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1.  Toward Individualized Breast Cancer Therapy: Translating Biological Concepts to the Bedside 
The Oncologist  2012;17(4):577-584.
The management of hormone receptor–positive, human epidermal growth factor receptor 2–positive, and triple-negative breast cancers is reviewed, emphasizing changes that occurred in recent years and focusing on potential mechanisms of drug resistance. Strategies to prevent or overcome resistance to specific therapeutic agents are also highlighted.
The management of breast cancer has changed dramatically over the past 20 years. Based on gene expression profiles, or proteomics of three or four biomarkers, it is apparent that there are multiple subtypes with different clinical characteristics, clinical courses, and sensitivities to existing therapies. This manuscript reviews the management of hormone receptor–positive, human epidermal growth factor receptor 2–positive, and triple-negative breast cancers, emphasizing changes that have occurred in recent years and focusing on potential mechanisms of drug resistance. I also highlight strategies to prevent or overcome resistance to specific therapeutic agents. As a result of enhanced biological understanding of the molecular anomalies that drive the development, progression, and dissemination of breast cancer, a number of novel, molecularly targeted agents have been added to standard therapies. Chemotherapy, endocrine therapy, and targeted treatments have markedly reduced the risk for recurrence and mortality after primary treatment of breast cancer and have increased the 5- and 10-year survival rates. The challenges with novel therapeutics include the absence of accurate predictive biomarkers to identify those patient who will derive substantial benefit and those patients whose tumors are resistant to specific antitumor agents. As we move forward with increasing molecular segmentation of breast cancer and develop new, highly targeted agents, molecular diagnostics must accompany molecular therapeutics to implement the concept of personalized cancer therapy.
doi:10.1634/theoncologist.2012-0032
PMCID: PMC3336824  PMID: 22474069
2.  Everolimus Plus Exemestane for the Treatment of Advanced Breast Cancer: A Review of Subanalyses from BOLERO-21 
Neoplasia (New York, N.Y.)  2015;17(3):279-288.
Hormone receptor–positive breast cancer is typically managed with endocrine therapies. However, resistance to endocrine therapy results in disease progression in a large proportion of breast cancers. Through the understanding of the mechanisms of endocrine resistance, identification of implicated pathways and targets has led to the development of novel agents targeting these pathways. Phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway aberrations are common in breast cancer, with increased PI3K/AKT/mTOR signaling associated with resistance to endocrine and human epidermal growth factor receptor 2 (HER2)–targeted therapies. The mTOR inhibitor everolimus, in combination with exemestane, has been approved for patients with advanced hormone receptor–positive/HER2-negative breast cancer who progress on prior nonsteroidal aromatase inhibitor therapy based on results reported in the Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study. This review will summarize the overall findings from BOLERO-2 and will consider available subanalyses by age, Asian origin, visceral or bone metastases, and prior therapy, with the aim of identifying populations most likely to benefit from everolimus therapy. The review will also summarize safety findings and their management and the effects of everolimus on quality of life.
doi:10.1016/j.neo.2015.01.005
PMCID: PMC4372651  PMID: 25810012
AE, adverse event; BSAP, bone-specific alkaline phosphatase; CBR, clinical benefit rate; CR, complete response; CTX, C-terminal cross-linking telopeptide of type 1 collagen; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; NIP, noninfectious pneumonitis; ORR, objective response rate; PI3K/AKT/mTOR, phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin; PFS, progression-free survival; P1NP, amino-terminal propeptide of type 1 collagen; PR, partial response; QoL, quality of life; TDD, time to definitive deterioration
3.  Randomized Double-Blind Placebo-Controlled Trial of Acetyl-L-Carnitine for the Prevention of Taxane-Induced Neuropathy in Women Undergoing Adjuvant Breast Cancer Therapy 
Journal of Clinical Oncology  2013;31(20):2627-2633.
Purpose
Chemotherapy-induced peripheral neuropathy (CIPN) is common and leads to suboptimal treatment. Acetyl-L-carnitine (ALC) is a natural compound involved in neuronal protection. Studies have suggested ALC may be effective for the prevention and treatment of CIPN.
Patients and Methods
A 24-week randomized double-blind trial comparing ALC (3,000 mg per day) with placebo in women undergoing adjuvant taxane-based chemotherapy was conducted. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the Functional Assessment of Cancer Therapy (FACT) –Taxane scale at 12 weeks. Secondary objectives included changes in 24-week end points, functional status (FACT–Trial Outcome Index [TOI]), fatigue (Functional Assessment of Chronic Illness Therapy [FACIT] –Fatigue), and NTX grade.
Results
A total of 409 patients were evaluable (208 received ALC; 201, placebo). In a multivariate linear regression, week-12 scores were 0.9 points lower (more CIPN) with ALC than placebo (95% CI, −2.2 to 0.4; P = .17), whereas week-24 scores were 1.8 points lower with ALC (95% CI, −3.2 to −0.4; P = .01). Patients receiving ALC were more likely to have a > 5-point decrease in FACT-NTX scores (38% v 28%; P = .05), and FACT-TOI scores were 3.5 points lower with ALC (P = .03). Grade 3 to 4 neurotoxicity was more frequent in the ALC arm (eight v one). No differences between arms were observed for FACIT-Fatigue or other toxicities. Serum carnitine level increased with ALC but remained stable with placebo.
Conclusion
There was no evidence that ALC affected CIPN at 12 weeks; however, ALC significantly increased CIPN by 24 weeks. This is the first study to our knowledge showing that a nutritional supplement increased CIPN. Patients should be discouraged from using supplements without proven efficacy.
doi:10.1200/JCO.2012.44.8738
PMCID: PMC3699727  PMID: 23733756
4.  Anthracycline Regimen Adherence in Older Patients with Early Breast Cancer 
The Oncologist  2012;17(3):303-311.
The Surveillance, Epidemiology, and End Results–Medicare linked database was used to describe the extent of nonadherence to anthracycline-based chemotherapy regimens in older patients with early breast cancer and to explore factors associated with nonadherence.
Learning Objectives
After completing this course, the reader will be able to: Describe rates of adherence to anthracycline-based chemotherapy in elderly patients with early breast cancer, using a population-based database.Identify a subset of early breast cancer patients with a higher likelihood of non-adherence to the course of chemotherapy treatment.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
Rates of anthracycline adherence in breast cancer (BC) patients are unknown, but noncompletion of chemotherapy is associated with worse outcomes.
Methods.
Using the Surveillance, Epidemiology, and End Results–Medicare database, we obtained demographics, comorbidities, tumor characteristics, and treatment and hospitalization data from stage I–III BC patients diagnosed at age ≥66 years in 1996–2005 treated with surgery who had anthracycline claims. We compared variables between patients with claims for less than four cycles, considered nonadherent cases, and those with claims for four or more cycles using logistic regression analyses.
Results.
The sample included 7,399 patients, of whom 1,222 (16.5%) were nonadherent cases. Two hundred forty-three (3.3%) patients had one claim, 298 (4.0%) had two claims, and 681 (9.2%) had three claims. The multivariate regression model showed statistically significant associations between nonadherence and older age, black race, unmarried status, diagnosis before the year 2001, and hospitalizations.
Conclusions.
Eighty-three percent of older patients with early-stage BC completed at least four cycles of an anthracycline-based chemotherapy regimen. We identified a subset of patients with a higher likelihood of not adhering to the course of treatment. Further research is warranted to develop interventions to enhance adherence.
doi:10.1634/theoncologist.2011-0316
PMCID: PMC3316913  PMID: 22371383
Adherence to chemotherapy; Anthracyclines; Early breast cancer; Elderly patients with breast cancer; SEER–Medicare database
5.  Loss of Human Epidermal Growth Factor Receptor 2 (HER2) Expression in Metastatic Sites of HER2-Overexpressing Primary Breast Tumors 
Journal of Clinical Oncology  2011;30(6):593-599.
Purpose
We evaluated whether patients with human epidermal growth factor receptor 2 (HER2) –positive primary breast tumors had metastatic tumors that were HER2 positive (concordant) or HER2 negative (discordant). We then evaluated whether treatment with trastuzumab or chemotherapy before biopsy of the metastasis had any effect on the rate of HER2 discordance. We also compared the overall survival durations of patients with HER2-concordant and -discordant tumors.
Patients and Methods
We retrospectively identified all patients who initially had been diagnosed with HER2-positive (immunohistochemistry 3+ and/or fluorescent in situ hybridization positive) primary breast cancer between 1997 and 2008 at MD Anderson Cancer Center who also had metastatic tumor biopsy results available for review.
Results
We included 182 patients who met our criteria. Forty-three (24%) of the 182 patients with HER2-positive primary tumors had HER2-negative metastatic tumors. The HER2 discordance rates differed significantly on the basis of whether patients received chemotherapy (P = .022) but not on the basis of whether patients received trastuzumab (P = .296). Patients with discordant HER2 status had shorter overall survival than did patients with concordant HER2 status (hazard ratio [HR], 0.43; P = .003). A survival difference remained among the 67 patients who received trastuzumab (HR, 0.56; P = .083) and 101 patients who did not (HR, 0.53; P = .033) before their metastasis biopsies.
Conclusion
We confirmed that loss of HER2-positive status in metastatic tumors can occur in patients with primary HER2-positive breast cancer. Our data strongly support the need for biopsies of metastatic lesions to accurately determine patient prognosis and appropriate use of targeted therapy.
doi:10.1200/JCO.2010.33.8889
PMCID: PMC3295557  PMID: 22124109
6.  Phase II Trial of Simple Oral Therapy with Capecitabine and Cyclophosphamide in Patients with Metastatic Breast Cancer: SWOG S0430 
The Oncologist  2012;17(2):179-187.
A simple oral combination of capecitabine and cyclophosphamide for the treatment of patients with metastatic breast cancer was evaluated. The addition of cyclophosphamide did not result in outcomes superior to those seen with capecitabine alone.
Learning Objectives:
After completing this course, the reader will be able to: Compare outcomes in patients treated with capecitabine plus CPA with those of capecitabine monotherapy and combination therapy with bevacizumab, sorafenib, or ixabepilone.Identify patients for whom single-agent capecitabine is recommended.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
Interest in oral agents for the treatment of metastatic breast cancer (MBC) has increased because many patients prefer oral to i.v. regimens. We evaluated a simple oral combination of capecitabine with cyclophosphamide (CPA) for MBC.
Methods.
The trial was designed to determine whether or not combination therapy would achieve a 42% response rate (RR) using the Response Evaluation Criteria in Solid Tumors (RECIST) in MBC. Patients with two or fewer prior chemotherapy regimens for MBC were eligible. Those with estrogen receptor–positive MBC had to have progressed on endocrine therapy. Patients had measurable disease or elevated mucin (MUC)-1 antigen and received CPA, 100 mg daily on days 1–14, and capecitabine, 1,500 mg twice daily on days 8–21, in 21-day cycles.
Results.
In 96 eligible patients, the median progression-free survival (PFS) interval was 5.9 months (95% confidence interval [CI], 3.7–8.0 months) and median overall survival (OS) time was 18.8 months (95% CI, 13.1–22.0 months). The RR was 36% (95% CI, 26%–48%) in 80 patients with measurable disease. The MUC-1 antigen RR was 33% (95% CI, 20%–48%), occurring in 15 of 46 patients with elevated MUC-1 antigen. Toxicity was mild, with no treatment-related deaths.
Conclusions.
PFS, OS, and RR outcomes with capecitabine plus CPA compare favorably with those of capecitabine monotherapy and combination therapy with bevacizumab, sorafenib, or ixabepilone. The addition of these other agents to capecitabine does not improve OS time in MBC patients, and this single-arm study does not suggest that the addition of CPA to capecitabine has this potential in an unselected MBC population. When OS prolongation is the goal, clinicians should choose single-agent capecitabine.
doi:10.1634/theoncologist.2011-0235
PMCID: PMC3286166  PMID: 22267853
Metastatic breast cancer; Capecitabine; Cyclophosphamide; Oral therapy
7.  Novel Staging System for Predicting Disease-Specific Survival in Patients With Breast Cancer Treated With Surgery As the First Intervention: Time to Modify the Current American Joint Committee on Cancer Staging System 
Journal of Clinical Oncology  2011;29(35):4654-4661.
Purpose
American Joint Committee on Cancer (AJCC) staging is used to determine breast cancer prognosis, yet patient survival within each stage shows wide variation. We hypothesized that differences in biology influence this variation and that addition of biologic markers to AJCC staging improves determination of prognosis.
Patients and Methods
We identified a cohort of 3,728 patients who underwent surgery as the first intervention between 1997 and 2006. A Cox proportional hazards model, with backward stepwise exclusion of factors and stratification on pathologic stage (PS), was used to test the significance of adding grade (G), lymphovascular invasion (L), estrogen receptor (ER) status (E), progesterone receptor (PR) status, combined ER and PR status (EP), or combined ER, PR, and human epidermal growth factor receptor 2 status (M). We assigned values of 0 to 2 to these disease-specific survival (DSS) –associated factors and assessed six different staging systems: PS, PS + G, PS + G L, PS + G E, PS + G EP, and PS + G M. We compared 5-year DSS rates, Akaike's information criterion (AIC), and Harrell's concordance index (C-index) between systems. Surveillance, Epidemiology, and End Results data were used as the external validation cohort (n = 26,711).
Results
Median follow-up was 6.5 years, and 5-year DSS rate was 97.4%. The PS + G E status staging system was most precise, with a low AIC (1,931.9) and the highest C-index (0.80). PS + G E status was confirmed to stratify outcomes in internal bootstrapping samples and the external validation cohort.
Conclusion
Our results validate an improved breast cancer staging system that incorporates grade and ER status. We recommend that biologic markers be incorporated into revised versions of the AJCC staging system.
doi:10.1200/JCO.2011.38.3174
PMCID: PMC3236648  PMID: 22084362
8.  Bevacizumab Treatment for Advanced Breast Cancer 
The Oncologist  2011;16(12):1684-1697.
The most promising breast cancer studies using bevacizumab combined with traditional cytotoxic agents in advanced breast cancer are outlined. The current indications for bevacizumab reviewed by the Oncologic Drug Advisory Committee are discussed and how benefit in patient clinical trials should be measured is proposed.
Significant advances in the treatment of patients with breast cancer have been made in the past 10 years. The current systemic treatment of breast cancer is characterized by the discovery of multiple cancer targets leading to treatments that are more sophisticated and specific than conventional cytotoxic chemotherapy. Two classes of compounds that have helped improve clinical outcomes are small molecules and monoclonal antibodies targeting specific tyrosine kinase receptors. Many novel targets have been discovered, and parallel multiple approaches to anticancer therapy have recently emerged from the literature. One promising strategy is targeting the proangiogenic vascular endothelial growth factors (VEGFs), either by ligand sequestration (preventing VEGF receptor binding) or inhibiting downstream receptor signaling. Bevacizumab, a monoclonal antibody directed against VEGF, has been shown to improve the efficacy of taxanes in frontline treatment of patients with metastatic breast cancer. This review outlines the most promising breast cancer studies using bevacizumab combined with traditional cytotoxic agents in advanced breast cancer. In addition, we discuss the current indications reviewed by the Oncologic Drug Advisory Committee and define our vision of how the benefit of patient clinical trials should be measured.
doi:10.1634/theoncologist.2011-0113
PMCID: PMC3248767  PMID: 21976315
Antiangiogenesis; Advanced breast cancer; Bevacizumab; FDA
9.  Phase III Randomized Trial of Dose Intensive Neoadjuvant Chemotherapy with or Without G-CSF in Locally Advanced Breast Cancer: Long-Term Results 
The Oncologist  2011;16(11):1527-1534.
The pathologic complete response rate, delivered dose intensity, disease-free survival and overall survival rates, and toxicity of breast cancer patients treated with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus dose-intense FAC plus G-CSF in the neoadjuvant setting were compared.
Learning Objectives
After completing this course, the reader will be able to: Compare outcomes in patients treated with standard fluorouracil, doxorubicin, and cyclophosphamide (FAC) and those treated with dose-intense FAC.Describe toxicity profiles in patients treated with standard fluorouracil, doxorubicin, and cyclophosphamide (FAC) and those treated with dose-intense FAC.
This article is available for continuing medical education credit at CME.TheOncologist.com
Objective.
To compare the pathologic complete response (pCR) rate of patients treated with 5-fluorouracil (5-FU), doxorubicin, and cyclophosphamide (FAC) versus dose-intense FAC plus G-CSF in the neoadjuvant setting and to compare the delivered dose intensity, disease-free survival (DFS) and overall survival (OS) times, and toxicity between treatment arms in patients with breast cancer.
Methods.
Patients were randomized to receive preoperative FAC (5-FU, 500 mg/m2; doxorubicin, 50 mg/m2; cyclophosphamide, 500 mg/m2) every 21 days for four cycles or dose-intense FAC (5-FU, 600 mg/m2; doxorubicin, 60 mg/m2; cyclophosphamide, 1,000 mg/m2) plus G-CSF every 18 days for four cycles.
Results.
Two hundred two patients were randomly assigned. The median follow-up was 7.5 years. Patients randomized to FAC plus G-CSF had a higher pCR rate as well as clinical complete response rate; however, these differences were not statistically different from those with the FAC arm. Patients in the FAC + G-CSF arm had a higher delivered dose intensity of doxorubicin in the neoadjuvant and adjuvant settings than those in the standard FAC arm. DFS and OS times were not significantly different between the two groups. However, the OS and DFS rates were significantly higher for patients who achieved a pCR than for those who did not. Thrombocytopenia, febrile neutropenia, and infection rates were higher in the FAC + G-CSF arm.
Conclusions.
A higher delivered dose intensity of doxorubicin with the FAC + G-CSF regimen did not result in a statistically significant higher pCR rate. However, patients who achieved a pCR experienced longer DFS and OS times.
doi:10.1634/theoncologist.2011-0134
PMCID: PMC3233286  PMID: 22042783
Breast cancer; Locally advanced; Dose intensity; Disease-free survival; Overall survival; G-CSF
10.  Hot Flashes: A Review of Pathophysiology and Treatment Modalities 
The Oncologist  2011;16(11):1658-1664.
Current options for the management of hot flashes are addressed, key endpoints from recent clinical trials are examined, and future directions are reviewed.
Many therapies are being studied for the treatment of hot flashes for individuals with cancer, yet few studies have demonstrated safe and effective clinical benefit for those who suffer from this distressing symptom. The purpose of this paper is to assess the current options for the management of hot flashes, examining key endpoints from recent clinical trials and reviewing future directions. Hot flashes are a common stressful symptom for individuals with cancer, particularly women with a history of breast cancer and men with prostate cancer. Lifestyle modifications are proposed as the first step in the management of less severe hot flashes. Several publications have addressed nonhormonal agents as a treatment option for hot flashes. Newer antidepressant and anticonvulsant agents have been studied and show potential in treating vasomotor symptoms. Although many complementary and alternative therapies, including herbal medications and phytoestrogens, have been studied for the treatment of hot flashes, none are clinically recommended at this time. Additionally, further evidence is needed for supportive exercise such as yoga and relaxation techniques. Acupuncture may warrant further investigation in the reduction and severity of hot flashes in both men and women. Hormonal therapies, including estrogens and progestogens, are the most well-known and efficient agents in alleviating hot flashes; however, the safety of these agents is disputable.
doi:10.1634/theoncologist.2011-0174
PMCID: PMC3233302  PMID: 22042786
Vasomotor symptoms; Hot flashes; Menopause; Therapy; Quality of life
11.  High-Dose Chemotherapy With Autologous Stem-Cell Support As Adjuvant Therapy in Breast Cancer: Overview of 15 Randomized Trials 
Journal of Clinical Oncology  2011;29(24):3214-3223.
Purpose
Adjuvant high-dose chemotherapy (HDC) with autologous hematopoietic stem-cell transplantation (AHST) for high-risk primary breast cancer has not been shown to prolong survival. Individual trials have had limited power to show overall benefit or benefits within subsets.
Methods
We assembled individual patient data from 15 randomized trials that compared HDC versus control therapy without stem-cell support. Prospectively defined primary end points were relapse-free survival (RFS) and overall survival (OS). We compared the effect of HDC versus control by using log-rank tests and proportional hazards regression, and we adjusted for clinically relevant covariates. Subset analyses were by age, number of positive lymph nodes, tumor size, histology, hormone receptor (HmR) status, and human epidermal growth factor receptor 2 (HER2) status.
Results
Of 6,210 total patients (n = 3,118, HDC; n = 3,092 control), the median age was 46 years; 69% were premenopausal, 29% were postmenopausal, and 2% were unknown menopausal status; 49.5% were HmR positive; 33.5% were HmR negative, and 17% were unknown HmR status. The median follow-up was 6 years. After analysis was adjusted for covariates, HDC was found to prolong relapse-free survival (RFS; hazard ratio [HR], 0.87; 95% CI, 0.81 to 0.93; P < .001) but not overall survival (OS; HR, 0.94; 95% CI, 0.87 to 1.02; P = .13). For OS, no covariates had statistically significant interactions with treatment effect, and no subsets evinced a significant effect of HDC. Younger patients had a significantly better RFS on HDC than did older patients.
Conclusion
Adjuvant HDC with AHST prolonged RFS in high-risk primary breast cancer compared with control, but this did not translate into a significant OS benefit. Whether HDC benefits patients in the context of targeted therapies is unknown.
doi:10.1200/JCO.2010.32.5910
PMCID: PMC4322115  PMID: 21768471
12.  Phase I/II Study of Trastuzumab in Combination With Everolimus (RAD001) in Patients With HER2-Overexpressing Metastatic Breast Cancer Who Progressed on Trastuzumab-Based Therapy 
Journal of Clinical Oncology  2011;29(23):3126-3132.
Purpose
Trastuzumab resistance has been linked to activation of the phosphoinositol 3-kinase (PI3K) pathway. Phosphatase and tensin homolog (PTEN) is a dual phosphatase that counteracts the PI3K function; PTEN loss leads to activation of the Akt cascade and the downstream mammalian target of rapamycin (mTOR). Preclinical studies demonstrated that mTOR inhibition sensitized the response to trastuzumab in mice with HER2 overexpressing and PTEN-deficient breast xenografts. Our trial evaluated the safety and efficacy of the combination of everolimus and trastuzumab in women with HER2-overexpressing metastatic breast cancer (MBC) that progressed on trastuzumab-based therapy.
Patients and Methods
This represents a pooled analysis (n = 47), stemming from two trials that occurred concurrently in The University of Texas MD Anderson Cancer Center, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute. Patients with HER2-overexpressing MBC who had progressed on trastuzumab-based therapy received trastuzumab every 3 weeks in combination with daily everolimus.
Results
Among 47 patients, the combination of everolimus and trastuzumab provided partial responses in seven patients (15%) and persistent stable disease (lasting 6 months or longer) in nine patients (19%), resulting in a clinical benefit rate of 34%. The median progression-free survival (PFS) was 4.1 month. Fatigue, infection, and mucositis were the predominant nonhematologic toxicities. Trastuzumab did not have significant influence on the pharmacokinetic profile of everolimus. Patients with PTEN loss demonstrated decreased overall survival (P = .048). However, PFS was not affected by PTEN loss.
Conclusion
Inhibition of mTOR results in clinical benefit and disease response in patients with trastuzumab-resistant HER2-overexpressing MBC.
doi:10.1200/JCO.2010.32.2321
PMCID: PMC3157979  PMID: 21730275
13.  FDG-PET/CT Compared with Conventional Imaging in the Detection of Distant Metastases of Primary Breast Cancer 
The Oncologist  2011;16(8):1111-1119.
The sensitivity and specificity of positron emission tomography–computed tomography were compared with those of conventional imaging (computed tomography, ultrasonography, radiography, and skeletal scintigraphy) for the detection of distant metastases in patients with primary breast cancer.
Purpose.
Evidence from studies with small numbers of patients indicates that 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) accurately detects distant metastases in the staging of primary breast cancer. We compared the sensitivity and specificity of PET/CT and conventional imaging (CT, ultrasonography, radiography, and skeletal scintigraphy) for the detection of distant metastases in patients with primary breast cancer.
Patients and Methods.
We performed a retrospective review that identified 225 patients with primary breast cancer seen from January 2000 to September 2009 for whom PET/CT data were available for review. Imaging findings were compared with findings on biopsy, subsequent imaging, or clinical follow-up. Sensitivity and specificity in the detection of distant metastases were calculated for PET/CT and conventional imaging. Fisher's exact tests were used to test the differences in sensitivity and specificity between PET/CT and conventional imaging.
Results.
The mean patient age at diagnosis was 53.4 years (range, 23–84 years). The sensitivity and specificity in the detection of distant metastases were 97.4% and 91.2%, respectively, for PET/CT and 85.9% and 67.3%, respectively, for conventional imaging. The sensitivity and specificity of PET/CT were significantly higher than those of conventional imaging (p = .009 and p < .001, respectively). Eleven cases of distant metastases detected by PET/CT were clinically occult and not evident on conventional imaging.
Conclusion.
PET/CT has higher sensitivity and specificity than conventional imaging in the detection of distant metastases of breast cancer. A prospective study is needed to determine whether PET/CT could replace conventional imaging to detect distant metastases in patients with primary breast cancer.
doi:10.1634/theoncologist.2011-0089
PMCID: PMC3228159  PMID: 21765193
Breast cancer; PET/CT; Primary staging
14.  Beta-Blocker Use Is Associated With Improved Relapse-Free Survival in Patients With Triple-Negative Breast Cancer 
Journal of Clinical Oncology  2011;29(19):2645-2652.
Purpose
To examine the association between beta-blocker (BB) intake, pathologic complete response (pCR) rates, and survival outcomes in patients with breast cancer treated with neoadjuvant chemotherapy.
Patients and Methods
We retrospectively reviewed 1,413 patients with breast cancer who received neoadjuvant chemotherapy between 1995 and 2007. Patients taking BBs at the start of neoadjuvant therapy were compared with patients with no BB intake. Rates of pCR between the groups were compared using a χ2 test. Cox proportional hazards models were fitted to determine the association between BB intake, relapse-free survival (RFS), and overall survival (OS).
Results
Patients who used BBs (n = 102) were compared with patients (n = 1,311) who did not. Patients receiving BBs tended to be older and obese (P < .001). The proportion of pCR was not significantly different between the groups (P = .48). After adjustment for age, race, stage, grade, receptor status, lymphovascular invasion, body mass index, diabetes, hypertension, and angiotensin-converting enzyme inhibitor use, BB intake was associated with a significantly better RFS (hazard ratio [HR], 0.52; 95% CI, 0.31 to 0.88) but not OS (P = .09). Among patients with triple-negative breast cancer (TNBC; n = 377), BB intake was associated with improved RFS (HR, 0.30; 95% CI, 0.10 to 0.87;P = .027) but not OS (HR, 0.35; 95% CI, 0.12 to 1.00;P = .05).
Conclusion
In this study, BB intake was associated with improved RFS in all patients with breast cancer and in patients with TNBC. Additional studies evaluating the potential benefits of beta-adrenergic blockade on breast cancer recurrence with a focus on TNBC are warranted.
doi:10.1200/JCO.2010.33.4441
PMCID: PMC3139371  PMID: 21632501
15.  Prognostic Impact of Phosphorylated HER-2 in HER-2+ Primary Breast Cancer 
The Oncologist  2011;16(7):956-965.
The prognostic value of the expression level of tyrosine 1248–phosphorylated human epidermal growth factor receptor (HER)-2 in patients with HER-2+ primary breast cancer is examined.
Purpose.
Tyrosine 1248 is one of the autophosphorylation sites of human epidermal growth factor receptor (HER)-2. We determined the prognostic value of the expression level of tyrosine 1248–phosphorylated HER-2 (pHER-2) in patients with HER-2+ primary breast cancer using a reverse-phase protein array.
Patients and Methods.
The optimal cutoff value of pHER-2 for segregating disease-free survival (DFS) was determined by receiver operating characteristic (ROC) curve analysis. Five-year DFS for pHER-2 expression level was estimated with the Kaplan-Meier method using both derivation (n = 162) and validation (n = 227) cohorts.
Results.
Of the 162 patients in the derivation cohort, 26 had high HER-2 expression levels. The area under the ROC curve for pHER-2 level and DFS was 0.662. Nineteen of the 162 patients (11.7%) had high pHER-2 expression levels (pHER-2high); 143 patients (88.3%) had low pHER-2 expression levels (pHER-2low). Among the 26 patients with high HER-2 expression levels, the 17 pHER-2high patients had a significantly lower 5-year DFS rate than the nine pHER-2low patients (23.5% versus 77.8%). On multivariate analysis, only pHER-2high independently predicted DFS in the Cox proportional hazards model. In the validation cohort, among 61 patients with high HER-2 expression, the difference in 5-year DFS rates between pHER-2high (n = 7) and pHER-2low (n = 54) patients was marginal (57.1% versus 81.5%).
Conclusion.
In patients with HER-2+ primary breast cancer, pHER-2high patients had a lower 5-year DFS rate than pHER-2low patients. Quantification of pHER-2 expression level may provide prognostic information beyond the current standard HER-2 status.
doi:10.1634/theoncologist.2010-0409
PMCID: PMC3228141  PMID: 21712485
Breast cancer; HER-2; Reverse-phase protein array; Metastases; Phosphorylation
16.  Initial Staging Impact of Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Locally Advanced Breast Cancer 
The Oncologist  2011;16(6):772-782.
The outcomes of breast cancer patients staged with conventional imaging were compared with those staged with conventional imaging plus positron emission tomography/computed tomography (PET/CT). Patients with inflammatory breast cancer may benefit from the addition of PET/CT to conventional imaging.
Purpose.
Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) may reveal distant metastases more accurately than conventional imaging (CT, skeletal scintigraphy, chest radiography). We hypothesized that patients diagnosed with stage III noninflammatory breast cancer (non-IBC) and IBC by conventional imaging with PET/CT have a better prognosis than patients diagnosed without PET/CT.
Patients and Methods.
We retrospectively identified 935 patients with stage III breast cancer in 2000–2009. We compared the relapse-free survival (RFS) and overall survival (OS) times of patients diagnosed by conventional imaging with those of patients diagnosed by conventional imaging plus PET/CT. Univariate and multivariate Cox proportional hazards regression models were used to assess associations between survival and PET/CT.
Results.
RFS and OS times were not significantly different between patients imaged with PET/CT and those imaged without PET/CT. However, the RFS time in IBC patients was significantly different between patients imaged with PET/CT and those imaged without PET/CT on both univariate (hazard ratio [HR], 0.43; p = .014) and multivariate (HR, 0.33; p = .004) analysis. There was a trend for a longer OS duration in IBC patients imaged with PET/CT.
Conclusion.
Among IBC patients, adding PET/CT to staging based on conventional imaging might detect patients with metastases that were not detected by conventional imaging. The use of conventional imaging with PET/CT for staging in non-IBC patients is not justified on the basis of these retrospective data. The use of conventional imaging plus PET/CT in staging IBC needs to be studied prospectively to determine whether it will improve prognosis.
doi:10.1634/theoncologist.2010-0378
PMCID: PMC3228212  PMID: 21632453
17.  Overweight, Obesity, Diabetes, and Risk of Breast Cancer: Interlocking Pieces of the Puzzle 
The Oncologist  2011;16(6):726-729.
This review summarizes the epidemiological evidence that implicates overweight status, but not consistently diabetes and insulin levels as risk factors of breast cancer.
We considered epidemiological data on overweight, diabetes, insulin, and breast cancer. Overweight is inversely related to premenopausal breast cancer, but there is definite evidence that, as compared with normal weight women, the relative risk (RR) for postmenopausal breast cancer is around 1.5 for overweight women and >2 for obese women, and that the association is stronger in elderly women. Overweight and obesity are strongly related to diabetes. Diabetes is associated with postmenopausal breast cancer, too, with summary RRs from meta-analyses of 1.15–1.20, but not with premenopausal breast cancer (RR, 0.9). There is no consistent evidence that fasting insulin is related to breast cancer risk. Thus, although overweight and obesity are strongly related to postmenopausal breast cancer, diabetes is only moderately related to it. Given the extent of the association, and the likely residual confounding by overweight, inference on causality for the diabetes–breast cancer relation remains open to discussion.
doi:10.1634/theoncologist.2011-0050
PMCID: PMC3228228  PMID: 21632448
Breast cancer; Diabetes; Overweight; Risk
18.  Treatment Outcome and Prognostic Factors for Patients with Bone-Only Metastases of Breast Cancer: A Single-Institution Retrospective Analysis 
The Oncologist  2011;16(2):155-164.
The study defines prognostic factors for breast cancer patients with bone-only metastases and examines progression-free and overall survival times in patients with hormone receptor–positive disease and bone-only metastases treated with different therapies.
Purpose.
Limited information is available about the optimal management and clinical outcome of bone-only metastases in breast cancer patients. The objective of this study was to define prognostic factors for patients with bone-only metastases. Our second objective was to compare progression-free survival (PFS) and overall survival (OS) between patients with hormone receptor (HR)+ tumors and bone-only metastases who received combinatory therapy (chemotherapy followed by endocrine therapy, or endocrine therapy combined with molecular targeted therapy) and those treated with endocrine or chemotherapy alone.
Patients and Methods.
We retrospectively identified 351 breast cancer patients diagnosed with bone-only metastasis in 1997–2008 at our institution.
Results.
Patients with metastasis detected at the time of their primary breast cancer diagnosis (rather than at recurrence), a single metastasis, or asymptomatic bone disease had a longer PFS interval, and patients with a performance status of 0–1, a single metastasis, or asymptomatic bone disease had a longer OS time. Among patients with HR+ human epidermal growth factor receptor (HER)-2− disease, combinatory therapy was associated with longer PFS and OS times than with endocrine therapy. In multivariate analyses, combinatory therapy was not associated with longer PFS or OS times than with endocrine therapy. Among patients with HER-2+ disease, trastuzumab led to a longer PFS interval but no difference in the OS time.
Conclusion.
Our results indicate that, for HR+ disease, a prospective trial of chemotherapy followed by endocrine therapy is warranted to determine whether it prolongs survival more than endocrine therapy alone in patients with bone-only metastases.
doi:10.1634/theoncologist.2010-0350
PMCID: PMC3228079  PMID: 21266401
Bone metastases; Breast cancer; Prognostic factor
19.  High Prevalence of Pre-invasive Lesions Adjacent to BRCA1/2-Associated Breast Cancers 
Purpose
Mutations in BRCA1 and BRCA2 increase a woman's lifetime risk of developing breast cancer to 43%-84%. It was originally postulated that BRCA1/2-associated breast cancers develop more rapidly than sporadic cancers and may lack pre-invasive lesions. More recent studies have found pre-invasive lesions in prophylactic mastectomy specimens from mutation carriers; however, there is little information on the presence of pre-invasive lesions in tissue adjacent to breast cancers. Our aim is to investigate the role of pre-invasive lesions in BRCA-associated breast carcinogenesis.
Methods
We retrospectively compared BRCA1/2-associated breast cancers and sporadic breast cancers for the prevalence of pre-invasive lesions (ductal carcinoma in situ [DCIS], lobular carcinoma in situ [LCIS], and atypical lobular hyperplasia [ALH]) in tissue adjacent to invasive breast cancers.
Results
Pathology was reviewed for 73 BRCA1/2-associated tumors from breast cancer patients. We selected 146 mutation-negative breast cancer patients as age-matched controls. Of BRCA1/2-associated breast cancers, 59% had at least one associated pre-invasive lesion compared with 75% of controls. Pre-invasive lesions were more prevalent in BRCA2 mutation carriers than in BRCA1 mutation carriers (70% vs. 52%, respectively). The most common pre-invasive lesion in both groups was DCIS; 56% of BRCA1/2-associated breast cancers and 71% of the sporadic breast cancers had adjacent intraductal disease, respectively.
Conclusions
Pre-invasive lesions, most notably DCIS, are common in BRCA1/2-associated breast cancers. These findings suggest that BRCA1/2-associated breast cancers progress through the same intermediate steps as sporadic breast cancers, and that DCIS should be considered as a part of the BRCA1/2 tumor spectrum.
doi:10.1158/1940-6207.CAPR-08-0050
PMCID: PMC4520422  PMID: 19174581
20.  Commentary: Role of Bone-Modifying Agents in Metastatic Breast Cancer 
Journal of Oncology Practice  2011;7(2):121-123.
doi:10.1200/JOP.2011.000218
PMCID: PMC3051858  PMID: 21731521
21.  Estrogen Receptor Expression and Docetaxel Efficacy in Patients with Metastatic Breast Cancer: A Pooled Analysis of Four Randomized Trials 
The Oncologist  2010;15(5):476-483.
The present study assessed the efficacy of docetaxel in patients with metastatic breast cancer according to estrogen receptor expression. Docetaxel produced a higher response rate and lower risk for disease progression to a statistically similar extent regardless of estrogen receptor expression in patients with metastatic breast cancer.
Background.
Differences in the efficacy of various chemotherapies in patients with estrogen receptor (ER)+ metastatic breast cancer are not well understood. In the present study, we assessed the efficacy of docetaxel in patients with metastatic breast cancer according to ER expression.
Methods.
The efficacy of docetaxel in terms of the response rate and progression-free survival (PFS) time was analyzed according to ER expression in four randomized trials comparing a docetaxel-based regimen with a nontaxane regimen that included a total of 1,631 patients. The odds ratio for tumor response was estimated with logistic regression and a hazard ratio (HR) for PFS was estimated with Cox proportional hazards models.
Findings.
ER expression was assessable in 1,037 patients included in these trials (64%). ER was expressed in 601 tumors (58%). Docetaxel was associated with a similarly higher response rate in both patients with ER+ (odds ratio, 2.90; 95% confidence interval [CI], 1.72–4.87) and patients with ER− (odds ratio, 2.55; 95% CI, 1.44–4.51) disease. The lower hazard for disease progression with docetaxel was also similar in ER+ (HR, 0.82; 95% CI, 0.67–1.00) and ER− (HR, 0.86; 95% CI, 0.70–1.07) cancers. The effect of docetaxel was not different in ER+ and ER− disease, in terms of both the response rate and PFS time (interaction test, p = .77 and p = .93).
Interpretation.
Docetaxel produces a higher response rate and lower risk for disease progression to a statistically similar extent in both patients with ER+ and patients with ER− metastatic breast cancer.
doi:10.1634/theoncologist.2009-0150
PMCID: PMC3227977  PMID: 20421265
Breast cancer; Docetaxel; Estrogen receptor; Metastasis
22.  A class I histone deacetylase inhibitor, entinostat, enhances lapatinib efficacy in HER2-overexpressing breast cancer cells through FOXO3-mediated Bim1 expression 
Purpose
Although there are effective HER2-targeted agents, novel combination strategies in HER2-overexpressing breast cancers are needed for patients whose tumors develop drug resistance. To develop new therapeutic strategy, we investigated the combinational effect of entinostat, an oral isoform-selective histone deacetylase type I inhibitor, and lapatinib, a HER2/EGFR dual tyrosine kinase inhibitor, in HER2+ breast cancer cells.
Methods
We assessed the combinational synergistic effect and its mechanism by CellTiter Blue assay, flow cytometry, anchorage-independent growth, quantitative real-time PCR, small interfering RNA, Western blotting, and mammary fat pad xenograft mouse models.
Results
We found that compared with entinostat or lapatinib alone, the two drugs in combination synergistically inhibited proliferation (P < 0.001) and reduced in vitro colony formation (P < 0.05) and resulted in significant in vivo tumor shrinkage or growth inhibition in two xenograft mouse models (BT474 and SUM190, P < 0.001). The synergistic anti-tumor activity of the entinostat/lapatinib combination was due to downregulation of phosphorylated Akt, which activated transcriptional activity of FOXO3, resulting in induction of Bim1 (a BH3 domain-containing pro-apoptotic protein). Furthermore, entinostat sensitized trastuzumab/lapatinib-resistance-HER2-overexpressing cells to the trastuzumab/lapatinib combination and enhanced the anti-proliferation effect compare with single or double combination treatment.
Conclusions
This study provides evidence that entinostat has enhanced anti-tumor effect in combination with HER2-targeted reagent, lapatinib, and resulting induction of apoptosis by FOXO3-mediated Bim1 expression. Our finding justifies for conducting a clinical trial of combinational treatment with entinostat, lapatinib and trastuzumab in patients with HER2-overexpressing breast cancer resistant to trastuzumab-based treatment.
doi:10.1007/s10549-014-3014-7
PMCID: PMC4119423  PMID: 24916181
Entinostat; Lapatinib; HER2-overexpressing breast cancer; FOXO3; Bim1
23.  Risk of Hospitalization According to Chemotherapy Regimen in Early-Stage Breast Cancer 
Journal of Clinical Oncology  2014;32(19):2010-2017.
Purpose
To compare the risk of hospitalization between patients with early-stage breast cancer who received different chemotherapy regimens.
Patient and Methods
We identified 3,567 patients older than age 65 years from the SEER/Texas Cancer Registry-Medicare database and 9,327 patients younger than age 65 years from the MarketScan database who were diagnosed with early-stage breast cancer between 2003 and 2007. The selection was nonrandomized and nonprospectively collected. We categorized patients according to the regimens they received: docetaxel (T) and cyclophosphamide (C), doxorubicin (A) and C, TAC, AC + T, dose-dense AC + paclitaxel (P) or AC + weekly P. We compared the rates of chemotherapy-related hospitalizations that occurred within 6 months of chemotherapy initiation and used multivariable logistic regression analysis to identify the factors associated with these hospitalizations.
Results
Among patients younger than age 65 years, the hospitalization rates ranged from 6.2% (dose-dense AC + P) to 10.0% (TAC), and those who received TAC and AC + T had significantly higher rates of hospitalization than did patients who received TC. Among patients older than age 65 years, these rates ranged from 12.7% (TC) to 24.2% (TAC) and the rates of hospitalization of patients who received TAC, AC + T, AC, or AC + weekly P were higher than those of patients who received TC.
Conclusion
TAC and AC + T were associated with the highest risk of hospitalization in patients younger than age 65 years. Among patients older than age 65 years, all regimens (aside from dose-dense AC + P) were associated with a higher risk of hospitalization than TC. Results may be affected by selection biases where less aggressive regimens are offered to frailer patients.
doi:10.1200/JCO.2013.49.3676
PMCID: PMC4164758  PMID: 24868022
24.  Staging of Breast Cancer in the Neoadjuvant Setting 
Cancer research  2008;68(16):6477-6481.
The use of neoadjuvant chemotherapy has become more prevalent in the treatment of breast cancer patients. The finding of a pathologic complete response to neoadjuvant chemotherapy (no evidence of residual invasive cancer in the breast and lymph nodes at the time of surgical resection) has been shown to correlate with improved survival. The current version of the American Joint Committee on Cancer (AJCC) staging for breast cancer has a pretreatment clinical stage designation that is determined by clinical and radiographic examination of the patient and a postoperative pathologic stage classification based on the findings in the breast and regional lymph nodes removed at surgery. Pathologic staging has not been validated for patients receiving neoadjuvant chemotherapy; thus, prognosis is determined for these patients based on the pretreatment clinical stage. We hypothesized that clinical and pathologic staging variables could be combined with biological tumor markers to provide a novel means of determining prognosis for patients treated with neoadjuvant chemotherapy. Two scoring systems, based on summing binary indicators for clinical and pathologic substages, negative estrogen receptor status, and grade 3 tumor pathology, were devised to predict 5-year patient outcomes. These scoring systems facilitated separation of the study population into more refined subgroups by outcome than the current AJCC staging system for breast cancer, and provide a novel means for evaluating prognosis after neo-adjuvant therapy.
doi:10.1158/0008-5472.CAN-07-6520
PMCID: PMC4441792  PMID: 18701468
25.  Prognostic Significance of HER-2 Status in Women With Inflammatory Breast Cancer 
Cancer  2008;112(9):1905-1911.
BACKGROUND
Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer with poorly understood prognostic variables. The purpose of this study was to define the prognostic impact of HER-2 status on survival outcomes of patients with IBC.
METHODS
In all, 179 patients with IBC, diagnosed between 1989 and 2005, with known HER-2 status, and treated with an anthracycline-based chemotherapy regimen without trastuzumab, were included in the analysis. Patients with HER-2-positive disease who received trastuzumab at the time of disease recurrence were included. Survival outcomes were estimated by the Kaplan-Meier product limit method and compared across groups using the log-rank statistic. A Cox proportional hazards model was fitted to determine the association of survival outcomes with HER-2 status after adjusting for patient and tumor characteristics.
RESULTS
A total of 111 patients (62%) had HER-2-negative disease and 68 (38%) had HER-2-positive disease. The median follow-up among all patients was 35 months. At the time of the analysis, 62 patients (55.9%) with HER-2-negative disease and 42 patients (61.8%) with HER-2-positive disease had a recurrence. Thirty-one patients (73.8%) with HER-2-positive disease who had a disease recurrence went on to receive trastuzumab. On univariate analysis, no statistically significant difference was observed for either recurrence-free survival (P = .75) or overall survival (P = .24) between patients who had HER-2-positive disease and those who had HER-2-negative disease. In a multivariate model, HER-2 status did not appear to significantly affect recurrence-free survival (hazards ratio [HR] of 0.75; 95% confidence interval [95% CI], 0.46–1.22 [P = .241]). In the multivariate model, patients with HER-2-positive disease had a decreased hazard of death (HR of 0.56; 95% CI, 0.34–0.93 [P = .024]) compared with patients with HER-2-negative disease.
CONCLUSIONS
HER-2 status, in the absence of trastuzumab, did not appear to significantly affect recurrence-free survival. After adjusting for other characteristics, the addition of trastuzumab in the metastatic setting significantly improved survival in the HER-2-positive group above and beyond that of the HER-2-negative group. This gives us further insight into the biology of this aggressive disease and underlines the major effect of targeted intervention.
doi:10.1002/cncr.23350
PMCID: PMC4437796  PMID: 18300243
inflammatory breast cancer; HER-2 status; survival outcomes; targeted intervention

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