MammaPrint的研究进展

乳腺癌是高度异质性疾病,即使临床分期及病理分级相同的患者,对治疗的反应和预后可能会大不相同。可能有相当比例的早期乳腺癌患者在没有明显获益的情况下,接受了不必要的辅助治疗。应用高通量基因测序分析技术,通过对特定"靶基因群"表达水平的检测,来提供更准确的预后信息,为选择治疗方案提供参考,是肿瘤精准治疗的重要研究方向。目前,已经研发出多个乳腺癌基因检测系统。其中,较有影响力、潜在价值较高且获美国FDA批准的2个多基因检测系统分别是Oncotype DX基因检测系统和MammaPrint基因检测系统。笔者详细地介绍了MammaPrint基因检测系统的开发、回顾性验证及大型前瞻性临床试验MINDACT研究,并对该系统的成本效益进行了分析。     

Selenium and the risk of postmenopausal breast cancer in the DOM cohort

Summary Selenium has been claimed to have chemo-preventive properties. However, data showing that in humans selenium levels are already decreased prior to diagnosis of breast cancer were not available. Such information is mandatory before oral selenium supplementation in the primary prevention of (breast) cancer in humans is acceptable. This question of a preventive-potential of selenium was evaluated in a case-control study nested in a cohort, because this design allows determination of the time-order of preceding selenium levels and subsequent cancer risk.The cohort consisted of 5577 women aged 55–70 years from the DOM project, a population based breast cancer screening program in the Netherlands. Instrumental Neutron Activation Analysis was used to measure the selenium content of toenail clippings. The 69 cases of breast cancer found during follow-up after screening represent recent tumours since all women had a negative screening mammogram 3–5 years previously.No decreased selenium levels, as measured in nail clippings from the big toes, could be detected in cases-to-be, either when compared to 4 age matched controls per case or when compared with a random control group drawn from the entire cohort. On the contrary, a tendency for slightly higher selenium levels among future cancer cases was observed.As to the sensitivity of detecting differences in selenium by nail clippings, lower selenium could be detected in nails of current smokers. The smoking-related decrease in nail selenium level was of the same order as the differences between breast cancer cases and controls, but was independent of the breast cancer risk.Results are similar to a comparable study on premenopausal breast cancer and argue against a preventive role for selenium on breast cancer risk.     

Family history of later-onset breast cancer,breast healthy behavior and invasive breast cancer among postmenopausal women: a cohort study

Introduction  

A family history of later-onset breast cancer (FHLBC) may suggest multi-factorial inheritance of breast cancer risk, including unhealthy lifestyle behaviors that may be shared within families. We assessed whether adherence to lifestyle behaviors recommended for breast cancer prevention--including maintaining a healthful body weight, being physically active and limiting alcohol intake--modifies breast cancer risk attributed to FHLBC in postmenopausal women.     

Pre-diagnostic alcohol consumption and postmenopausal breast cancer survival: a prospective patient cohort study

Study results on the association of alcohol consumption with breast cancer survival are inconsistent, partly due to the use of different survival outcomes. We assessed the association of pre-diagnostic alcohol consumption with survival and recurrence in a prospective cohort study in Germany including 2,522 postmenopausal breast cancer patients aged 50?C74?years. Patients were diagnosed between 2001 and 2005 and vital status, causes of death, and recurrences were verified through the end of 2009. Cox proportional hazards models were stratified by age at diagnosis and study center and adjusted for relevant prognostic factors. Alcohol consumption was non-linearly associated with increased breast cancer-specific mortality [e.g., ??12 vs. <0.5?g/day: hazard ratio (HR)?=?1.74, 95?% confidence interval (CI): 1.13, 2.67]. Results were independent of estrogen receptor status. A non-significantly decreased risk of mortality due to other causes was found (??12 vs. <0.5?g/day: HR?=?0.67, 95?% CI: 0.35, 1.29). Alcohol consumption was not associated with overall mortality (??12 vs. <0.5?g/day: HR?=?1.28, 95?% CI: 0.90, 1.81) and breast cancer recurrence (??12 vs. <0.5?g/day: HR?=?1.08, 95?% CI: 0.73, 1.58). In conclusion, our findings show that consumption of alcohol before diagnosis is non-linearly associated with increased breast cancer-specific mortality but may be associated with decreased risk of mortality due to other causes.     

Recreational physical activity and risk of postmenopausal breast cancer in a large cohort of US women

Due to its potential effects on ovarian hormone production, physical activity has been proposed as a modifiable risk factor for breast cancer. The authors analyzed data from the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort to examine the association between various measures of physical activity and postmenopausal breast cancer risk. Information on physical activity was obtained in 1992 via a self-administered questionnaire for 72,608 postmenopausal female participants who were cancer-free. During the five year prospective follow-up, 1520 incident breast cancer cases were identified among these women. Cox proportional hazards modeling was used to compute hazard rate ratios (RR) and to adjust for potential confounding factors including mammography. Women who were most physically active (>42.0 MET-h/week) at baseline had 29% lower incidence rates than active women with the least activity (>0–7.0 MET-h/week) (95% CI, 0.49–1.02). The difference in risk was largest for localized breast cancer, and for women who did not use hormone replacement therapy (HRT) at enrollment. Our findings are consistent with other studies that show lower risk of postmenopausal breast cancer associated with regular physical activity.     

Weight loss and postmenopausal breast cancer in a prospective cohort of overweight and obese US women

Overweight and obesity are associated with increased postmenopausal breast cancer risk; however, it is unclear whether losing excess weight will lower risk. Therefore, we examined the relationship between weight loss and postmenopausal breast cancer among 13,055 overweight and obese, cancer-free women who enrolled in the Cancer Prevention Study-II (CPS-II) Nutrition Cohort in 1992. During the 15 year follow-up, 816 postmenopausal breast cancer cases were diagnosed. Self-reported weight was collected before diagnosis at baseline and 10 years prior to baseline. The median weight loss was 11 lbs, but only 58% of the women maintained this weight loss through the first 5 year follow-up interval (1992–1997). Using both restricted cubic splines and multivariate Cox proportional hazards modeling, we observed no association between weight loss and postmenopausal breast cancer. The hazard ratio for 30+ pounds of weight loss compared to stable weight was 0.95 (95%: CI 0.47–1.95). An inverse association was, however, suggested among women who maintained ten or more pounds of weight loss through the next interval. There was no evidence of effect modification by postmenopausal hormone use, initial BMI, or other factors examined. In summary, weight loss was not associated with postmenopausal breast cancer in this study. Future studies should focus on sustained weight loss and whether the timing of weight loss is important.     

Dietary cadmium exposure and risk of postmenopausal breast cancer: a population-based prospective cohort study

The ubiquitous food contaminant cadmium has features of an estrogen mimetic that may promote the development of estrogen-dependent malignancies, such as breast cancer. However, no prospective studies of cadmium exposure and breast cancer risk have been reported. We examined the association between dietary cadmium exposure (at baseline, 1987) and the risk of overall and estrogen receptor (ER)-defined (ER(+) or ER(-)) breast cancer within a population-based prospective cohort of 55,987 postmenopausal women. During an average of 12.2 years of follow-up, 2,112 incident cases of invasive breast cancer were ascertained (1,626 ER(+) and 290 ER(-)). After adjusting for confounders, including consumption of whole grains and vegetables (which account for 40% of the dietary exposure, but also contain putative anticarcinogenic phytochemicals), dietary cadmium intake was positively associated with overall breast cancer tumors, comparing the highest tertile with the lowest [rate ratio (RR), 1.21; 95% confidence interval (CI), 1.07-1.36; P(trend) = 0.02]. Among lean and normal weight women, statistically significant associations were observed for all tumors (RR, 1.27; 95% CI, 1.07-1.50) and for ER(+) tumors (RR, 1.25; 95% CI, 1.03-1.52) and similar, but not statistically significant associations were found for ER(-) tumors (RR, 1.22; 95% CI, 0.76-1.93). The risk of breast cancer increased with increasing cadmium exposure similarly within each tertile of whole grain/vegetable consumption and decreased with increasing consumption of whole grain/vegetables within each tertile of cadmium exposure (P(interaction) = 0.73). Overall, these results suggest a role for dietary cadmium in postmenopausal breast cancer development.     

Body size and the risk of postmenopausal breast cancer subtypes in the California Teachers Study cohort

Purpose  

To evaluate how the association between body size and breast cancer risk varies by tumor receptor subtype, host factors, and other exposures among women in the California Teachers Study cohort.     

Serum 25-hydroxyvitamin D and postmenopausal breast cancer survival: a prospective patient cohort study

Introduction  

Vitamin D has been postulated to be involved in cancer prognosis. Thus far, only two studies reported on its association with recurrence and survival after breast cancer diagnosis yielding inconsistent results. Therefore, the aim of our study was to assess the effect of post-diagnostic serum 25-hydroxyvitamin D [25(OH)D] concentrations on overall survival and distant disease-free survival.     

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.     

Dietary fat and postmenopausal breast cancer.

BACKGROUND: Although the results of animal studies and cross-cultural comparisons generally support a role for dietary fat in the etiology of breast cancer, results of analytic epidemiology studies are equivocal. PURPOSE: The association between dietary fat and subsequent breast cancer was examined in a cohort of 34,388 postmenopausal women from Iowa. METHODS: Dietary habits were assessed by a food-frequency questionnaire mailed in January 1986. Through December 31, 1989, 459 incident cases of breast cancer occurred in this cohort. Proportional hazards regression was used to examine the dietary fat-breast cancer association while adjusting for potential confounders. The effects on this association of four analytic approaches to adjustment for energy intake were also considered. RESULTS: After adjustment for known determinants of breast cancer, a modest positive association of total fat intake with risk of breast cancer was seen. Polyunsaturated fat intake was also positively associated with breast cancer (relative risk from lowest to highest intake, 1.0, 1.25, 1.31, and 1.49; P for trend = .052). Different approaches to adjustment for energy intake, however, provided different impressions of the dietary fat-breast cancer association. One method, involving categorization of crude fat intake and inclusion of total energy intake in regression analysis, gave relative risk estimates from low to high fat intake of 1.0, 1.17, 1.25, and 1.38 (P for trend = .18). Another method, based on categorization of fat intake residuals in which the variation in fat due to total energy intake was removed, gave corresponding estimates of 1.0, 1.24, 1.30, and 1.16 (P for trend = .29). The former suggests increasing breast cancer risk with increasing fat intake; the latter suggests no association. CONCLUSIONS: These results are consistent with other cohort studies that have shown a weak association or no association between dietary fat and breast cancer. They are also consistent with studies suggesting that fat intake is a determinant of breast cancer, particularly after accounting for inaccuracies in dietary assessment. The effects of different energy-adjustment methods may account in part for the varying interpretations of four previous cohort studies of dietary fat and breast cancer. IMPLICATIONS: Further work is needed to clarify not only the nature of the dietary fat-breast cancer association, but also the impact of different analytic methods used in the investigation of diet-disease associations.     

Physical activity and breast cancer risk among pre- and postmenopausal women in the U.S. Radiologic Technologists cohort

To clarify aspects of the association between physical activity and breast cancer, such as activity intensity required, and possible effect modification by factors such as menopausal hormone therapy (MHT) use. We prospectively examined physical activity in relation to breast cancer risk among 45,631 women participating in the U.S. Radiologic Technologists cohort. Participants provided information at baseline regarding hours spent per week engaging in strenuous activity, walking/hiking for exercise, and walking at home or work. We estimated multivariable relative risks (RR) and 95% confidence intervals (CI) of breast cancer using Cox regression. We identified 864 incident-invasive breast cancers. Greatest risk reduction was observed among women who reported walking/hiking for exercise 10 or more hours per week (RR, 0.57; 95% CI, 0.34–0.95) compared with those reporting no walking/hiking. The association between walking/hiking for exercise and breast cancer was modified by MHT use (p for interaction = 0.039). Postmenopausal women who never used MHT had reduced risks of breast cancer associated with physical activity whereas no relation was observed among ever users of MHT. Our study suggests moderate intensity physical activity, such as walking, may protect against breast cancer. Further, the relation between physical activity and breast cancer may be modified by MHT use.     

Smoking and alcohol consumption in relation to risk of triple-negative breast cancer in a cohort of postmenopausal women

Purpose

Little is known about the risk factors for triple-negative breast cancer (TNBC), which has a worse prognosis compared to hormone receptor-positive breast cancer. We examined the association of smoking and alcohol intake with TNBC and estrogen receptor-positive (ER+) breast cancer.

Methods

Among 148,030 women enrolled in the Women??s Health Initiative, 300 TNBC cases and 2,479 ER+ cases were identified over a median of 8.0 years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).

Results

Cigarette smoking was not associated with TNBC, whereas drinkers had reduced risk compared to never drinkers. In contrast, both exposures showed slight positive associations with ER+ breast cancer: for women with ??40 pack-years of smoking, the HR was 1.24, 95% CI 1.06?C1.44; for women consuming ??7 servings of alcohol per week, the HR was 1.26, 95% CI 1.06?C1.50. Intakes of wine and hard liquor were also significantly positively associated with ER+ breast cancer.

Conclusions

These findings from a large cohort of postmenopausal women suggest that smoking and alcohol consumption are not associated with increased risk of TNBC, but may be modestly associated with increased risk of ER+ breast cancer.     

Effects of exemestane and tamoxifen in a postmenopausal breast cancer model.

PURPOSE: To optimize treatment strategies for postmenopausal breast cancer patients, we investigated the efficacy of the steroidal aromatase inhibitor exemestane alone or in combination with the antiestrogen tamoxifen in a xenograft model of postmenopausal breast cancer. We also determined the effects of these agents in sequential second-line therapy and the effect of the nonsteroidal aromatase inhibitor letrozole on tumors that progressed on the above treatments. Experimental: Aromatase-transfected human estrogen receptor-positive breast cancer cells (MCF-7Ca) were grown as tumors in ovariectomized athymic mice. Animals received subcutaneous injection with vehicle, tamoxifen, exemestane, tamoxifen plus exemestane, and letrozole. Tumor volumes were measured weekly. RESULTS: All treatments were effective initially in suppressing tumor growth as first-line therapy compared with vehicle treatment. Exemestane suppressed tumor growth to a greater extent than tamoxifen. However, the combination of tamoxifen plus exemestane was more effective than either drug alone. After tumor volumes doubled on initial treatment, the mice were crossed over to receive exemestane or tamoxifen. Tumor growth slowed briefly in mice treated with tamoxifen and crossed over to exemestane, but tumor growth continued unabated in those changed from exemestane to tamoxifen. However, letrozole was effective in both groups as third-line therapy for a limited period. Letrozole as initial single agent was the best overall treatment in terms of the degree of tumor suppression and the length of effectiveness of treatment. CONCLUSION: Exemestane was more effective in controlling tumor growth than tamoxifen. In addition, the combination of exemestane plus tamoxifen was clearly more effective than sequential use of these agents in the tumor model. However, the nonsteroidal aromatase inhibitor letrozole as first-line therapy was overall the most effective treatment in controlling tumor growth.     

Estrogen replacement therapy and risk of fatal breast cancer in a prospective cohort of postmenopausal women in the United States

This study examines the relationship between fatal breast cancer and use of estrogen replacement therapy (ERT) among women in a large prospective study in the United States. After nine years of follow-up, 1,469 breast cancer deaths were observedin a cohort of 422,373 postmenopausal women who were cancer free at study entry and who supplied information on estrogen use. Results from Cox proportional hazards modeling, adjusted for 11 other potential risk factors, showed that ever-use of ERT was associated with a significantly decreased risk of fatal breast cancer (rate ratio [RR]=0.84,95 percent confidence interval [CI]=0.75–0.94). There was a moderate trend (P=0.07) of decreasing risk with younger age at first use of ERT. This decreased risk was most pronounced in women who experienced natural menopause before the age of 40 years (RR=0.59, CI=0.40–0.87). There was no discernible trend of increasing risk with duration of use in estrogen users at baseline or former users, nor was there any trend in years since last use in former users. The relationship between ERT and breast cancer mortality differed by age at menarche and by a self-reported history of breast cysts. No increased risk of fatal breast cancer with ERT was observed with estrogen use status (baseline/former), age at first use, duration of use, or years since last use. These findings suggest that ever-use of ERT is associated with a 16 percent decreased risk of fatal breast cancer.     

Dietary fat, fat subtypes, and breast cancer in postmenopausal women: a prospective cohort study

BACKGROUND: The intake of total dietary fat and of certain fat subtypes has been shown to be strongly associated with breast cancer in international comparisons and in animal experiments. However, observational epidemiologic studies have generally reported either weak positive or no associations. To extend the prospective epidemiologic evidence on this question, we examined the association between adult dietary intake of fat, fat subtypes, and breast cancer in a large, prospective cohort of postmenopausal women. METHODS: Participants were selected from a national breast cancer mammography screening program conducted from 1973 through 1981 at 29 centers throughout the United States. From 1987 through 1989, 40022 postmenopausal women satisfactorily completed a mailed, self-administered questionnaire that included a 60-item National Cancer Institute/Block food-frequency questionnaire. Women were then followed for an average of 5.3 years; 996 women developed breast cancer. Risk was assessed by use of Cox proportional hazard regression, with age as the underlying time metric. All statistical tests were two-sided. RESULTS: Compared with women in the lowest quintile (Q1) of percentage of energy from total fat, the adjusted risk ratio (RR) and 95% confidence interval (CI) for women in the highest quintile (Q5) was 1.07 (95% CI = 0.86-1.32). In analyses stratified by history of benign breast disease (BBD), a positive association was observed among only women with no history of BBD (RR (Q5 versus Q1) = 2.20; 95% CI = 1.41-3.42; test for trend, P =.0003). The increased risk in these women appeared to be attributable to unsaturated fat intake and oleic acid in particular. CONCLUSIONS: In this study, there was no overall association between fat intake during adulthood and breast cancer risk; however, among women with no history of BBD, there appeared to be a positive association between total and unsaturated fat intake and breast cancer risk.     

Adiposity and breast cancer risk in postmenopausal women: Results from the UK Biobank prospective cohort

Body size is an important modifiable risk factor for postmenopausal breast cancer. However, it remains unclear whether direct measures of fat mass are better indicators of risk than anthropometric measures, or whether central adiposity may contribute to risk beyond overall adiposity. We analyzed data from 162,691 postmenopausal women in UK Biobank followed from 2006 to 2014. Body size was measured by trained technicians. Multivariable‐adjusted Cox regression was used to estimate relative risks. Analyses were stratified by age at recruitment, region and socioeconomic status, and adjusted for family history of breast cancer, age at menarche, age at first birth, parity, age at menopause, previous hormone replacement therapy use, smoking, alcohol intake, height, physical activity and ethnicity. We observed 2,913 incident invasive breast cancers during a mean 5.7 years of follow‐up. There was a continuous increase in risk of postmenopausal breast cancer with increasing adiposity, across all measures. The point estimate, comparing women in the top (median 37.6 kg) to bottom (median 17.6 kg) quartile of body fat mass was 1.70 (95% confidence interval 1.52–1.90). The magnitudes of the associations between per SD increase in BMI and body fat mass with breast cancer risk were similar, suggesting impedance measures of fat were not substantially better indicators of risk than anthropometric measures. After adjusting for body fat mass, the associations between anthropometric measures of central adiposity and breast cancer risk were attenuated. The magnitude of risk, across all measures of adiposity, was greater in women who had been postmenopausal for 12 or more years.