Higher Risk Of Breast Cancer Recurrence Research Articles

Abstract PS04-06: Breast cancer recurrence among women with pre-diagnostic major depression and co-existing substance abuse disorder: A retrospective study in the United States Veterans Health Administration Cohort

Abstract Background: Our prior study observed a 34% higher risk of breast cancer (BC) recurrence among women with major depressive disorder (MDD) at the time of their BC diagnosis compared to women without MDD after adjusting for sociodemographic, clinical, and prognostic factors. Given the high prevalence of substance abuse disorders among individuals with MDD and the positive association between alcohol use and mortality among BC survivors, we were interested to examine whether the risk of BC recurrence was compounded for women with both conditions. Objective: To investigate whether pre-diagnostic substance abuse disorders modify the association between MDD and BC recurrence. Methods: We established a retrospective cohort of women (age ≥ 18 years) with incident, early-stage BC diagnosed from 2010 through 2019 using the VHA’s electronic medical record database. A two-year window was used to identify women with MDD and co-existing substance abuse disorders prior to their BC diagnosis. We examined potential interactions between MDD and alcohol abuse and MDD and other substance abuse using multivariable proportional hazards regression, accounting for competing risk of death. Our outcome of interest was BC recurrence. The reference group for all analyses was women with BC alone. The models were adjusted for patient characteristics including age, race, ethnicity, marital status, rurality of primary residence, priority group rating (proxy for socioeconomic status), any homelessness or economic problems, comorbidity burden, body mass index, smoking status, receipt of a screening mammography, year of BC diagnosis, cancer stage, cancer subtype, and cancer treatment. Subgroup analyses were conducted by cancer subtype. Results: Our cohort comprised 6,045 women with BC, of whom 1,754 (29%) had a pre-diagnostic MDD diagnosis and 1,509 (25%) had a substance abuse disorder. Among women with MDD, 386 (22%) abused alcohol and 336 (19%) abused other substances. The median length of follow-up from BC diagnosis was 4.5 years (IQR=4.8 years). The average age at BC diagnosis was 57 years (SD=11 years) overall, 56 years (SD=10 years) among women with MDD, and 57 years (SD=9 years) among women with substance abuse disorders. On multivariable analysis, MDD (HR=1.33; 95% CI: 1.14, 1.53), alcohol abuse disorder (HR=1.37; 95% CI: 1.12, 1.68), and other substance abuse disorders (HR=1.33; 95% CI: 1.13, 1.56) were independent risk factors for BC recurrence. Further, there was a statistically significant interaction between pre-diagnostic MDD and alcohol abuse disorder (p-interaction=0.003). Women with BC who had both pre-diagnostic MDD and alcohol abuse disorder were at a 65% (HR=1.65; 95% CI: 1.29, 2.11) higher risk of BC recurrence compared to women with BC alone. A statistically significant interaction was also observed between pre-diagnostic MDD and other substance abuse disorders (p-interaction < 0.001). Women with BC who had both pre-diagnostic MDD and other substance abuse disorders were at a 90% (HR=1.90; 95% CI: 1.50, 2.42) higher risk of BC recurrence compared to women with BC alone. In subgroup analyses, the interaction between MDD and alcohol abuse disorders (p-interaction=0.001) and MDD and other substance abuse disorders (p-interaction < 0.001) was limited to women with estrogen receptor positive cancer but not estrogen receptor negative cancer. Conclusion: Women with incident BC who have prior diagnoses of both MDD and substance abuse disorder are at higher risk of recurrence than women with either exposure independently. Further research is needed to examine the etiology of our findings and to evaluate whether this newly defined risk group would benefit from closer monitoring and more tailored treatment options. Citation Format: Maya Aboumrad, Kala Visvanathan. Breast cancer recurrence among women with pre-diagnostic major depression and co-existing substance abuse disorder: A retrospective study in the United States Veterans Health Administration Cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS04-06.

Abstract P3-03-08: Depression and breast cancer recurrence among female veterans in the United States: a retrospective cohort study

Abstract Background: The importance of mental health to improve the quality of cancer survivorship and outcomes is gaining increased attention. Major depressive disorder (MDD) has been associated with higher breast cancer (BC) incidence, BC-specific and all-cause mortality. The effect of MDD on BC recurrence remains under-studied. The Veterans Health Administration (VHA) provides a unique opportunity to examine this relationship as it mandates annual MDD screening in the primary care setting and reports national screening rates of 96%. Objective: To examine the relationship between pre-existing MDD and BC recurrence among a diverse cohort of women in the United States. Methods: We established a retrospective cohort of women (age ≥ 18 years) diagnosed with early-stage incident BC from 2010 through 2019 using the VHA’s electronic medical record database. We used a two-year window to identify women with clinically diagnosed MDD prior to their BC diagnosis. Our outcome of interest was BC recurrence (local recurrence/second primary and distant recurrence). We used multivariable proportional hazards regression to examine the association between MDD and BC recurrence, accounting for competing risk of death. Our analyses were adjusted for age, race, ethnicity, marital status, priority group rating (proxy for socioeconomic status), rurality of primary residence, geographical region, cancer stage, year of BC diagnosis, and comorbidity burden. Priority group rating is a metric that incorporates patients’ income, receipt of VHA assistance benefits, capacity for gainful employment, and severity of service-connected conditions. We conducted subgroup analyses by tumor subtype. RESULTS: Our cohort consists of 6,045 women with BC, of whom 1,750 (29.0%) had a pre-existing MDD diagnosis. The median length of follow-up from BC diagnosis was 4.5 years (IQR=4.8 years). The average age at BC diagnosis was 57 years (SD=11 years) overall and 56 years (SD=10 years) among women with MDD. Sixty-one percent of women were white, 29% were black, 27% were married, and 28% were rural dwelling. Forty-four percent of invasive carcinomas were localized and 21% were regional. Thirty-five percent of patients had ductal carcinoma in situ. Women with MDD had a higher average Charlson Comorbidity Index score (mean=0.75, SD=1.13 vs. mean=0.58, SD=1.03) and proportion with a priority group rating between 1-4 (40% vs. 32%). The distribution of other described patient characteristics among women with MDD were similar to the overall cohort. On multivariable analysis, women with MDD had a 31% (95% CI: 1.11, 1.56) higher risk of BC recurrence compared to women without MDD. MDD was associated with a 29% (95% CI: 1.01, 1.66) and 33% (95% CI: 1.05, 1.67) higher risk of local recurrence/second primary and distant recurrence, respectively. The relationship between MDD and BC recurrence remained significant after adjusting for tumor subtype (HR=1.40, 95% CI: 1.07, 1.83). In subgroup analyses stratified by tumor subtype, MDD was associated with a higher risk of BC recurrence among women with estrogen receptor positive versus negative tumors (HR=1.65, 95% CI: 1.27, 2.14 vs. HR=0.71, 95% CI: 0.34, 1.46) and HER2/neu negative versus positive tumors (HR=1.53, 95% CI: 1.16, 2.00 vs. HR=1.24, 95% CI: 0.51, 2.96). The interaction between estrogen receptor status and MDD was statistically significant (p-interaction=0.02). CONCLUSION: Women with incident BC should be screened for MDD early in the cancer care continuum given the prevalence of MDD and association with increased risk of local recurrence/second primary and distant BC recurrence. Further research is needed to understand the interplay between these two diseases and their treatments. Citation Format: Maya Aboumrad, Brian Shiner, Avonne Connor, Bradley V. Watts, Kala Visvanathan. Depression and breast cancer recurrence among female veterans in the United States: a retrospective cohort study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-03-08.

Risk of recurrence among patients with HR-positive, HER2-negative, early breast cancer receiving adjuvant endocrine therapy: A systematic review and meta-analysis

BackgroundA systematic review and meta-analysis was conducted to assess breast cancer (BC) outcomes among patients with early-stage hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) BC, receiving adjuvant endocrine therapy. MethodsRandomized controlled trials (RCTs) and real-world evidence (RWE) studies were identified using Ovid MEDLINE®, Embase, and Evidence-Based Medicine Reviews. Clinical and methodological similarities including alignment of outcome definitions with standardized definitions for efficacy endpoints criteria were assessed to evaluate feasibility of conducting a meta-analysis. Where feasible, 5-year probabilities of BC recurrence or death were estimated using a Bayesian hierarchical arm-based model. ResultsOf 21 included studies, 8 RCTs and 4 RWE studies reported outcome data of interest. There was heterogeneity in outcome reporting, as well as variation in recurrence risk amongst studies with aligned reporting. Of the 12 studies, 10 were considered for inclusion in a meta-analysis of BC recurrence or death. Only a subgroup analysis of node-positive patients (3 studies; n = 7307) was deemed feasible. The 5-year probability of BC recurrence or death was 17.2% (95% credible interval: 14.6%–20.3%). ConclusionAlthough studies reporting recurrence outcomes were limited, there remains a high risk of BC recurrence, especially among node-positive patients. Approximately 1 in 6 women with node-positive HR+/HER2- early-stage BC receiving endocrine therapy experience recurrence or death within 5-years of initiating treatment, suggesting a need for novel treatments for this population.

Association of angiogenesis and inflammation-related gene functional polymorphisms with early-stage breast cancer prognosis.

Genetic variations in inflammation- and angiogenesis-related genes may alter the coded protein level and impact the pathogenesis of breast cancer (BC). The present study investigated the association of functional single nucleotide polymorphisms (SNPs) in the VEGFA, IL-1β, IL-1α and IL-6 genes with the early-stage BC phenotype and survival. Genomic DNA and clinical data were collected for 202 adult Eastern European (Lithuanian) women with primary I–II stage BC. Genotyping of the SNPs was performed using TaqMan SNP genotyping assays. Nine VEGFA, IL-1β, IL-1α and IL-6 polymorphisms were analysed. The VEGFA and IL-6 haplotypes were inferred using Phase software. Patients were prospectively followed-up for recurrence, occurrence of metastasis and mortality until April 30, 2019. All studied genotypes were in Hardy-Weinberg equilibrium and had the same distribution as the 1,000 Genomes project Phase 3 dataset for European population. Significant associations of the studied SNPs with clinicopathologic variables were observed between IL-1α rs1800587 C allele and larger primary tumour size; IL-6 rs1800797 A allele, rs1800797 GA genotype, rs1800795 C allele, IL-6 (rs1800797-re1800795) AC diplotype and hormonal receptor-positive disease; IL-6 rs1800797 A allele and HER2 negative status. In univariate Cox survival analysis, IL-1α rs1800587 CC and IL-6 rs1800797 GG genotype carriers exhibited worse disease-free survival (DFS), metastasis-free survival (MFS) and overall survival (OS). The IL-6 rs1800795 GG genotype was associated with worse OS. IL-6 (rs1800797, rs1800795) GG/GG diplotype carriers had shorter MFS and OS. Multivariate Cox survival analysis revealed that the IL-1α rs1800587 CC genotype was an independent negative prognostic factor for DFS, MFS and OS, and the IL6 GG/GG diplotype was an independent negative prognostic factor for MFS and OS. According to the present study, functional SNPs in the IL-1α and IL-6 genes may contribute to the identification of patients at higher risk of BC recurrence, development of metastases and worse OS among early-stage patients with BC.

Recurrence rates and long-term survival factors in young women with breast cancer.

Objectives:To evaluate the factors related to breast cancer (BC) recurrence as well as survival in women ≤40 years old.Methods:This is a retrospective medical record review of women aged ≤40 years diagnosed with BC stages I to III between January 2009 and June 2017 at King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia. Demographic data collected included patients’ initial presentation (including age and date of diagnosis), imaging studies, tumor characteristics, type of surgery, systemic therapy (if any) received, and site of first recurrence. Data was analyzed to assess recurrence rate, disease-free survival (DFS), and overall survival (OS), and determine associated factors. Descriptive statistics were used to calculate the mean, median, standard deviation, and quartiles. Chi-square test was performed to test the association between 2 variables. Kaplan-Meier analyses were performed to assess survival distribution.Results:A total of 117 patients were included for analysis. Median follow-up was 16 months (range 0 to 99). Five-year DFS 57% and OS was 89%. Adjuvant chemotherapy was associated with a better DFS (hazard ratio of 0.204; 95% confidence interval, 0.050 to 0.832; p=0.027). Higher tumor, node, metastasis stage was significantly associated with worse DFS (p=0.034). Fewer postoperative follow-up visits significantly predicted recurrence (p=0.003).Conclusion:We found a high risk of BC recurrence among patients at our institution. Higher cancer stage, nonuse adjuvant chemotherapy, and low follow-up rate were significant predictive factors for recurrence.

Abstract 248: Association of vitamin D related polymorphisms with hereditary breast cancer in 431 patients wild type for BRCA1 and BRCA2 mutations

Abstract Background: A high proportion of Breast Cancer (BC) patients with a positive family history is not explained by mutations in BRCA1 and BRCA2 genes and the biology and BC outcome are different compared to patients with BRCA mutations. Low serum 25-hydroxyvitamin D (25(OH)D) has been found to be associated with an increased cancer incidence and poorer prognosis. Single nucleotide polymorphisms (SNPs) of vitamin D receptor (VDR) and vitamin D binding protein (VDBP) genes (also called GC (Globulin Complex)), may contribute to final vitamin D activity. The aim of this study is to assess the role of 25(OH)D and VDBP serum levels, VDR and GC SNPs on BC recurrence and survival in a cohort of patients with positive family history, wild type (WT) for BRCA1 and BRCA2. Methods: VDR (ApaI, FokI, TaqI, BsmI) and GC (rs2282679, rs4588, rs7041) SNPs were analyzed, by TaqMan SNP Genotyping Assays (Thermo Fisher Scientific), for 431 WT patients. Serum levels of 25(OH)D and VDBP were measured using an electro-chemiluminescence immunoassay (Abbott) and Human Vitamin D BP Quantikine ELISA kit (R&D) respectively. Results: A cohort of 431 BC patients was followed from 2001 to 2015 (median follow-up 9 years). Women with the GC rs228679 variant had significantly lower levels of circulating VDBP and 25(OH)D compared to carriers of the major allele, whereas the GC rs7041 variant was associated with a greater level of VDBP and 25(OH)D. Multivariate Cox models showed that BsmI is significantly associated with BC outcome: patients with the major allele of BsmI (C) have half the risk of recurrence (CC vs. TT HR=0.43; 95%CI: 0.27-0.68; and CC vs. CT HR=0.66; 95%CI: 0.45-0.99). Finally, low serum VDBP concentrations are significantly associated with a higher risk of BC recurrence (VDBP<187 vs >321: HR=1.79; 95%CI: 1.03-3.13) and 25(OH)D>30 ng/ml in late summer/autumn vs <20 ng/ml in winter/spring is associated with a significant decrease risk of mortality (HR=0.44; 95%CI: 0.22-0.89). Conclusions: 25(OH)D and VDBP serum levels were related with survival and breast cancer recurrence and influenced by genetic variants of GC SNPs. An allele VDR dose-related decrease of breast cancer recurrence was achieved with the increasing number of allele C of BsmI rs1544410(C>T). Our study provides evidence for the pivotal role of vitamin D metabolism in breast cancer outcome of high risk patients with a positive family history, wild type for BRCA1 or BRCA2 genes. Citation Format: Valentina Aristarco, Davide Serrano, Monica Barile, Davide Bondavalli, Mariarosaria Calvello, Debora Macis, Harriet Johansson, Aliana Guerrieri Gonzaga, Irene Feroce, Valeria Pensotti, Sara Gandini, Bernardo Bonanni. Association of vitamin D related polymorphisms with hereditary breast cancer in 431 patients wild type for BRCA1 and BRCA2 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 248.

Abstract P3-12-11: Disparities in adjuvant hormone adherence in breast cancer patients within a universal healthcare model

Abstract Background: Patient adherence to adjuvant hormonal therapy for breast cancer (BC) is correlated with improved survival. Recent publications have demonstrated ethnic disparities in adjuvant hormone adherence (AHA) for privatized healthcare models. Objective: To identify disparities in AHA for BC patients within a universal healthcare system in Alberta, Canada. Methods: Patients diagnosed from 2007-2014 with stage I-III, ER+/HER2- BC receiving adjuvant FECD or DC chemotherapy and at least one month of adjuvant hormonal therapy in Alberta, Canada were retrospectively assessed. Hormone monotherapy (tamoxifen, AI), switch strategies (tam to AI), and treatment duration were collected. Compliance was assessed with central pharmacy data. Patient ethnicity was identified using patient first/last and parental last name via Onolytics® ethnographic software. Ethnicity was further verified using a centrally collected place of birth. Age, AJCC stage, psychiatric diagnoses (mood, bipolar), and comorbidity were collected. Log rank and Chi squared were used to assess difference between adjuvant hormonal therapy for variables at 1, 2, and 5 years. Log rank p-values at 2 years are reported. Results: A total of 2,399 ER+ patients were included for analysis. AHA was non-significant for ethnicity (p=0.797), comorbidity (p=0.623), psychiatric disorders (p=0.145), or elderly cohorts (p= 0.814). AHA by stage was significant with stage III > II > I (p=0.004) having the highest compliance rates. AHA was highest for planned hormonal switch strategies (p=0.004) compared to monotherapy. Hormone Adherence RatesCharacteristicsNo. of Patients% AdherenceEthnicity Caucasian211891.6Asian15293.4Middle Eastern/African9593.7Hispanic2491.7Age <65207791.8>6534192.1Comorbidity 096191.21-3134392.2>311493Psychiatric Dx Yes31189.7No210792.1Stage I45388.3II151292.1III45394.5Hormone Strategy Monotherapy173190.9Switch68794.2 Conclusion: AHA is not dependent on ethnicity, age, comorbidity, or psychiatric diagnosis in a universal healthcare model. Conversely, higher rates of AHA are seen with planned switch strategy compared to monotherapy, contradictory to the BIG I-98 trial. Patients with higher stage, and thus higher risk of BC recurrence have increased adherence compared to their low risk counterparts. Reinforcement of AHA for low/moderate risk BC patients, in addition to tamoxifen to AI switch strategies may improve overall adherence. Citation Format: Veitch ZW, Khan OF, Tilley D, Kostaras X, King K, Lupichuk S, Tang P. Disparities in adjuvant hormone adherence in breast cancer patients within a universal healthcare model [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-11.

Weight loss with mindful eating in African American women following treatment for breast cancer: a longitudinal study.

Women with higher body mass index (BMI) following breast cancer (BC) treatment are at higher risk of BC recurrence and death than women of normal weight. African American (AA) BC patients have the highest risk of BC recurrence and gain more weight after diagnosis than their white counterparts. The purpose of this study was to evaluate the association between a mindful eating intervention and weight loss in AA women following chemotherapy for BC. A single-group 24-week longitudinal pilot study with repeated measures was conducted. AA women (N = 22, BMI = 35.13 kg/m(2), range = 27.08-47.21) with stage I-III BC who had finished active cancer treatment received a 12-week mindful eating intervention with individual dietary counseling and group mindfulness sessions, followed by bi-weekly telephone follow-up for 12 weeks. Linear mixed models were used to evaluate the effects of the intervention and of baseline mindfulness on the weight change over time. In the overall group (N = 22), MEQ scores increased over time (p = 0.001) while weight decreased over time (-0.887 kg, p = 0.015). Weight loss over time was associated with higher T1 MEQ scores (p = 0.043). Participants in the higher MEQ group (n = 11) at T1 experienced significant weight loss over time (-1.166 kg, p = 0.044), whereas those in the low MEQ (n = 11) did not lose weight. Participants who were diagnosed with stage 1 BC experienced significant weight loss over time (-7.909 kg, p = 0.014). This study suggests that a mindful weight loss program may be effective for weight reduction and maintenance in some AA women who have completed treatment for BC, particularly those diagnosed with stage 1 BC and with initially higher mindful eating behaviors. Mindful weight loss program is proposed as a promising way in which to reduce obesity-related conditions in AA BC survivors.

Abstract CT309: Influencing the tumor microenvironment: A phase II study of copper-depletion using tetrathiomolybdate (TM) in patients (pts) with breast cancer (BC) at high risk for recurrence

Abstract Background: Bone marrow derived endothelial progenitor cells (EPCs) and copper-dependent angiogenic pathways are critical to the metastatic process. Copper depletion (CD) therapy inhibits tumor metastases in preclinical models. We hypothesized that TM-associated CD would reduce EPCs in pts at high risk for BC recurrence, and we explored the relationship between CD and its effects on the tumor microenvironment in pre-clinical models. Methods: In this single arm, phase II study, BC pts at high risk for recurrence, defined as node positive triple negative (TN), stage 3 and 4 with no evidence of disease (NED) were enrolled on a trial of CD with TM. We CD’d to maintain ceruloplasmin (Cp) between 5-17 mg/dl for 2 years or until relapse. The primary endpoint was change in EPCs measured before and during treatment with TM. Secondary endpoints included tolerability, safety, and efficacy of CD. Laboratory studies: MDA-LM2-luciferase cells were implanted into CB17-SCID mice gavaged with water or TM. The tumors were quantified by bioluminescence images (BLI). We measured Cp oxidase to determine copper status. Western blots were used to assess LOX activity, and IHC was used to quantify collagen cross-linking and CD11b+ macrophage infiltration. Results: We enrolled 43 pts. Treatment duration was 24 cycles (each cycle is 28 days) for the primary study. A total of 752 cycles were completed in 2 years. The mean age was 49 (range 29-66). Mean Cp level decreased from 29 at baseline to 16 (p<0.001) at 4 weeks. 94% of pts achieved CD by cycle 2. TM was well tolerated in most pts and the only grade 3 and 4 toxicities were neutropenia (3.9%) and anemia (0.1%). CD was most effective in TNBC pts with significantly reduced time to CD (P=0.0153). At one year of analysis, TM reduced EPCs (p=0.044). The 2-year analysis of effect of TM on EPCs is ongoing. The 2 year PFS for the entire cohort from the start of TM treatment was 81%. The overall survival from the start of treatment was 90.6% with median follow up of 4.5 years. In pre-clinical models, TM had no effects on the primary tumor, but decreased secondary metastases as seen by BLI. Western blots demonstrated decreased LOX, and IHC showed reduced collagen cross-linking with less CD11b+ macrophage recruitment.Conclusion: TM is safe, well tolerated and effective in achieving CD in breast cancer patients, and appears to affect the tumor microenvironment in pre-clinical models. Molecular subtype may affect CD and TM may be most effective in TN patients. Citation Format: Nancy Chan, Naomi Kornhauser, Maureen Ward, Amy Willis, Tessa Cigler, Ellen Chuang, Anne Moore, Diana Donovan, Sarah E. Schneider, Christina Lam, David J. Warren, Anna Rubinchik, Sandra Hurtado Rua, Sharrell Lee, Maureen Lane, Vivek Mittal, Linda Vahdat. Influencing the tumor microenvironment: A phase II study of copper-depletion using tetrathiomolybdate (TM) in patients (pts) with breast cancer (BC) at high risk for recurrence. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT309. doi:10.1158/1538-7445.AM2014-CT309

A Phase II Trial Tetrathiomolybdate (TM), a Copper Depleting Compound, and Its Effect on Circulating Endothelial Progenitor Cells (EPCs) in Patients with Breast Cancer (BC) at High Risk of Recurrence.

Abstract Background: EPCs are critical to tumor angiogenesis, are increased in BC patients (pts) and are probably an early marker for paclitaxel response. Copper is required for angiogenesis, and pre-clinical data suggest that TM, a copper-depleting compound, inhibits angiogenesis and maintains tumor dormancy. We sought to measure the effect of TM on circulating endothelial progenitor cells (EPCs) in pts at high risk of BC recurrence and to evaluate the effect of copper depletion on EPCs. Methods: This analysis is part of an ongoing phase II study of TM in BC pts at high risk of recurrence defined as any node positive triple negative (TN) BC, Stage III or IV with no evidence of disease (NED). All therapy other than hormonal was completed at least 6 weeks prior to study. Treatment: TM 180 mg daily to achieve a target ceruloplasmin (Cp) level of 5-15 mg/dL (copper depletion), and then 100 mg daily. We monitored levels of EPCs (CD45dim, CD133+, VEGFR2+), CEA, CA15-3, and Cp at baseline and monthly. Imaging studies are done every 6 months (mos). Results: 28 pts are enrolled and 304 cycles of TM have been administered. Adjuvant: 20 pts, Stage 4 NED: 8 pts, Triple negative: 8 pts (5 stage IV NED, 3 Adjuvant) The median age is 51 years (range: 29-64), median number of positive lymph nodes among Stage III patients is 7 (4-42). The median baseline Cp level was 28 mg/dL (21-43). Among 21 patients who have reached target Cp, the median time to target is 6 weeks (2-16 weeks). Two pts discontinued treatment before reaching target. The median baseline EPCs is 17.38 cells/ml (0.0-286.1) Although there was a trend toward increased EPCs at month 1, this was not statistically significant (p=0.8964) and the majority of pts EPCs were maintained below baseline over time when Cp levels were below target (ie. copper depleted). Toxicity: Grade 3/4 neutropenia occurred in 3 patients (0.02%) with 1 pt with febrile neutropenia. All resolved 5-13 days later with TM held and resumed at a lower dose in 2 patients. No other grade 3/4 toxicity was observed. Three patients were diagnosed with recurrent breast cancer at 1, 9 and 10 mos. An EPC rise preceded an abnormal marker or overt relapse by 3-5 months in 2 of 3 pts. Conclusions: TM is well tolerated in breast cancer patients. TM might contribute to maintaining EPCs below baseline in pts who are copper depleted. We postulate that the increased EPCs noted in both patients with recurrent disease 2-4 months prior to overt relapse could represent the turning on of an angiogenic switch, resulting in an outpouring of CEPCs to the new site of metastasis. Other studies geared toward understanding the mechanism for metastases are underway. The trial continues to accrue.Supported by the Susan B Komen for the Cure, NY Community Trust, Breast Cancer Alliance of Greenwich and the Madeline and Stephen Anbinder Foundation. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6090.