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1.  Association of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor-2 Genetic Polymorphisms With Outcome in a Trial of Paclitaxel Compared With Paclitaxel Plus Bevacizumab in Advanced Breast Cancer: ECOG 2100 
Journal of Clinical Oncology  2008;26(28):4672-4678.
Purpose
No biomarkers have been identified to predict outcome with the use of an antiangiogenesis agent for cancer. Vascular endothelial growth factor (VEGF) genetic variability has been associated with altered risk of breast cancer and variable promoter activity. Therefore, we evaluated the association of VEGF genotype with efficacy and toxicity in E2100, a phase III study comparing paclitaxel versus paclitaxel plus bevacizumab as initial chemotherapy for metastatic breast cancer.
Patients and Methods
DNA was extracted from tumor blocks of patients from E2100. Three hundred sixty-three samples were available to evaluate associations between genotype and outcome. Genotyping was performed for selected polymorphisms in VEGF and VEGF receptor 2. Testing for associations between each polymorphism and efficacy and toxicity was performed.
Results
The VEGF-2578 AA genotype was associated with a superior median overall survival (OS) in the combination arm when compared with the alternate genotypes combined (hazard ratio = 0.58; 95% CI, 0.36 to 0.93; P = .023). The VEGF-1154 A allele also demonstrated a superior median OS with an additive effect of each active allele in the combination arm but not the control arm (hazard ratio = 0.62; 95% CI, 0.46 to 0.83; P = .001). Two additional genotypes, VEGF-634 CC and VEGF-1498 TT, were associated with significantly less grade 3 or 4 hypertension in the combination arm when compared with the alternate genotypes combined (P = .005 and P = .022, respectively).
Conclusion
Our data support an association between VEGF genotype and median OS as well as grade 3 or 4 hypertension when using bevacizumab in metastatic breast cancer.
doi:10.1200/JCO.2008.16.1612
PMCID: PMC2653128  PMID: 18824714
2.  Prognostic Utility of the 21-Gene Assay in Hormone Receptor–Positive Operable Breast Cancer Compared With Classical Clinicopathologic Features 
Journal of Clinical Oncology  2008;26(25):4063-4071.
Purpose
Adjuvant! is a standardized validated decision aid that projects outcomes in operable breast cancer based on classical clinicopathologic features and therapy. Genomic classifiers offer the potential to more accurately identify individuals who benefit from chemotherapy than clinicopathologic features.
Patients and Methods
A sample of 465 patients with hormone receptor (HR) –positive breast cancer with zero to three positive axillary nodes who did (n = 99) or did not have recurrence after chemohormonal therapy had tumor tissue evaluated using a 21-gene assay. Histologic grade and HR expression were evaluated locally and in a central laboratory.
Results
Recurrence Score (RS) was a highly significant predictor of recurrence, including node-negative and node-positive disease (P < .001 for both) and when adjusted for other clinical variables. RS also predicted recurrence more accurately than clinical variables when integrated by an algorithm modeled after Adjuvant! that was adjusted to 5-year outcomes. The 5-year recurrence rate was only 5% or less for the estimated 46% of patients who have a low RS (< 18).
Conclusion
The 21-gene assay was a more accurate predictor of relapse than standard clinical features for individual patients with HR-positive operable breast cancer treated with chemohormonal therapy and provides information that is complementary to features typically used in anatomic staging, such as tumor size and lymph node involvement. The 21-gene assay may be used to select low-risk patients for abbreviated chemotherapy regimens similar to those used in our study or high-risk patients for more aggressive regimens or clinical trials evaluating novel treatments.
doi:10.1200/JCO.2007.14.4501
PMCID: PMC2654377  PMID: 18678838
3.  A phase II trial of capecitabine in combination with the farnesyltransferase inhibitor tipifarnib in patients with anthracycline-treated and taxane-resistant metastatic breast cancer: an Eastern Cooperative Oncology Group Study (E1103) 
Capecitabine produces an objective response rate of up to 25 % in anthracycline-treated, taxane-resistant metastatic breast cancer (MBC). The farnesyltransferase inhibitor tipifarnib inhibits Ras signaling and has clinical activity when used alone in MBC. The objective of this study was to determine the efficacy and safety of tipifarnib–capecitabine combination in MBC patients who were previously treated with an anthracycline and progressed on taxane therapy. Eligible patients received oral capecitabine 1,000 mg/m2 twice daily plus oral tipifarnib 300 mg twice daily on days 1–14 every 21 days. The primary endpoint was ORR. The trial was powered to detect an improvement in response rate from 25 to 40 %. Among 63 eligible, partial response occurred in six patients (9.5 %; 90 % CI 4.2–17.9 %), median progression-free survival was 2.6 months (95 % CI 2.1–4.4), and median overall survival was 11.4 months (95 % CI 7.7–14.0). Dose modifications were required for 43 patients (68 %) for either tipifarnib and/or capecitabine. Grades 3 and 4 toxicities were seen in 30 patients (44 %; 90 % CI 44.4–67.0 %) and 11 patients (16 %; 90 % CI 10.8–29.0 %), respectively. The most common grade 3 toxicities included neutropenia, nausea, and vomiting; and the most common grade 4 toxicity was neutropenia (8 out of 11 cases). The tipifarnib–capecitabine combination is not more effective than capecitabine alone in MBC patients who were previously treated with an anthracycline and taxane therapy.
doi:10.1007/s10549-012-2071-z
PMCID: PMC4596817  PMID: 22547107
Farnesyltransferase inhibitor; Tipifarnib; Capecitabine; Metastatic breast cancer
4.  Improving the quality of cancer care in America through health information technology 
A recent report from the Institute of Medicine titled Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis, identifies improvement in information technology (IT) as essential to improving the quality of cancer care in America. The report calls for implementation of a learning healthcare IT system: a system that supports patient–clinician interactions by providing patients and clinicians with the information and tools necessary to make well informed medical decisions and to support quality measurement and improvement. While some elements needed for a learning healthcare system are already in place for cancer, they are incompletely implemented, have functional deficiencies, and are not integrated in a way that creates a true learning healthcare system. To achieve the goal of a learning cancer care delivery system, clinicians, professional organizations, government, and the IT industry will have to partner, develop, and incentivize participation.
doi:10.1136/amiajnl-2013-002346
PMCID: PMC4147622  PMID: 24352553
Cancer; Learning healthcare system; Information technology
5.  Comparison of younger and older breast cancer survivors and age-matched controls on specific and overall QoL domains 
Cancer  2014;120(15):2237-2246.
Background
Younger survivors (YS) of breast cancer often report more survivorship symptoms such as fatigue, depression, sexual difficulty, and cognitive problems than older survivors (OS). We sought to determine the effect of breast cancer and age at diagnosis on Quality of Life (QoL) by comparing 3 groups: 1) YS diagnosed at age 45 or before, 2) OS diagnosed between 55 and 70, and, 3) for the YS, age-matched controls (AC) of women not diagnosed with breast cancer.
Methods
Using a large Eastern Cooperative Oncology Group (ECOG) data base, we recruited 505 YS who were ages 45 or younger when diagnosed and 622 OS diagnosed at 55 to 70. YS, OS, and AC were compared on physical, psychological, social, spiritual, and overall QoL variables.
Results
Compared to both AC and to OS, YS reported more depressive symptoms (p=.005) and fatigue (p<.001), poorer self-reported attention function (p<.001), and poorer sexual function (p<.001) than either comparison group. However, YS also reported a greater sense of personal growth (p<.001) and perceived less social constraint (p<.001) from their partner than AC.
Conclusions
YS reported worse functioning than AC relative to depression, fatigue, attention, sexual function, and spirituality. Perhaps even more important, YS fared worse than both AC and OS on body image, anxiety, sleep, marital satisfaction, and fear of recurrence, indicating that YS are at greater risk for long term QoL problems than survivors diagnosed at a later age.
doi:10.1002/cncr.28737
PMCID: PMC4158315  PMID: 24891116
Young survivors; Quality of Life; Breast Cancer; Comparison of Younger; Comparison of Older Survivors
6.  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
7.  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
8.  Effect of Unblinding on Participants’ Perceptions of Risk and Confidence in a Large Double-blind Clinical Trial of Chemotherapy for Breast Cancer 
JAMA oncology  2015;1(3):369-374.
Importance
Blinding patients to treatment regimen is an important component of high quality randomized clinical trials (RCT) although concern exists about how receipt of a placebo will impact participants’ views, particularly among patients with cancer.
Objective
To determine if unblinding of random assignment to placebo vs. experimental agent in a large adjuvant breast cancer chemotherapy randomized controlled trial was associated with perception of greater chance of cancer recurrence, and lower confidence in the decision to participate in the trial in participants who were randomized to placebo compared to those randomized to experimental therapy.
Design
Serial telephone based prospective surveys.
Setting
In ECOG5103, patients were randomized to receive standard adjuvant chemotherapy for breast cancer with either placebo or bevacizumab for either ~6 or ~12 months. Treatment assignment was unblinded by 24 weeks.
Participants
All patients enrolling in E5103 between 1/5-6/8/10 were included in this sub-study. Patients were surveyed after unblinding of their randomization allocation.
Main Outcome and Measure
Survey items including perceived risk of recurrence and confidence in study participation.
Results
571 patients on this sub-study started protocol therapy, 550 were still on study at unblinding and 492 responded to the unblinding survey. At unblinding, most respondents, 70% (336/477), felt they had at most a small risk of breast cancer recurrence, 71% (342/480) reported perceiving at most a small risk of serious problem with therapy; the vast majority reported feeling very informed and having high levels of confidence in their study participation (87% for both (421/483 and 420/483 respectively)). Participants who learned they had been randomized to placebo did not have greater perception of chance of recurrence (p=0.48) or fear of recurrence (p=0.69), feel less informed (p=0.86) or have lower confidence in trial participation (p=0.31) compared to those who had been randomized to experimental therapy. Patients who learned they had been randomized to bevacizumab perceived higher risk of having a serious problem caused by treatment (p=0.01).
Conclusions and Relevance
In a placebo-controlled, double-blinded RCT, unblinding to randomization allocation did not significantly affect most participants’ views except for chance of a serious problem from experimental treatment, regardless of receipt of placebo or experimental anti-cancer therapy along with standard chemotherapy.
Parent Trial Registration
NCT00433511
doi:10.1001/jamaoncol.2015.0246
PMCID: PMC4477538  PMID: 26114161
9.  Biomarker prediction of chemotherapy-related amenorrhea in premenopausal women with breast cancer participating in E5103 
This study aimed to investigate whether pre-chemotherapy anti-mullerian hormone (AMH) is a biomarker for chemotherapy-related amenorrhea (CRA) in breast cancer patients. A multicenter randomized controlled trial, ECOG5103, assigned patients with early stage breast cancer to standard doxorubicin-cyclophosphamide followed by paclitaxel with either placebo or one of two durations of bevacizumab therapy. Five hundred ninety-one patients were part of the decision-making/quality of life substudy, in which there were surveys from baseline through 18-month follow-up. One hundred twenty-four women were included in this analysis of menses data because they were premenopausal at enrollment, responded to the 12-month survey, had not undergone bilateral oophorectomy or ovarian function suppression before that survey, and had serum banked for research before chemotherapy. One hundred of the 124 also responded to the 18-month survey. Median age was 45 years (range 25–55), and median serum AMH level was 0.11 ng/mL (range 0.01–8.63) prior to treatment. Eighty-two percent had CRA at 12 months, and 81 % at 18 months. In multivariate analyses, older age (p = 0.0003) was the only statistically significant predictor of 12-month CRA, but at 18-months, lower pre-chemotherapy AMH (p = 0.04) and older age (p = 0.008) were both statistically significant predictors of CRA. Race, bevacizumab therapy, and tamoxifen use were not statistically significantly associated with CRA after adjustment for AMH and age. Pre-chemotherapy AMH level is a potential novel biomarker for CRA in premenopausal women with early stage breast cancer. Further research to evaluate the clinical utility of AMH testing is warranted.
doi:10.1007/s10549-014-2891-0
PMCID: PMC4334112  PMID: 24584876
Breast neoplasms; Fertility; Biomarkers; Chemotherapy; Adjuvant
10.  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
11.  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
12.  Delivering High-Quality Cancer Care: The Critical Role of Quality Measurement 
In 1999, the Institute of Medicine (IOM) published Ensuring Quality Cancer Care, an influential report that described an ideal cancer care system and issued ten recommendations to address pervasive gaps in the understanding and delivery of quality cancer care. Despite generating much fervor, the report’s recommendations—including two recommendations related to quality measurement—remain largely unfulfilled.
Amidst continuing concerns regarding increasing costs and questionable quality of care, the IOM charged a new committee with revisiting the 1999 report and with reassessing national cancer care, with a focus on the aging US population. The committee identified high-quality patient-clinician relationships and interactions as central drivers of quality and attributed existing quality gaps, in part, to the nation’s inability to measure and improve cancer care delivery in a systematic way. In 2013, the committee published its findings in Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis, which included two recommendations that emphasize coordinated, patient-centered quality measurement and information technology enhancements: Develop a national quality reporting program for cancer care as part of a learning health care system; and,Develop an ethically sound learning health care information technology system for cancer that enables real-time analysis of data from cancer patients in a variety of care settings.
These recommendations underscore the need for independent national oversight, public-private collaboration, and substantial funding to create robust, patient-centered quality measurement and learning enterprises to improve the quality, accessibility, and affordability of cancer care in America.
doi:10.1016/j.hjdsi.2013.11.003
PMCID: PMC4021589  PMID: 24839592
13.  Predicting early brain metastases based on clinicopathological factors and gene expression analysis in advanced HER2-positive breast cancer patients 
Journal of Neuro-Oncology  2015;122(1):205-216.
The overexpression or amplification of the human epidermal growth factor receptor 2 gene (HER2/neu) is associated with high risk of brain metastasis (BM). The identification of patients at highest immediate risk of BM could optimize screening and facilitate interventional trials. We performed gene expression analysis using complementary deoxyribonucleic acid-mediated annealing, selection, extension and ligation and real-time quantitative reverse transcription PCR (qRT-PCR) in primary tumor samples from two independent cohorts of advanced HER2 positive breast cancer patients. Additionally, we analyzed predictive relevance of clinicopathological factors in this series. Study group included discovery Cohort A (84 patients) and validation Cohort B (75 patients). The only independent variables associated with the development of early BM in both cohorts were the visceral location of first distant relapse [Cohort A: hazard ratio (HR) 7.4, 95 % CI 2.4–22.3; p < 0.001; Cohort B: HR 6.1, 95 % CI 1.5–25.6; p = 0.01] and the lack of trastuzumab administration in the metastatic setting (Cohort A: HR 5.0, 95 % CI 1.4–10.0; p = 0.009; Cohort B: HR 10.0, 95 % CI 2.0–100.0; p = 0.008). A profile including 13 genes was associated with early (≤36 months) symptomatic BM in the discovery cohort. This was refined by qRT-PCR to a 3-gene classifier (RAD51, HDGF, TPR) highly predictive of early BM (HR 5.3, 95 % CI 1.6–16.7; p = 0.005; multivariate analysis). However, predictive value of the classifier was not confirmed in the independent validation Cohort B. The presence of visceral metastases and the lack of trastuzumab administration in the metastatic setting apparently increase the likelihood of early BM in advanced HER2-positive breast cancer.
doi:10.1007/s11060-014-1704-y
PMCID: PMC4353882  PMID: 25559688
Breast cancer; Brain metastasis; HER2; RAD51; HDGF; TPR
14.  Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing 
Triple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of actionable therapeutic targets (ER−,PR−,HER2−). Microdissected normal ductal epithelium from healthy volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular signatures. Differential gene expression of TNBC compared with normal comparators demonstrated important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for negative studies and over-expression in studies with drug activity. Next, by comparing each individual TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes dysregulated in >90% of TNBCs revealing an over-expressed central network. In conclusion, Use of microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos.
doi:10.1007/s10549-013-2780-y
PMCID: PMC3901081  PMID: 24292813
triple-negative breast cancer; RNA-seq; TCGA; normal breast; adjacent normal; ductal epithelium
15.  Impact of c-MYC Protein Expression on Outcome of Patients with Early-Stage HER2+ Breast Cancer Treated with Adjuvant Trastuzumab NCCTG (Alliance) N9831 
Purpose
This study investigated the association between tumor MYC protein expression and disease-free survival (DFS) of patients randomized to receive chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the N9831 (Alliance) adjuvant HER2+ trastuzumab breast cancer trial.
Patients/Methods
This analysis included 1736 patients randomized to Arms A, B, and C on N9831. Nuclear MYC protein expression was determined in tissue microarray (TMA) sections containing three biopsies per patient or whole tissue sections (WS) using standard immunohistochemistry (clone 9E10). A tumor was considered positive for MYC protein overexpression (MYC+) if the nuclear 3+ staining percentage was >30%.
Results
574 (33%) tumors were MYC+. MYC+ was associated with hormone receptor positivity (χ2 p=0.006), tumors ≥ 2 cm (χ2 p=0.02), and a higher rate of nodal positivity (χ2 p<0.001). Hazard ratios (HRs) for DFS (median follow-up: 6.1 years) for Arm C versus A were 0.52 (p=0.006) and 0.65 (p=0.006) for patients with MYC+ and MYC- tumors, respectively (interaction p=0.40). For Arm B versus A, HRs for patients with MYC+ and MYC- tumors were 0.79 (p=0.21) and 0.74 (p=0.04), respectively (interaction p=0.71). For Arm C versus B, HRs for patients with MYC+ and MYC- tumors were 0.56 (p=0.02) and 0.89 (p=0.49), respectively (interaction p=0.17).
Conclusions
Our data do not support an impact of tumor MYC protein expression on differential benefit from adjuvant trastuzumab.
doi:10.1158/1078-0432.CCR-13-0558
PMCID: PMC3805021  PMID: 23965903
trastuzumab; HER2-positive; breast cancer; MYC protein expression; disease-free survival
16.  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
17.  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
18.  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
19.  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
20.  Wnt signaling in triple negative breast cancer is associated with metastasis 
BMC Cancer  2013;13:537.
Background
Triple Negative subset of (TN) Breast Cancers (BC), a close associate of the basal-like subtype (with limited discordance) is an aggressive form of the disease which convey unpredictable, and poor prognosis due to limited treatment options and lack of proven effective targeted therapies.
Methods
We conducted an expression study of 240 formalin-fixed, paraffin-embedded (FFPE) primary biopsies from two cohorts, including 130 TN tumors, to identify molecular mechanisms of TN disease.
Results
The annotation of differentially expressed genes in TN tumors contained an overrepresentation of canonical Wnt signaling components in our cohort and others. These observations were supported by upregulation of experimentally induced oncogenic Wnt/β-catenin genes in TN tumors, recapitulated using targets induced by Wnt3A. A functional blockade of Wnt/β-catenin pathway by either a pharmacological Wnt-antagonist, WntC59, sulidac sulfide, or β-catenin (functional read out of Wnt/β-catenin pathway) SiRNA mediated genetic manipulation demonstrated that a functional perturbation of the pathway is causal to the metastasis- associated phenotypes including fibronectin-directed migration, F-actin organization, and invasion in TNBC cells. A classifier, trained on microarray data from β-catenin transfected mammary cells, identified a disproportionate number of TNBC breast tumors as compared to other breast cancer subtypes in a meta-analysis of 11 studies and 1,878 breast cancer patients, including the two cohorts published here. Patients identified by the Wnt/β-catenin classifier had a greater risk of lung and brain, but not bone metastases.
Conclusion
These data implicate transcriptional Wnt signaling as a hallmark of TNBC disease associated with specific metastatic pathways.
doi:10.1186/1471-2407-13-537
PMCID: PMC4226307  PMID: 24209998
Breast cancer; Triple negative; Wnt; FFPE; Microarray
22.  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
23.  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
24.  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
25.  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

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