Estrogen receptor quantitative measures and breast cancer survival.

PURPOSE: While the estrogen receptor (ER) is the single most widely used biomarker to evaluate breast cancer outcomes, aspects of ER marker biology remain poorly understood. We sought to determine whether quantitative measures of ER, such as protein expression and intensity, were associated with survival, or with survival disparities experienced by Hispanic women. METHODS: A case-cohort study included a 15% random sample of invasive breast cancer cases diagnosed from 1997 to 2009 in six New Mexico counties and all deaths due to breast cancer-related causes. Pathology reports and tissue microarrays served as sources of ER information. Analyses were restricted to women with ≥1% ER immunohistochemical staining. Hazard ratios (HR) and 95% confidence intervals (CI) for breast cancer death were estimated using Cox proportional hazards models. RESULTS: Included women represented 4336 ER+ breast cancer cases and 448 deaths. Median follow-up was 93 months. ER percent expression was not associated with breast cancer survival after adjustment for standard prognostic factors (p trend = 0.76). ER intensity remained a strong and independent risk factor for breast cancer survival in multivariate analyses: Women whose tumors expressed ER at intensity = 2 (HR 0.6; 95% CI 0.4-1.0) or 3 (HR 0.5; 95% CI 0.2-0.9) had a reduced risk of breast cancer mortality, compared to ER intensity = 1 (p trend = 0.02). Neither ER protein expression nor intensity influenced Hispanic survival disparities. CONCLUSIONS: Estrogen receptor percent positive staining is not independently related to breast cancer survival after adjustment for other survival-related factors. ER intensity, in contrast, demonstrates promise for prognostic utility.

Understanding benign breast disease and subsequent breast cancer in Hispanic white females; a step closer to evidence-based management.

Background While Hispanic white females (HW) have lower incidence of breast cancer (BC) than non-Hispanic white females (NHW), BC risk is unclear for HW females after benign breast disease (BBD). Methods We compared BBD characteristics and subsequent BC risk among HW and NHW females in New Mexico using a population-based collection of benign breast biopsies (1996-2007). BBD was categorized as non-proliferative disease (NPD), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH). BC risk was assessed as absolute risk (AR) using cumulative incidence and relative risk (RR) by comparing the number of BC events in BBDs to non-BBD. Results This study included 3,684 HW and 6,587 NHW females with BBD. HW females had similar proportions of NPD (58.6%vs.54.3%), PDWA (21.4%vs.23.5%), and AH (3.6%vs.3.3%) as NHW. BC risk among all females with BBD was higher than population-based expected rates (RR=1.87) and was similar for HW and NHW subgroups (RR=1.99vs.1.84). As expected, BC risk increased with increasing BBD severity, both overall [RR=1.81 (NPD), 1.85 (PDWA) and 3.10 (AH)] and in the HW and NHW subgroups. Adjusted AR of BC at 5 years also increased with the severity of BBD (HW vs. NHW;NPD: 1.4 vs. 2.1%; PDWA: 1.5 vs. 2.7%; AH: 6 vs. 4.8%). Conclusions We found similar BC RRs and ARs in HW and NHW. Risk counseling should ensure that HW females receive breast cancer clinical management warranted by their similar absolute risks. Impact The present population-based provides evidence for clinical management of HW females with BBD for the prevention of BC.

Temporal trends in breast cancer survival by race and ethnicity: A population-based cohort study.

INTRODUCTION: Differences in breast cancer survival by race and ethnicity are often assumed to be a fairly recent phenomenon, and are hypothesized to have arisen due to gaps in receipt of screening or therapy. The emergence of these differences in calendar time have implications for identification of their origin. We sought to determine whether breast cancer survival differences by race or ethnicity arose in tandem with the advent of screening or therapeutic advances. MATERIALS AND METHODS: A cohort of women diagnosed with invasive breast cancer from 1975-2009 in 18 population-based registries were followed for five-year breast cancer cause-specific survival. Differences in survival according to race/ethnicity and estrogen receptor status were quantified in Cox proportional hazards models, with estimation of hazard ratios (HR), 95% confidence intervals (CI), and absolute risk differences. For 2010, we also assessed differences in survival by breast cancer subtypes defined by hormone receptor and Her2/neu status. RESULTS: Among over 930,000 women, initial differences in five-year breast cancer-specific survival by race became apparent among 1975-1979 diagnoses and continued to be evident, with stronger disparities apparent in those of Black vs. White Non-Hispanic (WNH) race and among estrogen-receptor positive vs. negative disease. Within breast cancer subtype, all included race/ethnic groups experienced disparate survival in comparison with WNH women for triple-negative disease. Black women had a consistent gap in absolute survival of .10-.12, compared with WNH women, from 1975-1979 through all included time periods, such that 5- year survival of Black women diagnosed in 2005-09 lagged more than 20 years behind that of WNH women. DISCUSSION: Survival differed by race for diagnoses that predate the introduction of mammographic screening and most therapeutic advances. Absolute differences in survival by race and ethnicity have remained almost constant over 40 years of observation, suggesting early origins for some contributors.

Obesity and survival among a cohort of breast cancer patients is partially mediated by tumor characteristics.

Obesity exerts adverse effects on breast cancer survival, but the means have not been fully elucidated. We evaluated obesity as a contributor to breast cancer survival according to tumor molecular subtypes in a population-based case-cohort study using data from the Surveillance Epidemiology and End Results (SEER) program. We determined whether obese women were more likely to be diagnosed with poor prognosis tumor characteristics and quantified the contribution of obesity to survival. Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated via Cox multivariate models. The effect of obesity on survival was evaluated among 859 incident breast cancers (subcohort; 15% random sample; median survival 7.8 years) and 697 deaths from breast cancer (cases; 100% sample). Obese women had a 1.7- and 1.8-fold increased risk of stage III/IV disease and grade 3/4 tumors, respectively. Obese women with Luminal A- and Luminal B-like breast cancer were 1.8 (95% CI 1.3-2.5) and 2.2 (95% CI 0.9-5.0) times more likely to die from their cancer compared to normal weight women. In mediation analyses, the proportion of excess mortality attributable to tumor characteristics was 36.1% overall and 41% and 38% for Luminal A- and Luminal B-like disease, respectively. Obesity was not associated with breast cancer-specific mortality among women who had Her2-overexpressing or triple-negative tumors. Obesity may influence hormone-positive breast cancer-specific mortality in part through fostering poor prognosis tumors. When tumor biology is considered as part of the causal pathway, the public health impact of obesity on breast cancer survival may be greater than previously estimated.

A two-gene expression ratio of homeobox 13 and interleukin-17B receptor for prediction of recurrence and survival in women receiving adjuvant tamoxifen.

PURPOSE: In the adjuvant treatment of estrogen receptor (ER)-positive breast cancer, additional markers are needed to identify women at high risk for recurrence. EXPERIMENTAL DESIGN: We examined the association between the ratio of the homeobox 13 (HOXB13) to interleukin-17B receptor (IL-17BR) expression and the clinical outcomes of relapse and survival in women with ER-positive breast cancer enrolled onto a North Central Cancer Treatment Group adjuvant tamoxifen trial (NCCTG 89-30-52). RESULTS: Tumor blocks were obtained from 211 of 256 eligible patients, and quantitative reverse transcription-PCR profiles for HOXB13 and IL-17BR were obtained from 206 patients. The cut point for the two-gene log 2(expression ratio) that best discriminated clinical outcome (recurrence and survival) was selected and identified women with significantly worse relapse-free survival (RFS), disease-free survival (DFS), and overall survival (OS), independent of standard prognostic markers. The cut point differed as a function of nodal status [node negative (59th percentile) versus node positive (90th percentile)]. In the node-positive cohort (n = 86), the HOXB13/IL-17BR ratio was not associated with relapse or survival. In contrast, in the node-negative cohort (n = 130), a high HOXB13/IL-17BR ratio was associated with significantly worse RFS [hazard ratio (HR), 1.98; P = 0.031], DFS (HR, 2.03; P = 0.015), and OS (HR, 2.4; P = 0.014), independent of standard prognostic markers. CONCLUSION: A high HOXB13/IL-17BR expression ratio is associated with increased relapse and death in patients with resected node-negative, ER-positive breast cancer treated with tamoxifen and may identify patients in whom alternative therapies should be studied.

Evaluation of a panel of tumor markers for molecular detection of circulating cancer cells in women with suspected breast cancer.

PURPOSE: We examined the feasibility of using molecular characterization of circulating tumor cells as a method for early detection of breast cancer. RESEARCH DESIGN: Women without a prior history of cancer who had a breast abnormality detected on imaging followed by a breast biopsy were enrolled in this study. Density gradient centrifugation and immunomagnetic capture were used to enrich for epithelial cells from approximately 20 mL of blood. Real-time reverse transcription-PCR was used to quantitate the expression levels of the highly breast-specific genes, mammaglobin, gamma-aminobutyric acid type A receptor pi subunit (GABA A(pi)), B305D-C, and B726P in the epithelial cell-enriched samples. RESULTS: The assay was technically feasible in 154 of 199 accrued patients. From their clinical assessment, 100 patients had benign breast disease, 10 patients had ductal carcinoma in situ, and 44 patients had invasive breast cancer. We constructed a diagnostic test that classified patients with mammaglobin levels of at least 32.2 copies/pg beta-actin (units) in their circulating epithelial cells as positive for invasive breast cancer. This resulted in a sensitivity and specificity of 63.3% and 75.0%, respectively. A diagnostic test that classified patients as positive for invasive breast cancer when either mammaglobin levels were >46.3 units or B305D-C levels were >11.6 units increased the sensitivity and specificity to 70.5% and 81.0%, respectively. In the latter test, 12 of the 14 node-positive breast cancer patients were correctly identified. Including GABA A(pi) and B726P in the test did not increase its diagnostic potential. CONCLUSIONS: These results suggest that molecular characterization of circulating epithelial cells using mammaglobin and B305D-C offers potential for early detection of invasive breast cancer.

Method of detection and breast cancer survival disparities in Hispanic women.

BACKGROUND: Hispanic women in New Mexico (NM) are more likely than non-Hispanic women to die of breast cancer-related causes. We determined whether survival differences between Hispanic and non-Hispanic women might be attributable to the method of detection, an independent breast cancer prognostic factor in previous studies. METHODS: White women diagnosed with invasive breast cancer from 1995 through 2004 were identified from NM Surveillance Epidemiology End Results (SEER) files (n = 5,067) and matched to NM Mammography Project records. Method of cancer detection was categorized as "symptomatic" or "screen-detected." The proportion of Hispanic survival disparity accounted for by included variables was assessed using Cox models. RESULTS: In the median follow-up of 87 months, 490 breast cancer deaths occurred. Symptomatic versus screen-detection was classifiable for 3,891 women (76.8%), and was independently related to breast cancer-specific survival [hazard ratio (HR), 1.6; 95% confidence interval (95% CI), 1.3-2.0]. Hispanic women had a 1.5-fold increased risk of breast cancer-related death, relative to non-Hispanic women (95% CI, 1.2-1.8). After adjustment for detection method, the Hispanic HR declined from 1.50 to 1.45 (10%), but after inclusion of other prognostic indicators the Hispanic HR equaled 1.23 (95% CI, 1.01-1.48). CONCLUSIONS: Although the Hispanic HR declined 50% after adjustment, the decrease was largely due to adverse tumor prognostic characteristics. IMPACT: Reduction of disparate survival in Hispanic women may rely not only on increased detection of tumors when asymptomatic but on the development of greater understanding of biological factors that predispose to poor prognosis tumors.

The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.

BACKGROUND: Tamoxifen is biotransformed to the potent anti-estrogen, endoxifen, by the cytochrome P450 (CYP) 2D6 enzyme. CYP2D6 genetic variation and inhibitors of the enzyme markedly reduce endoxifen plasma concentrations in tamoxifen-treated patients. Using a North Central Cancer Treatment Group adjuvant tamoxifen trial, we performed a comprehensive evaluation of CYP2D6 metabolism by assessing the combined effect of genetic variation and inhibition of the enzyme system on breast cancer recurrence and death. METHODS: Medical records were reviewed at each randomizing site to determine whether CYP2D6 inhibitors were co-prescribed with tamoxifen. Extensive metabolizers were defined as patients without a *4 allele (i.e., wt/wt) who were not co-prescribed a CYP2D6 inhibitor. Patients with decreased CYP2D6 metabolism were classified as intermediate or poor metabolizers (PM) based on the presence of one or two CYP2D6*4 alleles or the co-administration of a moderate or potent CYP2D6 inhibitor. The association between CYP2D6 metabolism and clinical outcome was assessed using Cox modeling. RESULTS: Medication history was available in 225/256 eligible patients and CYP2D6*4 genotype in 190 patients. Thirteen patients (6%) were co-prescribed a CYP2D6 inhibitor [potent (n = 3), moderate (n = 10)], resulting in the following CYP2D6 metabolism: extensive (n = 115) and decreased (n = 65). In the multivariate analysis, patients with decreased metabolism had significantly shorter time to recurrence (p = 0.034; adj HR = 1.91; 95% CI 1.05-3.45) and worse relapse-free survival (RFS) (p = 0.017; adj HR = 1.74; 1.10-2.74); relative to patients with extensive metabolism. Cox' modeling demonstrated that compared to extensive metabolizers, PM had the most significant risk of breast cancer relapse (HR 3.12, p = 0.007). CONCLUSION: CYP2D6 metabolism, as measured by genetic variation and enzyme inhibition, is an independent predictor of breast cancer outcome in post-menopausal women receiving tamoxifen for early breast cancer. Determination of CYP2D6 genotype may be of value in selecting adjuvant hormonal therapy and it appears CYP2D6 inhibitors should be avoided in tamoxifen-treated women.