cancer incidence among postmenopausal women

BackgroundBisphosphonates are common medications for the treatment of osteoporosis in older populations. Several studies, including the Women’s Health Initiative (WHI), have found inverse associations of bisphosphonate use with risk of breast and endometrial cancer, but little is known about its association with other common malignancies. The objective of this study was to evaluate the association of bisphosphonate use on the incidence of lung cancer in the WHI.Patients and methodsThe association between oral bisphosphonate use and lung cancer risk was examined in 151 432 postmenopausal women enrolled into the WHI in 1993–1998. At baseline and during follow-up, participants completed an inventory of regularly used medications including bisphosphonates.ResultsAfter a mean follow-up of 13.3 years, 2511 women were diagnosed with incident lung cancer. There was no evidence of a difference in lung cancer incidence between oral bisphosphonate users and never users (adjusted hazard ratio = 0.91; 95% confidence intervals, 0.80–1.04; P = 0.16). However, an inverse association was observed among those who were never smokers (hazard ratio = 0.57, 95% confidence interval, 0.39–0.84; P < 0.01).ConclusionIn this large prospective cohort of postmenopausal women, oral bisphosphonate use was associated with significantly lower lung cancer risk among never smokers, suggesting bisphosphonates may have a protective effect against lung cancer. Additional studies are needed to confirm our findings.     

Urinary hydroxyestrogens and breast cancer risk among postmenopausal women: a prospective study.

BACKGROUND: It has been suggested that a low level of the 2-hydroxyestrogen metabolites (2-OHE) and a high level of 16alpha-hydroxyestrone (16alpha-OHE1) are associated with an enhanced risk of breast cancer. We examined the association between the metabolite levels and breast cancer in a nested case-control study, which also addressed hormone replacement therapy (HRT) and estrogen receptor status of the tumors. METHODS: 24,697 postmenopausal Danish women were enrolled in the "Diet, Cancer and Health" cohort. During follow-up, 426 breast cancer cases were identified and controls were matched by age at diagnosis, baseline age, and HRT use. The concentrations of 2-OHE and 16alpha-OHE1 in spot urine were measured by an enzyme immunoassay. Incidence rate ratios (IRR) and 95% confidence intervals (95% CI) were estimated for total and estrogen receptor-specific breast cancer and were stratified according to HRT use. RESULTS: A higher incidence of estrogen receptor-positive breast cancer with an enhanced 2-OHE level was observed among current HRT users, IRR per doubling = 1.30 (95% CI, 1.02-1.66), whereas no association was seen among nonusers of HRT, IRR per doubling = 1.00 (95% CI, 0.69-1.45). The association between estrogen receptor-positive breast cancer and the 16alpha-OHE1 metabolite level was in the opposite direction but slightly weaker and statistically insignificant. For estrogen receptor-negative breast cancer, no significant associations were seen. CONCLUSIONS: The risk of breast cancer, in particular the estrogen receptor-positive type, was enhanced among postmenopausal women using estradiol-based HRT and among those who had a high 2-OHE concentration.     

Incidence of breast cancer among postmenopausal, hypertensive women

Elevated blood pressure has been proposed to be a risk factor for breast cancer but the results remain controversial. In this study, the incidence of breast cancer among 9,112 postmenopausal, hypertensive women included in the community-based hypertension register of the North Karelia project was assessed through the Finnish Cancer Registry. The mean follow-up time was 27 years. The incidence of breast cancer in hypertensive women in our cohort was similar to the age and period specific population-based rates for Eastern Finland [the standardised incidence ratio 0.96 (95% confidence interval 0.86-1.05)]. In the Cox regression analysis, there was no association between blood pressure levels, or use of antihypertensive (AH) drugs, and breast cancer incidence, when all women were considered. There was a statistically significant interaction of the use of AH drugs at baseline and the diastolic blood pressure (DBP). Among women who were not using AH drugs at baseline, the DBP level was positively associated with the subsequent risk of breast cancer (hazard ratio 1.26/10 mm Hg, 95% confidence interval 1.06-1.46). In women with AH drugs at baseline, the DBP had an opposite effect of borderline significance (hazard ratio 0.90/10 mm Hg, 95% confidence interval 0.78-1.01). In conclusion, breast cancer incidence among postmenopausal hypertensive patients in general does not differ from that of general population. Elevated DBP levels may be associated with an increased breast cancer risk among nonpharmacologically treated women.     

Effect of family history,obesity and exercise on breast cancer risk among postmenopausal women

We examined effects of obesity and lifetime exercise patterns on postmenopausal breast cancer risk according to family history in a large population-based case control study conducted in Los Angeles County, California, because we hypothesized that both factors would affect risk through similar mechanistic pathways, and that their effects would be stronger among women with a family history. We studied 1883 postmenopausal breast cancer case subjects and 1628 postmenopausal control subjects ranging in age from 55-72 years. Cases were diagnosed with incident breast cancer in the late 1980s and 1990s. Controls were individually matched to case subjects on age, ethnic origin and neighborhood. In-person interviews determined known breast cancer risk factors including: height, weight, lifetime exercise, and family history of breast and other cancers. Breast cancer risk was raised among women who had at least 1 first-degree relative with breast cancer (odds ratio [OR] = 1.68; 95% confidence interval [CI] = 1.36-2.08). Risk increased with increasing levels of body-mass index (wt-kg/ht-m(2)) (p-trend = 0.005). Breast cancer risk was reduced among women who maintained, on average, 17.6 metabolic equivalent of energy expenditure (MET)-hr of activity/week from menarche onward (OR = 0.66; 95% CI = 0.48-0.90). Body-mass index, adjusted for lifetime exercise, was strongly associated with breast cancer risk among women with a positive family history of breast cancer (p-trend < 0.0001), but only weakly associated among women with no family history (p-trend = 0.08; homogeneity of trends p = 0.0005). In contrast, the risk reduction associated with exercise activity, adjusting for body-mass index, was limited to women without a family history of breast cancer (p-trend = 0.001; homogeneity of trends p = 0.005). Body-mass index and exercise activity, both modifiable risk factors for breast cancer, seem to have differential effects depending on a woman's family history of breast cancer, and may impact risk through different biological mechanisms.     

Circulating prolactin and breast cancer risk among pre- and postmenopausal women in the EPIC cohort

BackgroundExperimental and epidemiological evidence suggests that prolactin might play a role in the etiology of breast cancer. We analyzed the relationship of prediagnostic circulating prolactin levels with the risk of breast cancer by menopausal status, use of postmenopausal hormone replacement therapy (HRT) at blood donation, and by estrogen and progesterone receptor status of the breast tumors.Patients and methodsConditional logistic regression was used to analyze the data from a case–control study nested within the prospective European EPIC cohort, including 2250 invasive breast cancer and their matched control subjects.ResultsStatistically significant heterogeneity in the association of prolactin levels with breast cancer risk between women who were either pre- or postmenopausal at the time of blood donation was observed (P_het = 0.04). Higher serum levels of prolactin were associated with significant increase in the risk of breast cancer among postmenopausal women [odds ratio (OR)_Q4–Q1 = 1.29 (95% confidence interval, CI, 1.05–1.58), P_trend = 0.09]; however, this increase in risk seemed to be confined to women who used postmenopausal HRT at blood donation [OR_Q4–Q1 = 1.45 (95% CI 1.08–1.95), P_trend = 0.01], whereas no statistically significant association was found for the non-users of HRT [OR_Q4–Q1 = 1.11 (95%CI 0.83–1.49), P_trend = 0.80] (P_het = 0.08). Among premenopausal women, a statistically non-significant inverse association was observed [OR_Q4–Q1 = 0.70 (95% CI 0.48–1.03), P_trend = 0.16]. There was no heterogeneity in the prolactin–breast cancer association by hormone receptor status of the tumor.ConclusionOur study indicates that higher circulating levels of prolactin among the postmenopausal HRT users at baseline may be associated with increased breast cancer risk.     

Aromatase inhibitors and the risk of colorectal cancer in postmenopausal women with breast cancer

BackgroundA large trial of postmenopausal women with breast cancer reported an imbalance in colorectal cancer events with aromatase inhibitors (AIs), compared with tamoxifen in the adjuvant setting. This unexpected signal was observed within 3 years of randomization. To date, no observational studies have examined this important safety question in the natural setting of clinical practice. Thus, the objective of this study was to determine whether AIs, when compared with tamoxifen, are associated with increased risk of colorectal cancer in postmenopausal women with breast cancer.Patients and methodsUsing the UK Clinical Practice Research Datalink, we identified women, at least 55 years of age, with breast cancer newly treated with either AIs or tamoxifen between 1 January 1996 and 30 September 2015, with follow-up until 30 September 2016. High-dimensional propensity score-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of incident colorectal cancer associated with AIs when compared with tamoxifen overall, by cumulative duration of use, and time since initiation. All exposures were lagged by 1 year for latency considerations.ResultsA total of 9701 and 8893 patients initiated AIs and tamoxifen as first-line hormonal therapy (median follow-up of 2.4 and 2.9 years, respectively). Compared with tamoxifen, AIs were not associated with an increased risk of colorectal cancer (incidence rates of 150 per 100 000 person-years in both groups; adjusted HR: 0.90, 95% CI: 0.53–1.52). Similarly, there was no evidence of an association with cumulative duration of use (P-heterogeneity = 0.54), and time since initiation (P-heterogeneity = 0.66).ConclusionsIn this first population-based study, the use of AIs was not associated with an increased risk of colorectal cancer. These findings should provide reassurance to the concerned stakeholders.