Breast Cancer-specific Survival For Women Research Articles

CD163+ macrophages in the triple-negative breast tumor microenvironment are associated with improved survival in the Women’s Circle of Health Study and the Women’s Circle of Health Follow-Up Study

BackgroundTumor-associated macrophages (TAMs) are a prominent immune subpopulation in the tumor microenvironment that could potentially serve as therapeutic targets for breast cancer. Thus, it is important to characterize this cell population across different tumor subtypes including patterns of association with demographic and prognostic factors, and breast cancer outcomes.MethodsWe investigated CD163+ macrophages in relation to clinicopathologic variables and breast cancer outcomes in the Women’s Circle of Health Study and Women’s Circle of Health Follow-up Study populations of predominantly Black women with breast cancer. We evaluated 611 invasive breast tumor samples (507 from Black women, 104 from White women) with immunohistochemical staining of tissue microarray slides followed by digital image analysis. Multivariable Cox proportional hazards models were used to estimate hazard ratios for overall survival (OS) and breast cancer-specific survival (BCSS) for 546 cases with available survival data (median follow-up time 9.68 years (IQR: 7.43–12.33).ResultsWomen with triple-negative breast cancer showed significantly improved OS in relation to increased levels of tumor-infiltrating CD163+ macrophages in age-adjusted (Q3 vs. Q1: HR = 0.36; 95% CI 0.16–0.83) and fully adjusted models (Q3 vs. Q1: HR = 0.30; 95% CI 0.12–0.73). A similar, but non-statistically significant, association was observed for BCSS. Macrophage infiltration in luminal and HER2+ tumors was not associated with OS or BCSS. In a multivariate regression model that adjusted for age, subtype, grade, and tumor size, there was no significant difference in CD163+ macrophage density between Black and White women (RR = 0.88; 95% CI 0.71–1.10).ConclusionsIn contrast to previous studies, we observed that higher densities of CD163+ macrophages are independently associated with improved OS and BCSS in women with invasive triple-negative breast cancer.Trial registrationNot applicable.

Treatment intervals and survival for women diagnosed with early breast cancer in Queensland: the Breast Cancer Outcomes Study, a population-based cohort study.

To assess associations between breast cancer-specific survival and timeliness of treatment, based on 2020 Australian guidelines for the treatment of early breast cancer. Population-based cohort study; analysis of linked Queensland Cancer Register, patient medical record, and National Death Index data, supplemented by telephone interviews. Women aged 20-79 years diagnosed with invasive breast cancer during 1 March 2010 - 30 June 2013, followed to 31 December 2020. Breast cancer-specific survival for women who received or did not receive treatment within the recommended timeframe, overall and for six treatment intervals; optimal cut-points for each treatment interval; characteristics of women for whom treatment was not provided within the recommended timeframe. Of 5426 eligible women, 4762 could be invited for interviews; complete data were available for 3044 women (56% of eligible women, 65% of invited women). Incomplete compliance with guideline interval recommendations was identified for 1375 women (45%); their risk of death from breast cancer during the follow-up period was greater than for those for whom guideline compliance was complete (adjusted hazard ratio [aHR], 1.43; 95% confidence interval [CI], 1.04-1.96). Risk of death was greater for women for whom the diagnosis to surgery interval exceeded 29 days (aHR, 1.76; 95% CI, 1.19-2.59), the surgery to chemotherapy interval exceeded 36 days (aHR, 1.63; 95% CI, 1.13-2.36), or the chemotherapy to radiotherapy interval exceeded 31 days (aHR, 1.83; 95% CI, 1.19-2.80). Treatment intervals longer than recommended were more frequent for women for whom breast cancer was detected by public facility screening (adjusted odds ratio [aOR], 1.58; 95% CI, 1.22-2.04) or by symptoms (aOR, 1.39; 95% CI, 1.09-1.79) than when cancer had been detected in private facilities, and for women without private health insurance (aOR, 1.96; 95% CI, 1.66-2.32) or living outside major cities (aOR, 1.38; 95% CI, 1.18-1.62). Breast cancer-specific survival was poorer for women for whom the diagnosis to surgery, surgery to chemotherapy, or chemotherapy to radiotherapy intervals exceeded guideline-recommended limits. Our findings support 2020 Australian guideline recommendations regarding timely care.

Why is renal impairment associated with poorer cancer specific survival in breast cancer patients?: a comparison with patients with other comorbidities

BackgroundOur aim is to assess whether the poor breast cancer specific survival (BCSS) seen in women with breast cancer and impaired renal function can be explained by associations with other prognostic factors.MethodsThe study group was a consecutive series of patients undergoing breast ultrasound (US) who had invasive breast cancer (n = 1171). All women had their US diameter and mean stiffness (kPa) at shear wave elastography (SWE) recorded. The core biopsy grade and receptor status were noted. Core biopsy of abnormal axillary nodes and the patient referral source was also noted. Survival including cause of death was ascertained. Comorbidities at diagnosis were recorded. Patients were divided into those with a GFR<60 (“renal group”), those with other comorbidities and those with none. BCSS was assessed using Kaplan–Meier survival curves and Cox proportional hazards regression.ResultsOne thousand, one hundred and forty-one patients constituted the study group. 107 (9%) patients had impaired renal function, 182 (16%) had other comorbidities while 852 (75%) had no comorbidities. Mean follow-up was 5.8 years. 109 breast cancer and 122 non-breast cancer deaths occurred. BCSS in the renal group was significantly worse than the other groups. Women with renal comorbidity were older, more likely to present symptomatically, have a pre-operative diagnosis of axillary metastases, and have larger and stiffer cancers. Cox proportional hazards regression showed that renal impairment maintained independent significance.ConclusionThe poor BCSS in women with impaired renal function is partially explained by advanced tumour stage at presentation. However, impaired renal function maintains an independent prognostic effect.

Adjuvant Chemotherapy for Breast Cancer in Older Women: An Analysis of Retrospective English Cancer Registration Data

AimsAdjuvant chemotherapy is recommended as a treatment for women with high recurrence risk early breast cancer. Older women are less likely to receive chemotherapy than younger women. This study investigated the impact of chemotherapy on breast cancer-specific survival in women aged 70 + years using English registry data. Materials and methodsCancer registration data were obtained from two English regions from 2002 to 2012 (n = 29 728). The impact of patient-level characteristics on the probability of receiving adjuvant chemotherapy was explored using logistic regression. Survival modelling was undertaken to show the effect of chemotherapy and age/health status on breast cancer-specific survival. Missing data were handled using multiple imputation. ResultsIn total, 11 735 surgically treated early breast cancer patients were identified. Use of adjuvant chemotherapy has increased over time. Younger age at diagnosis, increased nodal involvement, tumour size and grade, oestrogen receptor-negative or human epidermal growth factor receptor 2-positive disease were all associated with increased probability of receiving chemotherapy. Chemotherapy was associated with a significant reduction in the hazard of breast cancer-specific mortality in women with high risk cancer, after adjusting for patient-level characteristics (hazard ratio 0.74, 95% confidence interval 0.67–0.81). DiscussionChemotherapy is associated with an improved breast cancer-specific survival in older women with early breast cancer at high risk of recurrence . Lower rates of chemotherapy use in older women may, therefore, contribute to inferior cancer outcomes. Decisions on potential benefits for individual patients should be made on the basis of life expectancy, treatment tolerance and patient preference.

21-Gene Recurrence Score Assay and Outcomes of Adjuvant Radiotherapy in Elderly Women With Early-Stage Breast Cancer After Breast-Conserving Surgery.

Introduction: To assess the role of the 21-gene recurrence score (RS) assay on decision-making of postoperative radiotherapy (RT) following breast-conserving surgery (BCS) in elderly women with early-stage breast cancer.Methods: The 21-gene RS for elderly (≥65 years) women with stage T1–2N0M0 estrogen receptor-positive breast cancer who underwent BCS from 2004 to 2015 was obtained from the Surveillance, Epidemiology, and End Results program. We estimated the association of 21-gene RS and adjuvant RT related to breast cancer-specific survival (BCSS) using propensity score matching (PSM).Results: We identified 18,456 patients, of which 15,326 (83.0%) received postoperative RT. Of identified patients, 58.9, 34.0, and 7.1% of patients had a low-, intermediate-, and high-risk RS, respectively. Receipt of postoperative RT was not related to the year of diagnosis according to the 21-gene RS groups. Multivariate analysis suggested that receipt of postoperative RT was an independent predictor of better BCSS before (hazard ratio [HR] 0.587, 95% confidence interval [CI] 0.426–0.809, P = 0.001) and after (HR 0.613, 95%CI 0.390–0.963, P = 0.034) PSM. However, subgroups analyses indicated that receipt of postoperative RT was related to better BCSS in women with intermediate-risk RS before (HR 0.467, 95%CI 0.283–0.772, P = 0.003) and after (HR 0.389, 95%CI 0.179–0.846, P = 0.017) PSM, but not in women with low- and high-risk RS groups before and after PSM.Conclusions: Although causation cannot be implied, adjuvant RT in elderly women was associated with a greater effect size in patients with an intermediate-risk RS.

Bisphosphonate Use and Risk of Recurrence, Second Primary Breast Cancer, and Breast Cancer Mortality in a Population-Based Cohort of Breast Cancer Patients.

Background: Studies of bisphosphonate use and breast cancer recurrence have produced conflicting results. Analyses of large adjuvant trials suggest that bisphosphonates reduce recurrence risk only in postmenopausal women.Methods: We assessed the effect of noncancer treatment-related bisphosphonate use on breast cancer outcomes in a population-based prognostic cohort of women with early-stage invasive breast cancer (n = 1,813; median follow-up = 11.8 years). Using medical record, interview, and cancer registry data, information was assembled on risk factors, cancer treatment, medication use, and outcomes. Statistical analyses used Cox proportional hazards regression models.Results: Bisphosphonate use was associated with a significantly decreased risk of a breast cancer event [locoregional/distant recurrence or second primary breast cancer; HR ever use, 0.65; 95% confidence interval (CI), 0.47-0.90]. Reduced risks were observed in both pre/peri and postmenopausal women, in both ER-negative and ER-positive breast cancers, and for both earlier and later recurrences. Bisphosphonate use was also associated with a significantly decreased risk of breast cancer mortality (HR, 0.40; 95% CI, 0.23-0.69).Conclusions: Bisphosphonate use was associated with a reduction in risk of breast cancer events and improved breast cancer-specific survival in women with early-stage breast cancer. We hypothesize that the benefit of bisphosphonates on breast cancer outcomes may be present primarily in women with low bone density and regardless of menopausal status.Impact: Our findings suggest further consideration of bone density status as a modifier of bisphosphonate's potential beneficial benefits on breast cancer outcomes is warranted. Cancer Epidemiol Biomarkers Prev; 27(2); 165-73. ©2017 AACR.

The prognostic effect of estrogen receptor status differs for younger versus older breast cancer patients.

To estimate the prognostic impact of estrogen receptor (ER)-status among women with primary invasive breast cancer, according to age at diagnosis. We studied 1910 women with primary invasive breast cancer (stages I-III) who were treated at Women's College Hospital between 1987 and 2000. For each patient, we obtained information on age at diagnosis, tumour size, lymph node status, ER-status, treatments received (radiotherapy, chemotherapy and tamoxifen) and dates and causes of death. Patients were followed from the date of diagnosis until the date of death from breast cancer or the date of last follow-up. We used the Kaplan-Meier method to estimate the 15-year actuarial rates of breast cancer-specific survival for women with ER-positive and ER-negative breast cancer, according to age at diagnosis (categories). We used the Cox proportional hazards model to estimate the adjusted hazard ratios for death from breast cancer associated with positive ER-status (compared to negative ER-status), stratified by age at diagnosis. We identified 1347 women with ER-positive breast cancer (70.5%) and 563 women with ER-negative breast cancer (29.5%). Among all 1910 women in the cohort, the actuarial rate of breast cancer-specific survival at 15years was 77% for those with ER-positive breast cancer compared to 70% for those with ER-negative breast cancer (adjusted HR=0.69; 95% CI0.56-0.85; p=0.0006). The prognostic impact of ER-status differed according to age at diagnosis. Among 213 women diagnosed before age 40, breast cancer-specific survival at 15years was worse for those with ER-positive breast cancer than for those with ER-negative breast cancer (55 vs. 61%; adjusted HR=0.90; 95% CI0.57-1.41; p=0.64). In contrast, among 1697 women diagnosed between ages 40 and 75, breast cancer-specific survival at 15years was better for those with ER-positive breast cancer than for those with ER-negative breast cancer (78 vs. 72%; adjusted HR=0.60; 95% CI0.47-0.76; p<0.0001). Positive ER-status is a favourable prognostic factor among women diagnosed with breast cancer at or above age 40, but not among women diagnosed before age 40.

(S002) Population-Based Analysis of the Effect of Margin Status on 10-Year Local Recurrence and Breast Cancer-Specific Survival in Women Treated With Breast-Conserving Therapy

(S002) Population-Based Analysis of the Effect of Margin Status on 10-Year Local Recurrence and Breast Cancer-Specific Survival in Women Treated With Breast-Conserving Therapy

Use of Oral Contraceptives and Breast Cancer Survival

Introduction: Oral contraceptives (OC) have been shown to give a transient increased breast cancer risk. However, studies on breast cancer survival after OC use are sparse and conflicting.Aim: The aim of this study was to examine previous use of OC in relation to survival after breast cancer diagnosis.Methods: Data was collected from Malmo Diet and Cancer Study, with baseline examinations between 1991 and 1996. Out of 17035 women who completed all study parts, 765 women with incident breast cancer were included in this study. Kaplan Meier and Cox Proportional Hazards analyses, with 95% confidence intervals (CI), were used to study OC in relation to breast cancer-specific and overall survival. All analyses were stratified on age at diagnosis.Results: Women who had ever used OC were younger and more often had grade III tumors than those who had never used OC. Breast cancer-specific survival in women who ever had used OC was better when adjusting for BMI, socioeconomic status as well as tumor characteristics. However, when adjusting for age at diagnosis, the results did not remain significant (0.68, CI 95% 0.39- 1.18). Stratified analyses on age at diagnosis (40-55, 56-70 and ≥ 71) showed no statistically significant associations.Conclusion: In this study we could not demonstrate a significant effect of OC use on breast cancer survival. (Less)

Breastfeeding Associated with Reduced Mortality in Women with Breast Cancer.

To study whether breastfeeding affects survival from breast cancer. There are few studies on the relationship between breastfeeding, reproductive health, and breast cancer survival. This study is a follow-up of an earlier study showing no convincing associations between breastfeeding and breast cancer prognostic parameters. From a cohort of 629 women with primary breast cancer having undergone surgery between 1988 and 1992, 341 were traced and consequently studied 20 years later regarding breastfeeding and reproductive variables, as well as for prognostic parameters such as the Nottingham histological grade, tumor size, lymph node status, and vascular invasion (VI). Multivariate Cox regression analyses were used. Increased breast cancer mortality was associated with the Nottingham prognostic index (hazard rate ratio (HR) 4.47; 95% confidence interval (CI) 2.04-9.79), VI (HR 3.44; CI 2.03-5.82), fewer pregnancies (three categories; >2, 1-2, 0) (HR per category 2.04; CI 1.34-3.11), and breastfeeding ≤6 months (HR 2.74; CI 1.41-5.35). The HRs for overall mortality were, as expected, lower for the Nottingham prognostic index (HR 1.28; CI 0.89-1.85) and VI (HR 2.09; CI 1.38-3.17), and they were slightly lower for the number of pregnancies (HR 1.61; CI 1.48-4.59), but notably similar for breastfeeding (HR 3.01;CI 1.92-4.73). A total breastfeeding history >6 months and pregnancy are associated with both greater overall and breast cancer-specific survival for women diagnosed with breast cancer, having lived long enough for other causes of death to contribute substantially to mortality.

ERK/MAPK regulates ERRγ expression, transcriptional activity and receptor-mediated tamoxifen resistance in ER+ breast cancer.

Selective estrogen receptor modulators such as tamoxifen (TAM) significantly improve breast cancer-specific survival for women with estrogen receptor-positive (ER+) disease. However, resistance to TAM remains a major clinical problem. The resistant phenotype is usually not driven by loss or mutation of the estrogen receptor; instead, changes in multiple proliferative and/or survival pathways over-ride the inhibitory effects of TAM. Estrogen-related receptorγ (ERRγ) is an orphan member of the nuclear receptor superfamily that promotes TAM resistance in ER+ breast cancer cells. This study sought to clarify the mechanism(s) by which this orphan nuclear receptor is regulated, and hence affects TAM resistance. mRNA and protein expression/phosphorylation were monitored by RT-PCR and western blotting, respectively. Site-directed mutagenesis was used to disrupt consensus extracellular signal-regulated kinase (ERK) target sites. Cell proliferation and cell-cycle progression were measured by flow cytometric methods. ERRγ transcriptional activity was assessed by dual-luciferase promoter-reporter assays. We show that ERRγ protein levels are affected by the activation state of ERK/mitogen-activated protein kinase, and mutation of consensus ERK target sites impairs ERRγ-driven transcriptional activity and TAM resistance. These findings shed new light on the functional significance of ERRγ in ER+ breast cancer, and are the first to demonstrate a role for kinase regulation of this orphan nuclear receptor.

Survival of patients with BRCA1-associated breast cancer diagnosed in an MRI-based surveillance program

We report the 5- and 10-year survival rate of women diagnosed with breast cancer in the context of an annual MRI-based surveillance program. In 2001, as part of a national initiative, women in Norway with a BRCA1 mutation were offered annual screening with breast MRI in addition to mammography. 802 women with a BRCA1 mutation were screened one or more times and followed for a mean of 4.2 years. As of December 2011, 68 of 802 women in the screening program were diagnosed with DCIS or invasive breast cancer (8.5 %), including eight prevalent, 50 incident screen-detected and eight interval cancers. Two latent cancers were detected at prophylactic mastectomy. Sixty-three of the cancers were invasive and five were in situ. The mean tumour size was 1.4 cm (range 0.2-4.5 cm), and 85 % of the patients were node-negative. Ten of the 68 patients died of cancer in the follow-up period. The 5-year breast cancer-specific survival for women with cancer was 75 % (95 % CI 56-86 %) and the 10-year survival was 69 % (95 % CI: 48-83 %). The 5-year survival for women with Stage 1 breast cancer was 82 % compared to 98 % in the population. The 5- and 10-year survival of women with a BRCA1-associated breast cancer detected in a national MRI-based screening program in BRCA1 mutation carriers Norway was less than anticipated. The benefit of annual MRI surveillance on reducing breast cancer mortality in BRCA1 mutation carriers remains to be proven.

Abstract 3570: Phospho-dependent regulation of ERRγ expression, transcriptional activity, and Tamoxifen resistance in ER+ breast cancer.

Abstract Selective estrogen receptor modulators (SERMs) such as Tamoxifen (TAM) can significantly improve breast cancer-specific survival for women with ER-positive (ER+) disease. However, resistance to TAM remains a major clinical problem. Estrogen-related receptor gamma (ERRγ) is an orphan nuclear receptor with broad, structural similarities to classical ER that is widely implicated in the transcriptional regulation of energy homeostasis. We previously reported that ERRγ is upregulated during the acquisition of TAM resistance in ER+ breast cancer cell lines, exogenous expression of ERRγ is sufficient to induce TAM resistance, and ERRγ mRNA is significantly increased in tumor samples from women with ER+ breast cancer who relapse following TAM treatment. Because ERRγ has no known ligand, our recent studies have focused on understanding how the expression and activity of this orphan nuclear receptor is regulated, and how this contributes to the TAM resistant phenotype. We have found that TAM-resistant breast cancer cells in which endogenous ERRγ is upregulated show a concomitant hyper activation of p44/p42 ERK. Furthermore, ERK activity (but not that of JNK or p38 MAPK) directly enhances ERRγ protein stability via Serines 57, 81, and/or 219 of the receptor. Phospho-deficient ERRγ is impaired in its ability to induce TAM resistance, and this is associated with a significant reduction in transcriptional activity at the estrogen-related response element (ERRE) half-site, in particular. This led us to hypothesize that ERRγ action at ERREs is most relevant to the development of TAM resistance. We examined a meta-list of validated, ERRE-containing ERR target genes in association with distant metastasis-free survival (DMFS) within 5 years of primary diagnosis in each of 3 publicly available clinical datasets comprised of ER+ breast cancer patients treated with TAM, and obtained a list of 37 differentially expressed targets. The proximal promoter regions of these 37 genes are enriched for binding sites for ELK1, a well-known ERK substrate. Sub-network analysis reveals enrichment of genes whose protein products regulate the mitochondrial unfolded protein response (UPRmito). We also performed differential dependency network (DDN) analysis in an independent dataset using the full meta-list of ERRγ target genes and also identified genes associated with UPRmito. These data suggest a potentially novel role for ERK-mediated regulation of ERRγ in mitochondrial protein folding in TAM-resistant breast cancer. Citation Format: Rebecca B. Riggins, Mary M. Heckler, Hemang Thakor, Cara C. Schafer, Salendra Singh, Ye Tian, Yuriy Gusev, Subha Madhavan, Yue Wang. Phospho-dependent regulation of ERRγ expression, transcriptional activity, and Tamoxifen resistance in ER+ breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3570. doi:10.1158/1538-7445.AM2013-3570

Metachronous contralateral breast cancer: An analysis of risk factors and prognosis in 42,670 women in Sweden.

1568 Background: The number of breast cancer survivors is rising and therefore the number of women at risk of developing contralateral breast cancer (CBC). We analysed the risk of and prognosis after CBC in relation to tumour characteristics. Methods: In a cohort of 42,670 women diagnosed with primary breast cancer in Uppsala/Örebro and Stockholm regions in Sweden between 01/01/1992 and 12/31/2008, factors associated with the risk of developing metachronous CBC were assessed using Cox proportional hazard modelling. We also evaluated breast cancer-specific survival for women with CBC in comparison to women with unilateral breast cancer (UBC), where characteristics of the contralateral tumour were entered as time-dependent covariates. Results: Women aged < 50 at the initial cancer diagnosis had the highest incidence of CBC. We observed an increased risk of CBC in women with increasing tumour size (p-trend < 0.05) and with ≥10 affected lymph nodes compared to node-negative cancer (adjusted HR 1.8, 95% CI 1.2-2.7). Lobular histology of the initial cancer also increased the risk of CBC (adjusted HR 1.3, 95% CI 1.1-1.6). Women with CBC had a worse prognosis than women with UBC, especially women with a short interval between the two cancers (adjusted HR 2.8, 95% CI 2.3-3.5 for CBC ≤5 years and HR 2.1, 95% CI 1.5-2.9 for CBC >5 years, compared to UBC). Increasing size of the contralateral tumour further increased the risk of dying from breast cancer (p-trend < 0.0001), as did affected lymph nodes (HR 4.6, 95% CI 3.4-6.2 vs. HR 2.1, 95% CI 1.6-2.6), high grade (p-trend < 0.001), lobular histology (HR 3.8, 95% CI 2.6-5.6 vs. HR 2.3, 95% CI 1.8-2.9 for ductal) and hormone receptor negativity (ER: HR 4.9, 95% CI 3.6-6.5 vs. HR 1.7, 95% CI 1.3-2.2; PR: HR 3.5, 95% CI 2.7-4.6 vs. HR 1.6, 95% CI 1.2-2.2). Conclusions: The influence of advanced stage of breast cancer on the risk of CBC together with a substantially poor prognosis for women in whom CBC occurred shortly after the initial cancer may imply that for some women CBC is a manifestation of active disease rather than a new primary. These findings indicate that surveillance and treatment plans may have to be adapted accordingly for women with a short interval between the initial and CBC.

Effectiveness of tocotrienol-rich fraction combined with tamoxifen in the management of women with early breast cancer: a pilot clinical trial

IntroductionBasic research has indicated that tocotrienols have potent antiproliferative and proapoptotic effects that would be expected to reduce the effect of breast cancer.MethodsWe conducted a double-blinded, placebo-controlled pilot trial to test the effectiveness of adjuvant tocotrienol therapy in combination with tamoxifen for 5 years in women with early breast cancer. Two-hundred-forty women, aged between 40 and 60 years, with either tumor node metastases (TNM) Stage I or II breast cancer and estrogen receptor (ER)-positive tumors were nonrandomly assigned to two groups. The intervention group received tocotrienol-rich fraction (TRF) plus tamoxifen, whereas the control group received placebo plus tamoxifen, for 5 years.ResultsDuring the 5 years of the study, eight patients died of breast cancer, whereas in 36 patients, a local or systemic recurrence developed. Five-year breast cancer-specific survival was 98.3% (95% confidence interval (CI), 95.9% to 100%) in the intervention group and 95% (95% CI, 91.1% to 98.9%) in the control group, whereas the 5-year disease-free survival was 86.7% (95% CI, 80.6% to 92.8%) and 83.3% (95% CI, 76.6% to 90.0%), respectively. Risk of mortality due to breast cancer was 60% (HR, 0.40; 95% CI, 0.08 to 2.05) lower in the intervention group versus the controls after adjustment for age, ethnicity, stage, and lymph node status, but this was not statistically significant. Adjuvant TRF therapy was not associated with breast cancer recurrence (HR, 0.84; 95% CI, 0.43 to 1.65).ConclusionsFrom the current study, no association seems to exist between adjuvant tocotrienol therapy and breast cancer-specific survival in women with early breast cancer.Trial registrationClinicalTrials.gov Identifier: NCT01157026.

Aberrant inducible nitric oxide synthase expression predicts poor survival in estrogen receptor negative breast cancer, and is associated with a gene expression signature similar to that of basal-like breast cancer.

Abstract Abstract #5067 Background: Inducible nitric oxide synthase (iNOS) is a key enzyme in the inflammatory process, that catalyses the production nitric oxide (NO). NO is a free radical that affects the redox state of tumor cells and thus cell signaling. We hypothesized that iNOS expression is associated with markers of outcome and influences breast cancer survival by estrogen receptor (ER) α-independent mechanisms.&amp;#x2028; Method: 248 cases of incident breast cancer were examined by IHC for iNOS expression. Univariate and multivariate analyses were performed to assess correlations between iNOS expression and clinico-pathological features of breast cancer, and patient survival. In addition, 35 tumors were laser capture microdissected and the effect of iNOS on gene expression profiles analyzed by Affymetrix gene expression arrays.&amp;#x2028; Results: iNOS was moderately to strongly expressed in the majority of breast tumors (70%). iNOS was significantly associated markers of poor prognosis including p53 mutation accumulation, increased microvessel density, and high tumor grade. iNOS was not associated with race/ethnicity (143 African American, 105 Caucasian). In Cox regression analysis, high levels of iNOS expression was a predictor of both 5-year (Hazard Ratio - 5.41; 95% C.I. 1.25 to 23.48) and 10-year (H.R. 4.63; 95% C.I. 1.36 to 15.73) breast cancer-specific survival in women with ER-negative tumors. iNOS was not a predictor of ER positive breast cancer survival. Neither tumor p53 status nor chemotherapy modified these associations. Gene expression analysis identified changes in significant changes in gene expression with high levels of iNOS expression in ER negative breast cancer. This observation was not seen in ER positive breast cancer.&amp;#x2028; 44% of the iNOS associated genes had previously been found to be associated with the ER negative breast cancer subtype, basal-like breast cancer phenotype.&amp;#x2028; Discussion: These results suggest that iNOS contributes to the pathogenicity of ER-negative breast cancers and is a predictor of patient survival. The similarity of the iNOS induced gene signature to that of basal-like breast cancer, suggests that iNOS may play a role in the aggressive nature of basal-like breast cancer and may be a potential therapeutic target for the treatment of ER negative and basal-like breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5067.

Prognostic relevance of androgen receptor detection in operable breast cancer

Androgen receptor (AR) is relevant for prognostication in breast cancer. Different determination methods and cut-off levels hamper interpretation and comparisons of studies. Long-term prognostic evaluation of different AR assays in patients comprising operable breast cancers is scarce. AR was evaluated in 120 primary tumors using the dextran-coated charcoal method (charc-AR), and quantitative immunohistochemistry (IHC) on whole sections (WS) and tissue microarrays (TMA). Nuclear and cytoplasmic-AR localization was determined, and the prognostic importance of AR assays was assessed. Comparisons and correlations with the mitotic activity index (MAI), estrogen receptor (ERalpha), progesterone receptor (PR), HER-2, and histological grade (WHO I-III) were made. Nuclear-AR in WS, but not charc-AR, strongly correlated with MAI (P = 0.001). However, prognostic information appeared in univariate survival analyses only. Nuclear-AR in TMA was not prognostic. Charc-AR was independent prognostic in node positives both for relapse free survival (RFS) and breast cancer specific survival (BCSS). Both charc-AR and IHC cytoplasmic-AR provided independent prognostic survival information for BCSS in women <55 years. Methods that can detect AR localized in the cytoplasm yield important prognostic information, and further studies in patients with operable breast cancer are warranted.

Comparison of 1- and 2-year screening intervals for women undergoing screening mammography

We compared the long-term impact of 1- and 2-year screening mammography intervals using prognostic, screening, and outcome information for women aged 50–74 years obtained from the Screening Mammography Program of British Columbia in two time periods, prior to 1997 (policy of annual mammography) and after 1997 (biennial mammography). Survival was estimated for both periods using a prognostic model and the expected rate of interval and screen-detected cancers. The likelihood of a screen-detected cancer with annual screening was 2.32 per thousand screens and with biennial screening was 3.32 per thousand screens. The prognostic profile of screen-detected cancers was better than that of interval cancers. Among both screen-detected and interval cancers, the prognostic profiles with annual and biennial screening were similar. The estimated breast cancer-specific survival rates for women undergoing annual and biennial screening mammography were 95.2 and 94.6% at 5 years, and 90.4 and 89.2% at 10 years, respectively. Annual compared to biennial mammography was associated with a 1.2% increase in the estimated 10-year breast cancer-specific survival for women aged 50–74 years, diagnosed with invasive breast cancer after screening programme attendance.

Local recurrence in the breast after conservative surgery—a study of prognosis and prognostic factors in 391 women

In a population-based cohort of 6613 women with invasive breast cancer, who had breast-conserving surgery between 1981 and 1990, 391 recurrences in the operated breast were identified. The main aim of this study was to examine the prognosis and prognostic factors in different subgroups of local recurrences, characterised by the time to recurrence, location of recurrence and previously given radiotherapy. The median follow-up for women who had a local recurrence was 7.9 years. The life-table estimates for breast cancer-specific survival in women with local recurrences were 84.5% (standard error (S.E.) 1.8) at 5 years and 70.9% (S.E. 2.7) at 10 years. The risk of breast cancer death was highest among women who had an early (⩽2 years) recurrence in the same quadrant as the primary tumour, with a breast cancer-specific survival of 67.9% (S.E. 4.8) at 5 years and 56.0% (S.E. 5.9) at 10 years. There was a statistically significant difference in the probability of breast cancer-specific survival, as measured from the recurrence, between women who initially did or did not receive radiotherapy ( P=0.0123). However, when measured from primary treatment, there was no significant difference, indicating that the difference in prognosis could be due to a lead-time bias. Independent prognostic factors for breast cancer-specific survival in women with local recurrences were time to local recurrence and the Nottingham Prognostic Index (NPI).