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1.  Impact of PTEN Protein Expression on Benefit From Adjuvant Trastuzumab in Early-Stage Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer in the North Central Cancer Treatment Group N9831 Trial 
Journal of Clinical Oncology  2013;31(17):2115-2122.
Purpose
It has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) –positive trial—North Central Cancer Treatment Group (NCCTG) N9831.
Patients and Methods
The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with ≥ 1+ staining. Median follow-up was 6.0 years.
Results
Of 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74%) had PTEN-positive tumors. PTEN positivity was associated with hormone receptor negativity (χ2 P < .001) and nodal positivity (χ2 P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47).
Conclusion
In contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status.
doi:10.1200/JCO.2012.42.2642
PMCID: PMC3731983  PMID: 23650412
2.  Exemestane Versus Anastrozole in Postmenopausal Women With Early Breast Cancer: NCIC CTG MA.27—A Randomized Controlled Phase III Trial 
Journal of Clinical Oncology  2013;31(11):1398-1404.
Purpose
In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non–cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss.
Patients and Methods
We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease–free survival, incidence of contralateral new primary breast cancer, and safety.
Results
In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease–free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms.
Conclusion
This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor–positive breast cancer.
doi:10.1200/JCO.2012.44.7805
PMCID: PMC3612593  PMID: 23358971
3.  Cardiac Safety Analysis of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With or Without Trastuzumab in the North Central Cancer Treatment Group N9831 Adjuvant Breast Cancer Trial 
Purpose
To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial.
Patients and Methods
Patients with HER2-positive operable early breast cancer were randomized to 1 of 3 treatment arms: doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (Arm A); paclitaxel then trastuzumab (Arm B); or paclitaxel plus trastuzumab then trastuzumab alone (Arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18–21 months post-registration.
Results
A total of 1944 patients completed AC with a satisfactory LVEF and proceeded to post-AC therapy. Post-AC cardiac events (congestive heart failure [CHF] or cardiac death [CD]) were: Arm A, n=3 (2 CHF, 1 CD); Arm B, n=19 (18 CHF, 1 CD); Arm C, n=19 (all CHF); 3-year cumulative incidence was 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event after AC in Arms B and C were older age (P<.003), prior/current antihypertensive agents (P=.005), and lower registration LVEF (P=.033). Incidence of asymptomatic LVEF decreases requiring trastuzumab to be held was 8–10%; LVEF recovered and trastuzumab was restarted in approximately 50% of these patients.
Conclusion
The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus control arm but by <4%. Older age, lower registration LVEF, and antihypertensive medications increase the risk of cardiac dysfunction in patients receiving trastuzumab following AC.
doi:10.1200/JCO.2007.13.5467
PMCID: PMC4048960  PMID: 18250349
HER2; trastuzumab; adjuvant; breast cancer; doxorubicin; cyclophosphamide; paclitaxel; cardiac safety
4.  Small-Molecule Inhibition of the uPAR·uPA Interaction: Synthesis, Biochemical, Cellular, in vivo Pharmacokinetics and Efficacy Studies in Breast Cancer Metastasis 
Bioorganic & medicinal chemistry  2013;21(7):2145-2155.
The uPAR·uPA protein-protein interaction (PPI) is involved in signaling and proteolytic events that promote tumor invasion and metastasis. A previous study had identified 4 (IPR-803) from computational screening of a commercial chemical library and shown that the compound inhibited uPAR·uPA PPI in competition biochemical assays and invasion cellular studies. Here, we synthesize 4 to evaluate in vivo pharmacokinetic (PK) and efficacy studies in a murine breast cancer metastasis model. First, we show, using fluorescence polarization and saturation transfer difference (STD) NMR, that 4 binds directly to uPAR with sub-micromolar affinity of 0.2 μM. We show that 4 blocks invasion of breast MDA-MB-231, and inhibits matrix metalloproteinase (MMP) breakdown of the extracellular matrix (ECM). Derivatives of 4 also inhibited MMP activity and blocked invasion in a concentration-dependent manner. 4 also impaired MDA-MB-231 cell adhesion and migration. Extensive in vivo PK studies in NOD-SCID mice revealed a half-life of nearly 5 hours and peak concentration of 5 μM. Similar levels of the inhibitor were detected in tumor tissue up to 10 hours. Female NSG mice inoculated with highly malignant TMD-MDA-MB-231 in their mammary fat pads showed that 4 impaired metastasis to the lungs with only four of the treated mice showing severe or marked metastasis compared to ten for the untreated mice. Compound 4 is a promising template for the development of compounds with enhanced PK parameters and greater efficacy.
doi:10.1016/j.bmc.2012.12.047
PMCID: PMC3625246  PMID: 23411397
5.  Prognostic and predictive value of tumor vascular endothelial growth factor gene amplification in metastatic breast cancer treated with paclitaxel with and without bevacizumab; results from ECOG 2100 trial 
Purpose
Clinically validated biomarkers for anti-angiogenesis agents are not available. We have previously reported associations between candidate VEGFA SNPs and overall survival (OS) in E2100. The associations between tumor VEGFA amplification and outcome are evaluated here.
Patients and Methods
E2100 was a phase III trial comparing paclitaxel with or without bevacizumab for patients with metastatic breast cancer. Fluorescence in situ hybridization to assess gene amplification status for VEGFA was performed on paraffin embedded tumors from 363 patients in E2100. Evaluation for association between amplification status and outcomes was performed.
Results
ER+ or PR+ tumors were less likely to have VEGFA amplification compared with ER/PR-tumors (p=0.020). VEGFA amplification was associated with worse OS (20.2 vs. 25.3 months; p=0.013) in univariate analysis with a trend for worse OS in multivariate analysis (p=0.08). There was a significant interaction between VEGFA amplification, hormone-receptor status, and study arm. Patients with VEGFA amplification and triple negative breast cancers (TNBCs) or HER2 amplification had inferior OS (p=0.047); amplification did not affect OS for those who were ER+ or PR+ and HER2-. Those who received bevacizumab with VEGFA amplification had inferior PFS (p=0.010) and OS (p=0.042); no association was seen in the control arm. Test for interaction between study arm and VEGFA amplification with OS was not significant.
Conclusion
VEGFA amplification in univariate analysis was associated with poor outcomes; this was particularly prominent in HER2+ or TNBCs. Additional studies are necessary to confirm the trend for poor OS seen on multivariate analysis for patients treated with bevacizumab.
doi:10.1158/1078-0432.CCR-12-3029
PMCID: PMC3594423  PMID: 23340303
Breast cancer; VEGF amplification; bevacizumab
6.  Analysis of Early Hypertension and Clinical Outcome With Bevacizumab: Results From Seven Phase III Studies 
The Oncologist  2013;18(3):273-280.
To assess the prognostic and predictive value of bevacizumab-related hypertension, hypertension and efficacy outcomes for seven company-sponsored placebo-controlled phase III studies of bevacizumab were analyzed. Early treatment-related BP increases were not found to have general prognostic importance for patients with advanced cancer.
Background.
Hypertension is associated with antivascular endothelial growth factor treatment, but the clinical implications of hypertension are uncertain. To assess the prognostic and predictive value of bevacizumab-related hypertension, a comprehensive analysis of whether hypertension and efficacy outcomes are associated was conducted on seven company-sponsored placebo-controlled phase III studies of bevacizumab.
Methods.
Patient-specific data were available from 6,486 patients with metastatic colorectal, breast, non-small cell lung, pancreatic, and renal cell cancers. Primary hypertension endpoint was a blood pressure (BP) increase of >20 mmHg systolic or >10 mmHg diastolic within the first 60 days of treatment. Additional endpoints included other predefined thresholds of change in BP and severity of hypertension graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events. To analyze the general prognostic importance of an early BP increase, multivariate Cox regression models were used to assess the correlation between BP changes and progression-free (PFS) and overall survival (OS) outcomes in the control groups. To analyze whether early BP increases could predict for benefit from bevacizumab, similar analyses were conducted in the bevacizumab-treated and control groups.
Results.
In six of seven studies, early BP increase was neither predictive of clinical benefit from bevacizumab nor prognostic for the course of the disease. For study AVF2107g, early increased BP was associated with longer PFS and OS times in the bevacizumab group but shorter OS time in the control group.
Conclusions.
Early treatment-related BP increases do not predict clinical benefit from bevacizumab based on PFS or OS outcomes. BP increases do not appear to have general prognostic importance for patients with advanced cancer.
doi:10.1634/theoncologist.2012-0339
PMCID: PMC3607523  PMID: 23485622
Bevacizumab; Hypertension; Clinical outcome; Prognostic factor; Predictive factor
7.  Neuropathy Is Not Associated With Clinical Outcomes in Patients Receiving Adjuvant Taxane-Containing Therapy for Operable Breast Cancer 
Journal of Clinical Oncology  2012;30(25):3051-3057.
Purpose
Neuropathy is a common and potentially disabling complication of adjuvant taxane therapy. Recent studies have identified candidate single nucleotide polymorphisms associated with taxane-induced neuropathy. Therefore, we sought to determine whether neuropathy was associated with breast cancer recurrence in a clinical trial population who received adjuvant taxane therapy.
Patients and Methods
Trial E1199 included 4,554 eligible women with operable breast cancer who received up to four cycles of doxorubicin and cyclophosphamide every 3 weeks followed by paclitaxel 175 mg/m2 every 3 weeks for four cycles (P3), paclitaxel 80 mg/m2 weekly for 12 cycles (P1), docetaxel 100 mg/m2 every 3 weeks for four cycles (D3), or docetaxel 35 mg/m2 weekly for 12 cycles (D1). A Cox proportional hazards model was used to determine the relationship between neuropathy and disease-free survival (DFS), overall survival (OS), and recurrence-free survival (RFS) by treating neuropathy status as a time dependent covariate and using a landmark analysis.
Results
Of 4,554 patients who received at least one taxane dose, grade 2 to 4 neuropathy developed in 18%, 22%, 15%, and 13% of patients in the P3, P1, D3, and D1 arms, respectively. In a model that included age, race, obesity, menopausal status, tumor size, nodal status, treatment arm, neuropathy, and hyperglycemia, no significant relationship was found between neuropathy and DFS, OS, or RFS.
Conclusion
There was no association between taxane-induced neuropathy and outcome.
doi:10.1200/JCO.2011.39.8446
PMCID: PMC3732004  PMID: 22851566
9.  ASCO's Approach to a Learning Health Care System in Oncology 
Journal of Oncology Practice  2013;9(3):145-148.
ASCO's CancerLinQ, a learning information network for quality, collects clinical data in real time, analyzing and comparing it with existing guidelines and feeding that information back to participating physicians, driving higher quality and value and improving outcomes for our patients.
doi:10.1200/JOP.2013.000957
PMCID: PMC3651563  PMID: 23942494
10.  Identification of FDA-approved Drugs Targeting Breast Cancer Stem Cells Along With Biomarkers of Sensitivity 
Scientific Reports  2013;3:2530.
Recently developed genomics-based tools are allowing repositioning of Food and Drug Administration (FDA)-approved drugs as cancer treatments, which were employed to identify drugs that target cancer stem cells (CSCs) of breast cancer. Gene expression datasets of CSCs from six studies were subjected to connectivity map to identify drugs that may ameliorate gene expression patterns unique to CSCs. All-trans retinoic acid (ATRA) was negatively connected with gene expression in CSCs. ATRA reduced mammosphere-forming ability of a subset of breast cancer cells, which correlated with induction of apoptosis, reduced expression of SOX2 but elevated expression of its antagonist CDX2. SOX2/CDX2 ratio had prognostic relevance in CSC-enriched breast cancers. K-ras mutant breast cancer cell line enriched for CSCs was resistant to ATRA, which was reversed by MAP kinase inhibitors. Thus, ATRA alone or in combination can be tested for efficacy using SOX2, CDX2, and K-ras mutation/MAPK activation status as biomarkers of response.
doi:10.1038/srep02530
PMCID: PMC3965360  PMID: 23982413
11.  Prognostic value of biologic subtype and the 21-gene recurrence score relative to local recurrence after breast conservation treatment with radiation for early stage breast carcinoma: results from the Eastern Cooperative Oncology Group E2197 study 
The present study was performed to evaluate the significance of biologic subtype and 21-gene recurrence score relative to local recurrence and local–regional recurrence after breast conservation treatment with radiation. Eastern Cooperative Oncology Group E2197 was a prospective randomized clinical trial that compared two adjuvant systemic chemotherapy regimens for patients with operable breast carcinoma with 1–3 positive lymph nodes or negative lymph nodes with tumor size >1.0 cm. The study population was a subset of 388 patients with known 21-gene recurrence score and treated with breast conservation surgery, systemic chemotherapy, and definitive radiation treatment. Median follow-up was 9.7 years (range = 3.7–11.6 years). The 10-year rates of local recurrence and local–regional recurrence were 5.4 % and 6.6 %, respectively. Neither biologic subtype nor 21-gene Recurrence Score was associated with local recurrence or local–regional recurrence on univariate or multivariate analyses (all P ≥ 0.12). The 10-year rates of local recurrence were 4.9 % for hormone receptor positive, HER2-negative tumors, 6.0 % for triple negative tumors, and 6.4 % for HER2-positive tumors (P = 0.76), and the 10-year rates of local–regional recurrence were 6.3, 6.9, and 7.2 %, respectively (P = 0.79). For hormone receptor positive tumors, the 10-year rates of local recurrence were 3.2, 2.9, and 10.1 % for low, intermediate, and high 21-gene recurrence score, respectively (P = 0.17), and the 10-year rates of local–regional recurrence were 3.8, 5.1, and 12.0 %, respectively (P = 0.12). For hormone receptor- positive tumors, the 21-gene recurrence score evaluated as a continuous variable was significant for local–regional recurrence (hazard ratio 2.66; P = 0.03). The 10-year rates of local recurrence and local–regional recurrence were reasonably low in all subsets of patients. Neither biologic subtype nor 21-gene recurrence score should preclude breast conservation treatment with radiation.
doi:10.1007/s10549-012-2072-y
PMCID: PMC3552372  PMID: 22547108
Early stage breast carcinoma; Breast conservation treatment; Radiation treatment; 21-Gene recurrence score; Local recurrence; Local–regional recurrence
12.  A Randomized Trial of Combination Anastrozole plus Gefitinib and of Combination Fulvestrant plus Gefitinib in the Treatment of Postmenopausal Women with Hormone Receptor Positive Metastatic Breast Cancer 
Breast cancer research and treatment  2012;133(3):1049-1056.
INTRODUCTION
EGFR signalling pathways appear involved in endocrine therapy resistance in breast cancer. This trial estimates the antitumor efficacy and toxicity of the EGFR tyrosine kinase inhibitor gefitinib in combination with anastrozole or fulvestrant in postmenopausal hormone receptor positive breast cancer.
METHODS
Subjects with estrogen receptor and/or progesterone receptor positive, metastatic breast cancer were randomized into this phase II study of gefitinib (initial dose was 500 mg orally daily, due to high rate of diarrhea, starting dose was reduced to 250 mg orally daily) with either anastrozole 1 mg daily or fulvestrant 250 mg every 4 weeks. The primary endpoint was clinical benefit (complete responses plus partial responses plus stable disease for 6 months or longer).
RESULTS
141 eligible subjects were enrolled, 72 in the anastrozole plus gefitinib arm, and 69 in the fulvestrant plus gefitinib arm. Anastrozole plus gefitinib had a clinical benefit rate of 44% (95% confidence interval 33%–57%) and fulvestrant plus gefitinib 41% (95% confidence interval 29%–53%). Median progression-free survival was 5.3 months (95% confidence interval 3.1–10.4) versus 5.2 months (95% confidence intervals 2.9–8.2) for anastrozole plus gefitinib versus fulvestrant plus gefitinib, respectively. Median survival was 30.3 months (95% confidence interval 21.2–38.9+) versus 23.9 months (95% confidence interval 15.4–33,5) for anastrozole plus gefitinib versus fulvestrant plus gefitinib, respectively. In general, the toxicity is greater than expected for single agent endocrine therapy alone.
CONCLUSION
Anastrozole plus gefitinib and fulvestrant plus gefitinib have similar clinical benefit rates in the treatment of estrogen and/or progesterone receptor positive metastatic breast cancer, and the rates of response are not clearly superior to gefitinib or endocrine therapy alone.. Further studies of EGFR inhibition plus endocrine therapy do not appear warranted, but if performed should include attempts to identify biomarkers predictive of antitumor activity.
doi:10.1007/s10549-012-1997-5
PMCID: PMC3587179  PMID: 22418699
Metastatic breast cancer; gefitinib; anastrozole; fulvestrant; randomized phase II
13.  A Multigene Expression Assay to Predict Local Recurrence Risk for Ductal Carcinoma In Situ of the Breast 
Background
For women with ductal carcinoma in situ (DCIS) of the breast, the risk of developing an ipsilateral breast event (IBE; defined as local recurrence of DCIS or invasive carcinoma) after surgical excision without radiation is not well defined by clinical and pathologic characteristics.
Methods
The Oncotype DX breast cancer assay was performed for patients with DCIS treated with surgical excision without radiation in the Eastern Cooperative Oncology Group (ECOG) E5194 study. The association of the prospectively defined DCIS Score (calculated from seven cancer-related genes and five reference genes) with the risk of developing an IBE was analyzed using Cox regression. All statistical tests were two-sided.
Results
There were 327 patients with adequate tissue for analysis. The continuous DCIS Score was statistically significantly associated with the risk of developing an IBE (hazard ratio [HR] = 2.31, 95% confidence interval [CI] = 1.15 to 4.49; P = .02) when adjusted for tamoxifen use (prespecified primary analysis) and with invasive IBE (unadjusted HR = 3.68, 95% CI = 1.34 to 9.62; P = .01). For the prespecified DCIS risk groups of low, intermediate, and high, the 10-year risks of developing an IBE were 10.6%, 26.7%, and 25.9%, respectively, and for an invasive IBE, 3.7%, 12.3%, and 19.2%, respectively (both log rank P ≤ .006). In multivariable analyses, factors associated with IBE risk were DCIS Score, tumor size, and menopausal status (all P ≤ .02).
Conclusions
The DCIS Score quantifies IBE risk and invasive IBE risk, complements traditional clinical and pathologic factors, and provides a new clinical tool to improve selecting individualized treatment for women with DCIS who meet the ECOG E5194 criteria.
doi:10.1093/jnci/djt067
PMCID: PMC3653823  PMID: 23641039
14.  Race and Hormone Receptor–Positive Breast Cancer Outcomes in a Randomized Chemotherapy Trial 
Background
The association between black race and worse outcomes in operable breast cancer reported in previous studies has been attributed to a higher incidence of more aggressive triple-negative disease, disparities in care, and comorbidities. We evaluated associations between black race and outcomes, by tumor hormone receptor and HER2 expression, in patients who were treated with contemporary adjuvant therapy.
Methods
The effect of black race on disease-free and overall survival was evaluated using Cox proportional hazards models adjusted for multiple covariates in a clinical trial population that was treated with anthracycline- and taxane-containing chemotherapy. Categorical variables were compared using the Fisher exact test. All P values are two-sided.
Results
Of 4817 eligible patients, 405 (8.4%) were black. Compared with nonblack patients, black patients had a higher rate of triple-negative disease (31.9% vs 17.2%; P < .001) and a higher body mass index (median: 31.7 vs 27.4 kg/m2; P < .001). Black race was statistically significantly associated with worse disease-free survival (5-year disease-free survival, black vs nonblack: 76.7% vs 84.5%; hazard ratio of recurrence or death = 1.58, 95% confidence interval = 1.19 to 2.10, P = .0015) and overall survival (5-year overall survival, black vs nonblack: 87.6% vs 91.9%; hazard ratio of death = 1.49, 95% confidence interval = 1.05 to 2.12, P = .025) in patients with hormone receptor–positive HER2-negative disease but not in patients with triple-negative or HER2-positive disease. In a model that included black race, hormone receptor–positive HER2-negative disease vs other subtypes, and their interaction, the interaction term was statistically significant for disease-free survival (P = .027) but not for overall survival (P = .086).
Conclusion
Factors other than disparities in care or aggressive disease contribute to increased recurrence in black women with hormone receptor–positive breast cancer.
doi:10.1093/jnci/djr543
PMCID: PMC3295746  PMID: 22250182
15.  Obesity at Diagnosis Is Associated With Inferior Outcomes in Hormone Receptor-Positive Operable Breast Cancer 
Cancer  2012;118(23):5937-5946.
BACKGROUND
Obesity has been associated with inferior outcomes in operable breast cancer, but the relation between body mass index (BMI) and outcomes by breast cancer subtype has not been previously evaluated.
METHODS
The authors evaluated the relation between BMI and outcomes in 3 adjuvant trials coordinated by the Eastern Cooperative Oncology Group that included chemotherapy regimens with doxorubicin and cyclophosphamide, including E1199, E5188, and E3189. Results are expressed as hazard ratios (HRs) from Cox proportional hazards models (HR >1 indicates a worse outcome). All P values are 2-sided.
RESULTS
When evaluated as a continuous variable in trial E1199, increasing BMI within the obese (BMI, ≥30 kg/m2) and overweight (BMI, 25-29.9 kg/m2) ranges was associated with inferior outcomes in hormone receptor-positive, human epidermal growth receptor 2 (HER-2)/neu-negative disease for disease-free survival (DFS; P = .0006) and overall survival (OS; P = .0007), but not in HER-2/neu–overexpressing or triple-negative disease. When evaluated as a categorical variable, obesity was associated with inferior DFS (HR, 1.24; 95% confidence interval [CI], 1.06-1.46; P = .0008) and OS (HR, 1.37; 95% CI, 1.13-1.67; P = .002) in hormone receptor-positive disease, but not other subtypes. In a model including obesity, disease subtype, and their interaction, the interaction term was significant for OS (P = .02) and showed a strong trend for DFS (P = .07). Similar results were found in 2 other trials (E5188, E3189).
CONCLUSIONS
In a clinical trial population that excluded patients with significant comorbidities, obesity was associated with inferior outcomes specifically in patients with hormone receptor-positive operable breast cancer treated with standard chemohormonal therapy.
doi:10.1002/cncr.27527
PMCID: PMC3586227  PMID: 22926690
obesity; breast cancer; prognosis; hormone receptor positive; disparity
16.  Relationship Between Quantitative GRB7 RNA Expression and Recurrence after Adjuvant Anthracycline Chemotherapy in Triple Negative Breast Cancer 
Purpose
To perform an exploratory analysis of the relationship between gene expression and recurrence in patients with operable triple negative breast cancer (TNBC) treated with adjuvant doxorubicin-containing chemotherapy.
Experimental design
RNA was extracted from archived tumor samples derived from 246 patients with stage I-III TNBC treated with adjuvant doxorubicin-containing chemotherapy, and was analyzed by quantitative RT-PCR for a panel of 374 genes. The relationship between gene expression and recurrence was evaluated using weighted Cox proportional hazards model score tests.
Results
GRB7 was the only gene for which higher expression was significantly associated with increased recurrence in TNBC (Korn’s adjusted p value=0.04). In a Cox proportional hazards model adjusted for clinicopathologic features, higher GRB7 expression was associated with an increased recurrence risk (HR 2.31, p=0.04 using the median as the split). The 5-year recurrence rates were 10.5% (95% confidence intervals [CI] 7.8%, 14.1%) in the low and 20.4% (95% CI 16.5%, 25.0%) in the high GRB7 groups. External validation in other datasets indicated that GRB7 expression was not prognostic in two adjuvant trials including variable systemic therapy, but in two other trials showed that high GBR7 expression was associated with resistance to neoadjuvant doxorubicin and taxane therapy.
Conclusions
GRB7 was associated with an increased risk of recurrence in TNBC, suggesting that GRB7 or GRB7-dependent pathways may serve as potential biomarkers for therapeutic targets. Therapeutic targeting of one or more factors identified which function as interaction nodes or effectors should also be considered.
doi:10.1158/1078-0432.CCR-10-3357
PMCID: PMC3570203  PMID: 21933890
Breast cancer; GRB7 RNA expression; recurrence
17.  Cognitive Function in Breast Cancer Survivors Compared to Healthy Age- and Education-Matched Women 
The Clinical neuropsychologist  2009;23(4):661-674.
The cognitive function of breast cancer survivors (BC, n = 52) and individually-matched healthy controls (n = 52) was compared on a battery of sensitive neuropsychological tests. The BC group endorsed significantly higher levels of subjective memory loss and scored significantly worse than controls on learning and delayed recall indices from the Rey Auditory Verbal Learning Test (AVLT). Defining clinically significant impairment as scores at or below the 7th percentile of the control group, the rate of cognitive impairment in the BC sample was 17% for total learning on the AVLT, 17% for delayed recall on the AVLT, and 25% for either measure. Findings indicate that a sizeable percentage of breast cancer survivors have clinically significant cognitive impairment.
doi:10.1080/13854040802541439
PMCID: PMC3557514  PMID: 19156566
breast cancer; neuropsychological test; memory; cognition; mild cognitive impairment
18.  Virtual Screening Targeting the Urokinase Receptor, Biochemical and Cell-Based Studies, Synthesis, Pharmacokinetic Characterization, and Effect on Breast Tumor Metastasis 
Journal of Medicinal Chemistry  2011;54(20):7193-7205.
Virtual screening targeting the urokinase receptor (uPAR) led to (3R)-4-cyclohexyl-3-(hexahydrobenzo[d][1,3]dioxol-5-yl)-N-((hexahydrobenzo[d][1,3]dioxol-5-yl)methyl)butan-1-aminium 1 (IPR-1) and 4-(4-((3,5-dimethylcyclohexyl)carbamoyl)-2-(4-isopropylcyclohexyl)pyrazolidin-3-yl)piperidin-1-ium 3 (IPR-69). Synthesis of an analog of 1, namely 2 (IPR-9), and 3 led to breast MDA-MB-231 invasion, migration and adhesion assays with IC50 near 30 μM. Both compounds blocked angiogenesis with IC50 of 3 μM. Compounds 2 and 3 inhibited cell growth with IC50 of 6 and 18 μM and induced apoptosis. Biochemical assays revealed lead-like properties for 3, but not 2. Compound 3 administered orally reached peak concentration of nearly 40 μM with a half-life of about 2 hours. In NOD-SCID mice inoculated with breast TMD-231 cells in their mammary fat pads, compound 3 showed a 20% reduction in tumor volumes and less extensive metastasis was observed for the treated mice. The suitable pharmacokinetic properties of 3 and the encouraging preliminary results in metastasis make it an ideal starting point for next generation compounds.
doi:10.1021/jm200782y
PMCID: PMC3280887  PMID: 21851064
19.  Molecular Analysis of Thymoma 
PLoS ONE  2012;7(8):e42669.
Histologic classification of thymomas has significant limitations with respect to both subtype definitions and consistency. In order to better understand the biology of the disease processes, we performed whole genome gene expression analysis. RNA was extracted from fresh frozen tumors from 34 patients with thymomas and followup data was available. Using the Illumina BeadStudio® platform and Human Ref-8 Beadchip, gene expression data was analyzed with Partek Genomics Suite®, and Ingenuity Pathways Analysis (IPA). Unsupervised clustering of gene expression data, representing one of the largest series in literature, resulted in identification of four molecular clusters of tumors (C1–C4), which correlated with histology (P = 0.002). However, neither histology nor clusters correlated with clinical outcomes. Correlation of gene expression data with clinical data showed that a number of genes were associated with either advanced stage at diagnosis or development of recurrence or metastases. The top pathways associated with metastases were amino acid metabolisms, biosynthesis of steroids and glycosphingolipids, cell cycle checkpoint proteins and Notch signaling. The differential expression of some of the top genes related to both metastases and stage was confirmed by RT-PCR in all cases of metastases and matched nonmetastatic cases. A number of potential candidates for therapeutics were also identified.
doi:10.1371/journal.pone.0042669
PMCID: PMC3418289  PMID: 22912720
20.  Relationship Between Topoisomerase 2A RNA Expression and Recurrence after Adjuvant Chemotherapy for Breast Cancer 
Clinical Cancer Research  2009;15(24):7693-7700.
Purpose
To perform an exploratory analysis of the relationship between gene expression and recurrence in operable hormone receptor (HR)-positive, HER2-normal breast cancer patients treated with adjuvant doxorubicin-containing chemotherapy.
Experimental Design
RNA was extracted from archived tumor samples derived from 378 patients with stage I–III HR-positive, HER2-normal breast cancer and analyzed by RT-PCR for a panel of 374 genes, including the 21 gene Recurrence Score (RS). Patients were randomized to receive adjuvant doxorubicin plus cyclophosphamide or docetaxel in trial E2197, with no difference in recurrence seen in the treatment arms. All available recurrent cases were selected plus a non-recurrent cohort. Cox proportional hazard models were used to identify relationships between gene expression and recurrence.
Results
TOP2A expression exhibited the strongest association with increased recurrence risk (p=0.01), and was significantly associated with recurrence (p=0.008) in a multivariate analysis adjusted for clinicopathological features. Elevated TOP2A expression above the median was associated with a 2.6-fold increase (95% confidence intervals [CI], 1.3, 5.2 p=0.008) in risk of recurrence if the RS was less than 18, and a 2.0-fold increase (95% CI, 1.2, 3.2, p=0.003) if there was an intermediate RS of 18–30.
Conclusions
In patients with HR-positive, HER2-normal breast cancer, a population known to have a low incidence of TOP2A gene alterations thought to be predictive of anthracycline benefit, there is a range of TOP2A RNA expression that is strongly associated with recurrence after adjuvant anthracyclines which provides information complementary to RS, indicating that it merits further evaluation as a prognostic and predictive marker.
doi:10.1158/1078-0432.CCR-09-1450
PMCID: PMC3396025  PMID: 19996222
Breast cancer; TOP2A RNA expression; recurrence
21.  C-MYC Alterations and Association With Patient Outcome in Early-Stage HER2-Positive Breast Cancer From the North Central Cancer Treatment Group N9831 Adjuvant Trastuzumab Trial 
Journal of Clinical Oncology  2011;29(6):651-659.
Purpose
Findings from the human epidermal growth factor receptor 2 (HER2) –positive National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 trial suggested that MYC/HER2 coamplification (> 5.0 copies/nucleus) was associated with additional benefit from adjuvant trastuzumab in patients with early-stage breast cancer. To further explore this relationship, we investigated associations between MYC amplification and disease-free survival (DFS) in a similar adjuvant trastuzumab HER2-positive breast cancer trial—North Central Cancer Treatment Group (NCCTG) N9831.
Patients and Methods
This analysis included 799 patients randomly assigned to receive chemotherapy alone or with concurrent trastuzumab on N9831. Fluorescence in situ hybridization (FISH) was performed by using a dual-probe mixture for MYC and centromere 8 (MYC:CEP8) on tissue microarrays. MYC amplification was prespecified as MYC:CEP8 ratio > 2.2 or average MYC copies/nucleus > 5.0. Exploratory variables included polysomy 8.
Results
In comparing DFS (median follow-up, 4.0 years) between treatments, patients with MYC:CEP8 ratio ≤ 2.2 (n = 618; 77%) and > 2.2 (n = 181; 23%) had hazard ratios (HRs) of 0.46 (P < .001) and 0.67 (P = .33), respectively (interaction P = .38). Patients with MYC copies/nucleus ≤ 5.0 (n = 534; 67%) and > 5.0 (n = 265; 33%) had HRs of 0.52 (P = .002) and 0.48 (P = .02), respectively (interaction P = .94). Patients with MYC:CEP8 ratio < 1.3 with normal chromosome 8 copy number (n = 141; 18%) and ≥ 1.3 or < 1.3 with polysomy 8 (n = 658; 82%) had HRs of 0.66 (P = .28) and 0.44 (P < .001), respectively (interaction P = .23). Patients with MYC copies/nucleus < 2.5 (n = 130; 16%) and ≥ 2.5 (n = 669; 84%) had HRs of 1.07 (P = .87) and 0.42 (P < .001), respectively (interaction P = .05).
Conclusion
We did not confirm the B31 association between MYC amplification and additional trastuzumab benefit. Exploratory analyses revealed potential associations between alternative MYC/chromosome 8 copy number alterations and differential benefit of adjuvant trastuzumab.
doi:10.1200/JCO.2010.30.2125
PMCID: PMC3056653  PMID: 21245420
22.  PARP Inhibition: “Targeted” Therapy for Triple Negative Breast Cancer 
In contrast to endocrine-sensitive and HER2-positive breast cancer, novel agents capable of treating advanced triple negative breast cancer (TNBC) are lacking. PARP (Poly-(adenosine diphosphate [ADP]-ribose) polymerase) inhibitors are emerging as one of the most promising ‘targeted’ therapeutics to treat TNBC, with the intended ‘target’ being DNA repair. PARP's are a family of enzymes involved in multiple cellular processes including DNA repair. TNBC shares multiple clinico-pathologic features with BRCA-mutated breast cancers which harbor dysfunctional DNA repair mechanisms. Investigators hypothesized PARP inhibition, in conjunction with the loss of DNA-repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death. This hypothesis has borne out in both preclinical models and in clinical trials testing PARP inhibitors in both BRCA-deficient and TNBC. The focus of this review will include an overview of the preclinical rationale for evaluating PARP inhibitors in TNBC, the presumed mechanism of action of this novel therapeutic class, promising results from several influential clinical trials of PARP inhibition in advanced breast cancer (both TNBC and BRCA-deficient), proposed mechanisms of acquired resistance to PARP inhibitors, and, finally, conclude with current challenges and future directions for the development of PARP inhibitors in the treatment of breast cancer.
doi:10.1158/1078-0432.CCR-10-0939
PMCID: PMC2948607  PMID: 20858840
23.  HER2 and Chromosome 17 Effect on Patient Outcome in the N9831 Adjuvant Trastuzumab Trial 
Journal of Clinical Oncology  2010;28(28):4307-4315.
Purpose
We examined associations between tumor characteristics (human epidermal growth factor receptor 2 [HER2] protein expression, HER2 gene and chromosome 17 copy number, hormone receptor status) and disease-free survival (DFS) of patients in the N9831 adjuvant trastuzumab trial.
Patients and Methods
All patients (N = 1,888) underwent chemotherapy with doxorubicin and cyclophosphamide, followed by weekly paclitaxel with or without concurrent trastuzumab. HER2 status was determined by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) at a central laboratory, Mayo Clinic, Rochester, MN. Patients with conflicting local positive HER2 expression results but normal central laboratory testing were included in the analyses (n = 103).
Results
Patients with HER2-positive tumors (IHC 3+, FISH HER2/centromere 17 ratio ≥ 2.0, or both) benefited from trastuzumab, with hazard ratios (HRs) of 0.46, 0.49, and 0.45, respectively (all P < .0001). Patients with HER2-amplified tumors with polysomic (p17) or normal (n17) chromosome 17 copy number also benefited from trastuzumab, with HRs of 0.52 and 0.37, respectively (P < .006). Patients who received chemotherapy alone and had HER2-amplified and p17 tumors had a longer DFS than those who had n17 (78% v 68%; P = .04), irrespective of hormone receptor status or tumor grade. Patients with HER2-normal tumors by central testing (n = 103) seemed to benefit from trastuzumab, but the difference was not statistically significant (HR, 0.51; P = .14). Patients with hormone receptor–positive or –negative tumors benefited from the addition of trastuzumab, with HRs of 0.42 (P = .005) and 0.60 (P = .0001), respectively.
Conclusion
These results confirm that IHC or FISH HER2 testing is appropriate for patient selection for adjuvant trastuzumab therapy. Trastuzumab benefit seemed independent of HER2/centromere 17 ratio and chromosome 17 copy number.
doi:10.1200/JCO.2009.26.2154
PMCID: PMC2954132  PMID: 20697084
24.  Persistent upregulation of U6:SNORD44 small RNA ratio in the serum of breast cancer patients 
Introduction
Serum microRNAs have the potential to be valuable biomarkers of cancer. This investigation addresses two issues that impact their utility: a) appropriate normalization controls and b) whether their altered levels persist in patients who are clinically free of the disease.
Methods
Sera from 40 age-matched healthy women and 39 breast cancer patients without clinical disease at the time of serum collection were analyzed for microRNAs let-7f, miR-16, miR-21 and miR-155 using quantitative real-time PCR. U6 and 5S, which are transcribed by RNA polymerase III (RNAP-III) and the small nucleolar RNU44 (SNORD44), were also analyzed for normalization. Significant results from the initial study were verified using a second set of sera from 15 healthy patients, 15 breast cancer patients without clinical disease and 15 with metastatic disease, and a third set of 12 healthy and 18 patients with metastatic disease. U6 was further verified in the extended second cohort of 75 healthy and 68 breast cancer patients without clinical disease.
Results
U6:SNORD44 ratio was consistently higher in breast cancer patients with or without active disease (fold change range 1.5-6.6, p value range 0.0003 to 0.05). This increase in U6:SNORD44 ratio was observed in the sera of both estrogen receptor-positive (ER+) and ER-negative breast cancer patients. MiR-16 and 5S, which are often used as normalization controls for microRNAs, showed remarkable experimental variability and thus are not ideal for normalization.
Conclusions
Elevated serum U6 levels in breast cancer patients irrespective of disease activity at the time of serum collection suggest a new paradigm in cancer; persistent systemic changes during cancer progression, which result in elevated activity of RNAP-III and/or the stability/release pathways of U6 in non-cancer tissues. Additionally, these results highlight the need for developing standards for normalization between samples in microRNA-related studies for healthy versus cancer and for inter-laboratory reproducibility. Our studies rule out the utility of miR-16, U6 and 5S RNAs for this purpose.
doi:10.1186/bcr2943
PMCID: PMC3262198  PMID: 21914171
25.  A phase II trial of trastuzumab plus weekly ixabepilone and carboplatin in patients with HER2-positive metastatic breast cancer: an Eastern Cooperative Oncology Group Trial 
The epothilone B analogue, ixabepilone, binds to β-tubulin, is effective for taxane-refractory metastatic breast cancer (MBC), and may be given every 3 weeks or weekly. We evaluated the efficacy of weekly ixabepilone (I) plus trastuzumab (T) and carboplatin (C) as first line therapy in HER2 + MBC. Patients with HER2+ (3+ by IHC or FISH amplified) MBC received I (15 mg/m2 IV) and C (area under the curve, AUC = 2 IV) on days 1, 8, and 15 of a 28-day cycle for a maximum of 6 cycles, plus weekly T (4 mg/kg loading dose then 2 mg/kg IV) during chemotherapy then every 3 weeks (6 mg/kg IV) until disease progression. The primary objective was to determine whether the combination was associated with a response rate (RR) of at least 75%. Fifty-nine patients were treated, and 39 had HER2 overexpression confirmed in a central lab (cHER2+). For all treated patients, objective response occurred in 26 patients (44%; 95% CI 31–58%), median time to progression was 8.2 months (95% CI 6.3–9.9), and median overall survival was 34.7 months (95% CI 25.7 to [not reached]). Results were comparable for cHer2+ cancers. Grade 3–4 adverse events included neutropenia (49%), thrombocytopenia (14%), fatigue (12%), nausea (7%), diarrhea (7%), and neuropathy (7%). One patient died from treatment complications during cycle 1. Weekly ixabepilone and carboplatin plus trastuzumab have an acceptable toxicity profile, but are not likely to be associated with an RR of 75% in HER2+ MBC. Efficacy appears comparable to paclitaxel, carboplatin, and trastuzumab.
doi:10.1007/s10549-009-0658-9
PMCID: PMC3133687  PMID: 20012354
Weekly ixabepilone; Carboplatin; Trastuzumab; Breast cancer

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