Pooled analysis of the prognostic relevance of progesterone receptor status in five German cohort studies

The progesterone receptor (PR) has been increasingly well described as an important mediator of the pathogenesis and progression of breast cancer. The aim of this study was to assess the role of PR status as a prognostic factor in addition to other well-established prognostic factors. Data from five independent German breast cancer centers were pooled. A total of 7,965 breast cancer patients were included for whom information about their PR status was known, as well as other patient and tumor characteristics commonly used as prognostic factors. Cox proportional hazards models were built to compare the predictive value of PR status in addition to age at diagnosis, tumor size, nodal status, grading, and estrogen receptor (ER) status. PR status significantly increased the accuracy of prognostic predictions with regard to overall survival, distant disease-free survival, and local recurrence-free survival. There were differences with regard to its prognostic value relative to subgroups such as nodal status, ER status, and grading. The prognostic value of PR status was greatest in patients with a positive nodal status, negative ER status, and low grading. The PR-status adds prognostic value in addition to ER status and should not be omitted from clinical routine testing. The significantly greater prognostic value in node-positive and high-grade tumors suggests a greater role in the progression of advanced and aggressive tumors.     

Body weight and postmenopausal breast cancer risk defined by estrogen and progesterone receptor status among Swedish women: A prospective cohort study

Although obesity is one of the established risk factors for postmenopausal breast cancer, it is not clear whether this positive association differs across estrogen receptor (ER) and progesterone receptor (PR) status of breast tumors. We evaluated the association between body weight and ER/PR defined breast cancer risk stratified by postmenopausal hormone (PMH) use and a family history of breast cancer in the population-based Swedish Mammography Screening Cohort comprising 51,823 postmenopausal women. Relative body weight was measured by body mass index (kg/m2) based on self-reported weight and height collected in 1987 and 1997. Relative risks (RRs) were estimated by hazard ratios derived from Cox proportional hazards regression models. During an average of 8.3-year follow-up, 1,188 invasive breast cancer cases with known ER and PR status were diagnosed. When comparing to normal weight group, we observed a positive association between obesity and risk for the development of ER+ PR+ tumors (RR = 1.67, 95% CI = 1.34-2.07) and an inverse association for the development of all PR- tumors (RR = 0.68, 95% CI = 0.47-0.98). Statistically significant heterogeneity was observed in the RRs between ER+ PR+ tumors and all PR- tumors (p(heterogeneity) < 0.0001). The positive association of obesity with the development of ER+ PR+ tumors was confined to never-users of PMHs (RR = 1.90 (CI 95%:1.38-2.61)) and to those without a family history of breast cancer (RR = 1.82 (CI 95%:1.45-2.29)). Our results support the hypothesis that excess endogenous estrogen due to obesity contributes to an increased risk of ER+ PR+ postmenopausal breast cancer.     

Mouse mammary tumor like virus sequences in breast milk from healthy lactating women

Aspirin and other non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit aromatase activity and thus could selectively lower incidence of hormone receptor positive tumors. We assessed whether the association of aspirin and other NSAIDs with postmenopausal breast cancer risk differs by estrogen and progesterone receptor (ER and PR) status of the tumor. A population-based cohort of 26,580 postmenopausal women was linked to a SEER Cancer Registry to identify incident breast cancers. Regular use of aspirin and other NSAIDs was reported on a self-administered questionnaire mailed in 1992. Cox proportional hazards models were used to estimate multivariate relative risks (RRs) and 95% confidence intervals (CIs) of breast cancer incidence overall and by ER and PR status, adjusting for multiple breast cancer risk factors. Through 2005, 1,581 incident breast cancer cases were observed. Compared to aspirin never users, women who regularly consumed aspirin had a lower risk of breast cancer (RR = 0.80; 95% CI: 0.71–0.90), and there was evidence for lower risk with increasing frequency of use (RR = 0.71 for aspirin use 6 or more times/week vs. never use; P trend = 0.00001). Inverse associations for regular aspirin use were observed for ER+ (RR = 0.77; 95% CI 0.67–0.89), ER− (RR = 0.78; 95% CI 0.56–1.08), PR+ (RR = 0.79; 95% CI 0.68–0.92), and PR− (RR = 0.73; 95% CI 0.56–0.95) breast cancers. In contrast, use of other NSAIDs was not associated with breast cancer incidence overall (RR = 0.95, 95% CI: 0.85–1.07), or by ER or PR status. Aspirin, but not other NSAID use, was associated with about 20% lower risk of postmenopausal breast cancer and did not vary by ER or PR status of the tumor, suggesting that the hypothesized protective effects of aspirin may either be through cellular pathways independent of estrogen or progesterone signaling, or on tumor microenvironment.     

The role of human epidermal growth factor receptor 2 in the survival of women with estrogen and progesterone receptor-negative, invasive breast cancer: the California Cancer Registry, 1999-2004

BACKGROUND: Breast cancers that are negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) (triple negative [TN]) have been associated with high-grade histology, aggressive clinical behavior, and poor survival. It has been determined that breast cancers that are negative for ER and PR but positive for HER2 (double negative [DN]) share features with TN breast cancers. In this report, the authors quantified the contribution of HER2 as well as demographic and tumor characteristics to the survival of women with TN tumors, DN tumors, and other breast cancers (OBC). METHODS: In total, 61,309 women who were diagnosed with invasive breast cancer between 1999-2004 were identified in the California Cancer Registry. Demographic and tumor characteristics of women with TN tumors were compared with those from women with DN tumors and women with OBC. A compound proportional hazards regression analysis (PHPH) (a generalization of the Cox proportional hazards model) was used to model these characteristics. RESULTS: Women with TN tumors were younger, African American, Hispanic, and of lower socioeconomic status (SES), whereas women with DN tumors were slightly older; African American, and Asian/Pacific Islander. Women with TN and DN tumors presented with larger, higher grade, and higher stage than women with OBC. Survival among women with TN tumors was poorer compared with that among women with OBC but was nearly the same as that of women with DN tumors. Results of the regression analysis indicated that disease stage, tumor grade, SES, and race/ethnicity were significant risk factors for survival. Negative ER and PR status was associated with an increased risk of death. There was a small but significant difference in both long-term and short-term survival patients who had TN tumors compared with patients who had DN tumors. CONCLUSIONS: Patients with TN tumors shared many clinical, demographic, and tumor features and had survival that was very similar survival to that of patients with DN tumors, and survival for both groups contrasted greatly with survival for patients with OBC. Disease stage, tumor grade, SES, race/ethnicity, negative ER and PR status, rather than negative HER2 status, were risk factors for survival.     

Body weight at age 20 years, subsequent weight change and breast cancer risk defined by estrogen and progesterone receptor status--the Japan public health center-based prospective study

Few prospective studies have investigated the association between BMI at age 20 years (BMI20y) and breast cancer risk with consideration to estrogen/progesterone receptor status (ER/PR). We evaluated the association between BMI20y and ER/PR-defined breast cancer risk among 41,594 women in the population-based Japan Public Health Center-based Prospective Study. Anthropometric factors were assessed using self-reported questionnaires. Relative risks (RRs) were estimated by Cox proportional hazards regression models. Through to the end of 2006, 452 breast cancer cases were identified. We observed a statistically significant inverse association between BMI20y and breast cancer incidence [multivariable-adjusted RR for each 5-unit increment 0.75 (95%CI=0.61-0.92)], which was not modified by menopausal or recent BMI status. In contrast, recent BMI and subsequent BMI gain were not associated with increased risk among premenopausal women, but were substantially associated with increased risk among postmenopausal women [corresponding RR(recent BMI)=1.31 (95%CI=1.07-1.59); RR(subsequent BMI gain)=1.32 (95%CI=1.09-1.60)]. In subanalyses by receptor status (～50% of cases), the observed inverse association of BMI20y with risk was consistent with the result for ER-PR- [0.49 (95%CI=0.27-0.88)], while the observed positive associations of BMI gain with postmenopausal breast cancer risk appeared to be confined to ER+PR+ tumors [corresponding RR(for subsequent BMI gain)=2.24 (95%CI=1.50-3.34)]. Low BMI at age 20 years was substantially associated with an increased risk of breast cancer. In contrast, high recent BMI and subsequent BMI gain from age 20 were associated with increased risk of postmenopausal ER+PR+ tumors.     

Dietary acrylamide intake and estrogen and progesterone receptor-defined postmenopausal breast cancer risk

Acrylamide, a potential human carcinogen, has been discovered in a variety of heat-treated carbohydrate-rich food products. Previously, dietary acrylamide intake was shown to be associated with endocrine-related cancers in humans. We assessed the association between dietary acrylamide intake and risk of postmenopausal breast cancer stratified by estrogen and progesterone receptor status. This study was embedded within the Netherlands Cohort Study on diet and cancer, which was initiated in 1986 enrolling 62,573 women aged 55–69 years at baseline. After 13.3 years of follow-up, 2225 incident breast cancer cases were ascertained, with hormone receptor status information for 43%. Cox proportional hazards analysis was applied to determine hazard ratios in quintiles of dietary acrylamide intake stratifying on estrogen receptor (ER) and progesterone receptor (PR) and smoking status. No association was observed for overall breast cancer or receptor-negative breast cancer risk, irrespective of smoking status. A statistically non-significantly increased risk of ER positive, PR positive and joint receptor-positive breast cancer was found in never-smoking women. The multivariable-adjusted hazard ratios were 1.31 (95% CI: 0.87–1.97, P _trend = 0.26) for ER+, 1.47 (0.86–2.51, P _trend = 0.14) for PR+, and 1.43 (0.83–2.46, P _trend = 0.16) for ER+PR+, when comparing women in the highest quintile of acrylamide intake (median 36.8 μg/day) to women in the lowest (median 9.5 μg/day). This study showed some indications of a positive association between dietary acrylamide intake and receptor-positive breast cancer risk in postmenopausal never-smoking women. Further studies are needed to confirm or refute our observations.     

Relative weight at age 12 and risk of postmenopausal breast cancer

BACKGROUND: Early adolescent weight may affect the risk of postmenopausal breast cancer, and this association may be modified by a family history of breast or ovarian cancer in a first-degree relative, and/or estrogen (ER) and progesterone (PR) receptor status of the disease. METHODS: Relative weight at age 12 years (above, below, or average weight compared with peers) and family history were ascertained using a mailed questionnaire in 1986, in the Iowa Women's Health Study, a prospective cohort study of postmenopausal women. Incident breast cancer cases (including ER and PR status) were identified using the Iowa Surveillance, Epidemiology, and End Results Cancer Registry. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards regression, and were adjusted for breast cancer risk factors, including body mass index at age 18 years and body mass index at study baseline. RESULTS: Through 2003, 2,503 cases of postmenopausal breast cancer were identified among 35,941 women in the analytic cohort. Compared with women with average weight at age 12 years, there was no association of below average weight with risk of breast cancer (RR, 1.02; 95% CI, 0.92-1.13), whereas women with above average weight had a lower risk (RR, 0.85; 95% CI, 0.74-0.98). There was no evidence of an interaction between weight at age 12 years and family history (P = 0.44). The inverse association of above average weight with risk of breast cancer was strongest for PR- tumors (RR, 0.62; 95% CI, 0.43-0.89), intermediate for ER+ (RR, 0.80; 95% CI, 0.67-0.96) and ER- (RR, 0.77; 95% CI, 0.50-1.19) tumors, and weakest for PR+ tumors (RR, 0.90; 95% CI, 0.74-1.09). These associations were not modified by a family history (all P > 0.18). In a joint ER/PR analyses, the strongest inverse association with above average weight at age 12 years was seen for ER+/PR- (RR, 0.49; 95% CI, 0.29-0.85). CONCLUSION: Above average weight at age 12 years was inversely associated with risk of postmenopausal breast cancer, and was not modified by a family history of the disease. The inverse association was strongest for ER+/PR- tumors.     

Dietary fiber intake and risk of postmenopausal breast cancer defined by estrogen and progesterone receptor status--a prospective cohort study among Swedish women

There is few data on the association between dietary fiber intake and estrogen receptor (ER)/progesterone receptor (PR)-defined breast cancer risk. We evaluated the association between dietary fiber and ER/PR-defined breast cancer risk stratified by postmenopausal hormone use, alcohol intake, and family history of breast cancer in the population-based Swedish Mammography Screening Cohort comprising 51,823 postmenopausal women. Fiber intake was measured by food-frequency questionnaire collected in 1987 and 1997. Relative risks (RRs) were estimated by hazard ratio derived from Cox proportional hazard regression models. During an average of 8.3-year follow-up, 1,188 breast cancer cases with known ER/PR status were diagnosed. When comparing the highest to the lowest quintile, we observed non-significant inverse associations between total fiber intake and the risk of all tumor subtypes; the multivariate-adjusted RRs were 0.85 (95% CI: 0.69-1.05) for overall, 0.85 (0.64-1.13) for ER+PR+, 0.83 (0.52-1.31) for ER+PR- and 0.94 (0.49-1.80) for ER-PR-. For specific fiber, we observed statistically significant risk reductions for overall (34%) and for ER+PR+ (38%) for the highest versus lowest quintile of fruit fiber, and non-significant inverse associations for other subtypes of cancer and types of fiber. Among ever-users of postmenopausal hormone (PMH), total fiber intake and especially cereal fiber were statistically significantly associated with approximately 50% reduced risk for overall and ER+PR+ tumors when comparing the highest to the lowest quartile, but no association was observed among PMH never users. Our results suggest that dietary fiber intake from fruit and cereal may play a role in reducing breast cancer risk.     

Survival Benefit of Tamoxifen in Estrogen Receptor-Negative and Progesterone Receptor-Positive Low Grade Breast Cancer Patients

Purpose

This study aimed to analyze the efficacy and prognostic significance of adjuvant tamoxifen in breast cancer patients with various hormone receptor statuses.

Methods

Typically, 1,260 female breast cancer patients were recruited in this study. The correlation between estrogen receptor (ER)/progesterone receptor (PR) phenotypes and clinical characteristics was investigated, and the survival rate was assessed after 5-year follow-up.

Results

The 5-year overall survival (85%) was better in women under the age of 50 years. Patients with ER+/PR+ tumors had a better 5-year survival rate (94%); those with ER-/PR- tumors experienced the worst outcome (74% survival rate); whereas single-positive cases were in between. In 97 out of 128 patients with ER-/PR+ tumors, tamoxifen was given as adjuvant hormonal therapy, and it increased the survival benefit in the lower grade group in terms of overall survival and disease-free survival (p=0.01 and p=0.03, respectively).

Conclusion

For high-grade tumors with ER-/PR+, adjuvant tamoxifen therapy may have no survival benefit, whereas for the patients with low-grade ER-/PR+ tumors, adjuvant tamoxifen therapy is highly suggestive.     

Racial/ethnic differences in breast cancer survival by inflammatory status and hormonal receptor status: an analysis of the Surveillance,Epidemiology, and End Results data

Background

Compared to non-inflammatory breast cancer (non-IBC), inflammatory breast cancer (IBC) has less favorable survival and is more likely to be estrogen receptor (ER) and progesterone receptor (PR) negative. ER?/PR? tumors, regardless of histology, have less favorable survival. While black women are more likely to have IBC and ER?/PR? tumors than white women, it is unclear whether the racial disparity in survival is explained by these factors. The objective of this study was to assess racial/ethnic differences in breast cancer survival by inflammatory status and hormone receptor status.

Methods

This study examined breast cancer mortality among non-Hispanic white (NHW), Hispanic white, black, and Asian/Pacific Islander (API) women diagnosed between 1990 and 2004 using the National Cancer Institute’s Surveillance, Epidemiology, and End Results data. Kaplan–Meier survival curves and Cox proportional hazard ratios (HRs) assessed the relationship between race/ethnicity and survival.

Results

Black women had significantly poorer survival than NHW women regardless of inflammatory status and hormone receptor status. Compared to NHWs, the HRs for black women were 1.32 (95 % confidence interval (CI) 1.21–1.44), 1.43 (95 % CI 1.20–1.69), and 1.30 (95 % CI 1.16–1.47) for IBC, IBC with ER+/PR+, and with ER?/PR?, respectively. Similar HRs were found for non-IBC, non-IBC with ER+/PR?, and non-IBC with ER?/PR?. API women had significantly better survival than NHW women regardless of inflammatory status and hormone receptor status.

Conclusion

Compared to NHW women, black women had poorer survival regardless of inflammatory status and hormone receptor status and API women had better survival. These results suggest that factors other than inflammatory status and hormone receptor status may play a role in racial/ethnic disparities in breast cancer survival.     

Consumption of dairy and meat in relation to breast cancer risk in the Black Women’s Health Study

Purpose

Dairy and meat consumption may impact breast cancer risk through modification of hormones (e.g., estrogen), through specific nutrients (e.g., vitamin D), or through products formed in processing/cooking (e.g., heterocyclic amines). Results relating meat and dairy intake to breast cancer risk have been conflicting. Thus, we examined the risk of breast cancer in relation to intake of dairy and meat in a large prospective cohort study.

Methods

In the Black Women’s Health Study, 1,268 incident breast cancer cases were identified among 52,062 women during 12 years of follow-up. Multivariable (MV) relative risks (RRs) and 95 % confidence intervals (CIs) were calculated using Cox proportional hazards models.

Results

Null associations were observed for total milk (MV RR = 1.05, 95 % CI 0.74–1.46 comparing ≥1,000–0 g/week) and total meat (MV RR = 1.04, 95 % CI 0.85–1.28 comparing ≥1,000 < 400 g/week) intake and risk of breast cancer. Associations with intakes of specific types of dairy, specific types of meat, and dietary calcium and vitamin D were also null. The associations were not modified by reproductive (e.g., parity) or lifestyle factors (e.g., smoking). Associations with estrogen receptor (ER) positive (+), ER negative (?), progesterone receptor (PR) +, PR?, ER+/PR+, and ER?/PR? breast cancer were generally null.

Conclusions

This analysis of African-American women provides little support for associations of dairy and meat intake with breast cancer risk.     

HER2 status in hormone receptor positive premenopausal primary breast cancer adds prognostic, but not tamoxifen treatment predictive, information

BACKGROUND: Overexpression of human epidermal growth factor receptor 2 (HER2) or amplification of its gene is a prognostic factor in primary breast cancer and a predictor for tamoxifen treatment efficacy in oestrogen receptor (ER) positive disease. In the present study we explored a defined cohort of breast cancer patients included in a randomised trial in order to assess prognostic and tamoxifen treatment information yielded by HER2 status. METHODS: Premenopausal breast cancer patients with stage II tumours (n = 564) were included and allocated to 2 years of adjuvant tamoxifen treatment versus no adjuvant treatment. ER, progesterone receptor (PR) status and HER2 status was determined by immunohistochemistry using a tissue microarray. HER2 amplification was analysed by fluorescent in situ hybridisation and tumours being amplified and/or HER2 3+ were considered HER2+. HER2 status was evaluable in 83% of the patients and 12.6% were HER2+. In untreated patients, HER2 was a negative prognostic factor in ER+ patients, HR 2.95; 95% CI: 1.61-5.38, p < 0.001, but not in ER- patients, HR 0.67; 95% CI: 0.28-1.61, p = 0.4, and a significant interaction between the two markers was found, p < 0.01. HER2 status was not related to tamoxifen treatment efficacy in ER+ patients (term of interaction p = 0.95). When stratifying for PR status, similar results were achieved. DISCUSSION: HER2+ and ER+ breast cancer constituted a subgroup of tumours with poor prognosis in premenopausal breast cancer, whereas no treatment interaction was found between HER2 status and tamoxifen in ER+ tumours. The poor prognosis in HER2+ and ER+ patients may interfere with the interpretation of HER2 data in non-randomised trials of adjuvant tamoxifen.     

High progesterone receptor expression correlates to the effect of adjuvant tamoxifen in premenopausal breast cancer patients.

PURPOSE: Tamoxifen has long been the drug of choice in adjuvant endocrine therapy of steroid hormone receptor-positive breast cancer, and it still remains important due to its well-documented beneficial effect. Hormone receptor status is often reported as "positive" or "negative" using 10% positive nuclei as a cutoff. In this study, we aimed to assess whether a further subclassification of hormone receptor status could enhance the treatment predictive value. EXPERIMENTAL DESIGN: The immunohistochemical expression of estrogen receptor (ER) and progesterone receptor (PR) was quantified in tissue microarrays with tumors from 500 premenopausal breast cancer patients previously included in a randomized trial of adjuvant tamoxifen compared with an untreated control group. RESULTS: Our findings show a gradually increasing tamoxifen effect in tumors with >10% ER-positive nuclei. However, when analyzing tamoxifen response according to various PR fractions, we found that it was primarily patients with tumors showing >75% PR-positive nuclei that responded to tamoxifen treatment, with an improved recurrence-free [relative risk, 0.42 (0.25-0.70); P = 0.001] as well as overall [relative risk, 0.49 (0.28-0.84); P = 0.010] survival. CONCLUSIONS: Adjuvant tamoxifen improved recurrence-free and overall survival for premenopausal patients with tumors showing >75% PR-positive nuclei. No effect could be shown in tumors with fewer PR-positive nuclei. The PR was a stronger predictor of treatment response than the ER. Based on these findings, we suggest the implementation of a fractioned rather than dichotomized immunohistochemical evaluation of hormone receptors in clinical practice, possibly with greater emphasis on the PR than the ER.     

Coffee intake and breast cancer risk in the NIH-AARP diet and health study cohort

There are several biologic mechanisms whereby coffee might reduce breast cancer risk. Caffeine and caffeic acid, major coffee constituents, have been shown to suppress mammary tumor formation in animal models and to inhibit DNA methylation in human breast cancer cells, respectively. Coffee may also reduce risk through decreasing inflammation and influencing estrogen metabolism. However, epidemiologic studies have been inconsistent and few studies have examined the association by estrogen and progesterone receptor (ER/PR) status. We evaluated coffee intake for its effect on incident breast cancer in the National Institutes of Health-AARP Diet and Health Study cohort, which included 198,404 women aged 50-71 with no history of cancer, who in 1995-1996 completed a questionnaire capturing usual coffee intake over the past year. State cancer registry and mortality index linkage identified 9,915 primary incident breast carcinomas through December 2006; available information on hormone receptor (HR) status identified 2,051 ER+/PR+ and 453 ER-/PR- cancers. In multivariable proportional hazards models, coffee intake was not associated with breast cancer risk (p-value for trend = 0.38; relative risk = 0.98, 95% confidence interval: 0.91-1.07, for four or more cups per day as compared to women who never drank coffee), and results did not vary by body mass index or history of benign breast biopsy (p-value for interaction > 0.10). We found no evidence of a relationship with either caffeinated or decaffeinated coffee. Null findings persisted for risk of both HR-positive and -negative breast cancers. These findings from a large prospective cohort do not support a role of coffee intake in breast carcinogenesis.     

Can molecular markers predict when to implement treatment with aromatase inhibitors in invasive breast cancer?

PURPOSE: Resistance to tamoxifen is linked to overexpression of HER2, and aromatase inhibitors show particular benefit in progesterone receptor (PR)-negative patients. We previously reported reduced survival in patients overexpressing HER1, HER2, and HER3. We now show that both HER1-3 and PR status predicts for early relapse in estrogen receptor (ER)-positive tamoxifen-treated breast cancer patients. EXPERIMENTAL DESIGN: Tissue microarray technology was used to analyze 402 ER-positive tamoxifen-treated patients. Immunohistochemistry using epidermal growth factor receptor, HER2, HER3, HER4, and PR antibodies was done. Kaplan-Meier life table and Cox Regression analysis (log-rank testing of differences in breast cancer-related relapse on tamoxifen) was done. RESULTS: HER1-3 (but not HER4) overexpression predicted for early relapse on tamoxifen (P = 0.0060). PR-negative cases were also significantly more likely to relapse while on tamoxifen (P= 0.017). HER1-3-positive and/or PR-negative patients combined as a "high-risk" group were significantly more likely to relapse on tamoxifen in univariate (P < 0.0001) and Cox's multivariate analysis (P = 0.0069). However, this applied to early relapse on tamoxifen only, as any disease relapse after 3 years of tamoxifen was unrelated to PR/HER status. CONCLUSIONS: We show that HER1-3 and PR status can identify time-dependent de novo tamoxifen resistance with risk declining markedly after 3 years of tamoxifen treatment. These results parallel data from the ATAC and Intergroup Exemastane Study trials which suggest that whereas PR-negative patients derive greater benefit from initial aromatase inhibitor treatment, PR status has no effect on response when given as delayed treatment to those disease free on tamoxifen after 3 years.     

Telomere DNA content predicts breast cancer-free survival interval.

BACKGROUND: Telomeres are nucleoprotein complexes that protect chromosome ends from degradation and recombination. Critically shortened telomeres generate genomic instability. It has been postulated that the extent of telomere DNA loss is related to the degree of genomic instability within a tumor and therefore may presage clinical outcome. The objective of this investigation was to evaluate the hypothesis that telomere DNA content (TC) in breast tumor tissues predicts breast cancer-free survival interval. MATERIALS AND METHODS: Slot blot titration assay was used to quantitate TC in 530 archival breast tumor tissues in a population-based cohort. The relationships between TC, 12 risk factors for breast cancer adverse events (i.e., death due to breast cancer, breast cancer recurrence, or development of a new primary breast tumor), and breast cancer-free survival interval were evaluated by Fisher's exact test, log-rank analysis, and univariate and multivariate Cox proportional hazards models. RESULTS: TC was independent of each of the 12 risk factors. Ethnicity, tumor-node-metastasis stage, estrogen receptor, progesterone receptor, and p53 status, chemotherapy sequence, adjuvant therapy, and TC each conferred significant relative hazards. The best overall multivariate Cox proportional hazards model included TC, p53 status, tumor-node-metastasis stage, and estrogen receptor status as independent predictors of breast cancer-free survival interval (P < 0.00005). Low TC (< or =200% of standard), relative to the high-TC group (>200% of standard), conferred an adjusted relative hazard of 2.88 (95% confidence interval, 1.16-7.15; P = 0.022) for breast cancer-related adverse events. CONCLUSIONS: TC in breast cancer tissue is an independent predictor in this group of breast cancer-free survival interval.     

Quantitative in situ analysis of beta-catenin expression in breast cancer shows decreased expression is associated with poor outcome

The role of beta-catenin in breast cancer and its prognostic value is controversial. The prognostic value had been assessed previously in a series of nonquantitative immunohistochemical studies with conflicting results. In efforts to clarify the relationship between beta-catenin protein expression and breast cancer prognosis, we have assessed a retrospective 600 case cohort of breast cancer tumors from the Yale Pathology archives on tissue microarrays. They were assessed using automated quantitative analysis (AQUA) with a series of array-embedded cell lines for which the beta-catenin concentration was standardized by an ELISA assay. The expression levels of the standard clinical markers HER2, estrogen receptor (ER), progesterone receptor (PR), and Ki-67 were also assessed on the same cohort. X-tile software was used to select optimal protein concentration cutpoints and to evaluate the outcome using a training set and a validation set. We found that low-level expression of membranous beta-catenin is associated with significantly worse outcome (38% versus 76%, 10-year survival, validation set log-rank P = 0.0016). Multivariate analysis of this marker, assessed in a proportional hazards model with tumor size, age, node status, nuclear grade, ER, PR, HER2, and Ki-67, is still highly significant with a hazard ratio of 6.8 (P < 0.0001, 95% confidence interval, 3.1-15.1). These results suggest that loss of beta-catenin expression at the membrane, as assessed by objective quantitative analysis methods, may be useful as a prognostic marker or may be part of a useful algorithm for prognosis in breast cancer.     

Long-term meat intake and risk of breast cancer by oestrogen and progesterone receptor status in a cohort of Swedish women

Red meat intake has been postulated to increase the risk of breast cancer but epidemiologic studies have yielded inconsistent results. Data on meat intake in relation to hormone receptor-defined breast cancer are sparse. We examined the association of meat intake with incidence of breast cancer defined by oestrogen receptor (ER) and progesterone receptor (PR) status in the Swedish Mammography Cohort, a population-based cohort of 61,433 women. Dietary intake was assessed at baseline in 1987–1990 and again in 1997. Cox proportional hazards models were used to estimate relative risks for the association between long-term meat intake and breast cancer risk. During a mean follow-up of 17.4 years, 2952 incident cases of invasive breast cancer were ascertained. We found no association of total red meat, fresh red meat or processed meat intake with breast cancer risk. The multivariate relative risks (95% confidence interval) for the highest quintile of total red meat intake (?98 g/d) compared with the lowest quintile (<46 g/d) were 0.98 (0.86–1.12) for overall breast cancer, 1.10 (0.90–1.34) for ER+/PR+ tumours, 0.86 (0.60–1.23) for ER+/PR– tumours and 1.12 (0.70–1.79) for ER–/PR– tumours. Intake of pan-fried meat was positively associated with a risk of ER+/PR– tumours; the multivariate relative risk for the highest compared with the lowest quartile of intake was 1.45 (95% confidence interval 1.03–2.03; P_trend = 0.03). These results do not support an association between red meat intake and overall breast cancer risk but suggest that fried meat intake may increase the risk of ER+/PR– breast cancer.     

Prognostic value of estrogen receptor α and progesterone receptor conversion in distant breast cancer metastases

BACKGROUND:

Changes in the receptor profile of primary breast cancers to their metastases (receptor conversion) have been described for the estrogen receptor α (ERα) and progesterone receptor (PR). The purpose of this study was to evaluate the impact of receptor conversion for ERα and PR on survival in a large group of distant non‐bone breast cancer metastases.

METHODS:

Receptor conversion was studied by immunohistochemistry in a group of 233 metastatic breast cancer patients. Kaplan‐Meier overall survival curves were plotted, and differences between the curves were analyzed by log‐rank analysis. The additional prognostic value of conversion to established prognosticators was studied by Cox regression.

RESULTS:

Overall survival of patients showing conversion from positive to negative ERα or PR, or from negative to positive ERα or PR, or remaining receptor negative was comparable, and significantly worse than patients remaining receptor positive. ERα or PR receptor conversion from positive in the primary breast tumor to negative in distant metastases has independent negative prognostic value.

CONCLUSIONS:

ERα or PR receptor conversion from positive in the primary breast cancer to negative in distant metastases has negative prognostic value. Cancer 2012. © 2012 American Cancer Society.