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This report describes a 42 year old male with a 5 year history of transient ischemic attacks (TIAs), migraines, previous strokes, and symptoms referable to a left middle cerebral artery (MCA) territory event. Computed tomography angiography (CTA) and magnetic resonance angiography (MRA) revealed severe stenoses in the proximal left MCA and proximal left anterior cerebral artery (ACA). Transcranial Doppler ultrasound/Transcranial Doppler imaging (TCD/TCI) and cerebral angiogram confirmed the stenoses with a mean flow velocity (MFV) at the proximal left MCA, with a velocity of 230 cm/s. A Wingspan Stent System stent was placed in the proximal left MCA. Cerebral angiogram and serial TCD examinations performed post stent placement showed a patent left MCA without stenosis and a MFV of 55 cm/s. The left ACA was occluded following proximal left MCA stent placement. This case highlights the usefulness of TCD in the assessment of the MCA and other basal cerebral arteries.

Background While cardiac dysfunction has been described following traumatic brain injury (TBI), its association with systemic and cerebral hemodynamics is not known. We examined the contemporaneous relationship between early cardiac function with systemic and cerebral hemodynamic parameters after moderate-severe TBI. Methods Bedside transthoracic echocardiography (TTE) and transcranial Doppler (TCD) ultrasonography were performed within 24 h in patients > 18 years with isolated moderate-severe TBI. Systemic hemodynamic parameters were quantified using routine monitoring [heart rate and mean arterial pressures (MAP)] and calculation from echocardiographic data [stroke volume index (SVI), cardiac index (CI), and systemic vascular resistance index (SVRI)]. Systolic dysfunction was defined using TTE as global longitudinal strain (GLS) > -16%. Mean middle cerebral artery velocity (FVm) was the measure of cerebral hemodynamics and quantified using TCD. Results Among 15 patients [mean age 43 ± 13 years, GCS 5 ± 3, 73% male], 15 TTE and 15 TCD exams were performed simultaneously. Five (33%) patients had systolic dysfunction, with significantly worse GLS (median [IQR] −12.1% [−14.1, −12] vs. −19.1% [−19.9, −17.7], p = 0.004). Median (IQR) MAP was 97 (89, 107) mmHg, SVI (29.0 [20.5, 31.0] mL m−2), and CI (2.83 [2.05, 3.10] L/min m−2) were low to normal, while SVRI (2704 dyne sec/cm5 m−2 [2210, 4084]) was normal to high. None of the patients had abnormal TCDs. Higher GLS (reduced systolic function) was associated with lower SVI (r2 = 0.274, p = 0.03) but not other parameters. Conclusion Systemic hemodynamic parameters were consistent with an early catecholamine-excess state. While reduced systolic function was associated with lower SVI, there was no relationship with reduced cerebral perfusion, possibly due to normal MAP.

Background The demand for total hip and total knee arthroplasty in the USA is projected to increase significantly. Traditionally, face-to-face physical therapy has been an essential component of recovery in patients after total joint arthroplasty. Emerging technology allows telerehabilitation, or virtual physical therapy, which may reduce costs and increase standardization, but its effects on outcomes are not known. Questions/Purpose We sought to review our initial experience using a telerehabilitation protocol for patients after primary total hip or total knee arthroplasty. Methods In this pilot study, we retrospectively compared our first 40 telerehabilitation patients after a primary total hip or knee arthroplasty with a historical cohort or literature referenced values and evaluated (1) readmission rates at 90 days, (2) emergency department visits, (3) patient-reported outcome scores, (4) incidence of closed knee manipulation within 90 days of primary total knee arthroplasty, and (5) patient satisfaction surveys. Results We observed no increase in the telerehabilitation group at 90 days in readmissions, emergency department visits, or closed knee manipulations. Accuracy of telerehabilitation exercises performed was 92%. Patient-reported outcome scores showed improvements comparable with traditional therapy. Extremely high patient satisfaction scores were reported with the telerehabilitation protocol. Conclusion Our early experience demonstrates the feasibility of implementing a telerehabilitation program following primary total hip or knee arthroplasty without compromising clinical quality and with high patient satisfaction. Electronic supplementary material The online version of this article (10.1007/s11420-019-09715-w) contains supplementary material, which is available to authorized users.

Background Scalp cooling has demonstrated efficacy in preventing hair loss in women with early stage breast cancer receiving neo/adjuvant chemotherapy. Data from 2 prospective trials (Rugo et al, and Nangia et al, JAMA 2017) led to FDA clearance of 2 automated scalp-cooling devices to prevent chemotherapy induced alopecia (CIA). Although scalp metastases from breast cancer are rare, historical concerns about scalp cooling included a theoretical increase in risk of recurrence in scalp due to reduced delivery of chemotherapy to the scalp. Methods We conducted a multicenter prospective trial evaluating the efficacy and safety of the DigniCap in women with stage I-II breast cancer receiving neo/adjuvant chemotherapy excluding sequential or combination anthracycline/taxanes with concurrent matched controls. The primary endpoint was unblinded patient self-assessment of 5 photographs using the Dean scale to estimate hair loss 4 weeks following the last dose of chemotherapy, with success defined as a Dean score of 0-2 (≤ 50% hair loss); additional endpoints included quality of life (QOL) and both short and long-term safety. Results 106 patients using the scalp cooling device and 16 concurrent controls were enrolled. As previously reported, the use of scalp cooling was associated with less alopecia and improvement in several measures of QOL (Rugo et al, JAMA 2017). 91 patients have follow-up (FU) out to 3 years; 73 with estrogen receptor (ER) positive and 18 with ER negative disease. 5 DigniCap patients have developed recurrent breast cancer in breast (n=1), liver (n=1), bone, liver and breast (n=1), bone, liver, lung, and nodes (1), and bone, breast, GI tract and bladder (n=1). Of 12 control patients with available FU, 1 developed metastases to liver. 2 patients have died of metastatic disease, one in the DigniCap arm and one in the control arm. No new safety signals have been detected. Conclusion Scalp cooling using the DigniCap system in patients with early stage breast cancer receiving taxane based neo/adjuvant chemotherapy is safe and effective. No scalp metastases have been reported 3 years following completion of study treatment. 4 year FU data will be presented. The study was funded by The Lazlo Tauber Family Foundation (UCSF), the Anne Moore Breast Cancer Research Fund (Weil Cornell), and the Friedman Family Foundation (Mount Sinai Beth Israel), as well as partially by Dignitana. Citation Format: Rugo HS, Klein P, Melin SA, Hurvitz SA, Melisko ME, Moore A, D'Agostino, Jr. RB, Deluca A, Cigler T. Long-term safety follow-up of patients with early stage breast cancer treated with scalp cooling on the Dignitana scalp cooling trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-17-04.

Expression of inflammatory (interleukin-6 [IL-6]) and vascular homeostatic (angiopoietin-2 [AP-2], endothelin-1 [ET-1], endocan-2 [EC-2]) biomarkers in pediatric traumatic brain injury (TBI) was examined in this prospective, observational cohort study of 28 children hospitalized with mild, moderate, and severe TBI by clinical measures (age, sex, Glasgow Coma Scale score [GCS], Injury Severity Score [ISS], and cerebral autoregulation status). Biomarker patterns suggest an inverse relationship between GCS and AP-2, GCS and IL-6, ISS and ET-1, but a direct relationship between GCS and ET-1 and ISS and AP-2. Biomarker patterns suggest an inverse relationship between AP-2 and ET-1, AP-2 and EC-2, but a direct relationship between AP-2 and IL-6, IL-6 and EC-2, and IL-6 and ET-1. Plasma concentrations of inflammatory and vascular homeostatic biomarkers suggest a role for inflammation and disruption of vascular homeostasis during the first 10 days across the severity spectrum of pediatric TBI. Although not statistically significant, without impact on cerebral autoregulation, biomarker patterns suggest a relationship between inflammation and alterations in vascular homeostasis. The large variation in biomarker levels within TBI severity and age groups, and by sex suggests other contributory factors to biomarker expression.

Purpose: National Comprehensive Cancer Network guidelines recommend delivery of adjuvant chemotherapy in node-negative triple negative breast cancer (TNBC) if the tumor is > 1 cm and consideration of adjuvant chemotherapy for T1b but not T1a disease. These recommendations are based upon sparse data regarding the role of adjuvant chemotherapy in T1a and T1b node-negative TNBC. Our objective was to clarify the benefits of chemotherapy for patients with T1N0 TNBC, stratified by tumor size.Methods: We performed a retrospective analysis of survival outcomes in an IRB-approved prospectively-maintained database of TNBC patients treated at two academic institutions in the United States from 1999-2018. Primary tumor size, histology, and nodal status were based upon definitive surgical pathology. Mean follow-up was 5.3 years.Results: 756 TNBC cases were analyzed; 258 T1N0 TNBC patients were identified. Adjuvant chemotherapy was delivered to 30.5% of T1a, 64.7% T1b, and 83.9% T1c (p < 0.0001). Factors associated with delivery of adjuvant chemotherapy were age, histology, high-grade disease, and postoperative adjuvant radiation therapy. At a mean follow-up of 5.3 years, increase in overall survival was associated with use of chemotherapy in patients with T1c disease (93.2% v. 75.2% p = 0.008) but not in those with T1a (100% v. 100% p = 0.3778) or T1b (100% v. 95.8% p = 0.2362) disease.Conclusion: Our data support current guidelines indicating benefit from adjuvant chemotherapy in node-negative TNBC associated with T1c tumors but excellent outcomes were observed in cases of T1a and T1b disease, regardless of whether adjuvant chemotherapy was delivered.

Despite the success of vaccines and selected repurposed treatments, COVID-19 is likely to remain a global health problem and further chemotherapeutics are required. Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials without characterisation of Pharmacokinetics (PK)/Pharmacodynamics (PD) including safety in COVID-19. One such drug is Nafamostat Mesylate (Nafamostat), a synthetic serine protease inhibitor with anticoagulant and anti-inflammatory properties. Preclinical data has demonstrated that it is has potent antiviral activity against SARS-CoV-2 by directly inhibiting the transmembrane protease serine 2 (TMPRSS2) dependent stage of host cell entry.MethodsWe present the findings of a phase Ib/II open label, platform randomised controlled trial (RCT), exploring the safety of intravenous Nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), Nafamostat or an alternative therapy. Secondary endpoints included clinical endpoints such as number of oxygen free days and clinical improvement/ deterioration, PK/PD, thromboelastometry, D Dimers, cytokines, immune cell flow cytometry and viral load.ResultsData is reported from 42 patients, 21 of which were randomly assigned to receive intravenous Nafamostat. The Nafamostat group developed significantly higher plasma creatinine levels, more adverse events and a lower number of oxygen free days. There were no other statistically significant differences in the primary or secondary endpoints between Nafamostat and SoC. PK data demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We observed an antifibrinolytic profile, and no significant anticoagulant effects in thromboelastometry. Participants in the Nafamostat group had higher D Dimers compared to SoC. There were no differences in cytokine profile and immune cell phenotype and viral loads between the groups.ConclusionIn hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous Nafamostat. Given the number of negative trials with repurposed drugs, our experimental medicine trial highlights the value of PK/PD studies prior to selecting drugs for efficacy trials. Given the mechanism of action, further evaluation of Nafamostat delivered via a different route may be warranted. This trial demonstrates the importance of experimental trials in new disease entities such as COVID-19 prior to selecting drugs for larger trials.

Background: Metals have emerged as a viable therapeutic target for a new generation of anti-cancer and anti-metastatic agents. Copper, an essential trace element, serves as an important catalytic cofactor in several biological functions and has emerged as an essential factor in carcinogenesis. Among other elements, bone marrow derived VEGFR2+ endothelial progenitor cells (EPCs) and copper-dependent lysyl oxidase (LOX) are key elements in tumor progression. We hypothesized tetrathiomolybdate (TM)-associated copper depletion (CD) inhibits tumor metastases by reducing the number of EPCs and other copper dependent processes in the pre-metastatic niche. These results are an update of our previously reported study (Chan N, Willis A, Kornhauser N et al. Influencing the Tumor Microenvironment: Phase 2 Study of Copper Depletion with Tetrathiomolybdate in High Risk Breast Cancer and Preclinical Models of Lung Metastases. Clin Cancer Res. October 21, 2016) with longer follow-up. Methods: A single arm phase II study of breast cancer (BC) patients (pts) at high risk for recurrence, defined as node+ triple negative (TNBC), stage 3 and 4 with no evidence of disease (NED) were enrolled on a trial of CD with TM. TM was given to maintain ceruloplasmin (Cp) levels between 8-16 mg/dl for two years with an extension phase or until relapse. The primary endpoint was a change in EPCs measured by flow cytometry before and during treatment. Secondary endpoints included tolerability, safety, PFS and LOXL-2 levels. Results: Seventy-five pts received 2778 cycles of TM on the primary and extension study. The primary study treatment duration was 24 cycles (each cycle is 28 days) plus an extension phase. The median age is 51 years (range 29-66). Forty-five pts have stage 2/3 BC and 30 with stage 4 NED. Forty-eight percent of pts are TNBC and 40% of pts are stage 4 NED. Median Cp levels were monitored with each cycle. A decrease from 28 to 16 (p Conclusions: TM is safe, well tolerated and appears to affect multiple components of the tumor microenvironment that have been identified in pre-clinical models as important for progression. Ongoing studies in banked specimens are underway to further delineate its effect on copper dependent processes necessary for metastases. Randomized trials are warranted, especially in patients who are at high risk for relapse such as those with TNBC. Citation Format: Sahota S, Willis A, Kornhauser N, Ward M, Cobham M, Cigler T, Moore A, Andreopoulou E, Fitzpatrick V, Schneider S, Prima N, Wiener A, Ko D, De Laurentiis A, Warren JD, Rubinchik A, Mittal V, Vahdat LT. A phase II study of copper-depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence: Updated results [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 P1-10-02.

Background Carotid intraplaque hemorrhage (IPH) seen on vessel wall MRI is associated with an increased risk of stroke or transient ischemic attack, as are microembolic signals (MES) detected by transcranial Doppler (TCD). We sought to examine the association between IPH and MES in acute stroke patients with symptomatic carotid atherosclerosis. Methods Through a retrospective chart review, we included patients from 2011 to 2013 with acute ischemic stroke due to carotid atherosclerosis of varying stenosis who had both 3D volumetric MRI of the neck and TCD emboli monitoring. Results Twenty-four patients met the inclusion criteria. Mean time from stroke to MRI was 1.4 ± 1.9 days and to TCD was 2.6 ± 2.4 days. MES was seen in 10 patients (42%) and IPH was present in seven patients (29%), but we did not find a relationship between MES and IPH ( p = 0.64). Conclusion In patients with recent acute ischemic stroke attributed to carotid atherosclerosis, we did not detect an association between the presence of IPH and MES. While this small study may be underpowered, an alternate explanation is that MES and IPH reflect vulnerable carotid atherosclerosis through different mechanisms. This untested concept warrants prospective study in a larger cohort.

Background: Most women consider hair to be an important part of body image. Alopecia is an emotionally traumatic side effect for breast cancer patients undergoing adjuvant chemotherapy. The DigniCap™ Scalp Cooling System is the first scalp cooling system cleared by the US Food and Drug Administration to reduce the likelihood of chemotherapy induced alopecia. Methods: Quality of Life (QOL) data were collected as part of a prospective clinical trial evaluating the clinical performance of scalp cooling in women with early stage BC receiving adjuvant chemotherapy. The study's primary endpoint was hair loss as evaluated by patient self-assessment. Treatment success was defined as ≤ 50% hair loss. QOL was evaluated by the EORTC-QLQ-BR23 (BR23) administered at baseline, last chemotherapy cycle, and one month later. For BR23, 4 response categories were collapsed to 2 categories (Not at all/A little bit and Quite a bit/Very much) for analysis. QOL was compared between those with success vs. failure of scalp cooling. Results: 101 patients were evaluable for the primary endpoint: Success was seen in 67 (66.3%) pts. QOL at study entry was comparable between pts with scalp cooling success or failure for each item in the BR23 questionnaire. Results reported as percentages of patients in each group who answered either quite a bit or very much to body image-related questions on the BR23 questionnaire are displayed in Table 1. BR23 results (% quite a bit/very much) one month after chemotherapyBR23 ItemsTreatment Success % (95% CI)Treatment Failure % (95% CI)Felt physically less attractive18.5% (9.0%, 27.9%)52.2% (31.8%, 72.6%)Felt less feminine15.4% (6.6%, 24.2%)29.1% (19.2%, 59.1%)Found it difficult to see themselves naked13.8% (5.5%, 22.2%)21.7% (4.9%, 38.6%)Felt dissatisfied with their body12.3% (4.3%, 20.3%)26.1% (8.1%, 44.0%) Conclusions: Women with breast cancer using scalp cooling during chemotherapy who had hair preservation experienced improved quality of life, according to self-assessment of body image, compared to women who had significant hair loss. Citation Format: Cigler T, Melin SA, Klein P, Hurvitz SA, Melisko M, Moore A, Park GD, Bageman E, Ver Hoeve ES, Rugo HS. Body image in women with breast cancer using a scalp cooling system to reduce chemotherapy induced alopecia [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-17.

Transcranial Doppler (TCD) monitoring of the intracranial vessels is useful for the detection of microembolic signals (MES), which can help with risk stratification and evaluation of therapies. The presence of any emboli during a TCD exam is concerning and treatment is controversial. In this case, an unusual high count of emboli were detected in all vessels, which prompted a change in clinical management. It is now believed that the injectable cardiovascular ultrasound contrast agent (Definity®) was the cause of the large number of MES. Ramanathan reported a similar case in which an unusual amount of MES were detected during emboli monitoring (EM) and were felt to be contamination from Definity® contrast injected 2 hours prior to the EM exam. When unexpectedly faced with numerous MES, practitioners should consider other factors that can influence the results of TCD with EM.

Background: An echocardiogram or transcranial Doppler (TCD) bubble study to test for a right-to-left shunt (RLS) is a standard component of an ischemic stroke workup. Because the pathway for an intracradiac RLS, such as a patent foramen ovale (PFO), is more direct, it has been proposed that the late appearance of a RLS suggests an extracardiac pathway. We sought to characterize a cohort of ischemic stroke patients with late RLS (LRLS) on TCD. Methods: We searched the medical record of a Comprehensive Stroke Center for patients with ischemic stroke who had a TCD and echocardiogram bubble study during 2011-2013. LRLS was defined as TCD bubbles appearing more than 18 cardiac cycles after contrast injection. TOAST stroke etiology classification was performed by a vascular neurologist blinded to TCD results. Results: 124 patients met inclusion criteria, of which 67/124 (54%) had RLS on TCD; and 32/67 (48%) had LRLS. In the 35/67 patients with normal RLS on TCD, 23% did not have RLS on echocardiography, consistent with prior reports of TCD’s superiority for detecting RLS. In the 32/67 patients with LRLS on TCD, 56% were negative for RLS by echocardiography. In the cohort of 124 patients, the percentage of TOAST classification 4 (stroke of other determined cause) was 26%, while in the 32 patients with LRLS the percentage of TOAST 4 was significantly higher at 52%(p=0.005) (Table 1). The increase in TOAST 4 in LRLS patients was created by an even distribution of decreases in the other TOAST categories. The most common TOAST 4 stroke etiology in LRLS patients was PFO with concurrent deep venous thrombosis. Conclusion: This preliminary data supports prior studies that have shown superiority of TCD over echocardiography for detection of RLS, and challenge the prevailing notion that extracardiac shunt, such as pulmonary AVM, is the most common cause of LRLS in ischemic stroke patients. This subgroup of patients warrants further research to clarify mechanisms of ischemic stroke in patients with RLS.

The aromatase inhibitor (AI)-associated musculoskeletal (MSK) pain symptoms are often debilitating and limit compliance with this important hormonal breast cancer therapy. The etiology of this syndrome is unknown. Hypovitaminosis D has been suggested as a possible risk factor for the development of MSK symptoms in women starting AIs. The objective of this substudy was to define the prevalence of low 25(OH)D in this population, to assess risk of low levels on developing pain and to define a target therapeutic goal for 25(OH)D in this population. This analysis was part of a 6-month prospective cohort study examining the MSK side effects of adjuvant AI therapy in postmenopausal women. Patients were evaluated by a rheumatologist with a joint examination, had 25(OH)D levels measured and completed quality of life questionnaires at baseline, 3 and 6 months. Symptomatic patients were defined as those that self-reported new or worsening MSK symptoms. Of 52 patients, 28 (54%) were symptomatic, and two (3.8%) stopped AIs due to MSK ailments. Thirteen patients had objective evidence of tendonitis on rheumatologic examination. Thirty-three percent of all subjects had baseline 25(OH)D levels40 ng/mL, 19.2% had levels30 ng/mL and 5.8% had levels20 ng/mL. Symptomatic patients were more likely to have had baseline levels below 40 ng/mL, compared with asymptomatic patients (46.4% versus 16.7%, p = 0.037). In multivariate regression analyses, levels40 ng/mL were associated with developing objective tenosynovitis (p = 0.033) but not with developing nonspecific myalgias. Our findings suggest hypovitaminosis D may be contributing to the AI-associated MSK pain syndrome and in particular to the development of tendonitis. Repletion to 25(OH)D levels40 ng/mL is advisable. Further research should be carried out on identifying additional modifiable risk factors for this syndrome.

Background: Copper is an important catalytic cofactor in several biological functions and is essential for lysyl oxidase (LOX), a key enzyme in cross-linking collagen, which may play a role in tumor metastasis. We hypothesized that tetrathiomolybdate (TM)-associated copper depletion (CD) would inhibit tumor metastases by altering copper dependent collagen remodeling in the pre-metastatic niche. These results are an update of our previously reported clinical outcomes with longer follow-up and translational outcomes implicating the tumor microenvironment in metastatic transformation of BC. Methods: Pts at high risk for recurrence, node+ triple negative (TNBC) or stage 3/4 BC with no evidence of disease (NED), were enrolled on a phase II study of CD with TM. TM was given to maintain ceruloplasmin (Cp) levels between 8-16 mg/dl for two years (yrs) with an extension phase or until relapse. Median Cp levels were monitored with each cycle. Clinical endpoints included safety/tolerability and progression of disease (POD)/death. Event-free (EFS) and overall survival (OS) were calculated using Kaplan Meier survival analyses. Translational endpoints included markers of collagen cross-linking (LOXL-2), formation (PRO-C3), and degradation (C1M and C6M). Results: Seventy-five pts received 2993 cycles of TM on the primary (24 cycles, 28 days per cycle) and extension study. Median age was 51 yrs (range 29-66). Forty-five pts had stage 2/3 BC, and 30 pts were stage 4 NED. At a median follow-up of 8.4 yrs, the overall EFS was 71.4% and OS was 78.8%. The EFS and OS for the 36 pts with TNBC were 71.7% and 81%, and the EFS and OS for the 39 pts with Luminal/HER2+ BC were 71.2% and 78.6% respectively. TM was well tolerated with grade 3/4 toxicities including: neutropenia (1.9%), febrile neutropenia (0.03%), and fatigue (0.2%). LOXL2 levels were significantly decreased at 12 and 24 cycles compared with baseline (p Citation Format: Liu YL, Bager CL, Willumsen N, Kornhauser N, Cobham M, Andreopoulou E, Cigler T, Moore A, LaPolla D, Fitzpatrick V, Ward M, Warren JD, Mittal V, Vahdat LT. A phase II study of copper-depletion using tetrathiomolybdate (TM) in patients (pts) with high risk breast cancer (BC): Role of collagen processing and tumor microenvironment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD9-07.

Background: Peripheral neuropathy is a dose-limiting toxicity of most microtubule-stabilizing chemotherapeutic agents. Ixabepilone, a semisynthetic analog of the natural epothilone B, has activity in a wide range of tumors including taxane-resistant disease. In this study, we sought to understand the effect of ixabepilone on the development of peripheral neuropathy both clinically and its effect at the ultrastructural level of the peripheral nerves and circulating factors over time. Parallel studies in animal models of neuropathy were performed at the same time (Proc AACR 2010 Abstract 4184). Methods: This open-label, non-randomized phase II study enrolled 14 patients with metastatic breast cancer. Ixabepilone was administered by 2 schedules: the FDA approved dose of 40 mg/m2 every 3 weeks (q3w) and 16 mg/m2 on day 1, 8, and 15 of a 28-day cycle (weekly). Five controls, 2 with residual taxane-associated peripheral neuropathy and 3 with no prior chemotherapy or peripheral neuropathy, were also accrued. The primary objectives were to characterize the natural history of ixabepilone-associated peripheral neuropathy using the Total Neuropathy Score Clinical (TNSc) assessment tool prior to each cycle and to correlate changes in the ultrastructure of dermal myelinated nerve fibers via a 3 mm punch biopsy of an area 10 cm above the lateral malleolus every 2 cycles with electron microscopy (EM), as well as circulating factors (both inflammatory and neurotrophic) considered to be important in the pathogenesis of chemotherapy-induced peripheral neuropathy. Secondary objectives included progression-free survival (PFS) and non-neurologic toxicity. Results: 14 patients were enrolled and were equally divided between the 2 schedules of ixabepilone chemotherapy. There were no differences in baseline characteristics between the two groups. Mean age was 54 years (range 32–71). Mean number of previous chemotherapy regimens was 3.5 (range 0–8). 57% of patients had received a taxane in the adjuvant setting and 64% in the metastatic setting. The mean neuropathy score (TNSc) at baseline was 4.6 (range 1–11). At a mean cumulative dose of 185 mg/m2, the TNSc with ixabepilone q3w schedule was 3.7 points higher/worse (95% CI: 2.2–5.3, p = 0.03) than the mean score observed in patients on the weekly schedule. The sensory component was most significantly affected, predominantly numbness. In 3 patients, the chemotherapy schedule was changed from every 3 weeks to weekly due to > grade 2 toxicity at a mean cumulative dose of 107 mg/m2, and TNSc decreased/improved by 2.7 points. PFS in patients on q3w ixabepilone was 133 days (range 28–280) and in patients on weekly ixabepilone was 179 days (range 66–336), nonsignificant. Evaluation of EM and circulating factors is ongoing. Conclusions: Weekly ixabepilone appears to have a more favorable neurotoxicity profile compared to the standard q3w schedule. Integration of the EM data and the circulating factor data are underway and will be presented. Ixabepilone-associated peripheral neuropathy may improve in patients switched to weekly ixabepilone without compromising efficacy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-07.

Background: Bone marrow-derived endothelial progenitor cells (EPCs) constitute an important part of the tumor microenvironment and are critical for metastatic progression in preclinical models and breast cancer patients (Jain et al, Breast Cancer Res Treat, 2012). Tetrathiomolybdate (TM), a copper-depleting compound inhibits angiogenesis, tumor growth, and metastasis. This study explores the effect of TM on EPCs in patients at high risk for breast cancer recurrence. Methods: This phase II study enrolled stage 3, 4 without evidence of disease (NED), and any node-positive triple negative breast cancer patient. Only concomitant hormone therapy was allowed. Patients received induction TM 180 mg daily at baseline followed by an equal or lower daily dose (median 100 mg, range 0–140) to maintain ceruloplasmin (Cp) level < 17 mg/dl (target for copper depletion). We monitored EPCs (CD45dim/CD133+/VEGFR2+), Cp, CEA, and CA15-3 at baseline and monthly. Wilcoxon signed-rank was used to compare Cp and EPC levels between baseline and subsequent time points. All p-values were two-sided with statistical significance evaluated at the 0.05 alpha level. Results: 50 patients (33 adjuvant, 17 Stage 4 NED, and 22 triple negative) were enrolled. In the first 40 patients enrolled who had received at least 24 months of TM, EPC and Cp data were available for analysis. Of these 40 patients, 1 patient did not take TM due to patient preference, and 736 cycles of TM (average 18.9 per patient) were administered. Median age was 50 years (range 29–66). Median number of tumor size and positive lymph nodes among adjuvant patients were 3.5 cm (range 1.2–7) and 9 (range 0–42), respectively. Of the patients receiving hormone therapy, 11 patients were on tamoxifen and 16 patients were on an aromatase inhibitor. Median baseline Cp level was 30 mg/dL (range 20–47). 71% patients adequately copper depleted at month 1 to a mean Cp of 14.8 mg/dL. A larger proportion of triple negative patients copper depleted (82%) compared to hormone receptor positive subtypes (47%) and HER2/neu positive subtypes (67%). Median EPCs/ml decreased from baseline to last dose by 16 in patients that achieved the copper depletion target, p = 0.014. Conversely, in patients that did not copper deplete, median EPCs/ml increased by 136, p = 0.005. Of the 50 patients on study, 7 patients relapsed in which a significant increase in EPCs preceded an objective clinical relapse and a tumor marker rise by a median of 1 month. Only grade 3/4 toxicity was hematologic, occurred in 49 cycles (6.7%), and resolved in 5–13 days with TM held and resumed at a lower dose. Conclusions: TM is a well-tolerated oral copper chelator that may contribute to maintaining EPCs below baseline in copper-depleted patients. Molecular subtype may impact on the ability to copper deplete. EPCs may have potential as a surrogate marker for early relapse and as a therapeutic target for interrupting the metastatic progression. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-04.

BACKGROUND: Although the routine use of treatment plans and summaries (TPSs) has been recommended to improve the quality of cancer care, limited data exist about their impact on quality, including patient satisfaction and coordination of care. METHODS: Patients received TPSs as part of the American Society of Clinical Oncology Breast Cancer Registry (BCR) pilot program of 20 community oncology practices. Participants were surveyed 2 to 4 weeks after receiving a TPS to evaluate their perceptions of the document. Patients who were receiving chemotherapy received the TPS as separate plan and summary documents (at the start and the end of treatment) and could complete 2 surveys. Others received a single integrated TPS. Eligible survey participants had stage 0 through III breast cancer and were enrolled in the BCR. RESULTS: Of 292 consented patients, 174 (60%) completed at least 1 survey. Of 157 patients who recalled receiving a TPS, 148 (94%) believed that the documents improved patient-physician communication, and 128 (82%) believed that they improved communication between physicians; 113 (72%) said the documents increased their peace of mind, whereas 2 (1%) had less peace of mind. Of 152 patients (97%) who still had their documents, 147 (97%) said they were useful, and 94 (62%) had given or planned to give the documents to another physician. All 63 patients who were surveyed after receiving a summary recommended that practices continue to provide TPSs to patients. CONCLUSIONS: Participants in this study expressed high satisfaction with TPSs. Additional research is needed to study the broad-scale implementation of the BCR and to evaluate the impact of routine use of TPSs on the quality of care delivered. Cancer 2013. © 2012 American Cancer Society.

Objective. To define the musculoskeletal syndrome associated with use of aromatase inhibitors (AIs), specifically, to describe its incidence, time to onset, risk factors, and clinical presentation. Methods. Postmenopausal women with hormone-sensitive, nonmetastatic breast cancer starting AI therapy were enrolled in this prospective cohort study. They underwent complete rheumatologic evaluation and contrast-enhanced magnetic resonance imaging (MRI) of the hands and wrists prior to starting AI, at 3 and 6 months. The primary outcome was change in grip strength. Results. Twenty-eight (54%) of 52 women reported new or worsening musculoskeletal symptoms. Two discontinued AIs due to pain. Mean time to symptom onset was 6 weeks (range 2–18 weeks), and 75% of symptomatic patients developed symptoms by 8 weeks. Later-stage cancer and worse quality of life (QOL) pretreatment were significantly associated with symptom development. Sixty-eight percent of symptomatic subjects had involvement of the hands; however, there was no difference in the mean change in grip strength (2.9 kg versus 1.3 kg; P 0.6). Among symptomatic subjects, 46% had evidence of focal tenosynovitis of the hands and feet on examination. Although some symptomatic subjects had new MRI abnormalities, Rheumatoid Arthritis Magnetic Resonance Imaging Scoring did not significantly change. Conclusion. The incidence of AI-associated musculoskeletal syndrome is more than 50%, with most women developing symptoms by 8 weeks. The key finding in symptomatic women was focal tenosynovitis of the hands and feet, without evidence of autoimmune disease or systemic inflammation. Later-stage cancer and poorer QOL were predictive of symptom development.

Purpose Most menopausal women experience vasomotor symptoms, vulvar-vaginal atrophy, and/or bone loss. Although available estrogen and progestin therapies are effective in treating menopausal symptoms and preventing bone loss, some women may seek a therapy that provides symptom relief and has an improved tolerability profile. One option is a tissue-selective estrogen complex (TSEC), or the pairing of estrogen(s) with a selective estrogen receptor modulator (SERM) to achieve the benefits of each component with fewer side effects. The first TSEC in clinical development combines the SERM bazedoxifene (BZA) with conjugated estrogens (CEs). The purpose of this article is to review published data for BZA/CE. Data sources Data were obtained from phase 3 BZA/CE clinical trial study articles. Conclusions Daily BZA 20 mg/CE 0.625 mg or 0.45 mg effectively relieved hot flushes, maintained or increased bone mineral density, treated vulvar-vaginal atrophy, and improved quality of life. Further, BZA prevented stimulation of the endometrium by CE, and resulted in rates of amenorrhea and breast pain similar to placebo. Implications for practice These results support the use of a TSEC consisting of BZA/CE as a promising therapy for managing the signs and symptoms from reduced estrogen levels associated with menopause.

A 40-year-old woman with prior history of headaches, left-sided weakness, and diplopia was diagnosed with right sigmoid and transverse sinus thrombosis; increased intracranial pressure and associated cerebral venous infarction that underwent 12 months anticoagulation and then stopped. She has been off anticoagulation for about a year then started not “feeling right,” and was diagnosed with pneumonia and pulmonary embolism. During her course of hospitalization, she presented with progressive headache, possible left-sided weakness, associated blurry vision, nausea, and vomiting. Magnetic resonance venogram (MRV) shows lack of flow-related signals within the left half of the distal superior sagittal sinus, left transverse sinus, and nonocclusive thrombus in the left sigmoid sinus. Mechanical sinus thrombectomy attempted without significant difference in clot burden. A transcranial Doppler (TCD) emboli monitoring exam was ordered and was performed on the bilateral internal jugular for 15 min each. Microembolic signals detected: 52 emboli per hour right internal jugular vein (IJV), and 32 emboli per hour left IJV. She was discharged on methazolamide, furosemide, topiramate, and lifelong warfarin. No major events have been reported since discharge from 2008 to 2016.

Animal models have demonstrated the critical role of bone marrow-derived VEGFR1(+) hematopoietic progenitor cells (HPCs) and VEGFR2(+) endothelial progenitor cells (EPCs) in metastatic progression. We explored whether these cells could predict relapse and response in breast cancer (BC) patients. One hundred and thirty-two patients with stages 1-4 BC were enrolled on 2 studies. Circulating CD45(+)/CD34(+)/VEGFR1(+) HPCs and CD45(dim)/CD133(+)/VEGFR2(+) EPCs were assessed from peripheral blood mononuclear cells using flow cytometry. Changes in HPCs and EPCs were analyzed in (1) patients without overt disease that relapsed and (2) metastatic patients according to response by RECIST. At study entry, 102 patients were without evidence of disease and 30 patients had metastatic BC. Seven patients without evidence of BC by exam, labs, and imaging developed recurrence while on study. Median HPC/ml (range) increased from 645.8 (23.5-1,914) to 2,899 (1,176-37,336), P = 0.016, followed by an increase in median EPC/ml from 21.3 (4.7-42.5) to 94.7 (28.2-201.3), P = 0.016, prior to clinical relapse. In metastatic patients with progressive disease, median HPC/ml increased from 1,696 (10-16,470) to 5,124 (374-77,605), P = 0.0009, and median EPC/ml increased from 26 (0-560) to 71 (0-615) prior to progression, P = 0.10. In patients with responding disease, median HPC/ml decreased from 6,147 (912-85,070) to 633 (47-18,065), P = 0.05, and EPC/ml decreased from 46 (0-197) to 23 (0-105), P = 0.41, at response. There were no significant changes in these cells over time in patients with stable disease. Circulating bone marrow-derived HPCs and EPCs predict relapse and disease progression in BC patients.

Background We analysed the influence of gender on use and outcomes of first-line HAART in a UK cohort. Methods Analyses included heterosexuals starting HAART from 1998-2007 with pre-treatment CD4+ T-cell count 3 and viral load (VL)>500 copies/ml. Virological suppression (500 copies/ml), CD4+ T-cell counts at 6 and 12 months, clinical events and treatment discontinuation/switch in the first year of HAART were compared using linear, logistic and Cox regression. Results Compared with women ( n=2,179), men ( n=1,487) were older and had lower CD4+ T-cell count and higher VL at start of HAART. Median follow-up was 3.8 years (IQR 2.0-6.2). At 6 and 12 months, 72.7% and 75.3% had VL≤50 copies/ml, with no large differences between genders at either time after adjustment for confounders (6 months, OR 0.92 [95% CI 0.76-1.13]; 12 months, OR 1.06 [95% CI 0.85-1.31]). Overall, 79.4% patients achieved virological suppression and 19.2% experienced virological rebound, without gender differences, although men had an increased risk of rebound after excluding pregnant women (adjusted relative hazard [RH] 1.33 [95% CI 1.04–1.71]). Mean CD4+ T-cell count increases at 6 and 12 months were, respectively, 11 2 and 156 cells/mm3 overall, with mean differences between men and women of -14.6 cells/mm3 (95% CI -24.6—4.5) and -12.1 cells/mm3 (95% CI -24.4– 0.2) at 6 and 12 months, respectively. Clinical progression was similar in men and women, but men were less likely to experience treatment discontinuation/switch (adjusted RH 0.72 [95% CI 0.63–0.83]). Conclusions Despite higher discontinuation rates among women, men had an increased risk of virological rebound and slightly poorer CD4+ T-cell count responses. Identifying the reasons underlying treatment discontinuation/switch may help optimize treatment strategies for both genders.

Background: Bone marrow (BM) derived endothelial progenitor cells (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 copperdepleting compound, inhibits angiogenesis and maintains tumor dormancy through unknown mechanisms. We sought to measure the effect of TM on BM derived EPCs in pts at high risk of BC recurrence and to evaluate the effect of copper depletion on their absolute number. 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). Initial study duration is 24 mos. Extension study for an additional 24 mos in selected pts. Results: 40 pts are enrolled and 566 cycles of TM have been administered. Adjuvant: 28 pts, Stage 4 NED: 12 pts, Triple negative: 11 pts (4 stage 4 NED, 7 Adjuvant). Median age is 51 yrs (range: 29-64). Median number of positive lymph nodes among Stage 2/3 pts is 7 (4-42). Median baseline Cp level is 29 mg/dL (21-47). Among 36 pts who have reached target Cp, the median time to target is 4 wks (2-20 wks). Four pts discontinued treatment before reaching target. The median baseline EPCs is 0.01 cells/ml (0.0-0.286), and the majority of pts’ EPCs were maintained below baseline when Cp levels remained below target (i.e. copper depleted). Toxicity: Grade 3/4 neutropenia occurred in 15 cycles (2.6%) with 1 pt with febrile neutropenia. One cycle was complicated by Grade 3 anemia. All resolved 5-13 days later with TM held and resumed at a lower dose. No other grade 3/4 toxicity was observed. Six pts were diagnosed with recurrent breast cancer at 1, 2, 2, 9, 10 and 10 mos. An EPC rise preceded an abnormal marker or overt relapse by 3-5 months in 4 of 6 pts (2 pts too early to tell). 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 4 pts with recurrent disease 2-4 months prior to overt relapse could represent the turning on of an angiogenic switch, resulting in an outpouring of BM derived EPCs to the new site of metastasis. Other studies geared toward understanding the mechanism for metastases are underway. The trial continues to accrue. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-16-14.

Background: The etiology of Aromatase Inhibitor (AI) associated musculoskeletal symptoms remains unclear. It has been proposed that musculoskeletal side effects are related to the estrogen depletion achieved on AI therapy. Estrogen depletion with AI therapy is known to result in endocrine side effects. The 18-item Functional Assessment of Cancer Therapy Breast Cancer-Endocrine Subscale (FACTB-ES) is a reliable and well validated quality of life questionnaire shown to be sensitive to changes in endocrine symptoms in breast cancer patients. The objective of this study was to determine whether among women with breast cancer treated with adjuvant AI therapy, self reported musculoskeletal side effects correlate with increased hormonal side effects as measured by the FACTB-ES. Methods: In this 6 month, single center, prospective cohort study, post-menopausal women with hormone-sensitive, non-metastatic breast cancer prescribed AIs by their treating oncologist were evaluated by a rheumatologist at baseline (before starting the AI) and at 6 months. Women who reported new or worsening musculoskeletal symptoms since starting the AI were classified as symptomatic. The FACTB-ES was administered at each visit. Changes in scores between baseline and 6 months were compared between the symptomatic and asymptomatic groups Results: Thirty-five subjects completed the 6 month follow up period. Nineteen (54%) were symptomatic and n=2 (5.7%) discontinued the AI due to these musculoskeletal symptoms. Mean time to onset of symptoms was 6 weeks (range 2 to 18 weeks). Baseline characteristics including age, ethnicity and body mass index did not differ between the groups. There was no significant difference in hormonal symptoms between groups. Both groups had equivalent worsening of their endocrine symptoms as seen by the reduction in their FACTB-score. The mean change in FACTB-ES score was -2.52 (range: -31.00, 23.00) in the symptomatic women versus -2.06 (range: -19.00, 22.21) in the asymptomatic women (Wilcoxon rank sum p=0.95). Conclusions: These data suggest that endocrine symptoms as measured by the FACTB-ES do not correlate with the development of musculoskeletal pain in women treated with adjuvant AI therapy for breast cancer. Though larger studies are necessary to confirm these results, the musculoskeletal symptoms associated with AI use may not be estrogen-dependent. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-15-06.

Metastases to the contralateral axillary lymph nodes in breast cancer patients are uncommon. Involvement of the contralateral axilla is a manifestation of systemic disease (stage IV) or a regional metastasis from a new occult primary (T0N1, stage II). The uncertain laterality of the cancer responsible for these metastases complicates overall disease staging and is a management dilemma for clinicians. Seven women who developed contralateral axillary metastases (CAM), but did not have evidence of systemic disease were identified. Patient demographics, histopathologic tumor characteristics, treatment and outcome were examined. The median age was 49 years. A family history of breast cancer was present in six (86%). The initial breast cancers were located in all quadrants. They were generally hormone receptor negative, HER-2/neu overexpressing and associated with lymphovascular invasion. There was a median interval of 71 months between initial breast cancer diagnosis and CAM presentation. Surgical management of the CAM included simple excision in one (14%) and axillary lymph node dissection in five (71%). Adjuvant treatment consisted of chemotherapy in seven (100%) and hormonal therapy in one (14%). The median follow-up from the diagnosis of CAM was 35 months and three women were alive without disease, two were alive with disease and two had died of disease. With surgical treatment, there were no axillary recurrences in this series. When patients present with CAM and no evidence of systemic disease or a new primary in the contralateral breast, surgical treatment should be considered for local control and possibly improved relapse-free survival.

Tumor growth and metastasis is dependent on the formation and assembly of new blood vessels, a process known as neo-angiogenesis. Both pre-existing and circulating vascular cells have been shown to contribute to the assembly of tumor neo-vessels in specific tumors. Mobilization of endothelial progenitor cells (EPCs) from the bone marrow constitutes a crucial step in the formation of de novo blood vessels, and levels of peripheral blood EPCs have been shown to be increased in certain malignant states. However, the role of circulating EPCs in breast cancer is largely unknown. We recruited twenty-five patients with biopsy-proven invasive breast cancer at Weill Cornell Breast Center to participate in a pilot study investigating the correlation of circulating EPCs to extent of disease and initiation of chemotherapy. For each patient, a baseline sample was drawn before systemic treatment, and for seventeen of those patients, a second sample was taken after the first round of chemotherapy. Levels of peripheral blood EPCs, as defined by co-expression of CD133 and VEGFR2, were quantified by flow cytometry. Breast cancer patients with stage III & IV disease had statistically higher levels of circulating EPCs than did patients with stage I & II disease (median = 165,000 EPCs/5 x 10(6)MNCs vs. median = 6,920 EPCs/5 x 10(6)MNCs, respectively, P < 0.0001). In addition, in late-stage patients, levels of EPCs demonstrated a statistically significant drop after initiation of chemotherapy (median = 162,500 EPCs/5 x 10(6)MNCs [pre] vs. median = 117,500 EPCs/5 x 10(6)MNCs [post], P = 0.01). These results suggest that circulating EPCs may serve as a potential tumor biomarker in breast cancer and that EPCs may represent a plausible target for future therapeutic intervention.

Although the association between patent foramen ovale and ischemic stroke is controversial, the evaluation for a right-to-left shunt remains part of the standard workup for cryptogenic stroke. Transthoracic and transesophageal echocardiogram (TTE and TEE) are the screening test and gold standard to evaluate for right-to-left shunt, respectively. Studies comparing TTE or TEE to transcranial Doppler (TCD) have shown that 15-25 % of patients test positive for right-to-left shunt on TCD but are negative on TTE or TEE. We sought to further explore this phenomenon in patients with recent ischemic stroke. Between 2011 and 2013, 109 ischemic stroke patients had both a TCD and TTE or TEE bubble study. We abstracted 12 comorbid medical conditions and stroke subtype according to the TOAST classification. The majority of TCD and TTE or TEE showed agreement on right-to-left shunt status (80/109, 73 %). Two percent (2/109) of patients were negative on TCD and positive on TTE or TEE, while 25 % (27/109) had a positive TCD and negative TTE or TEE (TCD+Echo-). The TCD+Echo- patients were more likely to have active malignancy and the delayed arrival of contrast bubbles than the remainder of the cohort (15 vs. 2 %, p = 0.032; 51 vs. 18 %, p = 0.001). Our results confirm previous reports that TCD is superior to echocardiography in the detection of right-to-left shunt. The TCD+Echo- patients were more likely to have active malignancy and findings suggestive of an extracardiac shunt. These results could lead to more comprehensive evaluation for occult malignancy or a pulmonary arteriovenous malformation, both potentially treatable etiologies of ischemic stroke.

Background Variations in single nucleotide polymorphisms (SNPs) have been associated with enhanced drug efficacy and toxicity in cancer therapy. SNP variations in the ErbB2 gene have been identified that alter the protein sequence of the HER2-neu protein, but how these polymorphisms affect prognosis and response to HER2 targeted therapy is unknown. We examined eleven ErbB2 SNPs that alter the HER2-neu amino acid sequence to determine whether any of these particular polymorphisms were associated with increased trastuzumab cardiotoxicity in a case–control study. Methods 140 subjects were enrolled from a single institution under Weill Cornell Medical College IRB protocol #0804009734. Patients were eligible if they had histologically or cytologically proven HER2-neu positive breast cancer and more than 3 months of trastuzumab therapy. Cases had either symptomatic CHF or a decline in LVEF of 15% (or if the LVEF

To determine if chronic gastritis (CG) is associated with gastric dysrhythmia or delayed solid emptying in children with dyspepsia, 22 patients (7-15 years of age) with dyspepsia and normal gross endoscopies were studied. Antral biopsies were evaluated for chronic gastritis, and immunohistology was performed to determine densities of CD3+, CD20+, CD25+, and tryptase-positive cells. Electrogastrography (EGG) and gastric scintiscan evaluation were performed within 2-7 days of endoscopy. CG and increased immune cell densities were not associated with altered gastric emptying. Mean CD3+ cell counts were positively correlated with the percentage normal slow waves, and patients with a normal EGG had increased CD3+ cell density. In children with dyspepsia, chronic antral inflammation in the setting of a normal gross endoscopy is not associated with EGG abnormalities or delayed solid emptying. Chronic gastritis and gastric dysrhythmia may simply be two separate and distinct mechanisms resulting in the clinical entity of dyspepsia.

2557 Background: The tumor microenvironment (TME) plays a critical role in the spread of tumors. Bone marrow derived VEGFR2+endothelial progenitor cells (EPCs) and copper-dependent lysyl oxidase (LOX) are key in tumor progression. We hypothesized TM-associated copper depletion inhibits tumor metastases by reducing the number of EPCs and other copper dependent (CD) processes in the pre-metastatic niche. These results are an update with longer follow-up. Methods: Phase II study of BC pts at high risk for recurrence, defined as node+ triple negative (TNBC), stage 3 and 4 with no evidence of disease (NED) were enrolled on a trial of CD with TM. Ceruloplasmin (Cp) levels were maintained between 8-16 mg/dl for two years with an extension phase or until relapse. The primary endpoint was change in EPCs measured by flow cytometry before and during treatment. Secondary endpoints included tolerability, safety, PFS and LOXL-2 levels. Results: 75 pts received 2650 cycles of TM on primary and extension study. The median age is 51 years (range 29-66). Forty-five pts have stage 2/3 BC and 30 with stage 4 NED. TNBC pts were 48% and 40% of pts are stage 4 NED. Median Cp level decreased from 28 to 16 (p < 0.0001) after one cycle. Copper depletion was most efficient in TNBC where Cp levels dropped from 23.5 to 13 after one cycle. TM was well tolerated with grade 3/4 toxicities including: reversible neutropenia (2.3%), febrile neutropenia (0.04%), fatigue (0.2%). Five-year analysis showed a decrease in EPC’s (p = 0.004) and LOXL-2 (p < 0.001). At a median follow-up of 6.9 years, the EFS for 75 pts is 75.6%. PFS for 36 pts with TNBC is 79.2%. EFS for stage 2/3 TNBC is 90% and for stage IV TNBC is 66.7%. Conclusions: TM is safe, well tolerated and appears to affect multiple components of the TME creating an inhospitable environment for tumor progression especially in high risk patients such as TNBC. Randomized trials are warranted, especially in patients at high risk for relapse. Clinical trial information: UL1TR000457.

The widespread use of mammography has made the detection of increasingly small, often impalpable, invasive breast carcinomas possible. An enhanced understanding of morphological factors, among the foremost of which is size of invasive component of carcinoma, is changing the management of breast cancer. To the uninitiated, the determination of size of invasive component is seemingly simple but in practical terms is complicated by a number of ambiguous issues. Practical guidelines for the assessment of size of invasive carcinoma are proposed.

Adjuvant therapy for breast cancer — treatment after surgical removal of the tumor — is a major therapeutic advance that has had a considerable effect on prolonging disease-free and overall survival. Not all patients benefit from adjuvant therapy, however, and certain types of adjuvant therapy are not appropriate for some patients. For example, adjuvant treatment with tamoxifen, a selective estrogen-receptor modulator, has improved the 15-year survival rate among women with estrogen-receptor–positive breast cancer by 31%, but it does not benefit women with estrogen-receptor–negative disease.1 Trastuzumab, a monoclonal antibody against the human epidermal growth factor receptor type 2 (HER2), is associated . . .

BACKGROUND Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. This study explores the effect of tetrathiomolybdate (TM), an anti-angiogenic copper chelator, on EPCs in patients at high risk for breast cancer recurrence. PATIENTS AND METHODS This phase 2 study enrolled breast cancer patients with stage 3 and stage 4 without evidence of disease (NED), and stage 2 if triple-negative. TM 100 mg orally was administered to maintain ceruloplasmin

Background: The pre-metastatic niche mobilizes copper to assist in conditioning the tumor microenvironment facilitating tumor progression. This includes bone marrow derived VEGFR2+ endothelial progenitor cells (EPCs) and copper-dependent lysyl oxidase (LOX). We hypothesized that TM-associated CD would reduce EPCs and other copper dependent processes in the pre-metastatic niche in BC pts. Methods: Stage 2 triple negative BC, Stage 3 and stage 4 without any evidence of disease, (NED) BC pts, received oral TM to maintain ceruloplasmin (Cp) between 8-17mg/dL for 2 years or until relapse. Endpoints included change in EPCs, safety, disease-free (DFS) and overall survival (OS) and effect on biomarkers. Laboratory studies: MDA-LM2-luciferase cells were implanted into CB17-SCID mice, and treated with TM or water. Tumor progression was quantified by bioluminescence imaging (BLI), CD status by Cp oxidase levels, lysyl oxidase (LOXL2) activity by ELISA, and collagen deposition by Picrosirius Red staining and Second Harmonic Generation (SHG) imaging analysis. Results: 75 pts (45 stage 2/3 BC, 30 stage 4 NED) received over 2400 cycles of TM on the primary and extension studies. Median age: 51 yrs (range 29-66). Of the 75 pts, 48% had TNBC, 40% were stage 4 NED. Median Cp level decreased from 28 at baseline to 15.5 (p Conclusions: TM is safe, well tolerated and appears to affect multiple copper dependent biologic processes in the tumor microenvironment known to be important for tumor progression, most striking in TNBC. Randomized trials in a high risk for relapse population are warranted. Citation Format: Eleni Nackos, Sharrell Lee, Amy Willis, Naomi Kornhauser, Maureen Ward, Marta Cobham, Tessa Cigler, Anne Moore, Veronica Fitzpatrick, Sarah Schneider, Alysia Wiener, Jessica Guillaume-Abraham, Bo Ri Seo, J David Warren, Anna Rubinchik, Claudia Fischbach, Vivek Mittal, Linda Vahdat. Copper depletion as a strategy to affect the tumor microenvironment in breast cancer patients at high risk of relapse and in triple negative preclinical models of breast cancer: Updated results of a phase II study of tetrathiomolybdate (TM) in breast cancer (BC) patients (pts) at high risk for recurrence. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-349.

Breast cancer prognosis and breast cancer molecular subtype vary by race/ethnicity. We determined whether the distribution of breast cancer subtypes varies among different Asian ethnic groups. Using immunohistochemical surrogates for the four molecularly defined breast cancer subtypes, we characterized breast cancer subtype for 346 Asian subjects treated at two New York City institutions. We found that Chinese and Japanese had a higher proportion of good-prognosis luminal A cancers (66.7 and 80.0%, respectively) compared to Filipinos and Koreans (48.5 and 47.1%) (P = 0.001). Filipinos had a higher proportion of HER-2/neu positive cancers (45.6%) compared to other ethnic groups (23.6%) (P = 0.002). Koreans had a higher proportion of triple negative cancers (23.5%) compared to other ethnic groups (7.5%) (P = 0.06). The results suggest that differences exist in breast cancer tumor biology among distinct Asian ethnic groups and have implications for cancer care and research. Future studies of breast cancer in Asian-Americans should distinguish among the different ethnic groups.

The aims of this study were to determine the electrogastrographic patterns in children with functional dyspepsia and to investigate the correlations among electrogastrogram (EGG), gastric emptying (GE), and pain severity.We studied 30 children (19 F; mean age 11.4 years) with functional dyspepsia. Electrogastrography was performed for 30 minutes fasting and for 1 hour during a GE test after ingestion of an isotope-labeled solid meal. The percent emptying was measured every 10 minutes for 1 hour after the meal. The dominant frequency of the EGG, the change in the postprandial peak power (deltaP), and percent dysrhythmia during each recording session were calculated. Specific symptoms were graded from 0 (none) to 4 (severe) by the patient.Of 30 patients, 14 (47%) had slow GE, and 15 (50%) had abnormal EGG (dysrhythmiaor = 30% or deltaP0). GE was slow in 73% of patients with an abnormal EGG but was slow in only 20% of patients with normal EGG (P = 0.009). GE was negatively correlated with fasting bradygastria (r = -0.383, P = 0.04). Abdominal pain was the most severe dyspeptic symptom, both during fasting and after the meal. Patients with an abnormal EGG had an increased mean pain severity score (3.5 +/- 0.2 vs. 2.5 +/- 0.2, P = 0.002).Sixty percent of functional dyspepsia subjects had either slow GE or abnormal EGG. Patients with abnormal EGG were more likely to have slow GE. EGG abnormalities were associated with more severe postprandial pain and should be considered a possible mechanism for dyspeptic symptoms.

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 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

PURPOSE: Most breast cancer survivors experience hot flashes; many use complementary or alternative remedies for these symptoms. We undertook a randomized clinical trial of black cohosh, a widely used herbal remedy for menopausal symptoms, among breast cancer patients. PATIENTS AND METHODS: Patients diagnosed with breast cancer who had completed their primary treatment were randomly assigned to black cohosh or placebo, stratified on tamoxifen use. At enrollment, patients completed a questionnaire about demographic factors and menopausal symptoms. Before starting to take the pills and at 30 and 60 days, they completed a 4-day hot flash diary. At the final visit, they completed another menopausal symptom questionnaire. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured in a subset of patients at the first and final visits. RESULTS: Of 85 patients (59 on tamoxifen, 26 not on tamoxifen) enrolled in the study, 42 were assigned to treatment and 43 were assigned to placebo; 69 completed all three hot flash diaries. Both treatment and placebo groups reported declines in number and intensity of hot flashes; the differences between the groups were not statistically significant. Both groups also reported improvements in menopausal symptoms that were, for the most part, not significantly different. Changes in blood levels of FSH and LH also did not differ in the two groups. CONCLUSION: Black cohosh was not significantly more efficacious than placebo against most menopausal symptoms, including number and intensity of hot flashes. Our study illustrates the feasibility and value of standard clinical trial methodology in assessing the efficacy and safety of herbal agents.

Background: Treatment with trastuzumab prolongs overall survival when given to patients (pts) with Her2/neu+ breast cancer (BC). The primary toxicity of trastuzumab is cardiotoxicity and the incidence is estimated at 2-4% in the adjuvant setting. The mechanism for trastuzumab-induced cardiotoxicity is not known. Although Her2neu expression is usually not seen on cardiac myocytes, its expression has been shown to be upregulated after chemotherapy. Trastuzumab is a monoclonal antibody that binds to the extracellular domain of Her2/neu. We hypothesized that single nucleotide polymorphisms (SNPs) in the Her2/neu receptor may play a role in trastuzumab associated cardiotoxicity. Methods: 140 pts with BC who were treated with chemotherapy and trastuzumab were enrolled into an IRB approved protocol at the Weill Cornell Medical College between July 2008 and March 2013. Cardiotoxicity was defined as either symptomatic CHF, or a decline in LVEF of 15% (or if LVEF Results: 140 subjects (29 with cardiotoxicity and 111 without) had 11 SNPs sequenced. Median age of subjects was 56 years (range: 32-85), mean baseline LVEF was 65% (±6%). 16.4% of subjects had hypertension (HTN). 80% of patients were Caucasian, 10% East Asian, 7.1% African American, 2.9% South Asian. There were two SNPs for which there was variation seen among subjects: rs 1136201 (corresponding to codon 655) and rs61552325 (codon 1170). The frequencies of the codon 655 polymorphisms were: AA (Ile/Ile) 67.9%, AG (Ile/Val) 29.3%, and GG (Val/Val) 2.9%. The frequencies of the codon 1170 polymorphisms were: CC (Pro/Pro) 20.7%, GC (Ala/Pro) 45.7%, and GG (Ala/Ala) 33.6%. There was no association observed between the codon 655 polymorphism and cardiotoxicity (p = 0.96). A significant association between cardiotoxicity and the codon 1170 polymorphism was observed, with subjects having cardiotoxicity being more likely to carry the CC allele compared with subjects without cardiotoxicity (34.5% vs 17.1%, p = 0.04). This association persisted after multivariable adjustment for age, race, and HTN status (adjusted OR = 2.60, 95% CI = 1.02-6.62, p = 0.046). Conclusion: In this study, the Her2/neu 1170 Pro/Pro polymorphism was associated with trastuzumab cardiotoxicity. If confirmed in a larger series, this polymorphism could be used to identify pts who may be at increased risk for cardiotoxicity and who may benefit from treatments associated with less cardiotoxicity. Furthermore, the Her2/neu 1170 SNP has previously been implicated as a minor histocompatibility antigen, and our findings raise the possibility that immune mediated mechanisms may play a role in trastuzumab related cardiotoxicity. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-06.

e20641 Background: Chemotherapy induced alopecia (CIA) is a distressing adverse effect of many chemotherapy agents. The TC chemotherapy regimen (four cycles of docetaxel 75mg/m2 and cyclophosphamide 600mg/m2 given every 3 weeks apart) commonly used for aduvant therapy of breast cancer is associated with complete alopecia, with rare reports of permanent alopecia. Scalp cryotherapy has been reported to minimize or prevent CIA. Penguin cold caps are a commercially available scalp cooling product gaining increasing media attention. We conducted a prospective study aimed to assess efficacy of scalp cryotherpy in preventing CIA among women receiving adjuvant TC chemotherapy for early stage breast cancer who independently elected to use Penguin cold caps. Methods: Women at the Weill Cornell Breast Center who elected to use scalp cryotherapy with Penguin cold caps during adjuvant TC chemotherapy were asked to participate in the study. Degree of hair loss was rated by practitioner assessment using Dean’s alopecia scale (poor (>75% hair loss), moderate (50-75%), good (25-50%) or excellent (

Background: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. Tetrathiomolybdate (TM), a copper-depleting compound inhibits angiogenesis and maintains tumor dormancy. This study explores the effect of TM on EPCs in patients (pts) at high risk for breast cancer (BC) recurrence. Methods: This phase II study enrolled Stage 3, 4 without evidence of disease (NED), and any node-positive triple negative (TN) BC pts. Only concomitant hormonal therapy was allowed. Pts received induction TM 180 mg daily at baseline (with exception of one pt) followed by an equal or lower daily dose (median 100mg, range 0-140) to maintain ceruloplasmin (Cp) level < 17 mg/dl (target for copper depletion). We monitored EPCs (CD45dim/CD133+/VEGFR2+), Cp, CEA and CA15-3 at baseline and monthly. To assess the association between Cp and EPCs over time, 3 independent mixed effects linear models with subject as a random effect were used to account for the correlation between observations on the same subject. All p-values were two-sided with statistical significance evaluated at the 0.10 alpha level. Results: 40 pts (28 adjuvant, 12 Stage 4 NED, 11 TN) were enrolled and 426 cycles of TM (average 10.65 per pt) were administered in the first 12 months on study. Median age was 50 yrs (29-66). Median number of tumor size and positive lymph nodes among adjuvant pts were 3.5 cm (1.2-7) and 9 (0-42), respectively. Of the patients receiving hormone therapy, 10 patients were on tamoxifen and 15 patients were on an aromatase inhibitor. 20% of patients were receiving a proton pump inhibitor (PPI). Median baseline Cp level was 28 mg/dL (20-47). 75% pts adequately copper depleted at month 1. 91% of TN patients copper depleted compared to hormone receptor positive subtypes (38-43%) and HER2/neu positive subtypes (40-67%). EPCs/ml decreased from baseline to last dose by 12 in pts that were copper-depleted (p=0.10) and by −52 in pts that did not achieve the copper depletion target (p=0.95). Multivariable modeling revealed an association of EPCs with Cp over time (p=0.005), with type of hormone therapy administered (p=0.007), and with co-administration of a PPI (p=0.0008). Six pts relapsed while on study in which a 200-fold increase in EPCs preceded an objective clinical relapse and a tumor marker rise by median of 1 month. Only grade 3/4 toxicity was hematologic, occurred in 20 cycles (4.7%) and resolved in 5-13 days with TM held and resumed at lower dose. Conclusions: TM is a well-tolerated oral copper chelator that may contribute to maintaining EPCs below baseline in copper-depleted pts. PPI may facilitate TM absorption. Molecular subtype and hormone therapy may impact on the ability to copper deplete. EPCs may have potential as a surrogate marker for early relapse and as a therapeutic target for interrupting the metastatic progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2699. doi:1538-7445.AM2012-2699

1054 Background: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. Tetrathiomolybdate (TM), an oral copper-depleting compound, inhibits angiogenesis and maintains tumor dormancy. This study explores the effect of TM on EPCs in patients (pts) at high risk for breast cancer recurrence. Methods: This phase II study enrolled pts with stage III, stage IV without evidence of disease (NED) breast cancer, and stage II if triple negative (TN). Only concomitant hormone therapy was allowed. Pts received induction TM 180 mg daily followed by 100 mg daily to maintain ceruloplasmin (Cp) level < 17 mg/dL (target for copper depletion). TM was continued for 24 months (mo), or until relapse or toxicity, with an extension study for additional 24 mo in selected pts. We monitored EPCs (CD45dim/CD133+), Cp, CEA and CA15-3 at baseline (BL) and monthly. EPCs were quantitated from peripheral blood mononuclear cells by flow cytometry. Median BL EPCs was compared to subsequent time poi...

Background: BC can relapse years after initial diagnosis. In animal models, bone marrow (BM)-derived VEGFR1+ cells define the premetatastic niche and VEGFR2+ cells are critical for the transition from micro- to macrometastatic disease. We sought to define the temporal relationship of these circulating hemangiogenic progenitor cells in a cohort of BC patients (pts) that developed recurrent disease and whether quantitative changes in these cells could predict response to therapy in pts with established metastases. Methods: 125 pts with Stages I to IV BC enrolled in 2 studies. In Study #1 circulating VEGFR1+ (CD45+/CD34+/VEGFR1+) hematopoietic progenitor cells (HPCs) and VEGFR2+ (CD45dim/CD133+/ VEGFR2+) endothelial progenitor cells (EPCs) of adjuvant patients were assessed at baseline (BL), every 3 months (mo) for the first year, then every 6 mo. Stage IV pts had levels measured at BL (defined as when initiating new treatment (tx)), with subsequent 1 mo interval blood draws and accompanied by a clinical evaluation. Tx could include chemo-, hormone or biologic therapy. In Study #2, these cells were examined monthly in pts without overt evidence of BC. HPCs/EPCs were quantified from peripheral blood mononuclear cells using flow cytometry with commercially available antibodies. Statistical analysis is by Wilcoxon signed-rank test. Results: Data from both studies were combined to analyze 1) pts without overt BC who relapse and 2) stage IV pts according to response. Seven pts without evidence of BC based on physical exam, labs, and imaging developed recurrence while on study. In all 7 pts, there was a median (med) increase of 1,111% in HPCs preceding overt relapse (range 283% to 5800%). Med HPCs at BL 0.65/ul (range 0.02 to 1.22/ul) increased to 2.90/ul prior to relapse (range 1.18 to 34.94/ul), p=0.016. In 5 of 7 relapsed pts a 433% increase in EPCs occurred as HPCs decreased: med EPCs at BL 0.03/ul (range 0.015 to 0.21/ul) and at relapse 0.16/ul (range 0.03 to 0.27/ul). This pattern was not seen in non-relapsed pts. In 22 stage IV pts, HPCs and EPCs were evaluated over the course of 40 tx. For the 20 tx (16 pts) in which progression of disease (POD) was the outcome, HPCs increased prior to POD (median 7.45/ul, range 0.37 to 77.6/ul) from BL (med 1.70/ul, range 0.01 to 16.47/ul), p=0.001. Similarly, EPCs increased at relapse (med 0.07/ul, range 0 to 0.62/ul) from BL (med 0.03/ul, range 0 to 0.21/ul), p=0.04. For the 12 tx (11 pts) with disease responding to systemic tx, there was a reduction in HPCs (BL med 6.15/ul, range 0.91 to 85.1/ul) to a 3 mo time point (med 0.63/ul, range 0.05 to 18.1/ul), p=0.05. A trend was noted in med EPCs (0.05/ul at BL to 0.02/ul at 3 mo), p=0.37. There was no change in HPCs/EPCs in 8 tx (6 pts) with stable disease. Conclusion: BM-derived progenitor cells are important in the metastatic cascade and may represent a novel biomarker in following disease status and a new target for therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4720. doi:10.1158/1538-7445.AM2011-4720

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.