Race, Gene Expression Signatures, and Clinical Outcomes of Patients With High-Risk Early Breast Cancer.

Importance: There has been little consideration of genomic risk of recurrence by breast cancer subtype despite evidence of racial disparities in breast cancer outcomes. Objective: To evaluate associations between clinical trial end points, namely pathologic complete response (pCR) and distant recurrence-free survival (DRFS), and race and examine whether gene expression signatures are associated with outcomes by race. Design, Setting, and Participants: This retrospective cohort study used data from the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2 (I-SPY 2) multicenter clinical trial of neoadjuvant chemotherapy with novel agents and combinations for patients with previously untreated stage II/III breast cancer. Analyses were conducted of associations between race and short- and long-term outcomes, overall and by receptor subtypes, and their association with 28 expression biomarkers. The trial enrolled 990 female patients between March 30, 2010, and November 5, 2016, with a primary tumor size of 2.5 cm or greater and clinical or molecular high risk based on MammaPrint or hormone receptor (HR)-negative/ERBB2 (formerly HER2 or HER2/neu)-positive subtyping across 9 arms. This data analysis was performed between June 10, 2021, and October 20, 2022. Exposure: Race, tumor receptor subtypes, and genomic biomarker expression of early breast cancer. Main Outcomes and Measures: The primary outcomes were pCR and DRFS assessed by race, overall, and by tumor subtype using logistic regression and Cox proportional hazards regression models. The interaction between 28 expression biomarkers and race, considering pCR and DRFS overall and within subtypes, was also evaluated. Results: The analytic sample included 974 participants (excluding 16 self-reporting as American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or multiple races due to small sample sizes), including 68 Asian (7%), 120 Black (12%), and 786 White (81%) patients. Median (range) age at diagnosis was 47 (25-71) years for Asian, 49 (25-77) for Black, and 49 (23-73) years for White patients. The pCR rates were 32% (n = 22) for Asian, 30% for Black (n = 36), and 32% for White (n = 255) patients (P = .87). Black patients with HR-positive/ERBB2-negative tumors not achieving pCR had significantly worse DRFS than their White counterparts (hazard ratio, 2.28; 95% CI, 1.24-4.21; P = .01), with 5-year DRFS rates of 55% (n = 32) and 77% (n = 247), respectively. Black patients with HR-positive/ERBB2-negative tumors, compared with White patients, had higher expression of an interferon signature (mean [SD], 0.39 [0.87] and -0.10 [0.99]; P = .007) and, compared with Asian patients, had a higher mitotic score (mean [SD], 0.07 [1.08] and -0.69 [1.06]; P = .01) and lower estrogen receptor/progesterone receptor signature (mean [SD], 0.31 [0.90] and 1.08 [0.95]; P = .008). A transforming growth factor ß signature had a significant association with race relative to pCR and DRFS, with a higher signature associated with lower pCR and worse DRFS outcomes among Black patients only. Conclusions and Relevance: The findings show that women with early high-risk breast cancer who achieve pCR have similarly good outcomes regardless of race, but Black women with HR-positive/ERBB2-negative tumors without pCR may have worse DRFS than White women, highlighting the need to develop and test novel biomarker-informed therapies in diverse populations.

Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer.

HSP90 inhibitors destabilize oncoproteins associated with cell cycle, angiogenesis, RAS-MAPK activity, histone modification, kinases and growth factors. We evaluated the HSP90-inhibitor ganetespib in combination with standard chemotherapy in patients with high-risk early-stage breast cancer. I-SPY2 is a multicenter, phase II adaptively randomized neoadjuvant (NAC) clinical trial enrolling patients with stage II-III breast cancer with tumors 2.5 cm or larger on the basis of hormone receptors (HR), HER2 and Mammaprint status. Multiple novel investigational agents plus standard chemotherapy are evaluated in parallel for the primary endpoint of pathologic complete response (pCR). Patients with HER2-negative breast cancer were eligible for randomization to ganetespib from October 2014 to October 2015. Of 233 women included in the final analysis, 140 were randomized to the standard NAC control; 93 were randomized to receive 150 mg/m2 ganetespib every 3 weeks with weekly paclitaxel over 12 weeks, followed by AC. Arms were balanced for hormone receptor status (51-52% HR-positive). Ganetespib did not graduate in any of the biomarker signatures studied before reaching maximum enrollment. Final estimated pCR rates were 26% vs. 18% HER2-negative, 38% vs. 22% HR-negative/HER2-negative, and 15% vs. 14% HR-positive/HER2-negative for ganetespib vs control, respectively. The predicted probability of success in phase 3 testing was 47% HER2-negative, 72% HR-negative/HER2-negative, and 19% HR-positive/HER2-negative. Ganetespib added to standard therapy is unlikely to yield substantially higher pCR rates in HER2-negative breast cancer compared to standard NAC, and neither HSP90 pathway nor replicative stress expression markers predicted response. HSP90 inhibitors remain of limited clinical interest in breast cancer, potentially in other clinical settings such as HER2-positive disease or in combination with anti-PD1 neoadjuvant chemotherapy in triple negative breast cancer.Trial registration: www.clinicaltrials.gov/ct2/show/NCT01042379.

Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2+ breast cancer in the adaptively randomized I-SPY2 trial.

HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms 'graduate' in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome.

Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer.

I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY's prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.

Assessment of Residual Cancer Burden and Event-Free Survival in Neoadjuvant Treatment for High-risk Breast Cancer: An Analysis of Data From the I-SPY2 Randomized Clinical Trial.

IMPORTANCE: Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials. OBJECTIVE: To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival. DESIGN, SETTING, AND PARTICIPANTS: The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) and ERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate. INTERVENTIONS: Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery. MAIN OUTCOMES AND MEASURES: Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS). RESULTS: A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) and ERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01042379.

MK-2206 and Standard Neoadjuvant Chemotherapy Improves Response in Patients With Human Epidermal Growth Factor Receptor 2-Positive and/or Hormone Receptor-Negative Breast Cancers in the I-SPY 2 Trial.

PURPOSE: The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer. PATIENTS AND METHODS: I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week. RESULTS: MK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform). CONCLUSION: The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.

The Promoting Activity in Cancer Survivors (PACES) trial: a multiphase optimization of strategy approach to increasing physical activity in breast cancer survivors.

BACKGROUND: Despite the significant, empirically supported benefits of physical activity, the majority of breast cancer survivors do not meet recommended guidelines for physical activity. A variety of effective strategies to increase physical activity in breast cancer survivors have been identified. However, it is unknown which of these strategies is most effective or how these strategies might be combined to optimize intervention effectiveness. METHODS: The proposed trial uses multiphase optimization strategy (MOST) to evaluate four evidence-based intervention strategies for increasing physical activity in breast cancer survivors. We will enroll 500 breast cancer survivors, age 18 and older, who are 3-months to 5 years post-treatment. Using a full-factorial design, participants will be randomized to receive a combination: 1) supervised exercise, 2) facility access, 3) self-monitoring, and 4) group-based active living counseling. The primary outcome, moderate-to-vigorous physical activity (MVPA) will be measured at baseline, 3 months, and 6 months using an Actigraph GT3X+. To evaluate intervention effects, a linear mixed-effects model will be conducted with MVPA as the outcome and with time (3 months and 6 months) as the within-subjects factor and intervention (i.e., supervised exercise, facility access, self-monitoring, and active living counseling) as the between subjects factor, along with all two-way interactions. DISCUSSION: The purpose of the PACES study is to evaluate multiple strategies for increasing physical activity in breast cancer survivors. Results of this study will provide in an optimized intervention for increasing physical activity in breast cancer survivors. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03060941 . Registered February 23, 2017.

Continued Treatment Effect of Zoledronic Acid Dosing Every 12 vs 4 Weeks in Women With Breast Cancer Metastatic to Bone: The OPTIMIZE-2 Randomized Clinical Trial.

IMPORTANCE: Zoledronic acid, a potent bisphosphonate, is commonly administered to patients with bone metastases to reduce the risk of skeletal-related events (SREs). However, there have been concerns regarding its long-term monthly administration. OBJECTIVE: To examine whether zoledronic acid every 12 weeks was noninferior to zoledronic acid every 4 weeks in patients with metastatic breast cancer that involved the bone who had previously received a standard dosing regimen of zoledronic acid and/or pamidronate disodium. DESIGN, SETTING, AND PARTICIPANTS: OPTIMIZE-2 was a prospective, randomized, double-blind, multicenter phase 3 trial of intention-to-treat (full analysis set), evaluable (per protocol), and safety populations. Patients were randomized (1:1) to receive 4.0 mg of intravenous zoledronic acid every 4 or every 12 weeks with placebo for interim infusions for 1 year. The study was conducted at 102 clinical trial centers in the United States from March 3, 2006, to July 25, 2013. Data analysis was performed from October 7, 2013, to March 24, 2014. The study randomized 416 women (≥18 years old) with bone metastases from breast cancer who previously received 9 or more doses of zoledronic acid and/or pamidronate during the first 10 to 15 months of therapy. MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of patients with 1 or more SRE on study (SRE rate). The key secondary end points included time to first SRE and skeletal morbidity rate (SMR). RESULTS: A total of 416 women were randomized: 200 patients received zoledronic acid every 4 weeks (mean [SD] age, 59.2 [11.1] years; 173 were white [86.5%]), 203 patients received zoledronic acid every 12 weeks (mean [SD] age, 58.6 [11.2] years; 178 were white [87.7%]), and 13 patients received placebo (mean [SD] age, 60.8 [12.2] years; 13 were white [100%]). Baseline characteristics were similar in both zoledronic acid treatment arms. After 1 year of follow-up, SREs occurred in 44 patients (22.0%) in the zoledronic acid every 4 weeks group and 47 patients (23.2%) in the zoledronic acid every 12 weeks group (proportional difference of -1.2%; 1-sided 97.5% CI bound of the difference in SRE rate between arms, -9.8%; noninferiority P = .02). The time to first SRE between treatment groups was not statistically significantly different (hazard ratio [HR], 1.06; 95% CI, 0.70-1.60; P = .79). The mean (SD) SMR was 0.46 (1.06) vs 0.50 (1.50) events per year in the every 4 weeks vs every 12 weeks groups (P = .85). The safety profiles of the every 4 weeks and every 12 weeks groups were comparable, with 189 patients (95.5%) in the every 4 weeks group having at least 1 adverse event compared with 189 (93.5%) in the every 12 weeks group. CONCLUSIONS AND RELEVANCE: The every 12 weeks regimen of zoledronic acid was noninferior to the every 4 weeks regimen for the proportion of patients experiencing 1 or more SRE. These results may have a substantial influence on current clinical practice for treatment of patients with bone metastasis from breast cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00320710.

Genetic Ancestry using Mitochondrial DNA in patients with Triple-negative breast cancer (GAMiT study).

BACKGROUND: Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2)/neu receptors, and is aggressive and therapeutically challenging. Genetic ancestry testing is an emerging medical field. Mitochondrial DNA (mtDNA), which is distinct from nuclear DNA, is maternally inherited and allows for origin determination. Patients with TNBC tend to be younger and are more likely to be African American, making this an ideal disease for mtDNA exploration. To the authors' knowledge, the current study is the first to perform mtDNA for self-described African American, White, and Hispanic patients with TNBC to identify mtDNA patterns. METHODS: Patients with TNBC who were at any stage of therapy/survivorship were included. Self-reported ethnicity was confirmed at the time of the prospective buccal swab. Haplogroup prediction was performed on sequencing of hypervariable region 1. Using sequence similarity scores and lineage databases, sequence patterns were determined. Data regarding presentation and treatment, tumor features, and outcomes was collected. RESULTS: A total of 92 patients were included: 31 self-described African American, 31 White, and 30 Hispanic individuals. Hispanic patients were found to have the largest tumor size (4.5 cm; P = .01) and youngest age (41 years; P<.0001). Eight patients were BRCA1/2 mutation carriers. There were no differences noted among groups with regard to surgery, lymph node metastases, or survival. Analysis revealed Nigerian, Cameroon, or Sierra Leone ancestry and haplogroups A, U, H, or B to be the most common mtDNA patterns. Twelve discordances (13%) between mtDNA analysis and self-described ethnicity were identified among the 92 patients. The highest discordance (26%; 8 patients) was noted in self-described Hispanic patients: 3 had Nigerian ancestry, and 1 individual demonstrated haplogroup K mtDNA (Ashkenazi Jewish ancestry). CONCLUSIONS: Discordance between self-reported ethnicity and mtDNA analysis was identified in 13% of patients with TNBC. The identification of mtDNA patterns with a predisposition toward TNBC may allow for risk stratification. Cancer 2017;107-113. © 2016 American Cancer Society.

Adaptive Randomization of Neratinib in Early Breast Cancer.

BACKGROUND: The heterogeneity of breast cancer makes identifying effective therapies challenging. The I-SPY 2 trial, a multicenter, adaptive phase 2 trial of neoadjuvant therapy for high-risk clinical stage II or III breast cancer, evaluated multiple new agents added to standard chemotherapy to assess the effects on rates of pathological complete response (i.e., absence of residual cancer in the breast or lymph nodes at the time of surgery). METHODS: We used adaptive randomization to compare standard neoadjuvant chemotherapy plus the tyrosine kinase inhibitor neratinib with control. Eligible women were categorized according to eight biomarker subtypes on the basis of human epidermal growth factor receptor 2 (HER2) status, hormone-receptor status, and risk according to a 70-gene profile. Neratinib was evaluated against control with regard to 10 biomarker signatures (prospectively defined combinations of subtypes). The primary end point was pathological complete response. Volume changes on serial magnetic resonance imaging were used to assess the likelihood of such a response in each patient. Adaptive assignment to experimental groups within each disease subtype was based on Bayesian probabilities of the superiority of the treatment over control. Enrollment in the experimental group was stopped when the 85% Bayesian predictive probability of success in a confirmatory phase 3 trial of neoadjuvant therapy reached a prespecified threshold for any biomarker signature ("graduation"). Enrollment was stopped for futility if the probability fell to below 10% for every biomarker signature. RESULTS: Neratinib reached the prespecified efficacy threshold with regard to the HER2-positive, hormone-receptor-negative signature. Among patients with HER2-positive, hormone-receptor-negative cancer, the mean estimated rate of pathological complete response was 56% (95% Bayesian probability interval [PI], 37 to 73%) among 115 patients in the neratinib group, as compared with 33% among 78 controls (95% PI, 11 to 54%). The final predictive probability of success in phase 3 testing was 79%. CONCLUSIONS: Neratinib added to standard therapy was highly likely to result in higher rates of pathological complete response than standard chemotherapy with trastuzumab among patients with HER2-positive, hormone-receptor-negative breast cancer. (Funded by QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

Adaptive Randomization of Veliparib-Carboplatin Treatment in Breast Cancer.

BACKGROUND: The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin. METHODS: In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. RESULTS: With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib-carboplatin was greater than that of the control. CONCLUSIONS: The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

Bootcamp during neoadjuvant chemotherapy for breast cancer: a randomized pilot trial.

INTRODUCTION: Exercise may improve cancer outcomes. Neoadjuvant chemotherapy (NC) for breast cancer provides a unique setting to evaluate intervention effects. Treatments leading to decreased post-neoadjuvant Ki-67 levels, smaller tumor size, and higher pathologic response are associated with improved survival and lower recurrence. This randomized, prospective pilot trial evaluates the feasibility of supervised exercise during NC for breast cancer. METHODS: Stage II-III, ER positive, cancer patients with BMI > 25 receiving NC were randomized to standard NC with supervised bootcamp (NC + BC) or NC alone. Ki-67, C-peptide, BMI, and tumor size were measured before chemotherapy and at time of surgery. RESULTS: There were no initial differences between groups in regards to tumor size, C-peptide, BMI, and Ki-67. The NC + BC (n = 5) group had a lower mean BMI at the conclusion of NC compared with those (n = 5) in the NC group (28.0 versus 35.8, P = 0.03). Final tumor size was 2.59 cm in the NC + BC group versus 3.16 cm for NC (P = 0.76) Mean Ki-67 for NC + BC was 7% versus 29% with NC (P = 0.14). C-peptide (ng/mL) was equivalent between the two groups (4.55 NC + BC versus 4.74 NC, P = 0.85). CONCLUSIONS: Adding a supervised exercise program to NC is feasible, decreases BMI, and may lead to lower Ki-67 levels and improved survival.

Zoledronic acid effectively prevents aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z-FAST study 36-month follow-up results.

BACKGROUND: Postmenopausal women with breast cancer receiving adjuvant aromatase inhibitors (AIs) are at risk for accelerated bone loss and subsequent fractures. The ongoing Zometa-Femara Adjuvant Synergy Trial (Z-FAST) is evaluating the efficacy and safety of zoledronic acid in preventing such bone loss. PATIENTS AND METHODS: In this multicenter study, postmenopausal women with early hormone receptor-positive breast cancer receiving adjuvant letrozole were randomized to receive up-front or delayed-start zoledronic acid (ZA; 4 mg intravenously every 6 months) for 5 years. Delayed-start ZA was administered if the lumbar spine (LS) or total hip (TH) T score fell below -2.0 or a nontraumatic fracture occurred. The primary endpoint was to compare the change from baseline in LS bone mineral density (BMD) between groups at month 12; secondary endpoints, measured at other predetermined timepoints, included comparing changes in TH BMD, LS BMD, and markers of bone turnover, fracture incidence, and time to disease recurrence. Herein, we report the results of the 36-month interim analysis. RESULTS: Overall, 301 patients were randomized to each group. At month 36, the absolute difference in mean LS and TH BMDs between the up-front and delayed groups was 6.7% and 5.2%, respectively (P < .0001 for both). Although this study was not designed to show antifracture efficacy, the incidence of fractures was slightly higher in the delayed group (up-front, 17 [5.7%] vs. delayed, 19 [6.3%]) but not statistically significant (P = .8638). Pyrexia (27 [9%] vs. 6 [2%]; P = .0002) and bone pain (39 [13%] vs. 20 [6.7%]; P = .01) were more common in up-front patients; cough (13 [4.3%] vs. 27 [9%]; P = .03) was more common in delayed patients. No severe renal dysfunction or confirmed cases of osteonecrosis of the jaw were reported. Disease recurrence was reported in 9 up-front (3.0%) and 16 delayed (5.3%) patients (Kaplan-Meier analysis, P = .127), with an absolute decrease of 2.3%. CONCLUSION: Up-front ZA more effectively prevents AI-associated bone loss in postmenopausal women with early breast cancer than delaying therapy until substantial bone loss or fracture occurs.

Metastatic pleomorphic sarcoma to left atrium.

Although several thousand patients are diagnosed with sarcoma annually in the United States, metastases to the heart are very uncommon. In this case report, an overall low frequency cancer presents masquerading with common cardiac symptomology. This case illustrates the importance for detailed diagnostic cardiac evaluations and heightened suspicion by physicians to consider metastatic disease to the heart in cancer patients with cardiovascular complications. Also discussed is a review of surgical and chemotherapeutic options for this problem.

The direct thrombin inhibitors: their role and use for rational anticoagulation.

Major clinical advantages are achieved when direct thrombin inhibitors are used in venous thromboembolism. These agents provide more reliable anticoagulant response patterns because they are not significantly bound to plasma proteins and few, if any, drug-drug interactions are seen. The studies to date confirm that not all direct thrombin inhibitors are the same. The new reversible, short-acting catalytic site-specific drugs provide an excellent safety profile and high degree of efficacy for the prophylaxis and treatment of venous thromboembolism and pulmonary embolic states. The availability of the oral prodrug ximelagatran allows reproducible, effective, and safe direct thrombin inhibition without the requirement for coagulation laboratory monitoring; it appears destined to be the oral anticoagulant of the future.

MIB1 labeling index as an indicator of chemoresponse in carcinoma of the breast.

In this study, we determined the extent of variation in proliferative markers and hormone receptor status in breast carcinoma between core biopsies and subsequent resections, and determined the impact of clinical and histologic parameters on such variation. We performed a paired comparison of biomarkers in 87 core biopsies and subsequent resections of breast carcinomas in patients with and without preoperative chemotherapy. The markers included estrogen receptor, progesterone receptor, Her2/neu, DNA ploidy (diploidy versus nondiploidy), DNA index (difference of > or = 0.5), and MIB1 labeling index (<15% vs. >15%). The tumor biomarkers were evaluated with standard IHC and scored by automated cellular imaging systems. The number of patients showing prominent changes were as follows: ploidy, 12; DI, 15; ER, 6; PR, 15; MIB1, 17; and Her2/neu, 15. Seventeen of 87 patients sustained a significant change in MIB1 index (above or below 15%). The patients who received chemotherapy had a larger proportion with a change in MIB1 status (P < 0.05). DI showed a similar trend, although it was not statistically significant. Of the patients with MIB1 values higher in biopsy specimens, a majority showed values to decrease below 15%. MIB1 index reduction by greater than 25% was seen in 8 of 16 (50%) cases with chemotherapy, compared with only 3 of 32 (9%) without chemotherapy. MIB1 and DNA index values postchemotherapy can be a useful measure of chemoresponse. Our study underscores the need to perform prognostic markers on both biopsy and subsequent resections, especially in the setting of preoperative chemotherapy.

Aneusomy 17 in breast cancer: its role in HER-2/neu protein expression and implication for clinical assessment of HER-2/neu status.

HER-2/neu protein overexpression in breast cancer is mostly caused by HER-2/neu gene amplification. However, it is unclear whether aneusomy 17 may also play a role. Using immunohistochemistry assay (IHC) with DAKO antibody and manual quantitation, 189 specimens were selected from archival invasive breast cancer specimens, including most IHC-positive and some IHC-negative cases (n = 158 and 31, respectively). They were then analyzed by PathVysion fluorescence in situ hybridization (FISH) assay (Vysis, Inc., Downers Grove, IL) and by an image analyzer (ACIS; ChromaVision Medical Systems, Inc., San Juan Capistrano, CA)-assisted IHC quantitation. Ninety-two cases contained disomy 17 (chromosome 17 centromere, 1.76-2.25 signals per cell) whereas 97 cases had aneusomy 17, including 82 with low polysomy (2.26-3.75 signals per cell), 10 with high polysomy (> or =3.76 signals per cell), and 5 with hypodisomy (> or =1.75 signals per cell). HER-2/neu protein expression had the highest correlation with HER-2/neu gene dosage (copy number; r =.826), followed by the HER-2/neu gene to chromosome 17 ratio (r =.733). The lowest correlation was with the chromosome 17 copy number (r =.307), on which the 10 cases with high polysomy 17 had a disproportionately high impact. The FISH assay using the PathVysion criterion for HER-2/neu gene amplification (HER-2/neu gene to chromosome 17 ratio, > or = 2.00) achieved higher concordance with ACIS IHC than did an alternative FISH criterion (absolute HER-2/neu gene copy number, > or = 4.00 signals per cell). Most ACIS IHC-PathVysion FISH-discordant cases contained disomy or low polysomy 17, whereas all 10 cases with high polysomy 17 had no such discordance. However, two cases with monosomy 17 had ACIS IHC-PathVysion FISH discordance, i.e., with gene amplification, but no protein overexpression. Both cases would have had no gene amplification if the alternative FISH criterion had been used. In conclusion, aneusomy 17 is common in breast cancer. Except in a certain subset of cases, aneusomy 17 probably is not a significant factor for HER-2/neu protein expression or for clinical assessment of HER-2/neu status.